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Use of Intraoperative Radiation Therapy in Skull Base Oncology Open Access Journal of Neurology & Neurosurgery-Juniper Publishers

Authored by Akheel Mohammad

Opinion

Management of advanced and recurrent head and neck cancers constitutes multimodality treatment therapy; surgery, chemotherapy and radiation. Loco-regional relapse comprises a major hurdle for disease free survival patient, the role of intraoperative radiation therapy (IORT) has added in improving overall survival (OS) and local control of the disease. IORT allows delivery of a single tumoricidal dose of radiation to areas of potential residual microscopic disease while minimizing doses to normal tissues. Head and neck cancers (HNC) constitute 8th leading cause of cancer deaths globally. In developing countries its incidence is high due to tobacco use (smoke and smokeless form) and drinking habits in combination with poor socioeconomic status. HNC's encompasses diverse tumor types but around 90% of these tumors are squamous cell carcinomas (SCC) with further diversification in respect to etilogical factors, pathogenesis, and clinical behaviour. The overall impact of management of HNC's on functional activities like swallowing, speech and cosmesis affects the patient both psychological and socially. Inspite of several recent advances in surgery, chemotherapy and radiation therapy, the overall 5- year survival rate is still not improved and mainly influenced by disease staging, tumor margins, nodal diseases, extracapsular spread, perineural/ lymphovascular invasion and invasion of vital structures. Failure or recurrence rate for T4 lesions may vary between 19% to 35%. They may be either primary tumor site failure or distant site metastasis such as lungs, liver, bone and spine.

The recommended management of locally advanced tumors of head and neck are surgery and chemo radiation with/ without targeted therapy. Recurrences after irradiation may be addressed by salvage surgery if resection is possible, plus additional chemo radiation. There can be severe complications for surgery after radiation to the tissues. Recently, new radiation techniques such as intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) have improved oncological results with reduced toxicities but specific indications have not been defined yet. Reirradiation still poses a major challenge for the radiation oncologist.

In this cases either advanced lesions extending to infratemporal fossa, pterygoids and skull base where 1cm-1.5cm oncologic free margins cannot be obtained, Intraoperative radiation therapy (IORT) is an very good alternative to be considered. It not only achieves local control of advanced tumors or residual disease, but also as an adjuvant therapy in salvage surgery. IORT was pioneered by the Japanese in 1960's for treatment of gastrointestinal tumors and introduced in the United States and Europe in the 1970s, initially for abdominal and gynaecologic malignancies. IORT can be used as a boost to external beam radiation (EBRT) or as the sole irradiation modality in a previously irradiated field. IORT allows rapid delivery of large single doses of radiation to a visible tumor bed margins with exclusion/ shielding of critical anatomic structures from the treatment field. IORT is generally delivered from a linear accelerator using mainly an electron beam field or in some cases a photon beam field. The field is well visualized, which allows for relatively easy placement of the electron beam or the photon beam cone on the tumor bed. This allows a steep dose fall off while sparing normal anatomic tissues. Occasionally, IORT is combined with external radiation therapy (EBRT) to provide the best combination of local and loco regional treatment. With this IORT radiation energy to the surrounding structures including neurovascular and bony structures, except for the suture line, anastomosis is also kept in minimum levels.

Advantages of IORT are the decreased possibility of geographical and anatomical miss when radiation is delivered during the surgery. . There is also increased biological efficacy per unit dose because of the administration of radiation as a single fraction with no time elapsing between multiple fractions and no time elapsing between surgical excision and RT. IORT decreases the overall treatment time by reducing tumor cell repopulation during overall treatment. It also allows to increase the dose because it is estimated that the single high dose given by IORT is biologically equivalent to 3- to 4-fold that of conventional EBRT. IORT toxicity does not overlap with that of EBRT and when properly combined with EBRT, it can be used for increasing the dose while potentially decreasing toxicity.

Delivered IORT dose ranged from 7.5 to 30Gy, and median was 20Gy. However, in most contemporary studies done so far, a trend to lower the delivered doses trying to reduce toxicity and complications was noticed. Reported local control rates with the addition of IORT modality appear as high as 90% in a 2-year follow-up in selected cases where no residual disease is noticed after surgical excision. The combination of EBRT postoperatively seems to further improve local control. Furthermore, the length of hospital stay is not appreciably prolonged when IORT is used as a treatment adjunct to surgery. A benefit of the 2-year DFS has been reported as well. However, long-term survival rates do not seem to conform in all series. Some studies shows patients with advanced disease with carotid involvement, have the most dismal median OS of 1 year accompanied by high complication rates of 50%. This group of patients is at high risk for posttreatment cerebrovascular events and neurologic sequelae. These patients receive greatest benefit of IORT with some short term pain relief despite high rates of loco-regional failure. A good palliative effect has been obtained in these patients treated for extensive recurrence in previously irradiated fields. IORT is generally well tolerated without significantly increasing the rate of complications and in addition for symptomatic patients who have undergone a near total/subtotal resection, IORT as a boost seems to be a reasonable palliative approach if it is available. Hence IORT can be one of a good multimodality treatment for management of advanced/unrespectable tumors.

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Use of Sphenopalatine Ganglion Blockade in Chronic Migraine Management

Authored by Michelle Androulakis

Case Report

Chronic migraine (CM) is a debilitating neurological disorder which affects more than 4 million individuals in the United State and 2% of the global population [1] in 2015, the Health Care utilization was estimated at $5.4 billion and the total cost associated with management of comorbidities exceeded over $40 billion in united states [2,3]. Different acute and preventive therapies, which are available for chronic migraineurs, are generally sub-optimally effective and are accompanied by side effects that are difficult to tolerate. Currently, Botulinum toxin therapy (Botox) is the only FDA approved CM preventative therapy, however, it is expensive and up to 9% of patients experience side effects such as neck pain after the injections. Recently, SPG neuromodulation has gained interest among headache specialist in management of CM. A series of SPG blockade using intranasal bupivacaine was efficacious for acute pain reduction in CM. However, further investigation into the long term preventative benefit of SPG block is warranted as this study sample size was too small to reach its statistical significance [4,5].

Sphenopalatine ganglion (SPG) has been a very important target for headache management since the beginning of the 20th century. SPG is the largest extra cranially ganglion of the head and is likely to play an important role in migraine pathogenesis through the activation of trigemino-autonomic reflex [6]. Up to 70% of migraine patients have cranial autonomic symptoms such as eyelid edema, nasal congestion, lacrimation, conjunctival injection, rhinorrhea, and facial swelling [7]. SPG modulation via electrical stimulation, microvascular decompression, surgical or radiofrequency ablation, and radiosurgical lesion have been performed for head pain in operating room settings, however, adverse effects of these interventions can be extensive. The SPG is located just posterior/superior to the tail of the middle turbinate on the lateral nasal wall and superior to the pterygopalatine fossa.

Manipulation of this region was often very challenging, as there is no direct access to the SPG and it is covered by a thin layer of nasal mucosa (1-1.5mm). New methods to modulate the SPG with a topical, intranasal approach have proven to be among the safest, least invasive, and least costly of all SPG interventions in headache management.

Recently, several new devices have been developed which facilitate a more accurate and effective delivery of the local anesthetics into the SPG. The risks of this procedure are typically minimal and may include minor discomfort during and after the procedure, a numbing or burning sensation, bitter taste from the anesthesia, bleeding from the nose (rarely), and lightheadedness. These side effects typically resolve within minutes to a few hours. There is also a very small risk of allergic reactions.

Use of SPG block has been recommended by American Headache Society (AHS) as part of comprehensive headache management plan. Indeed, repetitive SPG blockade twice a week for 6 weeks provides an alternative migraine prophylaxis for those with chronic migraine but could not tolerate (i.e. needle phobia) or unresponsive to Botox therapy. SPG block generally provides a better outcome for treatment of CM with head pain in frontal and/orbital regions, and may also help CM patients with coexisting medication overuse headaches to wean off excessive use of pain medications.

Nausea, which has been suggested as one of the main contributing factors for migraine chronification, is also another possible symptom that can be relieved with a series of SPG block. The area postrema area, located at the infer posterior part of IV ventricle, is responsible for nausea and vomiting through its connection to the nucleus of the solitary tract. The superior salivatory nucleus (SSN) provides preganglionic parasympathetic innervation to SPG, but also receives inputs from multiple areas, such as nucleus of solitary tract, limbic, and cortical regions. Repetitive intranasal SPG blockade with bupivacaine may reduce nausea and vomiting via inhibition of superior salivatory nucleus given its direct connection with the nucleus of solitary tract.

The exact mechanism of SPG neuro modulation remains to be elucidated. It has been postulated that inhibition of the parasympathetic outflow from the SPG would inhibit pain and autonomic symptoms that accompanying recurrent migraine attacks. This inhibition of parasympathetic outflow would decrease activation of perivascular nociceptors in the cranial and meningeal vasculature, especially in the frontal regions of the brain [8-10]. Additionally, modulation of the SPG may in turn modulate brain networks activity involved in pain processing. In a recent resting state functional MRI connectivity study, our group demonstrated that a series of SPG block treatment in chronic migraine significantly improved two intrinsic resting state functional connectivity networks (manuscript in preparation). This increase in functional connectivity coherence may represent that after effective treatment, reorganization of resting state brain networks to normalized states may occur.

Additionally, reduced parasympathetic outflow due to repetitive SPG inhibition may help to restore baseline homeostasis of brain networks involved in pain processing, via improved mesocorticolimbic modulation [11-13]. A large double blinded, randomized, placebo controlled clinical trial is warranted to evaluate the efficacy of repetitive SPG block in CM (Figure 1 & 2).

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Corrosion Analysis of Orthodontic Wires: An Interaction Study of Wire Type, pH and Immersion Time | Juniper Publishers

Juniper Publishers-Open Access Journal of Dentistry & Oral Health

Authored by Nita Viwattanatipa

Abstract

Objectives: The objective of this study was to compare the effect of wire type, pH and immersion time upon mean corrosion rates of four orthodontic wires.

Materials and Methods:Four types of orthodontic wires,

a. Nickel-titanium (NiTi)

b. Regular stainless steel (SS)

c. Australian stainless steel (Aus) and

d. Titanium-molybdenum alloy (TMA) were immersed in artificial saliva, either at pH 6 or pH 2.5. The time of test was either as-received or 90 days immersion time. Corrosion analysis was performed using linear sweep voltammetry.

Results:3-way ANOVA statistical analysis showed that wire type, pH, immersion time and combination of these factors, both second order and third order interactions, accounted for significant differences of the mean corrosion rates. At baseline status, (as-received wires, at pH 6) post hoc multiple comparison test showed that the mean corrosion rates of NiTi > Aus >SS>TMA (P < 0.05). Interaction plots revealed that the corrosion susceptibility of these wires could be modulated by pH 2.5 and 90 days immersion time, with different extent across wire types. Under pH 2.5 and 90 days immersion time condition, SS showed statistically greatest increase of mean corrosion rates. However, TMA, Aus and NiTi mean corrosion rates were not different from each other (P<0.05). Therefore, interaction of pH and immersion time upon wire types could deviate the pattern of relative mean corrosion rates from the as-received status.

Conclusion: Corrosion behavior was dependent on the interactions of alloy type and the environment factors (pH and immersion time).

Keywords: Corrosion rates; Australian wire; Stainless steel wire; NiTi wire; TMA wire; pH; Immersion time

Abbrevations: NiTi: Nickel-Titanium; SS: Stainless Steel; AUS: Australian Stainless Steel and TMA: Titanium-Molybdenum Alloy

Introduction

Variety of metal alloy wires are used in modern orthodontic treatment, such as, Stainless Steel (SS), cobalt-chromium, Nickel-Titanium (NiTi), Beta-Titanium (TMA), etc. These metal alloy wires are subjected to biodegradation in oral environments leading to corrosion. Although the risk is low, corrosion products such as nickel and chromium may cause sensitivities or allergic reactions during orthodontic treatment [1-5]. Other consequences may involve discoloration or roughening of surface leading to friction between the bracket and the arch wire [1,2]. Several intrinsic and environmental factors influence the corrosion reactions of orthodontic wires such as, types of alloys, surface roughness, surface coating, electrolyte, pH value, aging, immersion time and temperature [1,3,4,6-12].

Orthodontic appliances rely on the formation of a passive surface oxide film to resist corrosion. The addition of nickel and chromium in stainless steel alloy imparts corrosion resistance. The chromium in the stainless-steel forms a protective, passivating oxide layer (Cr2O3) that provides a barrier to oxygen diffusion and other corrosive environments [2]. The Australian wires are special type of high tensile stainless-steel wire, with rougher surface than other stainless steel [13,14]. The corrosion resistance of nickel-titanium wire is due to the large amount of titanium in its compositions with passivation surface film of several oxides (TiO, TiO2, Ti2O5) [2]. The beta-titanium alloy wire has excellent corrosion resistance and biocompatibility which is due to the presence of titanium oxide (TiO2) [2,15,16].

Previous studies agreed that TMA wire possesses better corrosion resistance than other orthodontic wires [7,17]. Stainless steel showed greater corrosion than TMA [17,18]. However, the relative corrosion rates of NiTi were inconclusive [7]. Hunt et al. [18] reported the relative corrosion rates of the as-received orthodontic wires ranking from highest to lowest as NiTi > Australian stainless steel > TMA > chrome-cobalt. Sarkar et al. [17] showed relative corrosion rates of NiTi > Stainless steel > TMA. On the contrary, Rondelli [19] reported that NiTi possessed greater corrosion resistance than stainless steel. Kim [7] reported that nickel titanium alloy wires showed large variability in corrosion resistance.

Due to the information at present time may not be enough to ascertain how a given orthodontic wire alloy will undergo corrosion under complex environmental conditions. Few articles reported the corrosion rates in terms of interaction study. Therefore, it could be beneficial that more studies are to be conducted to gather more information. The objective of this study was to test the null hypotheses about the effects of wire type, pH and immersion time upon the means corrosion rates and investigate the interactions between these factors as well as the effects of individual factor.

Materials and Methods

The study comprised 20 experimental groups with 15 samples per group. Four types of arch wire, 10mm in length, 0.018” in diameter, were tested which consisted of

1. Nickel-titanium (NiTi) arch wire (G&H® Wire Company, IN, USA);

2. Regular stainless steel (SS) arch wire (Ormco, CA, USA);

3. A.J. Wilcock Australian stainless steel (Aus) arch wire (TP Orthodontics, IN, USA);

4. Titanium-molybdenum alloy (TMA) arch wire (Ormco, CA, USA).

The surface composition percentage was obtained by evaluation of these alloys using the Energy Dispersive Spectroscopy (EDS) analysis (Model 7021-J, Horiba Ltd., Kyoto, Japan).

The arch wires were immersed in artificial saliva. The chemical composition of the artificial saliva was modified Fusayama solution [10]. The composition was NaCl (0.4g/L), KCl (0.4g/L), CaCl2·2H2O (0.795g/L), NaH2PO4·H2O (0.690g/L), KSCN (0.3g/L), Na2S·9H2O (0.005g/L) and urea (1.0g/L). The electrolyte was adjusted either at pH 6 or pH 2.5. Each specimen was immersed in a glass cell vessel which contained 200ml of artificial saliva at 37 °C. The immersion interval was either at as-received or at 90 days.

Corrosion analysis

The testing apparatus consisted of a corrosion cell, the Auto lab testing machine PGSTAT20 and the General-Purpose Electrochemical Software (GPES) package (AUTOLAB, Netherlands), which recorded the corrosion behavior and performed the linear sweep voltammetry [20]. Determination of the open circuit potential (OCP) was done over a 30-minute period with a scanning rate of 1mV per minute. The polarization curves were assessed between +/- 150mV of the open circuit potential in order to obtain the corrosion and breakdown potentials.

The GPES computer program determined the corrosion potential by plotting the slope of the polarization curve. The corrosion potential was then used for calculation of the corrosion rates of wires (mm/year), by adding prerequisite parameters which were surface area, the equivalent weight, and density. The values used for calculation are shown in Table 1.

Statistical analysis

Data analyses were performed with statistical software SPSS 14.0. (SPSS Inc, Chicago, IL, USA). Descriptive mean corrosion rates and standard deviations were calculated for all experimental groups. In order to fit the dependent data with the assumption for general linear model, preliminary examination of the data required exclusion of some outliers. Therefore, the final number of specimens were as shown in Table 2. To run the analysis, log-transformed corrosion rates data was used. Levene’s test of equality of error variances demonstrated homogeneity of variances (P=0.13). Besides, the spread-versus-level plots revealed that there was no pattern for distribution of means and the standard deviations. So, the equal variances assumption was not violated for the variables.

The General Linear Model procedure, multivariate analysis, was used to test the null hypotheses about the effects of wire type, immersion time and pH on the log mean corrosion rates. Full factorial model with Type III sum-of-squares method were selected for statistic calculation. Post hoc multiple comparison test (Tukey’s) was performed for the baseline (as-received and pH 6) and the interaction effects.

Scanning electron microscope

Scanning electron microscope (S-3000N, Hitachi Corp., Japan) was used to examine the corroded surface in each wire group. All specimens were labeled, and gold spluttered before being subjectively examined.

Results

The results of the EDS testing for the surface chemical compositions of each wire alloy are listed in Table 1. The values were generally like the previous studies [21]. Table 2 shows the mean corrosion rates and standard deviations classified by independent variables.

Results of three-way ANOVA (Table 3) rejected the null hypotheses which indicated that all variables and their interactions significantly contribute to the model. Statistically significant differences among the log mean corrosion rates (P < 0.05) was found for the main effects, the second order interaction and the third order interaction. The relative extent of variables contribution to the model could be seen from the partial eta squared (Table 3). It could be interpreted that pH contributed most to the model (.660), followed by immersion time (.405). Whereas the wire x pH x time (.051) contributed least to the model. Post hoc multiple comparison test (Tukey’s) among the 4 orthodontic wires at baseline (as-received, at pH 6) and interaction effects were shown in Table 4 and Table 5 respectively. Post hoc test contrasting the main effect revealed that the mean corrosion rates of pH 2.5 was greater than pH 6, and the mean corrosion rates of 90-day immersion time was also greater than as-received (P < 0.05).

Figure 1A is the interaction plots between mean log corrosion rates (ordinate) and the 4 as-received orthodontic wires (abscissa), contrasting pH 2.5 and pH 6. Figure 1B is the interaction plots between mean log corrosion rates at the 90 days immersion-time orthodontic wires contrasting pH 2.5 and pH 6. The non-parallel lines in the two figures indicated interaction between these variables.

Scanning electron microscope

As shown in Figure 2, for as-received and pH 6 status (1st row), Aus wire shows remarkable longitudinal grooving, as a result of being drawn during production. NiTi shows the amorphous and smoothest surface. SS shows tiny pits and shallow grooves while TMA shows the largest pores and deep grooves. The most striking surface change was observed in 90 days at pH 2.5, especially for Aus. NiTi surface, however, showed the least change.

Discussion

The results of this study indicated that wire type, pH, immersion time and combination of these factors accounted for significant differences of mean corrosion rates. The greatest impact was pH, followed by time and the least was the wire*time*pH. In general, the interaction of pH 2.5 or 90 days immersion time upon the asreceived orthodontic wires resulted in increased mean corrosion rates. Dramatic change of mean corrosion rates was shown for all orthodontic wires when subjected to pH 2.5 and 90 days immersion time (Figure 1B). SS was significantly most affected by pH 2.5 and 90 days immersion time than the other three orthodontic wires (Figure 1B), (Table 5). Consequently, relative ranking of mean corrosion rates of all 4 orthodontic wires subjected to these two variables were differentially changed compared to the as-received status.

Comparison of mean corrosion rates across wire type for the as-received wire at pH 6 showed that NiTi was the highest, followed by Aus, SS and the least was TMA respectively (Table 4) and (Figure 1A). These results were partly in agreement with many studies [17,18]. Our result supported the findings by Sarkar et al. [17] and Hunt et al. [18] who reported the relative corrosion rates of NiTi was greater than SS/Aus and then TMA [17,18]. However, our results did not support Rondelli [19] who reported that NiTi had better corrosion resistance than stainless steel. This contradicting might be due to different NiTi components which were reported to show large variety among brands [7,22].

Orthodontic wires are subjected to corrosive environment in the oral cavity. Many ingested fluids can be corrosive because of their low pH, for example, fruit juices, vinegar, acidic carbonated drinks [23,24]. Fluoridated mouthwash could also create acidic environment. Reduction of pH may dissolve the surface oxide films and prevent its reformation which results in greater corrosion. This may explain why the PH 2.5 group showed significant higher mean corrosion rate than pH 6. This finding agreed with various reports [10,25,26]. Moreover, the 4 orthodontic wires in our study showed differential corrosion susceptibility when subjected to pH 2.5 (Figure 1A). The highest change which indicated the most susceptibility was found for SS, followed by TMA, Aus and NiTi respectively.

Regarding the immersion time, 90 days was chosen for this study as this may represent the average period that an orthodontic wire may be used in oral cavity before changing to a new stiffer wire. Interaction of pH 2.5 and immersion time for 90 days had significant influence by increasing corrosion rates of all 4 orthodontic wires, however with different susceptibility. The highest change which indicated the most susceptibility was found for SS, followed by TMA, Aus and NiTi respectively. Reduction of pH could destroy surface oxide layer. In addition, alloy aging may increase surface roughness as time went by, resulting in oxygendepleted area, which cause deeper crevice or pitting corrosion [14,24]. Similar results were reported by Huang et al. [10] who found that the amount of nickel and titanium ions released from NiTi wire in pH ≥3.75 solution at 1 day immersion time was much less than that in pH 2.5 solution, at 28 days. Kwon et al. [26] also reported increase of NiTi arch wire corrosion as the period of immersion in acidic fluoride solution increased and pH value decreased.

However, NiTi wire in our study was less susceptible to change in pH than the other 3 wires. However, this result should not be generalized for other NiTi brands. It should be noted that the results of NiTi corrosion were complex and varied greatly because this alloy have been vastly modified for various use in medical and dental fields. Several factors have been reported for some medical devices both in increasing or reducing NiTi corrosion rates, for example, loading, surface treatment, surface coating, sterilization techniques, pH, immersion time [7,10,17-19,22,27]. Consequently, contradicting results were reported in the past [7,17,18]. The difference findings could also be attributed to the formation, thermal process and polishing method of NiTi wire which were different greatly among manufacturers [22].

The results of variables interaction upon TMA should be further studied. It was interesting to observe that pH reduction and increased immersion time could increase TMA corrosion rates in our study. Although the as-received titanium alloys were exceptionally corrosion resistant because of the stability of the TiO2 oxide layer, they are not inert to corrosive attack. When the stable oxide layer is broken down or removed and is unable to reform on parts of the surface, titanium can be as corrosive as many other base metals [28]. Many laboratory studies have also demonstrated that, in a fluoridated, acidic environment, the corrosion susceptibility of titanium was increased [11,29,30].

in vitro studies of corrosion behavior can use various methodologies and outcomes, such as, potentiostatic, potentiodynamic, atomic absorption spectroscopy etc. Corrosion outcomes reported were varied such as Icorr (electric current), Ecorr (corrosion potential), Rp (Polarization Resistance), Bp (Breakdown Potential), μg/cm2. The strength of this study was that the kinetic corrosion reactions of the orthodontic wires with the outcome unit as corrosion rate (mm/year) were used. The findings of interaction of these variables will help adding more information into this field.

The weakness of this study was that it was an in vitro experiment. For in vitro study, the decreasing corrosion rate may result from the increase in metal ion contents in the saturated environment of artificial saliva [2]. This notion was supported by Huang et al. [10] who studied NiTi wire and found that the average ion released per day decreased with immersion time due to the accumulated amount of nickel and titanium ions as time went by. However, this situation does not occur in the oral cavity since these ions could be removed by food, fluids, and the toothbrush which will continue the corrosion [2]. pH 2.5 which was used in this study may be considered as extreme and rarely happened in the normal saliva. However, the values (pH 2.5-6.25) were previously experimented by Huang et al. [10] pH value of 2.5 was also reported for Cola soft drinks by Nordstrom et al. [31]. Inclusion of more orthodontic wires of different brands under various corrosive conditions are suggested for future study.

Implication for clinical practice: Orthodontists and patients should be warned of possible risks of wire corrosion when taking beverages, juice and sour fruits with low acidic pH, together with keeping the same arch wire in the oral cavity for a too long period of time, for example, when the patient continuously keeps breaking the appointment. These situations can increase the possibility of wire corrosion, regardless of wire materials. The bottom line is the interaction of several other corrosive factors may reduce passivity of surface oxide layer and modulate corrosion of orthodontic wires.

Conclusion

1. Wire type, pH, immersion time and combination of these factors, both second order and third order interactions, contribute to significant differences of the mean corrosion rates.

2. The mean corrosion rates of the as-received at pH 6 showed that NiTi >Aus >SS>TMA.

3. Corrosion behavior of Aus, NiTi, SS and TMA could change due to interaction of pH and/or immersion time.

4. At pH 2.5 and 90 days immersion time, the susceptibility of these orthodontic wires to corrosion could be modulated. The greatest increase mean corrosion rates were SS. However, TMA, Aus and NiTi mean corrosion rates were not significant different from each other.

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Key Role of the Diagnosis in Patients Suffering from Dementia

Authored by Amalia C Bruni

Abstract

The current number of people suffering from dementia is about 35.6 million and this number is destined to seriously growth. Dementia is mostly unknown and its in-vivo diagnosis frequently remains in the field of the uncertainty and probability. An early comprehension of the disease is crucial because it determines its impact on the person and on the family. The present opinion started from the analysis of the letter written by Robin Williams' wife about his illness (the Lewy Body Dementia) before, during and after death. Several issues arouse from the commentary and deal with the difficulties involved in the diagnosis; the role of cognitive reserve and the pitfalls growing in the couple, the lack of information, the awareness of the disease; the theme of the suicide linked to dementia and the role of neuropathology. All of these themes need a reflection and must be transformed into new attitudes towards dementias. The hope of Susan, and of many family members, is that the suffering of their relatives may one day help other patients, other families and doctors and researchers to fight these terrible diseases. With them and for them we will not surrender.

Keywords: Dementia; Lewy body dementia; Diagnosis; Behavioral disorders; Robin williams

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Introduction

Despite the great evolution and progression in research, dementia is still today an obscure and complex disease. Its intricate network of signs and symptoms constitutes a complicate path, difficult to understand for everyone involved: the patient, the family, the medical team. An early comprehension of the disease is crucial because it determines its impact on the person and on the family. Nowadays, to deal with dementia means to face an enemy who shows his name, face and weapons only when little or nothing can still be done. Many obstacles however to an early diagnosis are often ingrained just because of the nature of dementia. There is the person capable, more or less, consciously or not, to hide the symptoms and the first cognitive gaps. There is the resistance of family in front of unusual behaviors and a more common refusal and shame in front of the illness. There are vague symptoms, such as depression or anxiety, which not immediately, and perhaps not later, are linked to some neurodegeneration process. There is the probable diagnosis. There is a lack of support for caregivers, which are those who care for all the time. There is the neuropathology brought into play only at the end of this entire story. In 2014, the actor Robin Williams suicided in his house, his wife Susan has never accepted the word depression, which was immediately related to the extreme act of Robin. She argued that it was something more, something which was devastating his brain, a disease that she called the terrorist. In 2016, she wrote an editorial on neurology [1] to talk about what happened inside and outside the brain of his husband. It could have been the story of one of the many movies that Robin starred. Susan wrote a piece of poetry, but the aim was not writing to make a movie or a play, the aim was different. This was a prayer. Susan wrote to us, doctors and researchers, hoping to be able to understand again, even after all this time what happened, for what reason and to figure out if she could have helped him more or better. She pushed us to work, to move forward, not to give up despite failures and still to release ourselves from a deep sorrow, which consumes.

There are many Susan in the world who are unable to communicate, in such affective way, about this pain and try to get rid. Susan is all the families, all the caregivers who, next to their beloved, live similar stories, similar efforts, sometimes even worse as when, for example, there is an awareness of a genetic mutation and when, your loved one is 35-40 years-old and you have little children who do not understand why their daddy wants to play with their toys, why he gets angry and beats them if they steal the Legos or toy car. The editorial, beyond the emotions and feelings, is also an important educational piece which underlines some fundamental points about the complex issues generated by dementia. We can and must make some reflections on it and understand both strong and weak points of who suffer, who cares and who cures.

The difficulty of diagnosis

This is the big problem: today only 50% of patients with any kind of dementia receives diagnosis [2]. The others are ghosts, hidden in their houses or in nursing homes, unidentified or sweetened under shameful, non-specific, terminologies. Despite efforts in fighting the definition of "senile dementia" still today we hear and read about it. Of course, it has been profusely said, the aging phenomenon does not necessarily match with a behavioral and cognitive decline. The fact that this is, unfortunately, frequent is not necessary a physiologic consequence, it would be like saying that, during a varicella epidemic, to have the varicella is normal just because everybody has it. On the other side of the life curve there is the young patient: the one that, just because of his early age, could not suffer from dementia, the one that, because of a preeminent behavioral disorder, is relegated in the often-indistinguishable ravine of psychiatric diseases. How many diagnosis of schizophrenia in the presence of FTLD [3,4]. When symptoms invade behavior and mind they seem to sidetrack the doctor: it is not easy to recognize unspecific symptoms, such as depression or anxiety, as a possible sign of an incoming dementing disease. Although in the evaluation of a memory disorder there are neuropsychological tests, as the Free and Cued Selective Reminding Test (FRCST) [5,6], which address to the different forms of dementia, unfortunately this is not the case of behavioral disorders and more generally of mind disorders. The idea that the mind is separate from the brain is still rooted, although the existing criteria describing various types of dementia, Alzheimer's Disease [7], frontotemporal dementia [8] or as in this case, dementia with Lewy bodies [9], accurately depict symptoms and signs. And yet, how many patients come at such advanced stage that doctors cannot identify which path the disease has followed before spreading throughout the brain. One of the more important problems is the reconstruction of patient's personal history from its family that difficultly tends to recall sad and painful episodes and, frequently, doesnot remember the timing sequence of symptoms. Still it is precisely the sequence of a series of symptoms. Still it is precisely the sequence of a series of symptoms and signs that allow us to have the Gestalt of the disease and thus to assume a probable diagnosis. Family members, however, do not know what to look out for and the weight to give to apparently trivial situations. Preliminary data [10] from a research on a set of about two thousand patients with Alzheimer's disease have shown the presence of behavioral disorders, also gender- different, even before the onset of the disease, in agreement with other literature reports [11]. But this is not enough. We should cross sensitivity and specificity measures sifting to define a peculiar behavior as a clinical biomarker. Nevertheless we know it for sure, thanks to the studies of genetic mutations carrier subjects (DIAN and GENFI) respectively in Alzheimer's disease and Frontotemporal dementia, that neurodegenerative diseases and their pathological proteins counterparts, begin to wallow in our brains from 15 to 10 years before the onset of symptoms [12,13]. But what value of "risk" can we give to our boomer’s anxiety or post retirement depression? Much must still be done in terms of study and research in this direction, and much more needs to be built in sense of dissemination of knowledge in the whole community, not just the medical one. Dementia with Lewy bodies is a treacherous disease, perhaps even worse than Alzheimer's disease, but at least as the frontotemporal dementia. The behavioral signs and, above all, the fluctuations of the clinical course are so unlikely in DLB that family members frequently tell us that the patient "looks like he is acting intentionally". We know that the DLB has a variable prevalence between 0.3 and 24.4% in the studies [14], and these so widely variable data explain the difficulty of investigation and diagnosis. The disease is clinically characterized by a progressive cognitive decline, often hallucinations and delusions, parkinsonism and a floating attention. However, the criteria which permitted to distinguish the disease from the great syndromic cauldron of dementias, are poorly specific and not perfectly able to differentiate the overlapping forms with Alzheimer's disease, although the high prevalence of hallucinations delusions, anhedonia, anxiety and apathy that occur at the DLBonset seem to be very indicative [15]. Patients with DLB usually manifest at onset very mild cognitive impairment within a framework of psychotic subacute state, predominantly characterized by hallucinations and delusions [9].

Hallucinations are predominantly visual, detailed, often nocturnal, recurrent and almost constant during the course of the disease. Less frequently, patients also have auditory hallucinations and paranoid delusions. Often, depressive and anxious symptoms and behavioral disturbances associated with REM sleep (RBD) are frequently observed and they manifest as vivid and terrifying dreams associated with simple or complex motor behaviors seriously disturbing the bed partners. Less frequently, in the early stages, it may be present a rigid-akinetic extrapyramidal syndrome -no tremor-usually symmetrical, partially sensitive to dopaminergic therapy. Memory skills are relatively preserved, while attention is impaired together with visual-spatial disorders and difficulties in critic and judgment. Cognitive performances are highly fluctuating and they may occur with extreme variability (minutes or hours) over the same day. Despite Robin Williams lived in the US, the MECCA of the criteria and advanced medicine, he did not receive the diagnosis, neither early nor timely. The presence of depression, anxiety, the apparently hypochondriacs signs, tremor and the reduction of smell (typically parkinsonian latter) together with the sensitivity to antipsychotics (which worsen the clinical picture and is an important sign to suspect the disease) have not been pigeonholed temporally in the right direction and evaluated as pieces of a single puzzle that was in building.

Cognitive reserve

Robin Williams' story testifies how the onset of cognitive symptoms of a dementia disease can be postponed over time and altered by events and life experiences. The cognitive reserve model [16] tries to explain the discrepancy between brain damage and its function. High level of education, learning, skills and knowledge acquired during the whole life could explain the possibility for some individuals to resist as long as the neurodegeneration occurs, showing, at the beginning of the disease, only mild symptoms. In particular, and this is the case of Robin, an actor accustomed to exercise and strain memory, cognitive activity during adulthood could have an even more important role in the construction of this reserve [17]. In front of an atypical onset of the disease, this of course can put people and doctors off track, making difficult the choice for a diagnostic label.

The couple and the disease

A disruptive event such as a dementia not only affects the person but also "infects" emotionally whoever is around [18]. Both in a long-standing relationship and in a relatively recent love story, who joins the affected person takes the role of the "stronger": Susan takes care of Robin, she helps and supports him, supervising him and his symptoms. She gets stronger to brave one of the most difficult and intense moments in a relationship that paradoxically seems to strengthen thanks to the sharing of the disease. She is indulgent towards Robin's aggressive behavior, his fears and discomfort, his concern and his pleas for help. The role of the family caregiver in the containment of the disease is fundamental: an empathic environment is able for an adequate managing of behavioral disorders, and also to understand and analyze symptoms [19]. The acceptance of the disease is the difficult task for caregivers because they need to decode inexplicable attitudes, analyze behaviors and also discover the loved "nothing else or not different" from what he/she was before, but just different for the inability to express feelings.This should always be the correct management of behavioral problems: the "ecological" analysis and the acronym DICE (Describe, Investigate, Create, Evaluate) described by Kales [20] should be the guideline to be followed not only by the caregiver but also by all the nursing team. However, so complex and aggressive symptoms, the confusing diagnoses and the ambiguity, inevitably cause distresses even in strong relationships [21]. Recent studies report that the rate of separation and divorce in the presence of a serious illness of one of the spouses is lower when it is the man to be sick, emphasizing the greater "resilience" of women in providing care to the partner [22]. Susan clashes with the loss of identity of Robin, which only occasionally resurfaces during the fluctuations and, at one point, she seems to become almost an helpless spectator of the disease.

The lack of information

It is evident that the assistance to the patient becomes much more difficult because of the lack of information and training that caregivers should receive from the health personnel; caregiver NEEDS correct help and support in order to continue his/her existence alongside the loved one who becomes more and more a stranger [23]. Loneliness, confusion, feelings of inadequacy and of loss are the feelings most often expressed by family members, which start their journey of hope among various doctors, groping in the dark, also searching for a better diagnostic definition [24,25].

Awareness of the disease

Robin was aware and this has certainly increased pain and sufferings. However, the insight is also a powerful tool, if well directed, to the empowerment of the patient and for the doctor-patient relationship. If he had received a diagnosis (and treatment, however modest [26]) it could have been possible to reduce his anxiety. How many patients are convinced of "being wrong, mad or bad" when it is the behavioral disorder of the disease speaking for them. Maybe he would not commit suicide or may be yes....impossible to say. Insight is poorly tolerated by patients and not at all by the family however, the increasing pain linked with the insight sometimes gives to the patient one vital impulse (I am aware of what is happening to me and therefore I suffer but I am still alive). When it turns off with the worsening of the disease, a merciful oblivion and perhaps a greater serenity come.

Full insight is usually present in Alzheimer’s patients for a long time [27] and in many other forms of dementia. It is completely absent in patients with frontotemporal dementia-behavioral type [28]. How many times to the classical request: "What is the reason for this visit?" we hear answers like: "What do I know? They have brought me here, I’m fine". Robin, instead, asked the physician to make a more detailed diagnosis; Parkinson's diagnosis did not convince him, "Do I have Alzheimer's? Am I schizophrenic?" He asked, but they reassured him unnecessarily.

The theme of suicide

The depressive symptoms that occur in DLB are, like the cognitive symptoms, fluctuating, with alternating periods of relative comfort and periods of deep frustration able to cause, especially in the early stages, suicide attempts. This is probably related to the awareness of the disease and to the fear for future. Studies on the issue of suicide in patients with dementia are few, but the risk of suicide appears to be higher immediately after the communication of the diagnosis. This happens especially in young people having insight, who do not have depression, and severe cognitive impairment [29]. However, the risk of suicide remains high even after years from the diagnosis of Alzheimer's disease, highlighting the importance of paying attention to any signal that might suggest a suicidal intention [30]. We reflect on Robin’s bewilderment about the impotence and chilling fear of becoming like one of the characters in his "Awakening", or even on the possibility of experimenting terrifying hallucinations. However, because of his full awareness we could not exclude that his gesture might be interpreted as a final act of love for Susan, to free her from the burden of the disease.

The importance of neuropathology

In Susan's letter it strikes her need to know the diagnosis of the disease that took away her husband, this knowledge came only after his death, with the autopsy. Thus, finally, it reveals the origin of all the symptoms of the disease seemingly unrelated to each other. Neuropathology explains how the disruption of amygdala and medial nucleus of the thalamus, not specific but also present in DLB, is responsible for behavioral disorders for the close links with the prefrontal network, unfortunately, without any possibility of objectification [31]. The certitude of the diagnosis of dementia, given by the neuropathological examination, seems to be no longer useful for the family of the affected person [23], nor for the doctor. This misconception has led over the years to neglect almost entirely the neuropathological study and relegate it, exclusively in research settings. Susan’s reaction shows us how the diagnosis is important and the awareness of who has been the "demon" can only increase the acceptance of the disease and the loss of one's dear, in addition to the scientific implications that neuropathological diagnosis brings with it [32].

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Conclusion

Today, only the half of patients with any kind of dementia receives diagnosis. The narration of the personal pain of Robin Williams suffering from LBD, through his wife's pen, was the starter point to reflect on the complexity of these diseases. The reflections must be transformed into new attitudes towards dementias. The hope of Susan, and of many family members, is that the suffering of their relatives may one day help other patients, other families and doctors and researchers to fight these terrible diseases. Her commitment in supporting research through the Brain Foundation is, again, a way to sublimate the pain and emptiness of loss. How many Susan we encountered in our clinics, in our associations and at our side in our work of assistance and research, full of hope, pleading and willing to do everything, the ultimate, and the impossible to go on and fight on behalf of their loved ones. With them and for them we will not surrender.

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Protein Expression Profile of Oral Premalignant Lesions (OPLs) | Juniper Publishers

Juniper Publishers-Open Access Journal of Cell Science & Molecular Biology

Authored by Kamal Uddin Zaidi

Abstract

The progression in cure, early detection and degeneration of oral squamous cell carcinoma (OSCC) remain a key factor to improve the survival rate of patients, in which an elevated proportion of patients are diagnosed at an advanced stage. Current developments in molecular biology research enhanced the understanding of molecular process in OSCC progression and led to identification and characterization of numerous biomarkers. These biomarkers are expected to facilitate the early detection of primary and relapsed tumors. In the present research, we evaluate potential biomarkers for the early detection of OSCC.

Keywords: Carcinoma; Biomarkers; Protein; Serum; Cancer; Tumor

Introduction

Oral cancer is a subgroup of head and neck cancer which affects various regions within oral cavity i.e., lips, tongue, salivary glands, and gums. It is the sixth most common cancer, approximately 3% of the total cancer burden and results in 128,000 annual deaths globally [1,2]. The most common type of oral cancer is oral squamous cell carcinoma (OSCC), which accounts 90% of all oral cancer cases. Patients with OSCC are often diagnosed at a late stage, thus high recurrence rate occurs after treatment, especially in those with neck lymph node metastasis [3]. Despite clinical and treatment advances, the overall 5-year survival rates for oral cancer remains low and stagnant during past few decades [4,5]. Although OSCC is commonly diagnosed through oral examination followed by histopathology and computed tomography/positron emission tomography scanning, there has been continuous interest in developing serum protein biomarkers to aid the diagnosis. Tumor antigens are promising diagnostic biomarkers for human cancers showing the clinical utility of tumor antigens, such as carcinoembryonic antigen (CEA), CA-50, CA19-9 and squamous cell carcinoma antigen (SCCA) for OSCC detection [6-9].

Serum SCCA appeared to be more sensitive than the other tumor antigens and positive in 38.1% and 41.4% of OSCC patients under testing [8,10]. Studies also revealed other potential serum protein biomarkers i.e., CYFRA 21-1 (cytokeratin 19-fragments), tumor polypeptide antigen (TPA) and insulin-like growth factor binding protein 3 [9,11]. CYFRA 21-1 has been demonstrated as biomarker for other solid tumors, whereas TPA is a serine protease found in rapidly growing tissue due to its role in forming intermediate filaments of the cellular cytoskeleton, making it a promising candidate for cancer detection. Both CYFRA 21-1 and TPA levels were found to be significantly higher in OSCC patients compared to healthy controls and benign tumor patients, and both reduced in 2–3 weeks after surgical resection of their OSCC lesions [11]. Although the testing serum protein biomarkers as a simple diagnostic tool for oral/head and neck cancer has been well demonstrated but still needs to be further validated in large clinical trials. In this study, proteomics analysis of serum for early detection, evaluation, aggressiveness and occurrence of OSCC were summarized. The emphasis was placed on early detection by serum with histological defined oral carcinoma patients. Protein in tissues, saliva and serum may more accurately reflect the progression of OSCC, so novel approach for the depth research strategy and the sample choice for proteomics are of importance in OSCC biomarker discovery.

Material and Methods

Sample collection

Information about chewing habits and other characteristics of the study participants was acquired. Those with the habit were questioned for the frequency of the habit in number per day and duration of the habit in years. The type of lesion in the cases was decided on the basis of careful observation of the oral cavity and then blood samples were collected from People’s College of Dental Science and Research Centre, Bhanpur Bhopal, over a period of one month. 2-3ml of blood were taken as samples from the patients having oral premalignant lesions (OPL) (leukoplakia and/or erythroplakia) and stored in sterile vials containing 1.5mg/ml EDTA and stored at -20 °C. Individuals who were not addicted to smoking, tobacco or not habitual areca nut consumer and were not having any prior history of cancer and who had never smoked before in his or her lifetime are defined as a never smoker and were considered as control.

Determination of Protein Content

Lowry method

The protein content of serum was determined 1mg/mL stock solution of Bovine serum albumin (BSA) was prepared. BSA was dissolved in 0.1 N NaOH and used as standard [12]. For preparation of standard curve of BSA different concentration that is 100μg/mL to 1000μg/mL of BSA was prepared in clean glass tubes and volume was made up to 1mL using Millipore water. To each tube, 5mL of alkaline solution was added and the tubes were incubated at room temperature for 10min. After incubation, 0.5mL of Folin’s reagent was added and was incubated at room temperature in dark for 30 minutes. Violet to blue colour was developed. The intenity of colour was propotional to protein concentration. After incubation the absorbance was measured at 660nm. Standard curve was prepared by plotting protein (BSA) concentration on X-axis and O.D on Y-axis. A blank was prepared by taking 1mL of Millipore water in tube in which 5mL of alkaline solution and 0.5mL of Folin’s reagent were added. All the procedures were carried out in triplets. Estimation of protein contents was done in a same manner as BSA standard curve.

Sodium dodecyl sulphate polyacrylamide gel electrophoresis (sds-page)

Poly acrylamide gel electrophoresis in the presence of sodium dodecyl sulphate was performed according to LaemmLi [13]. The SDS-PAGE was performed using a 12% separating gel and 4% stacking gel. The samples were heated for 5min at 100 °C in capped vials with 1% (w/v) SDS in the presence of β-mercaptoethanol. Electrophoresis was performed at a 125 V for 4h in Tris- HCl buffer of pH 8.3. After electrophoresis, proteins in the separating gel were made visible by staining with Coomassie Brilliant Blue R-250. The standards were used to make a plot of log molecular weight versus mobility of the protein band were myosin (200kDa), β-galactosidase (120kDa), bovine serum albumin (91kDa), glutamate (62kDa), ovalbumin (43kDa), glyceraldehyde-3-phosphate dehydrogenase (36kDa), carbonic anhydrase (29kDa), myoglobin (26kDa), and lysozyme (14kDa) as markers [6] (Table 1).

Results and Discussion

The OPLs (leukoplakia/erythroplakia) case sample was collected from OPLs patients of PCDS&RC, People’s University, Bhopal the sample size was 20 in which 3 were females and 17 were males under the age group of 18 to 60. Taking into consideration the addictions, 11 of them were habitual of smoking either bidi or cigarette, 6 were betel nut consumers whereas most of them were pouch/gutkha consumers. Among the sample population, female: male ratio observed was 3:17, where females account for 30% and males 70%. Total population (OPLs cases) age range varies from 18 to 68 years, of which 18- 68 and 25-54 was age range of males and females respectively. Among the observed population 38% were smokers, 21% were betel nut consumers and majority i.e., 41% were pouch and gutkha consumers. Biomarkers have been wide accepted in other disciplines but there is no consensus for their use in oral malignancies. Despite recent advances in surgical, radiotherapy, and chemotherapy treatment protocols, the survival of patients with OSCC still lacks significant improvement. This unsatisfactory treatment may be explained by the fact that OSCCs frequently present with extensive local invasion and advanced stages [14,15]. That makes necessary the development of new tools for the diagnosis and prognosis.

Protein Profiling

Total protein

From the known concentration of protein, the standard curve was plotted, and protein content of the clinical isolates were observed. The total proteins were estimated which revealed the difference in Oral premalignant lesions. The protein concentration ranged from 3.2-11.8mg/mL. Control group the protein concentration ranged from 2.87-8.35 (Figure 1). Oxidation of protein plays an important role in pathogenesis of cancer and studies have demonstrated decreased protein levels in cases of OPMD’s and oral malignancy [16,17]. In oral cancer, tobacco and areca nut related habit leading to tissue damage and resultant free radicals play a major role as an aetiologic factor. These habits are seen commonly in all the ages and both the sex. The serum protein levels were decreased in OSMF, OL and NS but increased in OM. This difference was statistically significant. These findings are fill agreement of with the findings of Patidar et al. [18] and Rajendran et al. [19] in OSMF participants and Dawood et al. [20] in OM participants. In contrast our results did not simulate with the finding of Chandran et al. [16] in OM group where the plasma protein levels were found to be decreased. The increase in serum protein levels may be explained in terms of inflammatory reaction associated with oral malignancy.

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SDS-PAGE analysis of various samples revealed at least 06 types of banding patterns, with the number of bands ranging from 25 to 40. The maximum number of sample 26.6%) had a banding pattern with 04 bands. Proteins with molecular weights 66kDa, 75.0kDa, 95,110 and 140kDa were consistently present in the in the pattern. The pattern 2 showed number of 16.6 % sample had a banding pattern with 03 proteins bands with molecular weights 11.5,23, and 90.5kDa. The pattern 3 (10% sample) showed 04 proteins bands with molecular weights 118.5, 23, 66 and 97kDa. Pattern 4 showed number of 23.3 % sample had a banding pattern with 04 proteins bands with molecular weights 14, 18, 42 and130kDa. Pattern 05 also showed number of 10 % sample with 04 proteins bands with molecular weights 67.5,75,95 and110kDa. Pattern 6 revealed 03banding pattern with molecular weights14.5, 38.5, 55.5kDa. Feng et al. [21] measured the level of some biomarkers (SCCA, Cyfra 21-1, epidermal growth factor receptor (EGFR) and Cyclin D1) in an attempt to determine the usefulness of their combined determination in the diagnosis of OSCC. They concluded that Cyclin D1, the product of the CCND1 gene located on chromosome 11q13, had the highest diagnostic specificity. Moreover, the combined detection of EGFR and Cyclin D1 (36kDa) had the highest sensitivity, specificity and accuracy. A previous study Capaccio et al. [22] demonstrates that Cyclin D1expression was significantly associated with the presence of occult lymph node metastases. These data suggest that the immunohistochemical analysis of Cyclin D1 expression in diagnostic biopsy samples may be an additional tool for selecting patients to be treated with elective neck dissection.

The dendrogram showed that the samples [12] were grouped in two closely related clusters. The clusters of Oral Premalignant lesions were significantly different from an unrelated to that of the control. It was also seen that sample from control tended to fall close together on cluster analysis. In our study, the SDSPAGE pattern revealed several characteristic bands common to all samples.

The sample under study was divided in to 2 clusters with cluster 1 having 12 sample and cluster 2 with 18 samples having a similarity 82.5% and dissimilarity of 17.5% in the jaccard’s coefficient scale ion the dendogram (Figure 2). The cluster 1 was further divided into 1a and 1b with 3(OPLs-18, OPLs-08 OPLs-14,) and 9 (Control-10, Control-07, Control-6, Control-3, OPLs-16, OPLs-13, OPLs-07, OPLs-03, OPLs-05) sample respectively. The cluster 2 was also divided in to two sub-cluster 2a (1) (Control-1) and 2b (17) (OPLs-17, OPLs-04, OPLs-12, OPLs-20, OPLs-02, OPLs-10, Control-09, Control-08, Control-04, Control-02, OPLs-06, OPLs-15, Control-5, OPLs- 19, OPLs-11, OPLs-01, OPLs-09). Cluster 2a having 1 sample showed similarity 88.7% and dissimilarity of 10.5%. 2b showed similarity 87.3% and dissimilarity of 12.3% (Figure 2).

The sub-cluster 2(b) was also sub divided into sub sub cluster as 2b1 (OPLs-17, OPLs-04, OPLs-12) showed similarity 87.9% and dissimilarity of 12.1%. Cluster as 2bII (OPLs-20, OPLs-02, OPLs-10, Control-09, Control-08, Control-04, Control-02, OPLs- 06, OPLs-15, Control-5, OPLs-19, OPLs-11, OPLs-01) showed similarity 86.1% and dissimilarity of 13.9%. These differences between the samples are due to the difference in their protein profile which can be mediated due to the difference in the oral premalignant lesions therapy. The study clearly indicates that the profile of total protein from Oral Premalignant lesions can be used for developing classification pattern. The cluster 2bII was also sub divided into sub cluster as 2b1Ia and 2b1Ib (Control-09, Control-08, Control-04, Control-02, OPLs-06, OPLs- 15, Control-5, OPLs-19, OPLs-11, OPLs-01) showed similarity 87.9% and dissimilarity of 12.1% (Figure 2). Cluster analysis has been used, allowing one to make a more objective interpretation of immunoprofiles, based on staining with multiple antibodies, and holding great promise for the immunohistochemical classification of tumors [23].

Ideally, a good clinical test requires high sensitivity and specificity. The oral cavity is commonly subject to inflammation from a variety of causes, including trauma, dental plaque, infection and certain mucocutaneous inflammatory diseases. Whether such oral inflammation (non-neoplastic conditions) affects the levels of the potential OSCC serum biomarkers is essentially unknown, because most studies investigated the potential biomarker levels only in OSCC and non-OSCC, without regard to other inflammatory conditions present [24]. If any OSCC biomarkers levels increases in the presence of oral inflammation to the level of OSCC patients, it would result in a high false positive rate and greatly reduce the value of that biomarker in clinical use for detection. Many of reported potential OSCC biomarkers, such as IL-6 [25], IL-8, IL-1 β [26], basic fibroblast growth factor [27] and molecules related to oxidative stress [27] are known to be important factors involved in inflammation and/or wound healing [28]. Indeed, the levels of some of these constituents have been reported to be significantly higher or lower in periodontitis or OLP patients who did not have OSCC [29]. Therefore, research that validates any potential OSCC biomarker with individuals having common non-neoplastic oral inflammatory diseases is necessary in order to establish the reliability of that salivary OSCC biomarker

Conclusion

Serum biomarkers obtained represent a promising approach for oral cancer detection, and an area of strong research interest. However, some issues/challenges needs to be determined in order to establish this approach as a reliable, highly sensitive and specific for clinical use, including lack of consistency of serum sample collection, processing and storage; wide variability in the levels of potential oral carcinoma serum biomarkers in both non-cancerous individuals and oral carcinoma patients; and further validation of oral carcinoma serum biomarkers with individuals either a chronic oral inflammatory disease or other types of cancers, but do not have oral carcinoma. Research for eventual standardization especially biological and physiological variance affecting the potential biomarkers gained importance in serum diagnostics. This approach can be useful in monitoring non-cancerous disease activity applying serum biomarkers for other forms of cancer.

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Chronic Systemic Delusions | Juniper Publishers

Acquired brain injury

Juniper Publishers-Open Access Journal of Intellectual & Developmental Disabilities

Authored by Ronaldo Chicre Araujo

Mini Review

Systematic chronic delusions were described in detail by French and German psychiatry of the nineteenth and early twentieth centuries. These delusions are part of the pictures of psychosis characterized by permanent delusions. It must be considered that delusional ideas are not only the beliefs and conceptions by which the themes of delusional fiction are expressed, such as persecution, grandeur, jealousy, but also delirious ideas are considered ideofeffective phenomena in which delusion takes shape, such as intuitions, illusions, interpretations, hallucinations, imaginative and passionate exaltation. These delusional ideas cannot be conceived as mere errors of judgment [1]. From the classification of Kraepelin and later with the works of Bleuler, many of these delusions became part of schizophrenia. However, French psychiatry maintained the description of chronic delusions outside the schizophrenia group. Nowadays, the nosographic studies of the great classical figures of French psychiatry of the nineteenth and early twentieth centuries are increasingly giving rise to a more biological, neurological and pharmacological psychiatry.

The psychiatric clinic certainly represents one of the great endeavors of human knowledge [2]. For the diagnosis and therapeutic management, it is important to return to the classification of chronic delusional psychotic disorders proposed by the French nosography, in which chronic delusional psychoses are presented without a deficient evolution in systematized delusional psychoses (paranoia), and with a deficient evolution in schizophrenia . This work proposes to address the chronic delusions systematized that develop without progressively compromising the adaptive capacities of the individual. Systematic chronic delusions are also called paranoid psychoses, they are generally very well organized, with rich and consistent histories. They maintain over time their content and richness of detail [3].

These delusions are directly connected with the construction of the personality of the delirious and develop with coherence and clarity according to Kraepelin. They present a logical construction, from false elements, which are Clérambault’s postulates of the delirious fable. Its evolution is insidious and progressive. Interpretations, delusional perceptions, hallucinatory activities, and fabulations, which are characteristic symptoms of these delusions, are reducible to pathological beliefs. Due to their systematic form, these delusions are relatively coherent and present themselves to those who are close to the delusional many times plausibly. Therefore, their power of conviction is great and may cause others to participate actively in delirium, as induced delusions. In the group of chronic delusions systematized are classified as delusions of passion and claim.

The claim concerns procedural plaintiffs who go to court because of their conviction that they have been harmed, they feel betrayed and wronged, and can often commit a crime against their enemies; to inventors convinced that someone stole an idea from him to passionate idealists who, in defense of just cause, may commit violent acts. In the group of passionate delusions are the delirium of jealousy, in which the individual is certain that he is betrayed in his love relationship; and the erotomaniac delirium, in which the individual has the conviction that he is loved by someone. In the evolution of this delirium, three phases are considered, a phase of hope, a phase of resentment and a phase of rancor. In this last one, the individual can commit a crime against who left it.

The psychosis clinic presents different modalities. The study of paranoia allows us to apprehend the particularities of delusional propositions. To regroup the set of psychoses under the sole term of schizophrenia is the attempt to maintain an organicist reading of mental illness [4].

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Chronic Systemic Delusions | Juniper Publishers

Acquired brain injury

Juniper Publishers-Open Access Journal of Intellectual & Developmental Disabilities

Authored by Ronaldo Chicre Araujo

Mini Review

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Inhibitory Activity of Isoquercetin and Quercetin-4'-Glucoside on the Drug Targets of Staphalococus aureus Causing Bovine Mastitis - An In silico Approach | Juniper Publishers

Juniper Publishers-Open Access Journal of Nanomedicine

Authored by MS Latha

Abstract

Bovine mastitis is the inflammation of mammary glands of cattles leading to decrease in milk production and cause huge economic losses in diary industry. Among the mastitis causing pathogens, Staphalococus aureus bacterial infections are most common. Extracellular matrix binding protein and monofunctional glycosyltransferase inhibitors are the most potent drug molecules against Bovine mastitis caused by Staphalococus aureus bacteria. The affected animals treated with current extracellular matrix binding protein and monofunctional glycosyltransferase inhibitors are antibiotics with severe side effects. Crude extract of locally available plants in the Amaryllidacea family is known to be very effective against mastitis. Glucoside derivatives of Quercetin are the major flavonoids in Amaryllidacea family.

The docking study of these flavanoids using Schrodinger suit v.9.2 showed their inhibitory activity against the target proteins. The Crystal structure of the target protein was retrieved from Protein Data Bank. (PDB ID: 4KJM, 3HZS and 3VMQ) and the structure of the ligand molecules were collected from PUB CHEM NCBI. Isoquercetin and Quercetin-4’-glucoside shows better docking results compared to the commonly used antibiotic, pirlimycin hydrochloride. This study has revealed the superiority of Quercetin glucosides over the conventional drug as extracellular matrix binding protein and monofunctional glycosyltransferase inhibitors and it sets the necessity of further in vivo study of this compounds in future for the development of more promising drugs for Bovine mastitis.

keywords: Extracellular matrix binding protein; Monofunctional glycosyltransferase; Staphalococus aureus; Bovinemastitis; Docking; Extra precision

Introduction

Bovine mastitis is an inflammation to the mammary gland of cattle [1]. Causative of the inflammation include bacteria, virus and non bacterial pathogens. The infectious agents invade the udder through teat canal and multiply rapidly. Then due to an inflammatory reaction tissues get damaged [2]. Among the mastitis causing pathogens, Staphalococus aureus bacterial infections are very common. Staphalococus aureus is a gram positive round shaped bacterium. Bovine mastitis reduces the quantity of casein, lactoferrin and potassium in milk. As the major protein, casein in milk deteriorates; the calcium level in milk also decreases. During processing and storage also the milk proteins undergo deterioration [3]. Milk from affected animals show very high somatic cell count which lowers the quality of milk [4]. Hence, Bovine mastitis causes severe economic losses in diary industry [5]. Current treatment of mastitis includes antibiotic therapy. But the residues of antibiotics remain in milk causes severe side effects. And the antibiotic resistance developed in bacteria due to long series therapy decreases the effectiveness of the drug [6]. Pirlimycin hydrochloride (Pirsue) is the most common drug used against Bovine mastitis [7].

Extracellular matrix binding protein and monofunctional glycosyltransferase are two excellent drug targets for the prevention of mastitis [8]. In order to be infectious, bacteria’s had surface proteins of specific affinity for components in the extra cellular matrix. These proteins are called extracellular matrix binding proteins or receptions [9]. It has been reported that extracellular matrix binding protein of Staphalococus aureus are required for adhesion to and invasion of bovine mammary gland [10]. So, inhibition of which blocks the adherences capacity of the bacteria. Monofunctional glycosyltransferase are cell wall associated drug targets (PDB ID: 3HZS and 3VMQ) Inhibition of this protein results in bacterial cell lysis [11,12]. Current extracellular matrix binding protein and monofunctional glycosyltransferase inhibitors are antibiotics with decreased efficacy.

Glucoside derivatives of Quercetin are plant flavonoids possess enormous therapeutic applications [13]. The presence of sugar moiety increases its bioavailability. The present study focuses on the inhibitory activity of glucoside derivatives of Quercetin and Quercetin-4’-glucoside targeting the excellent drug targets in Staphalococus aureus causing Bovine mastitis. The in silico analysis using Schrodinger maestro module showed the binding interactions of these molecules with the target protein. Comparison of the results with the most commonly used commercially available drug reveals its potential anti mastitis activity.

Methodology

The docking studies were performed with Schrodinger Software Suit, LLC, New York, 2012. The 3D crystallographic structure of the target extracellular matrix binding protein (PDB ID:4KJM) was downloaded from Protein Data Bank [14] The protein complex was prepared by protein preparation wizard after pre-processing in Maestro 9.3.5 Version Schrodinger Software [15]. The minimization of the protein complex was continued using Optimized Potential for Liquid Simulations force field [16]. The 2Dstructures of the glucoside derivatives of quercetin and pirlimycin hydrochloride were imported from the project Table 1. These ligands were minimized and geometrically refined using Lig Prep module [17]. The extra precision (XP) mode of docking was used to find the interaction between the active site of extracellular matrix binding protein and the ligand molecules using Glide of the Schrodinger Software Suite [18].

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Results and Discussion

Structure of the ligands

i. 3D docking images of ligands with 4KJM (Extracellular matrix binding protein) (Figures 4-6).

ii. 3D Docking images of the ligands with 3HZS (Monofunctional glycosyltransferase) (Figures 7-9).

iii. 3Ddocking images of ligands with 3VMQ (Monofunctional glycosyltransferase) (Figures 10-12).

iv. 2D interaction of ligands with 4KJM (Figures 13-15).

V.2D interaction of ligands with 3HZS (Figures 16-18).

Vi. 2D interaction of ligands with 3VMQ (Figures 19-21).

From the docking results, it has been observed that the glucoside derivatives of quercetin possess excellent inhibitory activity towards all the three target proteins compared to the commercially available drug. Isoquercetin forms four hydrogen bonds with the active binding site of the extracellular matrix binding protein. ASN 66 and LYS 69 amino acid residues in the binding pocket of the target protein forms hydrogen bonds with hydroxyl groups in the ligand. Two water molecules present in the protein also forms hydrogen bonds with hydroxyl groups in the isoquercetin molecule. In addition to that there is a metal coordination between the metal Zn 203 and the ligand. All these interaction contributes the necessary binding energy for inhibitory action. Quercetin-4’-glucoside forms five hydrogen bonds with the active site of the target Extra cellular matrix binding protein. Hydroxyl groups in the ligand forms four hydrogen bond with 6ASN and 66ASN amino acid residues. Another hydrogen bond is formed between a nearby water molecule in the target protein and the ketogenic oxygen of the ligand molecule. The metal Zn 204 in the protein forms a metal coordination with hydroxyl group in the ligand. Two hydroxyl groups in Pirlimycin hydrochloride forms hydrogen bonds with 66ASN amino acid residue and a nearby water molecule.

Staphalococus aureus attach to the extracellular matrix of the mammary gland through the extracellular matrix binding protein (PDB ID: 4KJM) and then colonize and multiplies. The 4KJM inhibitors, Isoquercetin and Quercetin-4,-glucoside blocks the active site of the protein and causes the detachment of bacteria from the extracellular matrix. These inhibitory ligands have better docking scores and glucose moiety in isoquercetin and quercetin-4’-glucoside are responsible for the increased inhibitory action compared to the commercial drug.

Monofunctional glycosyltransferase (PDB ID: 3HZS and 3VMQ) are a class of another excellent drug targets in Staphalococus aureus causing Bovine mastitis. Three hydroxyl groups in Isoquercetin forms hydrogen bond with the backbone amide nitrogen atoms of 146ASN and 140 LYS of 3HZS. There is also three side-to-side hydrogen bonding interactions between hydroxyl groups in the ligand molecule and 137 GLN and 145ASP Quercetin-4’-glucoside forms four side-to-side hydrogen bonds with 66ASN, 6ASN, 6TYR. Pirlimycin hydrochloride forms two side-to-side hydrogen bonding interactions 136GLN and PHE. The N atom in the ligand also forms a back bone hydrogen bonding interaction with the 115THR of 4HZS.

From the docking score, it is evident that the glucoside derivatives of Quercetin are better inhibitors than the commercial drug. Isoquercetin possess two side-to-side hydrogen bonding interactions with 141ASNand 145ASP of Monofunctional glycosyltransferase, 3VMQ. There is two more hydrogen bonds between the ligand and 146ASN and 223VAL. Quercetin-4’-glucoside forms a side-to-side hydrogen bond with 111ASP and another with nitrogen atom of the amide group of 122THR. Pirlimycin hydrochloride forms four hydrogen bonds with 102GLU, 103ARG, 129GLN and 103ARG (side-to-side) of the monofunctional glycosyltransferase 3VMQ. Glycosyltransferase are associated with the bacterial cell wall biosynthesis. Inhibition of these essential targets results in bacterial cell lysis. Isoquercetin and Quercetin-4’-glucoside shows better docking than the commonly used drug against mastitis.

Conclusion

The glucoside derivatives of Quercetin (Isoquercetin and Quercetin-4’-glucoside) shows potent inhibitory activity towards the Extracellular matrix binding protein and monofunctional glycosyltransferase compared to the most common commercially available drug. By inhibiting Extracellular matrix binding protein, isoquercetin and Quercetin-4’-glucoside exterminate the adhesion capacity of the protein to the extracellular matrix of Bovine mammary gland which results in the detachment of bacteria from the gland or bacterial death. Monofunctional glycosyltransferase are essential for bacterial cell wall biosynthesis. Glucoside derivatives of Quercetin can act as an inhibitor of transglycosylation step which results in bacterial cell lysis. That is Isoquercetin and Quercetin-4’-glucoside inhibits both the indispensable drug targets in Staphalococus aureus which attributed to two different mechanisms. Thus, the antimastitis activity of plants in the Amaryllidacea family is due to the phytochemicals Isoquercetin and Quercetin-4’-glucoside. This study reveals the importance of glucoside derivatives of Quercetin in the treatment of mastitis by an in silico approach and sets the scope of further in vitro and in vivo analysis for the development of new promising drugs for mastitis.

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Science/Education Portraits III: Perceived Prevalence of Data Fabrication and/or Falsification in Research | Juniper Publishers

Juniper Publishers-Open Access Journal of Biotechnology & Microbiology

Authored by Maurice HT Ling

Abstract

Data fabrication or falsification are considered as “deadly sins” with high impact, above plagiarism, on scientific truth and public confidence. What is the estimated prevalence of data fabrication or falsification? A meta-survey published a decade ago estimated 14.12% of respondents having knowledge of a colleague who fabricated or falsified research data, or who altered or modified research data. This mini-review updates this meta-survey by examining surveys from 2009 to 2018. Results suggests that 17.7% of responses indicated knowledge of fellow scientist’s acts of data fabrication or data falsification. This is consistent with that of a decade ago, which suggests a critical need to address the worst type of research misconduct – data fabrication and falsification.

Keywords: Research integrity, Research misconduct, Fabrication, Falsification

Introduction

There is no doubt that research misconduct does occur, from the cautionary tale of Piltdown Man [1] to potential fraudulent reporting [2] to the more recent high-profile cases of Yoshihiro Sato [3], Steven A. Leadon [4], and Woo Suk Hwang [5]. Research misconduct does not only occur in biological sciences but other science as well; such as, physics [6], and chemistry [7]. Although research misconduct pre-dates the 20th century [8]; studies into the prevalence of research misconduct, especially on data fabrication and/or falsification in biological sciences, only exist post-1990s [9].

The prevalence of research misconduct is a perennial question and Richard Smith [10] quoted Mike Farthing for estimating about one serious case a year in each major institution in Britain. In an early survey, Geggie D [9] reported 10.8% (21 out of 194 respondents) having first-hand knowledge of scientists or doctors intentionally altering or fabricating data for publication, which may lead to loss of confidence and future participation by the public in clinical research [11]. A survey by Bouter et al. [12] ranked data fabrication and data falsification as having highest impact on scientific truth, above plagiarism.

In this mini-review, existing surveys on research misconduct were examined to determine the prevalence of data fabrication and/or data falsification in biological sciences. Fanelli D [13] defines data fabrication as invention of data or cases, and data falsification as wilful distortion of data or results. Hence, data fabrication and data falsification is not plausible to be deemed as honest mistakes or scientific disagreement [14], especially in the case of data fabrication.

Surveys in Research Data Fabrication and/or Falsification

Fanelli D [13] performed a first meta-survey on 21 published surveys (15 surveys from USA, 3 surveys from UK, 2 surveys with multinational sample, and 1 survey from Australia) between 1987 and 2008, amounting to 11647 respondents. Between 5.2% and 33.3% (with weighted estimate of 14.12%, implying 1644 respondents) of respondents replied affirmatively to having personal knowledge of a colleague who fabricated or falsified research data, or who altered or modified research data. The 95% confidence interval was calculated to be between 9.91% (1152 respondents) to 19.72% (2297 respondents). Since Fanelli D [13] analysed surveys published to 2008 inclusive, 10 published surveys from 2009 to 2018 are reviewed here:

I. Tavare A (15) reported on a British Medical Journal (BMJ) email survey of 9036 academics and clinicians, in United Kingdom, whom had either published in BMJ or acted as reviewers and received a response rate of 31% (2801 respondents). If these 2801 respondents, 13% (364 respondents) admitted knowledge of colleagues “inappropriately adjusting, excluding, altering, or fabricating data” for publication.

II. Sheldon T [16] reported a published survey on Dutch general practitioners’ specialists from hospital and social care (original survey published in Medics Contact, http://medischcontact.artsennet.nl/Nieuws-26/archief-6/ Tijdschriftartikel/113385/Liever-lezendan-doen.htm), in which 809 of 1635 (49.5%) responded. Of these 809 respondents, 15% (121 respondents) believed that they had witnessed “close hand scientific results that were invented” (data fabrication) and 22% (178 respondents) believed that they had witnessed “close hand research data that had been selected or statistically treated to achieve significant results” (which may constitute data falsification).

III. Grieneisen & Zhang [17] examined 4232 article retractions from 1928-2011 across 1796 unique journal titles and 3631 (85.8%) retractions were given justifications. found 602 (16.6%) articles were retracted due to fraudulent or fabricated results. The authors found a rise in the percentage of retractions from 1990 onwards, based on PubMed records or Web of Science records by publication year.

IV. Hofman et al. [18] surveyed 262 postgraduate students attending introductory PhD-courses across medical faculties in Norway in 2010/2011 and 189 (72.1%) anonymous questionnaires were returned. Of the respondents, 29.2% (55 respondents) and 23.8% (45 respondents) heard about someone whom during the last 12 months, both nationally and internationally, whom had fabricated data or falsified data respectively. Significantly, one respondent had reported pressure to fabricate or falsify data.

V. Okonta & Rossouw [19] surveyed 133 out of 150 (88.7% respondents) Nigerian researchers attending the conference. Of the 133 respondents, 120 (90.2%) perceived that data fabrication occurred in their workplace and 108 (81.2) perceived that selective omission of data (which may constitute data falsification) occurred in their workplace. However, only about half of the respondents were aware of at least one case of misconduct in their institute within the last 5 years.

VI. Hofmann et al. [20] surveyed 201 (90.5% respondents from 222 questionnaires issued) post-graduate students enrolled in the PhD program at Karolinska Institute in Stockholm and the University of Oslo. Of the 201 respondents, 105 (91.3% respondents) were from Karolinska Institute and 96 (89.7% respondents) were from University of Oslo. 27.6% (29 respondents) from Karolinska Institute and 25.3% (24 respondents) from University of Oslo heard about someone whom during the last 12 months, both nationally and internationally, whom had fabricated data; which gives a total of 53 (26.4%) respondents. 29.8% (31 respondents) from Karolinska Institute and 22.3% (21 respondents) from University of Oslo heard about someone whom during the last 12 months, both nationally and internationally, whom had falsified data; which gives a total of 52 (25.9%) respondents. Importantly, one respondent from University of Oslo reported to have falsified data in the last 12 months.

VII. Looi et al. [21] surveyed 151 journals across Asia Pacific Association of Medical Editors and received 54 (35.8%) responses. Of the 54 journals, 16 (29%) journals experienced data falsification and 15 (27%) journals experienced fraudulent data/ image manipulation.

VIII. Pupovac et al. [22] surveyed 1232 Croatian scientists at the University of Rijeka in 2012/2013 with 237 (19.2 %) respondents. Of the respondents, 69 (29.1 %) observed data falsification in fellow scientists and 46 (19.4 %) observed data fabrication in fellow scientists. More importantly, 22 (9.3 %) respondents admitted to data falsification and 9 (3.8 %) respondents admitted to data fabrication.

IX. Godecharle et al. [23] surveyed 2021 scientists in Belgium; of which, 1766 were from universities and 255 from industry. 617 (34.9%) and 100 (39.2%) responses were obtained from universities and industry respectively, yielding a final response rate of 35.5% (717 responses). Collectively, 4% (29 respondents) and 12% (86 respondents) reported to have observed data fabrication and data falsification respectively, with as high as 40% (287 respondents) reported observing data selection. More importantly, one respondent from the industry admitted to data fabrication, and as high as 15% of all respondents (108 respondents) admitted to data selection.

X. Felaefel et al. [24] collected 278 usable surveys out of 348 submitted surveys from students and academics in Cairo University, American University in Cairo and Suez Canal University in Egypt, Royal College of Surgeons in Ireland, Medical University of Bahrain, and Ain Wazein Hospital in Lebanon, using SurveyMonkey via recruitment email or hand distribution of survey forms at Cairo University, Egypt. 72 (25.9%) and 65 (23.4%) of 278 respondents had knowledge of data fabrication and data falsification (changing data without mentioning) in colleagues respectively. Of the 224 self-admission, 21 (9.7%) and 21 (9.7%) admitted to data fabrication and data falsification respectively.

XI. Collectively from these 10 published surveys, 7 surveys segregated between knowledge of fellow scientist’s acts of data fabrication and data falsification. These 7 surveys comprised of 2654 responses out of 5870 surveyed – response rate of 45.2%. Of which, 496 (18.7%) and 603 (22.7%) respondents reported knowledge of fellow scientist’s acts of data fabrication and data falsification respectively. Taking all 10 published surveys into consideration, 9140 responses out of 19289 were gathered (response rate of 47.4%); of which, 1622 (17.7%) responses indicated knowledge of fellow scientist’s acts of data fabrication or data falsification.

Concluding Remarks

Data fabrication or falsification are considered as “deadly sins” with the highest impact on scientific truth [12], leading to potential loss of public confidence [11]. Yet, proportion of published articles retracted dur to fraudulent or fabricated results appears to be increasing [17]. A decade ago, Fanelli D [13] reported an estimated 14.12% of respondents having knowledge of a colleague who fabricated or falsified research data, or who altered or modified research data the first meta-survey done in this field. This mini-review suggests that 17.7% of responses indicated knowledge of fellow scientist’s acts of data fabrication or data falsification. This result is within 95% confidence interval reported by Fanelli D [13], suggesting that this trend has not declined over 2 decades. This suggests a critical need to address the worst type of research misconduct - data fabrication and falsification.

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Individual Neuronal Apoptosis Provokes DeterminedNecrosis of the Regional Cerebral Infarct in Patients with Ischemic Stroke

Authored by Lawrence M Agius

Abstract

Interplay pathway dynamics are constitutive agonists in an evolving ischemic focus within the brain that is triggered by apoptotic programmed cell death that is subsequently established as a necrotic focus of infarction within the cerebral cortex of many patients with stroke. The evolutionary dynamics further permit the activation of potentially neuroprotective measures that primarily attempt limitation of involvement of adjacent less injured neurons but subsequently by the establishment of transformed penumbra to a necrotic focus of infarction. Within such contextual transformations, the individual apoptotic neuron determines the characterized infarcted region as necrotic focus formulation. Individual neuronal apoptosis provokes determined necrosis of the regional cerebral infarct in patients with ischemic stroke.

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Introduction

Stroke patients comprise a large number of patients with a highly significant degree of cerebral ischemia that is best exemplified by the transient focal ischemia models in experimental animals such as rat and mouse. Mechanisms include bioenergetic failure and loss of cell homeostasis, and also acidosis, excitotoxicity and disrupted blood-brain barrier [1]. A central issue is the series of set conditioning factors that induce apoptosis of individual neurons within the penumbral region of the cerebral cortex on the one hand and the development if neuronal necrosis on the other. Combined steroid administration inhibits ischemia-induced apoptosis of neutrons through involvement of the intrinsic pathways [2]. It would appear that a combination of both apoptosis and necrosis of neurons evolves in at least some of the patients, and indeed neurons may exhibit features of both these forms of neuronal cell death when electron microscopic studies are combined with molecular and biochemical modes of analysis. Whether necrosis or apoptosis occurs often depends on cell type, cell age and location in the brain. Apoptosis leader to protein crosslinking, DNA fragmentation, ligand expression for phagocytic cell receptors and subsequent phagocytic uptake [3].

Neuroprotection

It is idealized that a set of potentially neuroprotective mechanisms is activated within the penumbral region of an evolving cerebral infarct. Oxidative stress contributes to ischemia/reperfusion with blood-brain barrier disruption, inflammation necrosis and apoptosis; Nnclear factor-E2-related factor 2 is central to regulated antioxidant defence and may protect against ischemia-induced neuronal injury [4]. Such coupled phenomena are central to the establishment of the expanding infarct secondary to delayed death of more neurons in the few days following the primary acute infarction of the core lesion. Glycine inhibits tumor necrosis factor alpha and protects agains inflammation and gloss in hypoxia-ischemia of neurons [5]. Such considerations are believed to potentiate the possible beneficial attempts at reducing infarct size within the acute dimensions of ischemic injury to neurons.

Glial cells

Glial cells such as astrocytes and microglia are implicated in neuroprotection and indeed the cellular network of gap junctions between individual astrocytes are viewed as supportive elements in neuroprotection. The dimensions of complex control of ion-motive ATPase channels collaborate with the dynamics of possible recovery of related ischemic neurons that implicate a regional characterization and re-characterization of the ischemic injury not only to individual neurons but also to groups and sizeable aggregates of such neurons. Auto-antibodies to apolipoprotein A-1 are associated with poorer clinical recovery and increased brain lesion volume 3months after acute ischemic stroke [6].

Dynamics of ischemic injury

Genetic evidence exists that separates apoptosis from necrosis through different forms of nuclear pyknosis, with conservation of nuclear pyknosis in the propagation of necrosis [7]. Performance dynamics of the acute ischemic focus also implicates microglia that are implicated in removal of ischemic individual neurons following acute ischemic injury. The distributional coherence of integral groups of ischemic neurons is hence mirrored by presumably apoptotic individual neurons undergoing damage primarily to mitochondria and to lipid moieties of the plasma membrane of the cells. In such context, the evolving participation of apoptosis and necrosis would permit the progression of caspase pathway activation and the release of cytochrome c release from mitochondria. Also, destabilized cellular calcium homeostasis follows a stereotyped pattern of changes that invokes execution pathways of neuronal cell injury.

The phagocytic receptor CED-1 is activated through interaction with its ligand phosphatidylserine (PS) exposed on the surface of necrotic neutrons; calcium influx activates a neuronal PS-scramblase for PS exposure [8]. A complex array of executing agonists include excitotoxic, oxidative and lipid peroxidation, and metabolic insults such as hypoglycemia participates within contexts of activated apoptotic pathways, as evidenced by the neuroprotective effects of administered caspase inhibitors in the acute phase of ischemic insults. Epigenetic regulatory networks in ischemic stroke may protect against oxidative stress with induced DNA methylation, histone modification and microRNAs, with affected redox state in neutrons, glia and vascular endothelial cells [9].

Determined pathway events

Determined outcome of the ischemic individual neuron and also of groups of such neurons is affected by "ischemic preconditioning" whereby a mild episode of ischemia generates resistance to a second ischemic episode. Certainly, the panoramic contexts of evolving ischemic injury within neurons is programmed within the pathways primarily dictated by individual cellular responses to ischemia that however originates as a regional focus of groups of ischemic neurons. Platelet- activating factor receptor is expressed on cellular and nuclear membranes of leukocytes, platelets, endothelial cells, neurons and microglia; its deficiency is experimentally associated with prevention of caspase-3 activation and decreased vascular permeability and cerebral edema. Decreased brain levels of tumor necrosis factor-alpha, interleukin-1beta and the chemokine (C-X-C motif) ligand 1 may be crucial in global brain ischemia-reperfusion [10].

Particularly intriguing is the overlap of regional and individual cell ischemic episodes that determine the onset of a core of necrotic cerebral tissue in the first instance and the subsequent creation of a penumbra of regional and partially injured neurons and glial cells. It is further to such phenomena that the ischemic episodes are regional also as evidenced by activated neuroprotective mechanisms such as the action of neurotrophic factors and of some cytokines such as tumor necrosis factor alpha and interleukin 1-beta. The PPAR gamma agonist 15d-PGJ2 regulates microglial activation and decreases tumor necrosis factor aha and interleukin-1 expression. Fewer apoptotic cells and less CD68 positive staining in diabetic schema rats [11].

Chaperone dysfunctionality allows for an evolving train of events in the execution of both apoptosis and necrosis within the individually affected neurons and as further portrayed by the dynamics of the expanding penumbral region. 4'-O-beta- D-Glucosyl-5-O-Methylvisamminol, a natural histone H3 phosphorylation epigenetic suppressor is a neuroprotective factor by acting via the PI3K/Akt singling pathway in focal ischemia in rats [12]. It is further to such processes that the integral identity of cell-death phenomena permits the execution of individual cell damage as dictated by regional injuries to the cerebral cortex in particular. pH gradient difference around cerebral foci of ischemia may allow delivery of polyethylene glycol-conjugated urokinase nano gels with effective thrombolysis of the ischemic stroke [13].

Performance attributes

Performance attributes characterize hence the emergence of a necrotic core to the ischemic focus in a manner that potentiates the evolutional progression of the penumbral region of partially injured neurons. MicroRNA-9 is down regulated in mice with middle cerebral artery occlusion and oxygen-glucose deprivation neurons, with suppression of neuronal apoptosis on its up regulation [14]. The parameters of acquisition of cellular ischemic injury is mirrored in the evolutionary course dynamics of such events as the emergence of a multitude of agonists that portray the character of primary core necrosis by the penumbral region of conditioned delay of individual cell death within contexts of transforming apoptotic cascades within such individual neurons.

Apoptosis

The ischemic neuron undergoing apoptosis is generally associated with adjacent cells that do not show apoptosis phenotype characteristics and as such this has implicated microglial phagocytosis of the individually damaged neuron. Such a phenomenon however is contrary to the widespread focus of integral ischemic injury to the cerebral cortical region and is also at variance with a presumably programmed response to injury to cellular networks. Tissue necrosis in particular is a conceptual realization of regional fields of perfusion and re-perfusion events arising from compromised individual vessels of supply. Penehyclidine hydrochloride down regulates the phosphorylation of JNK, p38MAPK, and c-Jun and protects neutrons against ischemia/reperfusion [15]. Ongoing phenomena such as the no-reflow events within the vessels of supply allow for complicated series of processes involving neuroprotective measures. Scite;;arom down- regulates expression of angiotensin-converting enzyme and ATI receptor with neuroprotective effects [16]. The activation of heat shock protein such as HSP-70 and increased secretion of glucocorticoids during the acute ischemic episode allows for the emergence of constitutive pathways that on the one hand further injure the neurons and on the other hand actually enhance potential resistance to acute neuronal ischemia.

Apoptosis/necrosis interplay

The apoptotic neurons exhibit characteristic cell body shrinkage and condensation of chromatin that progresses as fragmentation of the DNA and the appearance of single- and double-strand breaks of the DNA molecules. Such events may be related to the cytoskeletal injuries that occur in individual neurons such as those caused by depolymerization of actin filaments by gelsolin. Release of calcium from endoplasmic reticulum stores is characterized as an end-pathway that is reflected in individual cell death. Mitochondrial dysfunction further correlates with the onset and participation of injurious events as evidenced by programmed cell death pathway activations. Apoptosis of individual ischemic neurons is hence a contextual setting for necrosis of core foci within the lesion as further indicated by the subsequent establishment of a truly necrotic focus of cerebral infarction. The delivery of multi-components would further confirm the derivation of programmed cell death as determining agonist series of pathway events in establishment of further increased injury to individual neurons and regional groups of ischemic neurons. Etanercept, a recombinant TNF receptor (p75)-Fc fusion protein, may with repeated administration prevent exacerbation of cerebral ischemic injury in the diabetic state, mainly through anti-inflammatory action [17].

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Conclusion

Dynamics of calcium influx and of calcium release intracellularly include the participation of neuronal programming in cell death that is regionally characterized by dynamics of individual neuronal self-programmed cell death. As is evidenced by such dynamics of processed de-control of agonists such as mitochondrial dysfunction with release of cytochrome c and the lipid peroxidation pathways on the one hand, and of the oxidative end-products primarily affecting membrane lipids and calcium membrane channels, on the other, there evolves a regional/individual cell interplay of integral ischemic and hypoxic elements in the pathogenesis of cerebral infarcts. In such terms, evolutionary dynamics is collaborated pathway event in re-characterized potential neuroprotection of adjacent neurons within the adjacent cerebral cortex in many patients suffering from ischemic stroke. On the other hand, the transforming dimensions of injury to neurons are interplay supportive elements that profile-determine cell apoptosis that, in turn, may lead to potential necrosis of cerebral tissue.

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Primary Brain Ewing Sarcoma/pPNET in Elder Adult

Authored by Rato J

Abstract

The Ewing sarcoma/peripheral primitive neuroectodermal tumour type tumour (EWS/pPNET) group includes those small round blue cell tumours with morphological attributes of the germinal neuroepithelium. It represents a group of rare primary intracranial tumours, mostly described in paediatric population. There are very rare reports of primary intracranial EWS / pPNET in elders. We report the case of an 83-year- old man, where a cerebellar-pontine lesion mimicking a meningioma turned out to be a EWS/pPNET. Genetic studies were not performed, as he was not to be submitted to chemotherapy.

Keywords: EWS/pPNET; Ewing sarcoma; Peripheral primitive neuroectodermal tumour; Cerebellar-pontine angle

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Introduction

Ewing sarcoma / peripheral primitive neuroectodermal tumour type tumour (EWS / pPNET) are very rare tumours (1% of all sarcomas); Ewing's sarcoma represents 5 to 15% of malignant bone and soft tissue tumours; two thirds of cases of Ewing's tumours occur before age 35 years, with a median age of 20 years [1]. Primary brain tumour cases in adults are found in reports literature [2,3]. Ewing sarcoma / peripheral primitive neuro ectodermal tumour type tumour (EWS / pPNET), belongs to a tumour family that shares clinicopathologic and molecular genetics features. Histologically, its family is recognized as a small, round, blue cell tumour, staining positively for CD99 and usual genetic features gene rearrangements between chromosome 22 and 11 (22q11 EWSR1/FLI1) or FUS (chromosome 16) [4]. Primary brain tumours of this sort are rare (a review of the literature revealed 19 cases), being the eldest a 67-year old female [5-22]. They are classified per the 2016 WHO Classification as mesenchymal, non-meningothelial tumours [4].

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Review of the Case

We report the case of an 83-year-old man, autonomous, who presented at the emergency department with complaints of numbness on the right side of the face lasting 3 months. The patient underwent a head-CT, which demonstrated the presence of an extra-axial lesion on the right cerebellar-pontine angle, approximately 2cm wide, and was referred for a neurosurgical appointment. He returned a month later to the emergency department complaining of a severe loss of balance that deemed him unable to walk. He repeated the head-scan which showed that the lesion had doubled in size within this timespan. A head- MRI was performed and the lesion resembled a meningioma. The patient underwent surgery 2 weeks later and total removal of the lesion was achieved via retrosigmoid craniotomy. In the immediate postoperative period, he presented a right peripheral facial palsy, House-Brackman 4, and therefore a tarsorrhaphy was performed. He recovered partially of his facial palsy, and is now able to walk. No further lesions were found and he is scheduled to start radiotherapy [23].

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Discussion

The histology of the lesion revealed a small, round cell tumour with an immunophenotype favouring the Ewing sarcoma / peripheral primitive neuroectodermal tumour type tumour (EWS / pPNET). Genetic studies were not performed in this case, since the patient was not to be submitted to chemotherapy. These are very rare tumours, mostly appearing on paediatric age and therefore the diagnosis and prognosis factors are unknown. Ibrahim et al. [24] in their recent review, proposed some possible prognostic factors, some of which are applicable to Ewing sarcoma in a broader sense. Specifically, age greater than 17 years, inaccessibility of the tumour for surgical resection, incomplete resection, multifocality, and tumour genetic factors (e.g. Type 1 fusion gene) appear to have negative prognostic implications. There is not enough data on the matter to draw a conclusion other than it is a diagnostical challenge to distinguish these tumours from other with similar characteristics; but it is fundamental to do so, ensuring that proper follow-up and complementary treatments are administered.

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Primary Brain Ewing Sarcoma/pPNET in Elder Adult

Authored by Rato J

Abstract

Keywords: EWS/pPNET; Ewing sarcoma; Peripheral primitive neuroectodermal tumour; Cerebellar-pontine angle

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Introduction

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Review of the Case

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Discussion

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Coexisting Traumatic Ipsilateral Extra and Subdural Hematoma- Is It Really Common?

Authored by Amit Kumar Ghosh

Introduction

A 37-year old man was admitted in neurosurgical unit after 6 hours of injury with history of road traffic accident and head injury. He was hemodynamically stable. His GCS was E2M5V2. Pupil was reacting bilaterally and there was mild left sided paucity of movement. There was no other major injury (spine, abdomen, and chest, long bones were normal). CT scan of brain showed extradural hematoma, mass effect, and skull fracture (Figure 1A).

Patient was taken for surgery after relevant preanaesthetic investigations within an hour. Right sided fronto-temporo- parietal standard trauma craniectomy was done. After evacuating extradural hematoma, dura was looking bluish and tense. So, dura had been opened and subdutal hematoma was seen and evacuated (Figure 1B). After proper hemostasis, augmentation duraplasty was done and bone flap was not replaced, kept in subcutaneous pocket in anterior abdominal wall. Patient was ventilated electively for next 24 hours and then weaned off ventilator. He became conscious, was obeying commands and talking (Figure 1B)

Post-operative CT scan of brain was done which showed craniectomised skull with post-hematoma-evacuated status (Figure 2).

Discussion

Coexisting extradural (EDH) and subdural hematoma (SDH) in the same side is rare phenomenon. As a mechanism, it is unusual to find both EDH and SDH on the same side in patients with head trauma [1]. unless there is direct trauma. Only four case reports have been found [1-4]. More commonly, EDH and SDH happens in opposite locations. EDHs are usually coup lesions and thought to be due to direct trauma with seepage of blood from a calvarial fracture or injury to the dural arteries [4]. Acute SDH, on the other hand, is generally countercoup in location, mostly venous in origin [4], due to brain shift causing damage to the cortical bridging veins [4].

When EDH and SDH happens in the same side, the cause of the EDH is direct injury of dural artery or seepage from fracture and the SDH is also due to direct injury of cortical artery and/ or vein. Aim of surgery is evacuation of extra and subdural hematoma, secure haemostasis, and augmentation duraplasty and also it is always safe to do a standard trauma decompressive craniectomy.

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Beauty, A Social Construct: The Curious Case of Cosmetic Surgeries | Juniper Publishers

Juniper Publishers-Open Access Journal of Dermatology & Cosmetics

Authored by Vandana Roy

Abstract

In this article we deconstruct the social norm of beauty and cosmetic beauty treatment, an issue that is seldom discussed in medical circles and is often lost to popular rhetoric. In doing so, we also reflect on the institutionalized system of social conditioning.

A Historical Perspective

Cosmetic surgery, as with reconstructive surgery, has its roots in plastic surgery (emerging from the Greek word ‘plastikos’, meaning to mold or form). The practice of surgically enhancing or restoring parts of the body goes back more than 4000 years. The oldest accounts of rudimentary surgical procedures is found in Egypt in the third millennia BCE. Ancient Indian texts of 500 BCE outline procedures for amputation and reconstruction. The rise of the Greek city-states and spread of the Roman Empire is also believed to have led to increasingly sophisticated surgical practices. Throughout the early Middle Ages as well, the practice of facial reconstruction continued. The fifth century witnessed a rise of barbarian tribes and Christianity and the fall of Rome. This prevented further developments in surgical techniques. However, medicine benefited from scientific advancement during the Renaissance, resulting in a higher success rate for surgeries. Reconstructive surgery experienced another period of decline during the 17th century but was soon revived in the 18th century. Nineteenth century provided impetus to medical progress and a wider variety of complex procedures. This included the first recorded instances of aesthetic nose reconstruction and breast augmentation. Advancements continued in the 20th century and poured into present developments of the 21st century.

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Desires and Demands in Contemporary Times

In recent years, the volume of individuals seeking cosmetic procedures has increased tremendously. In 2015, 21 million surgical and nonsurgical cosmetic procedures were performed worldwide. In the United Kingdom specifically, there has been a 300% rise in cosmetic procedures since 2002. The year 2016 witnessed a surge in the number of such treatments with the United States crossing four million operations. Presently, the top five countries in which the most surgical and nonsurgical procedures are performed are the United States, Brazil, South Korea, India, and Mexico. Such demand can be viewed from different perspectives. At one end it is a product of scientific progress, growing awareness, economic capacities and easier access and on the other, something on the lines of a self-inflicted pathology. This article dwells on the latter and attempts to address a deep-rooted problem of the social mind.

Lessons from History

History is witness to a number of unhealthy fashion trends, many of which today appear extremely irrational and even cruel. Interestingly, the common thread connecting all of them is the reinforcement of social norms and stereotypes. Forms of socialization which lie at the intersection of race, class and gender-based prejudices. To elaborate, hobble skirts and chopines restricted women’s movement and increased their dependence on others. Corsets deformed body structures, damaged organs and led to breathing problems. The Chinese practice of binding women’s feet to limit physical labor was regarded as a sign of wealthiness. Dyed crinolines and 17th century hairstyles made people vulnerable to poisoning and fire related injuries. Usage of makeup made of lead and arsenic, eating chalk and ‘blot letting’, reflected a blatantly racist obsession with white and pale skin. Lower classes faked gingivitis to ape tooth decays of the more privileged who had access to sugar. Furthermore, other practices like tooth lacquering, radium hair colors, mercury ridden hats, usage of belladonna to dilate pupils and even men wearing stiff high collars, all furthered societal expectations and notions of class superiority. Till the 1920’s, there was rampant usage of side lacers to compress women’s curves. Even today many ethnic tribes continue with practices which inflict bodily deformations. In the urban context as well, trends like high heels, skinny jeans and using excessive makeup dominate the fashion discourse. Cosmetic procedures are the latest addition to the kitty.

The Social Dilemma

What is it that leads the ‘intelligent human’ of today to succumb to archaic and regressive notions of beauty? What motivates them to risk aspects of their lives to cater to selflimiting rules of ‘acceptance’? The surprising part is that this anomaly is often placed in the illusory realm of ‘informed consent’. In common parlance, ‘to consent’ implies voluntary agreement to another’s proposal. The word ‘voluntary’ implies ‘doing, giving, or acting of one’s own free will.’ However, when the entire socio-cultural set up and individual attitudes validate certain behaviors, there is very less space left for an alternate narrative. Let alone free will.

Pierre Bourdieu once argued that nearly all aspects of taste reflect social class. Since time immemorial, societal standards of beauty have provided stepping stones to social ascent and class mobility. Better ‘looking’ individuals are considered to be healthier, skillfully intellectual and economically accomplished in their lives. Such an understanding stems from well entrenched stereotypes in complete disregard of individual merit and fundamental freedoms. An inferiority complex coupled with external pressures and self imposed demands, subconsciously coerce individuals into a vicious cycle of desire or rejection. Active and aggressive media has played a key role in forming societal perceptions of what is attractive and desirable. In addition, lifestyle changes reflect an image obsessed culture, reeking of deep-rooted insecurities. At the root of a submissive and conformist attitude lies a subconscious mind lacking selfesteem and self-worth. People continue to look for remedies in the wrong places. The only difference is that corsets and blot letting have given way to surgeries and cosmetic products. The biggest question is, how have ideas otherwise seen as deviant, problematic and inadequate retained control over minds of millions of individuals?

A Gendered Culture

‘Beauty’ is understood as a process of ongoing work and maintenance, its ‘need’ unfairly tilted towards the fairer sex. History has demonstrated the impact of dangerous beautification practices on women. Contemporary ideals aren’t far from reaching similar outcomes. Today, there is a powerful drive to conform to the pornographic ideal of what women should look like. There has been a growth in the number of adolescents who take to cosmetic surgeries to become more ‘perfect’. In many countries, the growth of the “mommy job” has provoked medical and cultural controversies. Presumably there is an underlying dissatisfaction which surgery does not solve. Furthermore, where does the disability dimension fit in here? What happens to the ‘abnormal’ when the new ‘normal’ itself is skewed? For those with dwarfism and related disorders, new norms become even more burdensome.

The massive pressure to live up to some ideal standard of beauty, particularly for women, reeks of patriarchal remnants of a male dominated society. This kind of conformity further nurtures objectification and sexualization, reducing women to the level of ‘chattel’ to feed the male gaze. There is a also a power struggle at play where biased standards help maintain the unequal status quo. Today, there is idolization of celebrities, beauty pageants and advertisements by cosmetic companies over sane medical advice. They set parameters of size, color and texture to be followed by the world at large. Moreover, people who deviate from such norms are made to feel stigmatized or ostracized from social spheres. The existence of male-supremacist, ageist, hetero sexist, racist, class-biased and to some extent, eugenicist standards reflect a failure of society as a whole. It is thus high time that we revisit and deconstruct skewed standards of beauty.

Mind Over Matter: Psychological Dimensions

Culturally imposed ideals create immense pressure of conformity. Consequently, they have been successful in engendering insecurities via their influence on perception of self and body image. Such perceptions often become distorted and discordant with reality, leading to serious psychological disorders. One such disorder is the body dysmorphic disorder (BDD). This is a psychiatric disorder characterized by preoccupation with an imagined defect in physical appearance or a distorted perception of one’s body image. It also has aspects of obsessive-compulsiveness including repetitive behaviors and referential thinking. Such preoccupation with self-image may lead to clinically significant distress or impairment in social and occupational functioning. With reference to cosmetic surgeries, patients with BDD often possess unrealistic expectations about the aesthetic outcomes of these surgeries and expect them to be a solution to their low self-confidence. Many medical practitioners who perform cosmetic surgery believe themselves to be contributing towards construction of individual identity as well. The notion that beauty treatments can act in much the same way as psychoanalysis has led countries like Brazil to open its gate of cosmetic procedures to lower income groups. This happens while the country continues its battles with diseases like tuberculosis and dengue. The philosophy behind such ‘philanthropy’ is that ‘beauty is a right’ and thus should be accessible to all social groups. While on one hand we may applaud such efforts of creating a more ‘egalitarian’ social order, on the other hand it is hard to overlook the self-evident undercurrents of social prejudice and capitalistic propaganda.

Medicalization of Beauty

Traditional notions of beauty embody a kind of hierarchy and repression which alienate individual agency and renders them as powerless victims. Such is the societal pressure which normalizes cosmetic procedures and subverts serious health effects. These include adverse effects due to cosmetic fillers like skin necrosis, ecchymosis, granuloma formation, irreversible blindness, anaphylaxis among others. Other dangers like heightened susceptibility to cancer and increased suicide rates. However, patients are often unaware of the risks which are hidden behind a veil of expectations and reassurances. Furthermore, quackery and inadequate standards such as lack of infection control also compound the problems of this under regulated field.

Role of Stakeholders

At the heart of any successful social transformation lies the power of united will and collective action. Thus, the consolidated and sustained effort by all stakeholders is the key to realizing an ecosystem conducive to tackle negative social norms. At the outset, government regulation is needed with respect to cosmetic procedures and the cosmetics industry. These regulations should encompass all private and public avenues and should also work against misleading advertising. Spreading awareness is the key to a better informed society. The state should fund and run specialized awareness sessions pertaining to psychological problems and aid mechanisms, gender sensitization as well as those aiming at spiritual and introspective personal development of individuals. NGO’s, medical professionals, academicians and members of the civil society, must come together to eradicate forms of social discrimination which undermine social institutions and individual agency around the world. This would help facilitate discussion, data collection, coalition building, and action that may eventually lead to behavioral changes.

Aesthetic surgery today seems to be passing through an ethical dilemma and an identity crisis. And rightly so for it strives to profit from an ideology that serves only vanity, bereft of real values. Nevertheless, there are exceptional cases where medical-aesthetic inputs have been vital in restoring morale by subverting stigmatization.

The Way Ahead

Beauty is unfair. The ‘attractive’ enjoy powers gained without merit. The perfectionist in humans seeks outward validation of external beauty over inner virtues. Scientific progress and an increase in human expertise to manipulate natural phenomena has paved the way for these desires to become a reality. There is no denying that advances in plastic and reconstructive surgery have revolutionized the treatment of patients suffering from disfiguring congenital abnormalities, burns and skin cancers. However, the increased demand for aesthetic surgery falls short of a collective psychopathology obsessed with appearance. This article expresses trepidation about such forms of social consciousness that first generates dissatisfaction and anxiety and then provides surgery as the solution to a cultural problem.

We have to work towards a social order which embraces people as they are and facilitates free choice, individual liberty and informed decision making. This is particularly pertinent when these decisions work towards framing cultural perceptions and expectations for millions around the world. We should open our hearts to diversification of beauty and aesthetic. Let our entertainment, fashion, capital and media revolve around heterogeneity of ideologies and cultures. In the words of Eleanor Roosevelt, “No one can make you feel inferior without your consent”. So, let us all come together and create a better society. A society, where principles of justice, equity, good conscience and humanity override primitive and archaic ideologies of naive men. A society where individual will be truly free and, discourse a product of informed thought.

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Amyotrophic Lateral Sclerosis

Authored by Aymeé Hernández

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder of unknown cause. More of 400.000 persons are affected by ALS at world level. It is characterized by diffuse involvement of cortical, bulbar and spinal motor neurons. Physiopathology is very complex, there are a lot of changes into the neurons and glia that cause apoptosis and cellular degeneration. The diagnostic of this disorder is based in demonstrating of abnormalities of upper and lower motor neurons. It is based in neurophysiological studies and clinical signs, it is supported by Scorial criteria. New images methods could diagnosis and prognosis evolution of ALS patients and this methods show some important structural and functional abnormalities in nervous structures.

Keywords: Amyotrophic lateral sclerosis (ALS); Magnetic resonance image; Tensor of diffusion

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Introduction

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of the voluntary way.

Upper and Lower motor neuron could degenerate. It the 3th more frequent neurodegenerative disease, overcome by Alzheimer and Parkinson Diseases. Some famous people like: Lu Gehrig, Jason Becker and Stephen Hawking have been affected by ALS [1].

Epidemiology

A. World Incidence: 2 x 100 000 inhabitants.

B. World Prevalence: 5 - 8.5 x 100 000 inhabitants.

C. Number of persons affected to world level: 400.000

D. Death in a year to world level: 100.000

E. Relation Man/Women: 2:1

F. Age of presentation: 40-60 years.

G. Survival: 3-5 years, 10 percent of the cases survival 1o or more years [2,3].

Forms of presentation

A. Familiar form (10% of cases).

B. Sporadic form (90% of cases) [2-4].

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Physiopathology

In ALS a multifactorial mechanism is proposed. Some factors are being in relation with ALS, some of them are: contact with heavy metals, organic solvents, organophosphorus substances, organochlorine substances, Selenium, Calcium, Magnesium, Manganese, Mercury, Lead, Cupper, Aluminum, Chrome, Tobaccoand Alcohol habits, Electric and Ellectro-magnetic fields. There are a lot of changes at cellular and molecular levels in neurons and glias. Superoxide Dismutase 1 enzyme (SOD1) dysfunction is the most general mechanism in ALS, it cause high levels of free radicals into de cell, destabilization of some important proteins and transporters, high levels of glutamate neurotransmitter outside the cell, glutamate mediated excitotoxicity, abnormalities of axonal transport, abnormalities of endoplasmic reticulum and mitochondria, abnormal proteins accumulation into the cells (Cytoplasmic Inclusions) . All of this changes could provoke apoptosis and neural degeneration [5,6].

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Diagnosis

Symptoms and signs include: muscular weakness, spasticity, hyper reflexia, clonus and Babinski sign, fasciculation, hypotonia and muscular atrophy. Diagnosis is based in Scorial criteria, it is support by clinical and neurophysiological examination and image techniques. Differential diagnosis of ALS is obligated with cervical spondylotic myelopathy, medullar tumor, syringomyelia. There is no an effective treatment for ALS [7-10].

New diagnosis techniques

Now days some magnetic resonance image techniques have been applied to diagnosis and prognosis the evolution of ALS patients, and some parameters have demonstrate abnormalities in non-motor structures:

A. Voxel based morphometry: It has showed diminish of gray matter in pre-central and frontal medium gyrus; diminish of white matter of upper frontal region, pre-central and lower temporal gyrus.

B. Diffusion Technique: It has showed:

1. Increase of Mean Coefficient of Diffusion (MCD) in precentral, post-central, lower frontal, angular, supramarginal and medium temporal gyrus, insula, putamen nucleus, orbito-frontal white matter, internal capsule, corpus callosum and cerebellum.

2. Diminish of Fractional Anisotropy (AF) in white matter in pre-central, lower frontal and pre-motor areas.

3. Cortical Thickness: It is diminished in primary motor cortex, lower parietal region and lower temporal gyrus.

4. Volumetric Analysis: Diminish of volume of hippocampus, basal ganglia and limbic structures. Increase of volume of lateral ventricles [11-15].

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Conclusion

Some markers of ALS need to be founded, new image techniques could be good candidates to show structural and functional abnormalities of nervous system structures in ALS patients.

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The Oral Health Status and Attitudes of Saudi Adolescent Male Students in Albaha Province: A Cross-Sectional Study

Juniper Publishers-Open Access Journal of Dentistry & Oral Health

Authored by Abdullah Ali Alzahrani

Abstract

Objectives: To explore and examine the oral health status of Saudi adolescent male students aged 12-15 years in Albaha province and evaluating the oral health attitudes of this population.

Methods: This was a cross-sectional study in which random sampling was used. Data was collected at schools of the subjects between November 2017 and February 2018. A clinical examination was carried out to evaluate the presence of tooth decay, plaque and gingival bleeding. Then a face-to-face interviews with the study participants were employed to measure their oral health attitudes using a pre-designed questionnaire. SPSS® version 20.0 was used to conduct the data analysis.

Results:Two hundred and forty-nine Saudi adolescent male students from three different territories in Albaha province were recruited. The rate of dental caries, plaque and gingival bleeding was determined to be high (76%, 94% and 86%, respectively). A 73% of the adolescents were seen to hold a moderate attitude towards the preservation of their oral health. Only 40% of the participants visited the dentist regularly and just 16% of the children reported brushing their teeth twice daily.

Conclusion: The oral health status of the studied population was poor. Moderately positive oral health attitudes were demonstrated overall. Further research into the implementation of oral health-based educational and preventive strategies is urgently required to advance the oral health status and practices of Albaha province community members.

Keywords: Dental caries; Periodontology; Dental hygiene, Children; Knowledge; Attitudes; Oral health

Abbrevations: DMFT: Decayed Missed and Filled teeth Index; PI: Plaque Index; GI: Gingival Index; WHO: World Health Organization

Introduction

There is a burgeoning amount of global literature on the impact of poor oral health status on quality of life, particularly that pertaining to adolescents. For example, tooth decay affects the willingness of children to speak, smile and eat [1]. Likewise, the adverse effects of periodontal disease on the quality of life of individuals have been observed to be substantial [2]. Thus, an exploration and evaluation of the oral health status of any community is warranted to inform the establishment and implementation of suitable oral health interventions to reduce these negative effects.

The prevalence of dental caries among the Saudi population, particularly among adolescents, is relatively high [3]. Nationally, dental caries in Saudi children was estimated to be 80% and 70% for primary dentition and permanent dentition, respectively, with respective mean Decayed, Missing or Filled Teeth (DMFT) index scores of 5.0 and 3.5, as per the findings of a systematic review [4]. Meanwhile, an overall prevalence of 73% for dental caries was reported in a sample of 711 Saudi schoolchildren in Dammam [5]. Similarly, a mean DMFT index score of 3.27 was found for 48 children in Tabuk [6]. The incidence of dental caries was also determined to be ≥ 80% in 1844 schoolchildren in Riyadh [7]. Similarly, tooth decay was identified in ≥78% of adolescents (n = 724) aged 12-14 years following a cross-sectional survey conducted in Jeddah [8].

Periodontal disease is regarded as one of the most common chronic illnesses worldwide. The association of periodontitis with several risk factors, including increased waist circumference, obesity, overweight and weight gain, is often used to explain the prevalence of periodontal disease [9]. The rate of plaque and gingivitis in Saudi children aged 7-15 years in Riyadh was reported to be 46% (n = 93) in another study [10]. A high incidence of plaque was also identified in 500 adolescents based in Jazan following a cross-sectional survey, where the mean plaque index (PI) score for male and female schoolchildren was found to be 0.69 and 0.66, respectively [11]. Additionally, gingivitis was seen to be pervasive in Saudi adults aged 18-40 years (n = 385, 100%), with a mean gingival index (GI) score of 1.68±0.31, indicating moderate gingival inflammation [12].

The health and well-being of individuals has been shown to be enhanced by positive attitudes to oral health [13], while the maintenance of sound oral hygiene habits and attitudes was found to have a strong association with healthy teeth and gums [14]. It was established that 33% of adolescents (n = 287) aged 15-18 years did not brush their teeth following a cross-sectional survey conducted in Riyadh [15]. It was demonstrated in other research on 917 Saudi schoolchildren, that despite having satisfactory attitudes and knowledge of oral health, 59% of them practiced poor oral hygiene [16].

However, despite an extensive evaluation of oral health in the different geographical areas of Saudi Arabia and in Saudi populations of varying ages, in which poor oral hygiene, habits and attitudes, and widespread dental caries and periodontal disease have been identified [5,13], yet a little is known in this regard among adolescents in Albaha province, Saudi Arabia. Moreover, the association of impacts resulted from oral diseases with individuals’ quality of life and well-being is well confirmed [17]. Thus, those two reasons may justify the importance of conducting the current study which aims to explore and examine the oral health status and attitudes of Saudi adolescent male students aged 12-15 years living in Albaha province.

Methods

Settings and participants

Three schools distributed across three different territories (Albaha, Alatawelah and Alaquiq) in Albaha province, Saudi Arabia, were randomly selected for inclusion in the study. Information sheets outlining the purpose of and methodology used in the research, and containing informed consent forms, were sent to the parents of students between September and October 2017, prior to conducting the study. The study subjects comprised Saudi adolescent male students aged 12-15 years. The participants were classified according to three different age groups; i.e., 12-13 years, 14 years and 15 years. They were interviewed to ascertain their attitudes to their oral health, and then underwent a clinical examination to assess for periodontal disease and dental caries to gauge their overall oral health status.

Ethical considerations

This study was approved by the Planning, Research and Studies Department at the Saudi Ministry of Education (Albaha branch) (approval reference number: 39195280). It can be confirmed that this study was conducted in accordance with ethical standards of the Saudi Ministry of Education and Albaha University. Parents of the participants were provided with written information sheets that outlined the objective and procedures to be used in the study. Informed written consent was obtained from the parents prior to conducting the study. The parents were reassured that all personal information would be kept confidential and were informed of the right to contribute and of the right to withdraw from the study without having to provide a reason why, and without prejudice, at any time.

Sampling and data collection

A randomized sampling technique was employed between November 2017 and February 2018 to select the study sample. The local education authority, the Albaha branch of the Saudi Ministry of Education, provided statistical information regarding the total number of students and details of schools in the region. One school was randomly chosen from each of the Albaha, Alatawelah and Alaquiq regions in Albaha province. The students were included in the study if their parents agreed that they could participate and if they provided informed written consent. However, female students were excluded from the study sample, mainly owing to cultural challenges in accessing this population at schools, particularly as the researchers were men. The sample size was calculated based on the total number of Saudi adolescent male students (n = 5479) aged 12-15 years living and registered in Albaha province, using an adjusted 95% confidence level. The sample size thought to have enough power and validity for the purpose of the study was consequently estimated to be 255 participants.

Clinical examination

The study participants were clinically examined at their schools for assessment of their periodontal and dental caries status. The PI and GI developed and published by the World Health Organization (WHO) [18] were used to assess gingival bleeding and perform a supragingival dental calculus evaluation of all teeth. The DMFT index, also established by the WHO [18] was employed to determine the significance of the dental decay. For quality reasons and based on the recommendations of the WHO [18], 10% of the randomly selected cases (i.e., 26 adolescents) were re-examined by an independent examiner to measure intraexaminer consistency and agreement regarding the oral health status evaluation. Interrater reliability was measured using Cohen’s kappa, and the values for dental caries, gingival bleeding and plaque were estimated to be 0.84, 0.87 and 0.91 respectively, demonstrating high consistency and agreement between the findings of the two examiners. The clinical examinations were performed under clinical conditions, using portable clinic lights and disposable examination kits, consisting of tweezers, sharp probes (number 4), a mouth mirror, cotton, gauze, a face mask, gloves, and CPI periodontal probes.

A face-to-face interview on attitudes to oral health

Prior to conducting the clinical examination, face-to-face interviews were conducted with the participants with a view to completing a pre-designed questionnaire on attitudes to oral health. The questionnaire was adapted from the Hiroshima University-Dental Behavioral Inventory [19], with minor modifications to ensure cultural applicability. The final version included 15 items that focused on the attitudes of the participants to their oral health and their sociodemographic backgrounds (Table 1).

To ensure that the risk of bias was kept to a minimum and to avoid influencing the clinical examinations owing to prior knowledge of attitudes to oral health, the investigators were asked to record the clinical examination findings separate from the questionnaire results.

Statistical analysis

The total number of statements reflective of a positive oral health attitude were added together to calculate the final score for attitudes to oral health based on the 15 items. The final score varied from 0-15; with a poor attitude to oral health classified as a score of 1-5, a moderate attitude categorized as a score of 6-10 and a sound attitude graded as a score of 11-15. The DMFT index, the PI and the GI were stratified as low or high strata, based on the median for each index. Statistical Package for the Social Sciences® version 20.0 was used to analyze the data. The chi-square test was employed to investigate an association between the categorical variables. Fisher’s exact test was utilized, as appropriate. The Kruskal-Wallis H test (a nonparametric [distribution free] test) was used to compare the medians from the different groups.

Results

The sociodemographic characteristics of the participants

Two hundred and eighty Saudi male adolescent students aged 12-15 years were invited from three schools to participate in the study. Eighteen students were absent on the day of the clinical examination and 13 students decided against participating. Thus, 249 adolescents were finally included in the research (i.e., a response rate of 89%). The sociodemographic characteristics of the participants were recorded according to their age and the geographical location of the school (Table 2).

Dental caries status

The prevalence of dental caries in the studied population was considerably high. Of the 249 participants, tooth decay was identified in 189 (76%) of them at the time of examination. Significantly, the DMFT values were observed to violate the normality assumption. The calculated mean for the DMFT value was 0.47±0.58. The percentage of filled teeth (FT) and decayed teeth (DT) according to the DMFT index was 2% and 77%, respectively. The mean DT, missing teeth (MT) and FT index scores were 0.52±0.60, 0.00±0.02 and 0.00±0.01, respectively. The difference in the DMFT index score for the different age groups and regions was statistically significant (p=<0.001 and 0.036, respectively) (Figure 1 & 2). The overall prevalence of dental caries, plaque and gingival bleeding in the different age groups and regions is summarised in Table 3.

Plaque and gingival bleeding

The prevalence of plaque and gingival bleeding was significantly high in the current study, affecting 235 (94%) and 215 cases (86%), respectively. Although the PI and GI values violated the normality assumption, the mean PI and GI value was 1.40 ± 0.67 and 1.08 ± 0.90, respectively. The difference in the GI scores for the different regions was found to have statistical significance (p = 0.003). However, this was not the case with respect to the difference in GI scores for the different age groups (p = 0.058). By contrast, statistical significance was attributed to the difference in PI values for the participants in the different regions and age groups (p= 0.025 and 0.004, respectively) (Figure 1 & 2).

Attitudes to the preservation of oral health

Three quarters of the adolescents (n = 186, 73%) were seen to hold a moderate attitude towards the preservation of their oral health. The approach to oral health was found to be poor for 61 of the study participants (25%) and sound for only six of them (2%). The identified differences in attitudes to oral health among the different age groups and regions (schools) was without statistical significance.

Surprisingly, 43% (n = 106) of the participants had not visited the dentist and only 16% (n = 39) reported brushing their teeth twice daily. A third of the sample (n = 89, 36%) preferred to clean their teeth using a toothbrush and toothpaste rather than miswak, an herbal chewing stick. Only 9% and 14% of the participants regularly used dental floss and mouthwash, respectively. Nevertheless, most of them admitted to being concerned about the color and appearance of their teeth and gums (81% and 77%, respectively). The attitudes of the study participants to their oral health are detailed in Table 4.

The association between the pooled scores for attitudes to oral health and the DMFT index and the GI was not found to be statistically significant (p = 0.741 and 0.352, respectively). Interestingly, statistical significance was reported for the association between the pooled scores for attitudes to oral health and the PI (p = 0.023). Several of the attitudes to oral health were shown to have a statistically significant association with the DMFT index, PI and GI on bivariate analysis. The correlation between activities such as visiting the dentist, using mouthwash, being concerned about bad breath, going for regular dental check-ups (even in the absence of toothache or complications) and using dye to identify plaque on the teeth and the DMFT index score was statistically significant (p = 0.001, 0.048, 0.01, 0.003 and 0.006, respectively). Likewise, the correlation between attitudes towards and factors linked to the preservation of oral health, such as visiting the dentist, brushing the teeth carefully, the absence of bleeding gums during brushing, and going for regular dental check-ups (even in the absence of toothache or complications) and the PI and GI scores was statistically significant. The findings of the bivariate analysis of the association between attitudes to oral health and the DMFT index scores, and PI and GI scores are detailed in Table 4.

Discussion

Dental epidemiology is performed to evaluate the oral health needs of a community to assist with the planning, assessment, implementation and auditing of preventive strategies and/or oral healthcare programmes to reduce the prevalence of dental disease [20,21]. However, there is a lack of studies in the dental literature on the oral health status and attitudes of schoolchildren in Albaha province, Saudi Arabia, and particularly those of adolescents aged 12-15 years. This is reflective of the significance of conducting a cross-sectional study in this regard, especially since dental disease is a public health problem globally [21], and such a study has not yet been published.

The overall incidence of dental caries, plaque and gingival bleeding in the studied population was found to be significantly high in the current study, consistent with the findings of previous research conducted in Saudi Arabia across several cities, including Dammam, Tabuk, Riyadh and Jeddah [5-8,10-12]. This might indicate that dental caries and periodontal disease in Saudi Arabia are not treated regularly, similar to conditions in several developing countries [22,23]. Nonetheless, there might be an essential need to develop focused oral disease prevention and health-promoting strategies, such as promoting the application of pit and fissure sealant and/or establishing oral health education school programmes across these communities [24,25].

The oral health status of Saudi children in Albaha province was shown to be relatively poor in the current study, with a statistically significant variation in the DMFT index, GI and PI values among the children in the different school regions. These findings might indicate that the unequal distribution of dental services and/ or challenges with accessibility and transportation to existing dental services in the Albaha region could be possible reasons for the variation in the DMFT index, PI and GI values [26]. Further research is warranted to explore this area in depth and validate the study findings in order to ensure that similar treatment protocols are applied across the different territories.

Interestingly, although the prevalence of dental caries, plaque and gingival bleeding was high in the current study, moderate attitudes to oral health were attributed to most of the study subjects (73%). These findings are like those of previous research carried out on Saudi children [27]. This may suggest the need for the implementation of a combination of several oral health-related educational and practice programmes at schools, in addition to a follow-up of the progress of and effort made by children to improve their oral health status [28,29].

It was demonstrated in the current study that roughly half of the participants (40%) believed in the importance of attending dental check-ups regularly, even in the absence of toothache or complications, but only 16% of them brushed their teeth twice daily and had been taught how to do it properly. Yet, evidence has shown that the oral health practices of parents’ influence their children’s dental status [30]. Potentially, this may signify that there is a crucial need to motivate parents and schoolchildren to adhere to sound oral health practices and lifestyles, particularly about controlling sugar consumption prior to and at bedtime, and using fluoride toothpaste [30,31].

There were limitations to the study. Female adolescents were not included in the study sample, mainly owing to cultural challenges in accessing this population at school, particularly as the researchers were men, thus impeding the ability to generalize the study findings. Even though this was a cross-sectional survey and that it involved a limited sample size, it nevertheless offers insight into the oral health status and attitudes of Saudi adolescent male students in Albaha province. A further limitation was the potential inhibition of the ability to evaluate the causal relationships between the study variables owing to the cross-sectional design. For instance, it was difficult to definitively claim that the high prevalence of dental caries was caused by poor attitudes to oral health. However, the study focus was to examine and explore the oral health conditions and attitudes of adolescents, rather than to measure causal associations.

Conclusion

A high prevalence of dental caries, plaque and gingival bleeding was identified in Saudi adolescent male students aged 12-15 years in Albaha province, following an exploration of their attitudes to oral health and an evaluation of their oral health status via a clinical examination. Nevertheless, most of the participants were observed to have moderate attitudes to their oral health. This may highlight the need for the implementation of oral health promotional and educational programs, in conjunction with the development of suitable oral health preventive strategies to ensure the restriction of sugar consumption, the use of fluoride toothpaste and the application of pit and fissure sealant. Future research may also be warranted into discrepancies in the distribution of dental services throughout the country and/or accessibility to existing dental services in Albaha province.

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