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irispublisherscancerresearch · 3 years ago

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A Simple Screening Test for Cancer-Iris Publishers

Authored by AbulKalam M Shamsuddin*

Abstract

Comparative and correlative studies of the pathology and pathogenesis of colon cancer in animal models and human disease have resulted in conceptualization of ‘field effect” theory, and identification of a simple carbohydrate marker that is expressed early during carcinogenesis. This assimilated body of knowledge has resulted in development of a simple screening test for cancers of the lung, breast, colorectum, uterus, pancreas, and prostate. The marker galactose-N acetyl-galactosamine (Gal-GalNAc) is expressed in the cell surface and secreted glycoproteins of otherwise normal appearing tissues remote from cancer or precancerous lesions and is detected by enzymatic oxidation (10 minutes) followed by color reaction (1 minute). The high sensitivity, specificity, and cost-effectiveness of this point-of-care test makes it a great tool in our strategies for early detection, hence control of cancer. It would also reduce the number of unnecessary and expensive procedures, thereby decreasing the total national health-care cost to the societies and governments, globally.

Keywords: Screening test; Lung cancer; Breast cancer; Prostate cancer; Colon cancer; FOBT

Abbreviations: AOM: azoxymethane; FOBT: fecal occult blood test; Gal-GalNAc: galactose-N acetyl- galactosamine; GOS: galactose oxidase Schiff; MNNG: N-methyl-N’-nitro-N-nitroso-guanidine; NCI: National Cancer Institute; T-Ag or TF-Ag: Thomsen-Friedenreich antigen

Introduction

Regrettably, in 2020 approximately 10 million people were killed by cancer; now-a-days there is hardly a family that is not affected by cancer. Additionally, the healthcare cost, and loss of productivity owing to morbidity and poor quality of life, has been immensely draining to families, societies, and governments alike, everywhere. This scourge has been around for a very long time with no end in sight. As in SARS-Cov-2 now, in 1971 President Richard Nixon had declared ‘War on Cancer’ to combat this menace. Alas, 50 years later, conquering cancer remains an elusive goal despite progress in treatment, albeit modest. Again, akin to SARS-Cov-2, prevention is our best alternative. Cancer prevention includes (a) detection at the very early stage of the disease (secondary prevention) to reduce cancer mortality and increase the survival rate of patients; and (b) etiology prevention or primary prevention to reverse precancerous lesions or in situ carcinomas (a cancer that is still confined) to normal or stop them from progressing to invasive malignancies in populations at high risk – ‘nipping in the bud’. Thus, early detection is fundamental to prevention, and the key is to find the marker which is differentially expressed in highrisk tissues (cancer and precancer) but not in normal. Biomarker(s) meeting this criterion is/are logical choice for establishing accurate methods to detect cancers at infancy; it may also help in monitoring the efficacy of chemoprevention program by serving as intermediate endpoint marker [1].

Fundamental to the success of prevention programs of any disease is the detection of the problems. It includes identification of people with existing disease and those who are at risk of developing the disease. Identification of people with cancer is relatively simple for most cancers because of signs and symptoms from the disease; the individual, now a patient seeks medical attention. Extensive work-up including a battery of diagnostic tests are performed and appropriate therapy is administered; regrettably, it is usually too late for many, if not for most as it does not prevent the disease. Hence the adage: an ounce of prevention is better than a pound of cure. For an effective prevention program, we must actively seek individuals with cancer or high risk thereof from an apparently healthy noncompliant population. This is done by separating i.e., screening individuals into groups with high and low probability of cancer with the help of rapid, simple, accurate, and inexpensive tests (screening tests). Implicit in the definition of screening is a promise that there is a benefit for those who participate; they will be followed with further diagnostic tests and future management of the problem. But a screening test is never intended to give the full diagnosis, hence the distinction from diagnostic tests [2]. An individual who is screening test positive will need to undergo diagnostic procedures to confirm the presence of the disease. Ideal screening tests should have a high sensitivity (proportion of diseased subjects who are test- positive) and specificity (proportion of non-diseased subjects who are testnegative), be simple and non- invasive or minimally invasive, easy to administer – therefore enjoying a high acceptability amongst populations and of course cost-effective. It would not be successful if it is shunned for discomfort, cultural, religious, or other reasons or just too expensive [2]. Currently, except for colon cancer, there are no true good screening tests for other cancers at early stages. Imaging technologies such as mammogram, chest X-ray, low dose CT etc. cannot detect early cancers, for a tumor must attain a minimum size before it can be ‘visible’ by these. And that is too late!

The Galactose Oxidase-Schiff Test

The Galactose Oxidase-Schiff Test is one such screening test that fits all the criteria of an ideal screening test as it is rapid, simple, non-invasive, easy to administer, and inexpensive. Its high accuracy has been consistently and reproducibly demonstrated independently by numerous investigators in three continents. That is not surprising because of extensive scientific research on carcinogenesis and operation of i) field-effect of carcinogens and ii) a marker differentially and specifically expressed during carcinogenesis, shared by both cancer and precancer, but not by normal or regenerating tissue.

Field-effect

I studied early detection of cancer using colon cancer as a model since 1975 at the University of Maryland School of Medicine as my PhD dissertation. The advantages of colon as a model include a) relatively easy access to samples, b) well known precancerous changes (polyps) and conditions e.g., ulcerative colitis, Crohn’s disease etc.; c) well developed animal models with d) well characterized steps of carcinogenesis viz. initiation → promotion → progression; etc. Both in vivo and in vitro carcinogenesis experiments with rats and mice were performed to see how colon cancer forms in them, and to identify the earliest recognizable changes by microscopy and histochemistry [3,4]. Colon tissue from rats and human were cultured in the Petri dishes and exposed to the carcinogens N-methyl-N’-nitro-N-nitroso- guanidine (MNNG) for rat colon [3], and fecapentaene-12 a suspected human carcinogen, for human colon explants [5]. The findings were correlated with in vivo animal models, and ultimately to the human disease [6]: what does the human colon near and far from the cancer look like (Figure 1)?

It has been observed that the earliest recognizable change in the carcinogen-exposed tissue is an alteration in the composition of secreted mucus that persists through precancerous and cancerous tissues. The microscopic and histochemical changes in the human colon away from cancer are identical to those seen in the colons of rats (mouse colon is distinctly different from human or rat colon [7]) treated with the carcinogen azoxymethane in vivo, or MNNG for rat explants and fecapentaene-12 for human explants in vitro in Petri dishes. These changes are therefore the earliest evidence (or markers) of cancer formation – even before a cancer has formed. Using high iron diamine alcian blue technique, the mucus in the colon away from the cancer that looked normal by naked eye appears as blue (Figure 2, lower frame) as opposed to black in truly normal human colon without cancer, in the upper frame (Figure 2). Also note that the colonic glands or crypts in a cancer bearing colon appear distorted – changes identical to the rat carcinogenesis models. It was reasoned that because of the generalized effect of the carcinogen throughout the entire field of the large intestine, it is most likely that the tissue away from an obvious cancer would be abnormal – Field-Effect. The carcinogens in our environment such as the air we breathe, the food we eat etc. expose the entire lung or large bowel. Therefore, it is logical that their effect would be observed throughout the exposed field. While the vast majority of the cells will undergo DNA repair, and other host defense mechanisms such as NK cell will prevent them to progress to cancer, a few cells will be promoted and even fewer progressed to precancer and cancer who may share the same early changes as the rest of the exposed tissue in the field. (Figures 2,3).

Field-Effect phenomenon indicates that the entire field bears the brunt of the carcinogenic assault and expresses variable changes throughout. In the schematic drawing of the large intestine (Figure 3), it is depicted that irrespective of where a cancer or a precancerous polyp may be, areas of the otherwise normal appearing mucosa will show expression of the marker perhaps in a patchy manner (it is not practical to sample the entire large intestine to see if every millimeter has the change; hence this assumption of “patchy”). Rectum being a part of the large intestinal “field” and a convenient sampling site is therefore likely to show the same changes. Since digital rectal examination is a part of routine physical examination (though not practiced diligently by many primary care physicians now-a-days), it is simple and noninvasive. It also allows the physician to examine the prostate in males, and uterus, cervix, and adnexa in females. Samples from lungs such as coughed up sputum, nipple aspirate from breast, endocervical mucus, or prostatic secretion are likewise simple and noninvasive.

The marker: gal-galnac

The observed mucin histochemical change has further been identified as due to a biochemical alteration in the cell surface and secreted glycoprotein – presence of the carbohydrate moiety D- galactose-ß-(1-3)-N-acetyl-D-galactosamine (Gal-GalNAc, also called Thomsen-Friedenreich antigen or T- Ag, or TF antigen, though it may be different). In normal cells, a terminal sialic acid blocks the T-Ag from being recognized by the lectin peanut agglutinin (PNA), or the enzyme galactose oxidase; in cancer and precancer owing to loss of the sialic acid it is now recognizable. D-galactose oxidase specifically oxidizes C-6 hydroxyl groups of D-galactopyranose and N-acetyl galactosamine residues of Gal-GalNAc, generating two vicinal aldehyde groups that react with basic fuchsin to give magenta/purple coloration. Thus, Gal- GalNAc can be visualized by a simple enzymatic reaction with galactose oxidase followed by Schiff’s reagent, resulting in the development of a simple test for early detection, initially of colorectal cancer [8] by using rectal mucus sample.

What is an Ideal Cancer Marker According to the National Cancer Institute (NCI)?

Kelloff et al of the Division of Cancer Control and Prevention (DCCP) at the National Cancer Institute [1] outlined six criteria for intermediate endpoint biomarkers of use in chemoprevention, and here is how Gal-GalNAc and STEDi live up to those expectations:

Is the intermediate biomarker differentially expressed in normal and high-risk tissue? YES!

Figure 4 shows the expression of Gal-GalNAc (magenta) in a colon cancer but, not by the normal human colon (Figure 5). The normal tissues were obtained from healthy normal people without any cancer. Note the absence of magenta color in the mucus of normal colonic goblet cells. Also note that the colonic glands or crypts in truly normal humans appear uniform test tube shaped as compared to the those in cancer-bearing colon or in rats treated with the carcinogen azoxymethane (see Figure 4-6).

At what stage of carcinogenesis does the marker appear?

The earlier a reliable marker appears in the carcinogenic process, the greater is the chance for successful intervention. Answer: Gal-GalNAc is expressed very early during carcinogenesis. Not only the marker is expressed early during the carcinogenesis in rats in vivo (Figure 6 left panel) but also by human precancerous polyp (right panel appearing as purplish). The colors are slightly different owing to different batch of staining and tissue preparation. The mucus alteration is also observed in rat and human explants exposed to carcinogens in vitro [4,5]. Note the distorted appearance of the colonic glands as opposed to uniform test tube shaped ones in normal (Figures 5,6).

Does the marker and its assay provide acceptable sensitivity, specificity, and accuracy?

Answer: Both the marker [9,10] and the assay [11-14, Table I] enjoy 70-100% sensitivity and specificity. That it is not expressed by regenerating cells following wounding is an added evidence that Gal-GalNAc is carcinogenesis specific [10]. Please see the results on colon cancer in the following Table: results on other organ sites are provided after this: (Table 1)

Table 1: Performance Summary of GOS Test for Colorectal Cancer.

The proof of field-Effect: Schematic diagram of the human large intestine depicting the location of the cancers detected by the rectal mucus test. That the “field-effect” phenomenon is operational is proved by the detection of cancers in the various segments of the colon remote from the rectum where the mucus was sampled from. Note that 4 of 5 cancers (80%) of the ascending (or the right) colon, 5 of 7 (71.4%) of the descending (or the left) colon and 29 of 33 (87.9%) of the sigmoid colon were detected in the two studies by Sakamoto et al [11,12] (Figure 7). The widely used current fecal occult blood test (FOBT) for colon cancer screening has been notoriously inaccurate; “Occult blood testing is, at best an imperfect approach to the screening of colorectal cancer” concluded Dr. Ahlquist [15]. And that is not surprising since blood is not a marker of cancer or precancer. A newer test combining FOBT and DNA in stool appears to have better sensitivity and specificity albeit at a very high price.

Gal-GalNAc is a common tumor marker: The usefulness of the tumor marker Gal-GalNAc in differentiating the benign from the malignant and pre-malignant lesions of the prostate was tested [16] yielding similarly high sensitivity and specificity (vide infra). Having determined that the principle is practicable in colon and prostate, studies were conducted on other cancers. The expression of Gal-GalNAc determined in a total of 133 tissue samples from 81 cases of the carcinomas of the breast, ovary, pancreas, stomach, and endometrium and 52 cases of respective normal controls [17]. None of the 52 cases of normal tissues (except 15 cases of stomach) showed expression of Gal-GalNAc. In contrast, 100% of adenocarcinomas from the breast (19 of 19), ovary (15 of 15), and pancreas (6 of 6), and 94.1% of stomach (16 of 17) cancers, and 91.7% (11 of 12) of uterine adenocarcinomas expressed Gal- GalNAc. The normal epithelia and their secretions in the vicinity of the carcinoma (within the “field”) in the breast, bronchus, endometrium, and pancreatic duct also expressed Gal-GalNAc in contrast to normal tissues obtained from non-cancerous individuals, which were totally non-reactive. Thus, the tumor marker Gal- GalNAc recognized by galactose oxidase-Schiff sequence was highly expressed not only by a variety of adenocarcinomas but also by the apparently normal-appearing epithelia and their secretions in the vicinity of carcinomas confirming the operation of a field effect phenomenon by carcinogenic agent(s) in these organs as well, setting the stage for identification of the marker in these secretions for mass screening for these cancers too [17].

Studies on lung cancer: Twelve of 12 pulmonary adenocarcinomas expressed Gal-GalNAc. The bronchial tissue away from the cancer were available in 4 cases, all of whom also expressed the marker both in the epithelial lining cells as well as in the secreted mucus [17]. Coughed-up sputum therefore can be used to screen people for cancers of the lungs. Indeed, three clinical studies on lung cancer were performed on coughed up sputum [18-20]. Lai et al [18] reported the results of their study on sputum specimens from 116 healthy persons; and 216 cases of benign and malignant lung diseases were tested for the marker Gal-GalNAc. The result showed that 165 of the 182 patients (90.7% sensitivity) with lung cancer, confirmed by cytology and histology, had positive results, whereas 22 of 116 (19.0%) healthy controls were positive (81.0% specificity, Table 2). In 28 cases of patients whose sputum cytology showed various degrees of dysplasia-a precancerous condition that progresses to cancer, 21 were found Gal-GalNAc positive, of which 15 patients were identified to have lung cancer on further work-up! Thus, the concept of “false positive” as generally used does not apply to Gal-GalNAc and the GOS Test since they take the precancerous lesions and early cancers into consideration. In addition, three cases of early lung cancer in this study were also positive, supporting the fact that Gal-GalNAc is expressed at an earlier stage in the malignant process of the lung as well. The studies by Cox & Miller [19] and Miller et al [20] had smaller sample size and showed sensitivities of 64.7 – 88% and specificities of 77.8 – 93.6%. The test revealed 20 of 23 lung cancers among 76 patients. The other 53 patients were either healthy or had benign lung disease such as bronchitis. Even more germane to the issue of prevention is the fact that 13 of 15 cancers detected were early stage (Stage I and II). Of note is that a tumor must attain a minimum size before it can be detected by imaging techniques. And that is late! (Figures 8,9) (Table 2).

Table 2: Lung Cancer study.

Breast cancer study: Gal-GalNAc is also expressed by the normal-looking breast tissue away from an obvious cancer by way of the field-effect phenomenon [17]. The marker was positive in 19 of 19 histological specimens of breast cancer giving it a 100% sensitivity. More importantly, and germane to our screening, the ducts away from the cancers and close to the nipple also express the marker both in the cells as well as in the secretions in the ducts. Thus, the nipple aspirate from a breast harboring a cancer should express the marker. Kumar et al [21] demonstrated that Gal-GalNAc (or TF antigen) is differentially expressed in nipple aspirate, albeit using a different technique – monoclonal anti- TF antibody. Nineteen of 25 cancer patients and none of the 25 healthy controls were positive yielding a 100% specificity and 76% sensitivity. The relatively low sensitivity of the test in nipple aspirate as opposed to tissue expression may be due to the use of different techniques for identifying the marker – galactose oxidase Schiff’s v monoclonal anti-TF antibody. Chagpar et al [22] also reported the utility of using nipple aspirate and Gal-GalNAc in screening for breast cancer. They investigated 23 women with biopsy confirmed, unilateral stage I or II breast cancer. They took samples (nipple aspirate by way of a suction cup attached to a syringe) from both breasts prior to surgery. Most, but not all the women were able to provide large enough fluid samples that could then be evaluated. Based on the resulting color of the test strips one could differentiate between a healthy and cancerous breast (Figures 10,11).

Prostate cancer study: The current screening test-PSA is inaccurate primarily because it is non-specific; its level goes up in benign conditions as well. The marker Gal-GalNAc is differentially and specifically expressed in prostate has also been observed in histological sections taken from 65 cases of adenocarcinoma [16]. While none of the 35 benign prostates and 11 foci of adenosis expressed Gal-GalNAc (100% specificity), 62 (95.4% sensitivity) of 65 adenocarcinomas expressed the marker. That the expression of the marker is not non-specific (meeting the NCI’s criteria #3) has been demonstrated by the absence in 25 samples of benign prostatic hyperplasia (BPH) and 11 of adenosis, neither of which are precancerous, nor were the normal prostates (10 samples) giving the marker a specificity of 100%. Notably, foci of prostatic intraepithelial neoplasia when present in some of the cancer specimens were also positive (Figure 12), demonstrating the useful of this marker in identifying early cancers [16]. As for colon, lungs, and breast, testing prostatic massage secretion or seminal fluid with GOS test should yield similar results (Figure 12).

Uterine cancer: Currently there are no screening tests for uterine cancers except for maybe the Pap smear wherein a uterine cancer could be detected by chance; but it is usually advanced when the cancer cells shed from endometrium are detected in Pap smear. Expression of Gal-GalNAc with high sensitivity (91.7%) was observed in 12 cases of uterine endometrial adenocarcinoma [17]. In all three cases where endocervical tissues was available, the endocervical mucus was positive for Gal- GalNAc. The photomicrograph (Figure 13) shows histological section of endocervix of a patient with endometrial adenocarcinoma; magenta coloration of the mucus in the endocervical glands and in endocervix is evident. Again, this supports the Field-Effect of carcinogenesis. More importantly, this makes it a simple, convenient, and non-invasive method of screening for endometrial adenocarcinoma while a gynecologist routinely collects samples for Pap smear (Figure13).

Pancreatic cancer: Pancreatic cancer is one of the deadliest of all cancers, primarily because of its silent inception; and owing to its location, signs and symptoms do not show till very late. All 6 of 6 cases of adenocarcinoma of pancreas were positive for Gal- GalNAc, and the normal ducts away from the cancers also showed positive reaction [17]. Thus, GOS test could be performed on fluid samples including pancreatic juice obtained during ERCP (endoscopic retrograde cholangiopancreatography) thereby providing additional value to the screening of the cancer. Figure 14 shows an adenocarcinoma of the pancreas with magenta color in the cancerous ducts and glands. (Figure14).

How easily can the marker be measured?

Answer: GOS test for detection of the marker is non-invasive done on mucus sample obtained during routine digital rectal examination, coughed-up sputum, nipple aspirate, prostatic massage secretion, endocervical mucus etc., and the entire assay period is ~15 min. This is the only point-of-care test for breast, lung, colon, prostate, and uterus; the results are available before the individual is ready to leave the doctor’s office. The test sample is placed on a special paper and reacted with galactose oxidase for 10 minutes, rinsed with distilled water, reacted with Schiff’s basic fuchsin for 1 minute, washed with tap water and dried. A pinkmagenta- purple color is positive, no color is negative (Figure 15). Positive indicates the presence of the marker Gal-GalNAc which is correlated with the presence of precancer, precancer or a high-risk thereof (Figure15).

Note: Though desirable, quantitative evaluation of the color reaction is neither practical nor meaningful as studies have shown no correlation between the intensity of color and the underlying disease.

Can the marker be modulated by chemo preventive agents?

Answer: YES! Sakamoto et al. [23] and Yang & Shamsuddin [24] have demonstrated that; indeed Gal-GalNAc expression can be suppressed by the chemo preventive agent IP6 [25,26]. Figure 16 shows that HT-29 human colon cancer cells express the marker Gal- GalNAc (magenta color in mucus of cells in left panel). Following IP6 treatment, HT-29 cells terminally differentiate and produce mucin, yet not Gal-GalNAc, akin to normal goblet cells (right panel showing a differentiated HT-29 cell that has a mucus vacuole yet not expressing the marker [23,24]. Clinical studies are needed to validate this, but that would take a very long time. In this regard of particular importance is the study on colon cancer by Vucenik et al [13] where 32 of 53 (60%) samples collected from patients after tumor resection showed persistence of the biochemical change; 5 out of these 32 (16%) post-operative cases with positive GOS Test had tumor recurrence within a year. Thus, persistently positive test may serve as a predictor of tumor recurrence (Figure16).

Does modulation of the intermediate biomarker correlate with a decrease in cancer rate?

This would require a long time-years if not decades, and additional resources.

In conclusion, GOS test is a point-of-care screening test that is very simple, rapid, non-invasive, and inexpensive yet accurate for identifying asymptomatic people who may be at high risk of cancer or precancer of the lung, breast, colon, pancreas, prostate, and uterus. It is based on robust scientific background; researched and validated over three decades in >20 independent clinical studies in North America, Europe, and Asia. It exploits a disaccharide marker expressed early during carcinogenesis that persists in precancer and cancer and, satisfies all the practical rigid criteria set forth by NCI for an ideal marker. Given the fact that cancers of the lungs, breast, colon, prostate, and uterus comprise the most cancers, it is in the interest of public health that they are identified at a very early stage, or even before they are formed. The sooner it is used, the more lives could be saved from these cancers.

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irispublisherscivilengineering · 3 years ago

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Computational Examination of Aerodynamics Forces and Evolution of Vortex Shedding of Flow Past Three Square Cylinders at Two Symmetrical Vee Shapes-Iris Publishers

Authored by Salwa Fezai*

Abstract

The flow past three square cylinders at two symmetrical vee shapes has been investigated by a finite-volume method numerical technique. The two-dimensional computations have been performed for different Reynolds number (Re) ranging from 1 to 180 in order to consider different flow regimes; the steady, the periodic and the turbulent flow. The validation of the code with the available literature results regarded both the reliability of the computed solutions and the overall resulting efficiency of the methods. Velocity profiles, vorticity contours and integral parameters such as Strouhal number, drag and lift coefficients have been presented and analyzed. Steady and unsteady regimes of flow have been observed by monotonously changing the Re value, leading to the prediction of the critical Reynolds number for each configuration considered. Furthermore, the change in the geometry of the obstacle is found to affect dramatically the emergence of the Hopf bifurcation points. The oscillatory periodic wake is also seen to be influenced by the Strouhal number, which varies with obstacle shape and the Re values. Relevant outcomes of this work are the estimation of the vortex shedding frequencies and the prediction of the best configuration considering the computation of the lift and drag coefficients.

Keywords:Staggered square cylinders; Flow regimes; Vortex shedding; Strouhal number; Numerical simulation; Critical Reynolds number; Lift and drag coefficients

Nomenclature

(Nomenclature)

Table 1:

Introduction

The analysis of incompressible fluid flow around bluff bodies has engaged a particular attention of researchers due to its great importance in both aerodynamics and engineering. This type of flow becomes more and more complicated when single bluff body is replaced with multiple bluff bodies in different shapes and arrangements. This complexity in flow causes strong interactions in wakes and considerably modifies the fluctuation of aerodynamic forces. Thus, it is important to understand the dramatic change in aerodynamics characteristics and evolution of vortex shedding frequency in the wake. In fact, many studies show that Reynolds number and the type of square cylinder arrangement has ability to change flow behavior for different flow states. In this vein, we may cite the work of Cheng et al. [1]. They have reported that the vortex shedding and wake development behind the square cylinder are significantly dependent on both the magnitude of the shear rate and the Reynolds number. One can also mention the numerical investigation of Berrone et al. [2]. Their results performed the influence of the Reynolds number on the appearance criteria of different regimes such as crawling scheme, the steady and unsteady with releases of vortices. In addition, Mukhopadhay et al. [3] analyzed the structure of a flow around a square obstacle for different Reynolds number and for different positions of the obstacle. They determined the critical Reynolds number from which the flow becomes periodic and they concluded that the frequency starts at Re = 87 for a blockage ratio B/H = 0.25.

To understand the appearance criteria of steady regime, one can also refer to the investigation of Fezai et al. [4] who analyzed the vortex at different arrangements of the two shapes. Analysis of the flow evolution shows that with increasing Re beyond a certain critical value, the flow becomes unstable and undergoes a bifurcation. The authors demonstrated that the transition to unsteady regime is performed by a Hopf bifurcation and the critical Reynolds number beyond which the flow becomes unsteady is hence determined for each configuration. Lankadasu & Vengadesan [5] observed that the critical Reynolds number is reduced with increasing shear. It was found that the mean drag coefficient decreases either with increasing shear for a particular Reynolds number or with increasing Reynolds number for a particular shear parameter. Sohankar & Etminan [6] investigated the fluid flow around tandem square cylinders in laminar flow regime. Their results showed that the flow was steady when Re≤35 and unsteady periodic when Re≥40. Gera et al. [7] used the Computational Fluid Dynamics (CFD) technique to investigate the 2D steady flow around a square obstacle. The simulation was performed for flow around the square shape end to analyze the wake behavior and Reynolds number was taken from nearly 50 to 250. The coefficient of lift and velocity in the wake region were monitored to calculate the Strouhal number. Bhattacharyya & Maiti [8] numerically analyzed the wake structure behind a square cylinder placed near the lower wall. They found that the wall causes a difference in strength between the two vortex rows and showed that the strength of the positive vortices from the bottom of the cylinder lowers with the decrease of the height between the barrier and the bottom wall. Subsequently, the average drag coefficient weakens with the reduction of the ratio of the standard height. They also proved that the cylinder has a large positive lift when brought close to the wall. The influence of the obstacle orientation has been analyzed by Sajjad & Sohn [9]. They observed that orientation of a square cylinder has a significant effect on the shape and size of the recirculation bubble. They concluded that wake formation and separation processes are asymmetric for angles 22.5 and 30 degrees. In addition, a minimum in drag coefficient and maximum in Strouhal number is observed at a square cylinder orientation of 22.5. The main reason for the minimum drags coefficient at 22.5 is attributed to the wake asymmetry originated from shear layers of unequal lengths on each side of the cylinder. The wake asymmetry increases the transverse velocity, which further increases the base pressure, and hence lowers drag. This factor (wake asymmetry) is counterbalanced by an increase in the projected area. However, it was revealed that the former has an overall stronger influence at small cylinder angles shown by the drag coefficient minimum at an orientation of 22.5. Furthermore, they observed that the separation distance between the alternating vortices depend upon the cylinder orientation. On another hand, it is known in literature that the flow structure around two square cylinders is more complex than that around a single square cylinder. For instance, Burattimi & Agrawal [10] analyzed the flow around two square cylinders at a Reynolds number of 73 and reported different ranges of the wake flow regimes. Abbasi & Islam [11] also simulated wake interactions of a flow around two square cylinders that are placed in line with a fixed space ratio equal to 3.5. They concluded that the unsteady regime appears when the Reynolds number reaches the value 55.

Rao et al. [12] investigated the effect of the space ratio on the flow around two square cylinders arranged side by side. They found that the frequency of vortex shedding is different in two wakes. The upper frequency is smaller than the lower frequency for small rations (s<1.4). However, when the space rations increase, the frequency of vortex shedding is almost equal in two wakes. They analyzed the influence of the space ratio and Reynolds number on the drag and lift force. The difference of time-averaged drag and lift coefficients of the cylinders decreases with the increase in space ratios. When s=2.0 and 2.5, the curves for the time-averaged drag and lift coefficient with different Reynolds numbers are seen to be smooth. The authors also reported that when s=1.5 and 1.8, the curves are smooth under Re<140, but will be fluctuant under Re>140 because of the nonlinear interaction between the wakes and the instability of flow which becomes stronger with the increase in Reynolds numbers. Furthermore, Adeeb et al. [13] investigated computationally the wake flow of two square cylinders by varying the corner radius to understand the effect of the gap spacing’s role and the wake flow pattern at Re = 100. They found that the flow characteristics and vortex shedding depend significantly on the corner radius and gap spacing. They concluded that a square cylinder exhibited the maximum average drag value and an inverse behavior was observed in the case of a circular cylinder. In addition, aerodynamic forces were reduced by rounding the corner radius. The staggered geometry of different square cylinders is much different from tandem and inline configurations because more than one spacing is introduced between the cylinders. In such case the flow characteristics become different from those in the case of single spacing. Compared to tandem and inline arrangement, the staggered arrangement has received very less attention of analysis. Among the authors who analyzed this type of arrangement, one can cite Lee & Yang [14]. The authors investigated the flow around two cylinders for Re ≤ 160. At staggered orientation of 45° and Re =160, they identified four different flow regimes. They reported that gap flow can induce separation on the downstream cylinder which asa result increases the vortex shedding phenomena. Aboueian & Sohankar [15] examined the effect of the gap spacing on the flow over two square cylinders in staggered arrangement at Re=150. By changing the gap spacing between cylinders, five different flow regimes are identified and classified. Islam et al. [16,17] examined the influence of separation rations and Reynolds number for flow around squares cylinders. They found that the flow structure depends on both separation ratio and Reynolds number. The average mean drag coefficient decreases while Strouhal number increases as the gap ratio (g) increases. They observed that as this parameter value increases the average mean drag coefficient and Strouhal number approaches to single rectangular cylinder value.

The flow behind three square cylinders in two different triangular arrangements was investigated numerically by Rahman et al. [18]. They reported that the Strouhal number varied between 0.0132 and 0.2003 in both arrangements. The authors also found that the mean drag coefficient and Strouhal number of all threesquare cylinders approached single square cylinder with the increase in the gap ratio. Yang et al. [19] analyzed numerically the flow pattern and vortex suppression regions for three circular cylinders with two different staggered arrangements. In the first arrangement a primary cylinder was placed in front of downstream two side by side cylinders and in the second arrangement a primary cylinder was placed in the wake of upstream two side by side cylinders. Their results show that in the first arrangement, the vortex shedding behind the primary cylinder was suppressed by the downstream two side by side cylinders at 100≤Re≤200. They also reported that in the second arrangement the vortex shedding of the primary cylinder was suppressed by the upstream two side by side cylinders at 103≤Re≤175. We can also mention the work of Yang et al. [20] who arranged three stationary circular cylinders in such a way that one cylinder was placed in front of two side by side cylinders and investigated the effect of the gap ratio in the range from g=1-10 for Re=200. They observed steady flow region at 1≤g≤1.2 and 2.5 ≤g≤3.1 and unsteady flow region at 1.3≤g≤2.4 and 3.2≤g≤10. They also found regular drag and lift coefficient in steady flow region which became irregular in unsteady flow region. From the previous studies about fluid interaction with solid bodies, it can be observed that there is very limited numerical work available about the flow mode transitions around three staggered square cylinders at low values of Re. The flow around bluff bodies of square cross section is an important fundamental problem of engineering. Also, the staggered square cylinders geometry is vital in the sense that it is very important in practical engineering applications. Therefore, a detailed analysis of flow past three staggered square cylinders is needed. Furthermore, this study will definitely enhance the fluid–structure interaction database. Keeping in view these facts the current numerical study is performed to fully analyze four important features of the flow past three staggered square cylinders in vee shape:

The first task is essentially composed of six parts. Firstly, we present the configuration of the physical problem. The second part is devoted to presentation of equations and boundary conditions. The numerical method used for solving the system of Navier-Stokes equations in its dimensionless form in the case of a two-dimensional (2D) incompressible flow is presented in the third part. The fourth part is dedicated to the validation of the numerical in-house code used and followed finally by results and discussions. The fifth part is devoted to results and discussions. Finally, we will draw conclusions from this study in a final part.

Physical Problem

(Figure 1) The configuration of the current problem is sketched in Figure 1. Two configurations will be considered by varying the arrangement of the three cylinders C1, C2 and C3. For the first configuration the obstacle is composed of three cylinders C1, C2 and C3 as shown in the figure. For the second configuration the arrangement of the three cylinders will be different from the first configuration. In Figure 2 we have schematized the two configurations that will be studied and examined (Figure 2).

Governing flow equations

The physical problem is governed by the Navier–Stokes equations for two-dimensional incompressible fluid flow. The continuity and momentum equations are written in dimensionless form expressed as follows:

In the momentum equation, a dimensionless number appears that is the Reynolds number

expressed by:

Boundary Conditions

The boundary conditions for this physical problem are as following:

1. At the channel entrance:

1. The horizontal u- velocity component has a uniform form u0=1 The vertical component of the velocity v is set to zero.

2. On the obstacle, non-slip conditions are imposed; u = 0 and v = 0

Numerical Method

The dimensionless Navier-Stokes equations were numerically solved utilizing the following numerical technique based on the finite volume method [22]. The temporal discretization of the time derivative is performed by an Euler backward second-order implicit scheme. Nonlinear terms are evaluated explicitly; then, viscous terms are treated implicitly. The strong velocity–pressure coupling present in the continuity and the momentum equations is handled by applying the projection method [23]. A Poisson equation, with the divergence of the intermediate velocity field as the source term, is then computed to obtain the pressure correction and the real velocity field. A finite volume method was utilized on a staggered grid system in order to discretize the system of equations to be solved. Furthermore, the QUICK scheme of Hayase et al. [24] is applied to minimize the numerical diffusion for the advective terms. The discretized equations are computed utilizing the red and black point successive over-relaxation method [25] with the choice of optimum relaxation factors. Besides, the resolution of the Poisson equation is performed by applying an accelerated full multi-grid method [26].

The convergence of the numerical results is established at each time step according to the following criterion:

Where f and t indicates the iteration, time levels. The generic variable f stands for u, v or p. In the above inequality, the subscript sequence (i, j) stands for the grid indexing in the x, and y directions respectively. In conclusion, it is worth noting that computations were performed by applying a developed home code named “NASIM” (Navier Stokes Incompressible Multigrid) [27,28] utilizing finite volume method and the numerical procedure described above.

Results and Discussion

Grid independence test

The construction of the mesh is the first step in any numerical simulation. The used meshes in this investigation are based on a staggered grid where scalar quantities (pressure ...) are located at the center of the cell, while the velocity components are defined at the centers of faces of the volume controls. In order to ensure accuracy, the grids have denser clustering at the vicinity of the barrier where strong gradients are expected. Conversely, away from the obstacle where the expected gradients are low, larger meshes are preferred.

It is worth noting that the grid independence study was conducted for two different non- uniform grids, namely, m*n=560*340 and m*n=768*160. In the current investigation, independence of numerical results from the mesh size was assumed when the difference in the simulated values computed between two consecutive grids was less than 1%. It was concluded from the deviation values obtained that, a non-uniform grid of m*n=768*160 is sufficiently fine to ensure the grid independent solution and provides a good compromise between accuracy and CPU time in the range of variables to be investigated. Hence, the grid m*n=768*160 is applied to perform all subsequent calculations. For better clarification, Figure 3 is schematized describing the mesh used in the present simulations (Figure 3).

Time step independence test

To ensure the accuracy of the results, it is necessary to verify the numerical procedure. The determination of the time step to be utilized in all calculations is very important, since a too large time step size will yield inaccurate results while an excessively smalltime step is computationally inefficient. Furthermore, several time step refinements were performed for the present simulations with non-uniform grid m*n=768*160. To ensure the temporal convergence of results, two Figures 4 & 5 are reported describing the temporal evolution of the lift coefficient and horizontal velocity components, respectively (Figures 4,5).

From Table 1, it is confirmed that the results of the calculations with the time step Δt = 0.001 are nearly identical to the results with Δt = 0.0025 and Δt = 0.0005. That’s why the time step Δt = 0.001 is applied in all simulations (Table 1).

Code validation

To give more confidence to the results of the current simulations, some quantitative and qualitative comparisons with other numerical investigations presented in the literature have been carried out. The physical problem that is used for the validation of the in-house code “NASIM” is the physical model investigated by Breuer et al. [29]. In the current study, validation of the simulations was carried out on a non-uniform mesh of dimension m*n =560*340 as the mesh used by Breuer et al. [29]. The study was conducted over a range of Reynolds number varying from 10 to 180 and analysis of the effect of this parameter on the evolution of the Strouhal number and lift and drag coefficients was carried out. Consequently, the effect of Re on the Strouhal number (Figure 6) was performed. It is noted that for relatively low Reynolds numbers (50 < Re < 130) the Strouhal number increases with Re values. A significant change in the structure of flow takes place, namely the movement of separation point of the trailing edge to the leading edge of the square cylinder. The Strouhal number is at a maximum at nearly Re = 140 then decreases again for higher Reynolds numbers (Figure 6).

The resulting physical parameter like St obtained from these computations is presented in table 2 along with percentage deviation in the code verification with Ref. [29] and Ref. [30]. It is clear from the results that deviation percentage with Ref. [30] is weaker with that of Ref. [29]. Note that the maximum deviation percentage with Ref. [29] and Ref. [30] is respectively 9.69% (when Re = 200) and 2.91% (when Re = 180). In fact, this percentage of maximum deviation has been obtained for the large Reynolds numbers and this leads to the weak refinement of the computing grid. In other words, in order to minimize the error, it is necessary to increase and further refine the mesh for large Reynolds values. In fact, by further incrementing the Reynolds number, more instabilities of the flow may occur, and this may cause the appearance of more vortices and small structures, and for a better visualization of the flow pattern and to capture its structures, the mesh must be further refined (Table 2).

As observed, Figure 5 and Table 2 confirm that our results are in good agreement with the results of Breuer et al. [29] & Galleti et al. [30] and this comparison validates our computer code making confidence on the presented results. It is also worth noting that validation of the computer code has already been presented by Fezai et al. [31,32] which is a contribution of the current investigation.

Analysis of the evolution of vortex shedding of flow

Steady regime

In the previous section, the code validation was discussed. More detailed flow pattern, which is greatly dependent on the geometry of the obstacle, is further investigated in Figure 7 where vorticity contours at Re = 1 relatively to the considered configurations are presented. It is clear that the flow is creeping and the viscous force being preponderant. It can be seen that the fluid remains attached to the obstacle for each configuration and no detachment is observed. Thus, we note the symmetry of the flow with respect to the longitudinal axis. The flow is formed by two almost symmetrical counter-rotating recirculating lobes attached to the obstacle. It is confirmed that the geometry of the obstacle did not modify the structure of the flow since both configurations have the same structure (Figure 7).

The intensity of the viscous force is reduced by augmenting Re to a certain value, during which the separation of the laminar boundary layers occurs. Figure 8 depicts the contours of the iso-vorticities of the two configurations considered for Re=10 and 20. It is observed that the wakes of the two configurations are similar. As displayed in the figure, the state of the flow remains steady. The flow is always symmetrical with respect to the longitudinal axis but loses its symmetry with respect to the upstream and the downstream. A wake appears formed by two symmetrical counter-rotating recirculating lobes attached to the obstacle and occupying the whole volume. Due to the increase of Re, the forces of inertia strengthen and prevent the boundary layer to remain attached to the obstacle and starts to favor a depression in the wake zone. We may note the beginning of birth of the vortex that develops far from the obstacle in the second configuration when Re = 20 because one approaches the bifurcation point towards the unsteady regime (Figure 8).

Hopf Bifurcation point

In this section the hop bifurcation point will be determined and discussed. It can be concluded that the flow is oscillatory from a certain Reynolds value. This periodic behavior occurs when the Reynolds number exceeds the critical value (Rec). It should be noted that the critical value of Re strongly depends on the geometry of the obstacle. Indeed, we consider performing several simulations for several Reynolds for both considered configurations. In order to compute the critical Reynolds number for each configuration, we start from Re = 20 and enhance it with the increment of 0.5 until we find the critical value. From the time when the perturbations change in an oscillatory trend, the flow after the critical point remains periodic in time and undergoes a critical value of Reynolds number. Besides, the square root of the amplitude of the solution increases with the bifurcation parameter. This means that the square of the amplitude of u and v velocity components must be proportional to the value of Re after the bifurcation. It should be noted that the amplitude of the velocity component (u or v) is defined

The values of the constants a and b are determined (see Figure 9) and the values of the critical Reynolds numbers Rec for the two configurations are reported in Table 3 (Figure 9).

The transition to the unsteady regime is found to begin in the second configuration and then in the first configuration. It is clear that the bifurcation points of the steady regime to the unsteady one is very much influenced by the change of the geometry of the obstacle. Therefore, the two configurations considered in this investigation generate a large reduction in the value of the critical Reynolds number. In addition, these obstacles accelerate the birth and generation of vortices. Therefore, we find that the two configurations generate a significant lessening in the critical value of the Reynolds number compared with a square cylinder (Rec=53).

The percentage reduction of Rec for both configurations was determined in Table 4. We determined that the best decline of Rec is seen for the second configuration and the smaller reduction corresponds to the first configuration (Table 3).

Table 2:Influence of time step (Δt) at Re = 50.

Table 3:Comparison of results for the flow past a single square cylinder in terms of percentage reduction.

Table 4:Comparison of results for the flow past a single square cylinder in terms of percentage reduction.

Table 5:Comparison of results for the flow past a single square cylinder in terms of percentage reduction.

Table 6:Mean values of the drag coefficient of both configurations for different Reynolds numbers.

Unsteady regime

As the Reynolds number exceeds the critical value, the flow becomes unsteady. At this stage, the instabilities are triggered which generates a noticeable change in the flow structure. To better analyze this change, Figure 10 is presented illustrating the effect of the Reynolds number on the iso-vorticities of the two configurations. For low Reynolds numbers (Re = 40 and 60), it is noted that the structure of the flow is similar in both configurations. A pair of vortices appears with opposing signs alternately separating behind each obstacle. In fact, the influence of the viscous force becomes negligible. However, the intensity of the inertial force strengthens with Reynolds increase so this force becomes dominant knowing that this number is defined as the ratio of the inertia force by the viscous force. As the Reynolds number augments, the shape and size of the vortices change in both configurations. This change is due to the influence of the obstacle geometry on the vortex structure. Therefore, we note that in the first configuration the shape of the vortices of negative sign becomes very elongated and these swirls dominate the wake, but the vortices of positive sign keep the round shape. Due to the lengthening of the negative sign vortices, the lateral and longitudinal spacing increases in the wake so this spacing causes a significant change in the fluctuation of the pressure. On the other hand, in the second configuration, the shape of the vortices of negative sign remains round but a significant change establishes in the shape of the vortices of positive sign which makes these vortices very elongated. The intensity of these positive vortices dominates and increases while increasing the Reynolds number. It can also be seen that the interaction between vortices of different intensities leads to a vortex structure proportional to the shape of the obstacle with a lateral and longitudinal spacing as proportional to the geometry of the obstacle.

It is clear that the flow pattern depends strongly on the shape of the obstacle. It can be deduced then that the two configurations generate a significant change in the characteristics of the wake be cause the lengthening of these vortices causes a remarkable spacing in the wake. Therefore, the spacing in the wake leads to diminishing the pressure and enhancing the speed. In order to verify the fluctuation of the velocity in the wake of both configurations, the variation of the horizontal component (u) of the velocity as a function of the Reynolds number is shown in Figure11. It can be seen that the velocity variation in both configurations increases monotonically as a function of the Reynolds number. However, it should be noted that the variation of the speed is very high in the second configuration and the smallest fluctuation of (u) is noted in the first configuration. It can be deduced that the second configuration causes a sharp decrease in the variation of the pressure compared with the first configuration (Figures 10,11).

Analysis of the fluctuation of Strouhal number

In this study, a fast Fourier transform of the time series for the lift coefficients is used to determine the Strouhal number. It can be seen in Figure 12 that the Strouhal number of the two configurations increases monotonously with Rewhen30 ≤ Re ≤ 80. This depends on the inertial force which strengthens with the increase of Re. When 30 ≤ Re ≤ 80, it is noted that the values of the frequency of detachment of the vortices are very close in both configurations. It is clear that the obstacles geometry has no effect on the evolution of the Strouhal number when the Reynolds number slightly varies. Moreover, we find that the first configurations reach the maximum before the second configuration. For the first configuration, this maximum is in the vicinity of a Reynolds which is equal to 90. On the other hand, for the second configuration, this maximum value was noted for a Reynolds number very close to 100 (Figure 12).

When Re ≥ 90, a considerable change in the fluctuation of the Strouhal number in both configurations is observed and at this stage appears the effect of the geometry and the symmetry of the configurations on the fluctuation of the Strouhal number. The values of St in the second configuration become greater than the values of St in the first configuration. This change can be due to the influence of the geometry of the obstacle on the detachment of the vortices. The first configuration hence generates a reduction in the fluctuation of St compared with the second one, and this reduction becomes very important for higher values of the Reynolds number.

Figure 13 illustrates a comparison between the values of St of both configurations with the case of a square cylinder. It is observed that the two configurations generate a significant reduction in the values of the Strouhal number compared with the square cylinder case. It is clear that this reduction becomes more significant with Re and seems to be very important when the Reynolds number has a value 160. The percentage of reduction of St for both configurations was determined in Table 4. We find that for low Reynolds numbers (Re = 60 and 80) the best reduction is caused by the second configuration and the lowest reduction corresponds to the first one. Starting from the value Re=100, the percentage of reduction augments in the first configuration and becomes the highest in this configuration compared to the other one. Note that the maximum reduction percentage in the first arrangement and the second one is respectively 29.10% (when Re = 140) and 27.90% (when Re = 160) (Table 4).

Analysis of the fluctuation of the average drag coefficient

The drag coefficient corresponds to the force applied to the body in the flow direction which is made dimensionless by the density of the fluid. Its velocity at upstream direction (U∞ ) is a characteristic surface calculated from the side of the shape and its size.

The drag coefficient is computed as follows:

The subscripts f, r, b and t refer to the front, rear, bottom and top surfaces of the obstacle.

The average values of the drag coefficient of the two configurations when Re varies from 1 to 180 are reported in Table 5 (Table 5).

Table 5 shows that the average drag coefficient (CD) of the two configurations has a fairly high value at Re = 1 since the velocity seems to be much weakened and hence a higher pressure is established. Thus, we may predict the higher value of CD in the first configuration and the lowest one in the second configuration. It can then be concluded that the first configuration generates a pressure rise when compared with the second one. When the Reynolds number is further raised, a sharp decrease is noticed in the fluctuation of the average drag coefficient and observed for both configurations. This decrease is related to the growth of the intensity of the forces of inertia and the lowering of the intensity of the viscous ones. In addition, it can be seen that when the flow remains steady (Re = 1-10-20), the highest values of CD are noted in the first configuration and the lowest values are obtained for the second configuration. The diminution in CD can be explained by the velocity strengthening as shown in Figure 12 and therefore the decrease in pressure because the change in pressure is inversely proportional to the speed variation. By further enhancing the Reynolds number, a decrease in the CD values is seen and this leads to lessening pressure and strengthening the speed (Figure 11). It should be noted that from a Re = 30 the CD values are very close in both configurations. Consequently, the influence of the geometry of the obstacle on the variation of the drag force strengthens and becomes significant while lowering the Reynolds number. However, the effect of the geometry decreases while increasing the Reynolds number. In the range 60 ≤ Re ≤ 180, the flow undergoes an unsteady behavior. The highest CD values are then noted in the second configuration. This is due to the enhancement in the intensity of the forces applied by the flow on this obstacle and to the decrease in pressure which becomes almost negligible. Conversely at steady state where the pressure forces are very high and the velocity variation is very low, CD values become very low in the first configuration when the flow state is unsteady.

Figure 14 is plotted in order to compare the values of the average drag coefficient of the two configurations considered in this study with the CD values of a square cylinder. It can be seen that the shape of the two configurations considerably modifies the variation of pressure and velocity in the flow. This results in a change in the fluctuation of the drag force. Therefore, it can be observed that the CD values noted in the flow around a square cylinder are very small compared to the values of the two configurations. It can be deduced then that the two configurations generate an enhancement in the intensity of the drag force compared to the case of a square cylinder.

Analysis of the fluctuation of the average lift coefficient

The subscripts f, r, b and t refer to the front, rear, bottom and top surfaces of the shape.

To understand the link between the fluctuation of the lift force and the shape of the obstacle, we present the figure 15. This figure shows the variation of the time average value of the lift coefficient versus the Reynolds number for both configurations. First, it is noted that the largest value of CL corresponds to the first configuration and the lowest value is related to the second one. As the Reynolds number augments, the curve relative to the second configuration exhibits a rising trend. By cons, in the first configuration the average value of the lift coefficient lowers. It is clear that the curves of the two configurations evolve symmetrically with respect to the curve of the square configuration. This indicates that the direction of the lift force applied to the first configuration is opposite to the direction of the lift force of the second configuration. Therefore, this reversal evolution in the direction of the lift force is due to the shape of both configurations. When 10 ≤ Re ≤ 180, the average lift coefficients of the first configuration are negative, while those of the second configuration are positive. It can be seen then that the geometry of the obstacle considerably affects the fluctuation of the lift force. Indeed, it can be observed that the first configuration generates a large reduction in the average lift coefficient compared with the square configuration. However, the second configuration generates a considerable enhancement in the values of the average lift coefficient (Figure 15).

Conclusion

The flow patterns past three square cylinders at two symmetrical vee shapes have been numerically performed for 1 ≤ Re ≤ 180. Two different arrangements were considered and compared in terms of flow behavior and characteristics. An accelerated multigrid implicit volume method was used as a numerical technique for the present study. Firstly, the computations were carried out for flow behind a single square cylinder in order to check the validity and accuracy of the in-house NASIM code. Then, the flow characteristics of both considered arrangements were investigated in terms of vorticity contour visualization, time evolutions analysis of drag and lift coefficients. Main findings are summarized below:

1. It is found that both the arrangements and the geometry of the obstacle affect the flow characteristics significantly as well as the appearance of bifurcation point from steady to the unsteady state. Indeed, it is seen that the transition to the unsteady state begins in the second configuration from (Rec = 22.37) and then emerge in the first configuration precisely at the value (Rec = 22.45). Besides, both configurations considered in this study generate an important decline in the critical Reynolds number value and accelerate the birth and vortices generation.

2. Influence of the obstacle geometry on the vortex detachment and the Strouhal number variation versus Re have been analyzed and discussed for the two configurations. It is seen that varying the arrangements leads to a considerable modification in the fluctuation of the Strouhal number.

3. In addition, fluid behavior of both arrangements were analyzed and compared with single cylinder case. The numerical results show that the two configurations generate a significant reduction in the values of the Strouhal number compared with the square cylinder. This reduction reinforces with increment in Re and becomes more significant when the Reynolds number reaches the value 160.

4. When analyzing the effect of the obstacle geometry on the flow structure and the frequency of vortices detachment, the results also suggest that both arrangements considerably modify the variation of pressure and velocity in the flow. This results in a variation in the typical fluctuations of the drag force.

5. Considering the geometry influence of both configurations on the lift, it is observed that the geometry of the obstacle noticeably affects the fluctuation of the lift force with symmetrical evolutions for both configurations. This reversal distribution trend demonstrates that the direction of the lift force applied to the first configuration is opposite to the lift force direction of the second one due to the shape of both of them.

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iriscomplimentarymedicine · 4 years ago

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Iris publishers-Online Journal of Complementary & Alternative Medicine(OJCAM)

Acceptability and Impact of a Breathing Awareness Meditation Application on Stress, Strain, Sleep Quality Among Caregivers of Kidney Transplant Recipients

Authored by Jessica Chandler*

Background:b> Caregivers are a crucial part of positive health outcomes for many chronically ill patients. Many caregivers experience stress and strain related to their caregiving role that may lead to neglecting their own health, both physical and mental, ultimately causing development of their own chronic illnesses.

Aim of the study:b> To evaluate acceptability and usability of a previously validated smartphone stress reduction app (Tension Tamer [TT]) among caregivers of kidney transplant recipients (KTR-Cs). An exploratory aim was to determine preliminary signals of efficacy of perceived stress, sleep quality, and blood pressure control.

Methods: A proof of concept randomized controlled trial with 20 KTR-Cs randomized into one of two groups: TT intervention arm or attention control (AC) arm. TT arm received a previously validated breathing awareness meditation (BAM) mobile application to use twice daily for three months while the AC arm received daily healthy education SMS messages. Study visits were conducted at baseline, 1-month, 2-month and 3-months visits.

Results:b> Mean age of the entire sample was 56.2±14.6 years, 72.7% female and 59.1% African American (40.9% white). Respondents averaged 19.3 ± 11.7 hours of caregiving/week, with 60% working full or part-time. There was a 100% participation rate and 90% retention rate. The majority of the sample (75%) at baseline self-reported high perceived stressed, 90% indicated poor sleep and 60.0% had high caregiver strain. Average adherence across the trial to the TT protocol (two 10 min sessions/day) was 71.8%. Compared to the AC group, the TT group experienced significantly greater improvements in perceived stress, caregiver strain, sleep quality and systolic blood pressure at 3-months (-8.7 vs +4.1mmHg, p<.05).

Conclusion: Results from this study indicate that a user friendly, BAM program may be efficacious in improving perceived stress, sleep quality and blood pressure control among KTR-Cs if tested in a properly powered RCT.

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irispublisherspsychology · 3 years ago

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Iris publishers-Open Access Journal of Addiction and Psychology (OAJAP)

The Secret of Human Existence Homeostasis: Spiritual Intelligence is the Hope of All Humanity

Authored by Ahed J Alkhatib*

Abstract

This study continues our descriptive and experimental studies addressing spiritual intelligence. As Zohar & Marshall pointed out that spiritual intelligence helps us to live life at a deeper level of meaning. We can also use the skills of spiritual intelligence (SQ) to deal with the problems of good and evil, life and death problems, and to help us understanding more deeply the causes of human suffering. Human beings are the only biological beings with spiritual intelligence. It has a capacity for harmony with oneself and others. Scientists believe that neither IQ nor social intelligence can adequately explain the complexity of the broad intelligence of the human mind. From the previous literature and studies about spiritual intelligence and neural basis, it is plausible to argue that through training programs to develop spiritual intelligence skills, we can modify the activity of the autonomic nervous system and increased control over its activities. The central component of any program to relief mental disorders and physical health problems is the development of the spiritual intelligence skills, which may be the hope of alleviating the suffering of patients in hospitals. We recommend the necessity and importance of applying the Biopsychosocial-Spiritual Model in all institutions that provide health care to patients with physical and psychological illnesses.

Keywords: Homeostasis; Spiritual intelligence; Biological basis; Mortality; Pain symptom Manage; Selye stress theory

Introduction

Positive psychology is based on a theory that stems from how the individual learns and how achieves a healthy, convincing, good and enjoyable life. The positive, and its commitment to care and development, leads to the understanding of the human being, the world and others around him, and even changes his negative thinking towards life as a whole. Positive psychology has defined as the scientific study of the strengths and virtues that empower individuals, institutions and societies to flourish. This has been based on the belief that human beings wish to lead a human life full of value and meaning in which they realize their ambitions and employ In which their human abilities to reach true satisfaction and happiness, and improve their general humanitarian experience in all areas of human value such as social relations, work, and even play [1].

Perhaps one of the most important psychological strengths in humans is intelligence, which has received a great deal of attention from psychologists over time, and even considered the IQ is the first factor of success and excellence, and that the highest people in intelligence reach the highest levels of success in education, work and various areas But scientists have recently discovered that other types of intelligence play an important role in success, especially in reality. Many intelligent people stumble and spend their lives in fear and tension, and others less intelligent take important and successful positions in life [2].

This means that intelligence is not only attributed to words, numbers, and logic, but also numerous types of intelligence have been described. There are creative, personal, sensory, physical, sexual, spiritual and spiritual intelligence, as well as numerical and verbal intelligence. Spiritual intelligence, as Amram & Dryer [3], is the ability to apply and use spiritual abilities and qualities that increase our effectiveness in life. Arnout [4] argued that if emotional intelligence is correlated between mind and emotion, Spiritual Intelligence is the most problematic of psychology schools, from psychoanalysis to knowledge, and equates man as being body, mind and spirit together.

Buzan [5] mentioned that Spiritual intelligence excels and competes with multiple intelligence and emotional intelligence to form a trilogy of excellence, success, and excellence. Many people consider spiritual intelligence the most important intelligence, with its power capable of changing their lives, civilizations, the course of history, and the entire planet.

Arnout [6] pointed out that with these rapid changes, the human being of the twenty-first century is exposed to many disasters and crises of physical, economic, environmental, natural, social and psychological, which makes a lot of stock of strength, will and hardness may be dispersed in the midst of these stressors, which is impossible to stop, but only to cope them effectively and positively.

The Biological Basis of Spiritual Intelligence

Thorndike explains biological intelligence: that intelligence and mental processes as a result of the work of a complex neurological system perform a function in a completely different way. This means that intelligence - as Thorndike goes - is determined by latent possibilities in the physical configuration of the organism inherited and not acquired, and the more complex the nervous system of the organism the more its intelligence. Gardner emphasized that there is a physiological and biological basis for the types of intelligence, and that the human brain is divided into two differentiated or asymmetrically differentiated anatomical. This anatomical variation is analogous to functional differences that reflect the difference of functions between the two parts.

Both Zohar & Marshall [7] noted that 40 Hertz were observed from the waves across the brain, and that these vibrations were linked to the ability of consciousness, and that they communicated cognitive events and cognitive comprehension During a more extensive gloss, and went on to say that these waves represent the neural base of spiritual intelligence. This is confirmed by Emmons [8] the data of spiritual intelligence collected neurological, evolutionary, and psychological evidence was consistent with Gardner’s criteria.

Since spiritual intelligence is the comprehensive intelligence of all intelligences, it was found that its components and dimensions have biological bases and in multiple locations of the brain, and will be presented as follows:

• After the overall picture and intuition, there was a correlation between mental processes such as language and logical processes with the left hemisphere of the brain, whereas the perception of the overall picture and intuition is linked to the right half [9]

• After sympathy and cooperation, Gallese [10] found that discoveries implying that biological research confirmed that the neuron system is a physiological basis for empathy and cooperation.

• Sublimation: Hamer [11] found that genes also play an important role in determining the ability to transcend the spiritual intelligence, which indicates that special processes occur in certain regions of the brain is responsible for this form of intelligence.

• Symbolic imagination and its role in intellectual evolution suggested that the brain has the ability to build symbolic figurative processes which led to profound reflective thinking about the meaning of life, experience, and human existence.

• Search for the meaning of life: At the end of 1990, it has been announced the neuroscientists have discovered the socalled God Spot God in the brain, a mass of nerve tissue in the temporal lobe of the brain, and this block to make the person raises the fundamental questions of meaning and existence, and make it Looking for substantive answers, optimal solutions to problems, making him aspire to the highest things to a dream of better growth, and being active when he has spiritual experiences “a deep sense of love”. The monitoring of nerve oscillations has led to a third type of thinking that results in cognitive processes that answer the questions of significance.

• Meditation: Studies found that those who were trained in meditation showed significantly greater activity in the cerebral cortex of the frontal and clear effects on the brain and immune functions. Lazar and his colleagues [12] found that the practice of meditation is associated with increased thickening of the cerebral cortex. It was found that meditators and dummies are the highest and thickest of these areas of the brain, while empathy and meditation are found to change electrical patterns in the brain, suggesting that the development of the qualities of spiritual intelligence, especially (sympathy and love) involves complementary mechanisms that may lead to short and longterm neurological changes in the brain.

• The skills of humor and spontaneity: Some researchers found that the skills of language humor, represented in the ability to recognize the pleasant and sarcastic hints (one of the components of spiritual intelligence), and ability to understand the interpretations of the metaphorical language - part of the function of the right hemisphere - which can be important in understanding the methods of ridicule and metaphor, so patients with right hemisphere tend to understand language in a literal manner.

The individual who has suffered damage to the Broca region may have substantial damage to linguistic intelligence and difficulty in speaking, reading, and writing, but he will still be able to sing, solve mathematical problems, meditate on feelings, and relate to others. When we use our minds for thought, this process involves not only the brain and the intelligent outcome, but also emotional or emotional intelligence, as well as spirituality, values, hopes and feasibility. The neurotransmitters in the brain are dedicated to linking mental, emotional, and spiritual experiences. Thus, we believe that spiritual intelligence works to activate the two hemispheres of the brain together. It performs functions from the right hemisphere as well as the left. This supports the “representative of intelligence” and refers to the integration of all other intelligences in spiritual intelligence and has a clear biological basis.

Singer & Gray [13] found that neurotransmitters in the brain are dedicated to connecting mental, emotional and spiritual experiences. Where the thinking in the scientific community that the brain is only able to produce two types of processes are: neurological processes that allow the brain to do rational and logical thinking, and the second type of nervous processes connecting thousands of neurons and the resulting emotional ideas. Neural oscilloscopes have led to a third type of thinking that results in cognitive processes that answer the questions of significance.

Deacon [14] examined the evolution of symbolic imagination and its role in mental development. He found that the brain has the ability to build symbolic processes of imagination that result in profound contemplative thinking about the meaning of life, life experiences, and human existence.

Zohar & Marshall [8] pointed out that the spiritual intelligence operates from the center of the brain (or the functions of the unified neuroscience). It integrates and harmonizes all kinds of intelligence. Spiritual intelligence makes us rational, emotional and spiritual beings integrated, which God has created in reality. All three types of intelligence (mental - emotional - spiritual) work together complementing each other, and our brains designed by the Creator so that they can achieve this integration. Every intelligence of these intelligences has its own area of strength in the brain, and it can function independently of other types of intelligences. That is, we do not have high or low abilities for the three types of intelligence at the same time. The individual does not need to have a great mental or spiritual intelligence to have high emotional intelligence, and the individual may possess a high intellectual intelligence but less emotional intelligence and spiritual both, and so on.

Since 1999, Gardner has emphasized the existence of a physiological and biological basis for the types of intelligence, and classical cognitive theories in the interpretation of intelligence have confirmed the association of mental processes such as language and logical processes to the left half of the brain. Perception of the overall picture and intuition (which are the two main components of intelligence) Spiritual) are associated with the right hemisphere.

Davison & his colleagues [15] found that those who received relaxation exercises to increase vigilance and meditation showed significant extra activity in the front of the cortex during training compared to other times. Lutz, et al. [16] found that the development of spiritual intelligence skills is associated with long-term and short-term changes to specific areas of the brain. Gallese [10] found that discoveries and biological research confirm that the Neuron System is a physiological basis for empathy and cooperation, which are spiritual intelligence skills. Also, Homer [11] found that genes also play an important role in determining the ability to excel.

We can say that the results of biological and neurological studies indicate that there is a relationship between the abilities and skills of spiritual intelligence, such as self-sufficiency, total thinking, perception of the whole picture, intuition, empathy, honesty, love and vigilance, and that these spiritual abilities have a biological basis associated with the occurrence of special processes In specific regions of the brain, as well as the possibility of genetic factors.

Sulmasy [17] noted that in “the Biopsychosocial-Spiritual Model of Care, everyone, according to this model, has a spiritual history. For many persons, this spiritual history unfolds within the context of an explicit religious tradition. But, regardless of how it has unfolded, this spiritual history helps shape who each patient is as a whole person, and when life-threatening illness strikes, it strikes each person in his or her totality. This totality includes not simply the biological, psychological, and social aspects of the person, but also the spiritual aspects of the whole person as well. This biopsychosocial-spiritual model is not a “dualism” in which a “soul” accidentally inhabits a body. Rather, in this model, the biological, the psychological, the social, and the spiritual are only distinct dimensions of the person, and no one aspect can be disaggregated from the whole. Each aspect can be affected differently by a person’s history and illness, and each aspect can interact and affect other aspects of the person.

If schizophrenia caused by increased activity of a neurodegenerative neurotransmitter in the brain, dopamine, and mania from increased norepinephrine or dopamine secretion, while depression from reduced norepinephrine activity, we argued that interventions based on spiritual intelligence and education of individuals suffering from these mental disorders of spiritual intelligence skills, to control the levels of chemical neurotransmitters in the brain?. Is it possible for spiritual intelligence interventions to balance the neural conductors and increase the effectiveness of drugs, especially as mental patients are still as they are in hospitals and the disorder state has not improved as needed? Can spiritual intelligence interventions mitigate the violent behavior of prisoners and criminals by affecting brain cells and parts responsible for emotions and behavior? Can spiritual intelligence interventions mitigate the violent behavior of prisoners and criminals by affecting brain cells and brain parts responsible for emotion and behavior? It can even reduce the frequency of obsessive-compulsive disorder patients in frequent self-destructive behaviors?.

And is the spiritual intelligence interventions benefit for addicted people to reduce their psychological dependence on drugs. Do spiritual intelligence interventions benefit to increased hope, optimism, forgiveness, positive attitude, gratitude, love of life, psychological well-being and the quality of life of chronically patients with cancer, kidney failure, HIV / AIDS and others? Do spiritual intelligence interventions help to increase the age of the elderly, their sense of happiness and achievement, and reduce their anxiety and death? Do spiritual intelligence interventions improve the mental, physical and psychological functioning of children with special needs? and is also help in achieving the normal path of physical, physiological, mental and social growth of ordinary children? These hypotheses need many experimental studies and will have many applications. It is considering a huge breakthrough in medical and psychological therapy if true.

Spiritual Intelligence and Human Existence Homeostasis

As mentioned by Jain and Purohit [18], spiritual intelligence is more than individual mental skill. In addition to self-awareness, it implies awareness of our relationship, it concerned with the internal life of mind and spirit and its association with being in the world. It implies a capability for a deep understanding of existential questions and insight into multiple levels of consciousness.

The concept of spiritual intelligence is related to human nature or what we call instinct. The nature of man is spirituality, religiosity and goodness, and therefore this nature must be preserved to organize human life. And commitment to worship as a way of life, and adherence to ethics that will sharpen the personality of man and strengthen the relationship between the servant and his Lord, and also between him and others, and increase the awareness of the person and the world and the whole universe, which leads to a balance in the life of the individual in the light of the standards and provisions.

Spirituality, as Wigglesworth [19] sees is “the innate human need to connect with something greater than ourselves, spirituality has always been seen by humanity as one of the fundamental requirements as it embodies the highest levels of cognitive, moral and emotional development and attempts to answer life questions [7] also argues with Emmons that spirituality represents a distinctive way of adaptation and represents a different understanding of science of values and goals in life. Thus Natti (2008) pointed out that spiritual intelligence is an essential capacity that shapes and guides all other abilities.

In his study of cognitive growth, Piaget pointed out that intelligence is an aspect of an individual’s adjustment to his environment and involves the interaction between two mental processes of assimilation and harmony. Baldwin [20] refereed that Piaget’s theory of cognitive development is a comprehensive theory of the nature and evolution of human intelligence. Piaget’s idea is originally conceived as the theory of the developmental stage. One of the basic concepts in this theory is the idea of assimilation and residence. Assimilation means how people perceive and adapt to new information and adapt new information to old cognitive schemes. In this process, new experiments are adapted to or similar to old ideas. Piaget emphasized that the human mind is programmed to harmony, which is believed to be what ultimately affects the structures through internal and external processes during the process of assimilation and representation.

From this point of view, Human homeostasis occurs as a result of the individual’s encounter with problems and difficulties and cannot solve them through his limited past experiences. In order to regain its equilibrium, it must undertake a structured and knowledgeable activity to seek new knowledge that will enable him to solve these problems and develop his / her cognitive structure and remove the tension and anxiety it has suffered.

According to the WHO [22], health is defined as a positive concept emphasizing social and personal resources, as well as physical capabilities. This stressed the important of identifying the health risks associated with different behavioral and social conditions and not just the biological illness itself or the medical factors only.

Because, as Foglio and Brody [19] mentioned “patients while struggle with the physical aspects of their disease, they have other pain as well: pain related to mental and spiritual suffering, to an inability to engage the deepest questions of life. Patients may be asking questions such as the following: Why is this happening to me now? What will happen to me after I die? Will my family survive my loss? Will I be missed? Will I be remembered? Is there a God? If so, will he be there for me? Will I have time to finish my life’s work? One physician who worked in the pediatric intensive care unit told me about his panic when his patients’ parents posed such questions. It is difficult to know what to say; there are no real answers. Nevertheless, people long for their physicians as well as their families and friends to sit with them and support them in their struggle. True healing requires answers to these questions.

From the previous view, biopsychosocial illness is possibly caused by excess stress. Lazarus and Folkman [23] pointed out that stressors are the situations in which individuals are faced with environmental or other demands which exceed their immediate ability to cope. Thus, we argued a Bio-Psychosocial-Spiritual Model which help healthcare providers to understanding and illness or problems of the person and formation of treatment plan. Shapiro [24] said that “change is constant. That’s the truth of being alive. Our bodies are constantly shifting, growing, shrinking, developing new set points for homeostasis, accommodating new information. Whether we look or not, this process is happening in every moment. When I lost my illusion of permanence and began actually to look at what life was offering to me, I discovered a wealth of possibilities I had never stopped to notice. I was stunned at the abundance. That abundance had been there all along. I had simply never looked”.

Thus, we illustrate the importance of spiritual intelligence in human health and homeostasis, from the results of studies by physicians and psychologists which research about the relations between spiritual intelligence and each of mortality and pain symptom manage.

Spiritual intelligence and mortality

The study of Strawbridge, Cohen, Shema and Kaplan [14] aimed to analyze the relationship between religious attendance and mortality. Results found that Lower mortality rates for frequent religious attenders are partly explained by improved health practices, increased social contacts, and more stable marriages occurring in conjunction with attendance. At the same time, the study conducted by Oman and Reed [24] that aimed to test the prospective relationship between attending religious services and all-cause mortality to determine, the results of analysis shown that lower mortality rates for those who attend religious services are only partly explained by the six possible confounders: demographics, health status, physical functioning, health habits, social functioning and support, and psychological state.

Li, Stamofer, Williams and VanderWeele examined the association between attendance at religious services and mortality, results illustrated that frequent attendance at religious services was associated with significantly lower risk of all-cause, cardiovascular, and cancer mortality among women. Religion and spirituality may be an underappreciated resource that physicians could explore with their patients, as appropriate. As well Williams and Sternthal [25] emphasized that health practices and social ties are important pathways by which religion can affect health. Other potential pathways include the provision of systems of meaning and feelings of strength to cope with stress and adversity. Thus D’Souza [26] argued that doctors and clinicians should not “prescribe” religious beliefs or activities or impose their religious or spiritual beliefs on patients. The task of in-depth religious counselling of patients is best done by trained clergy. In considering the spiritual dimension of the patient, the clinician is sending an important message that he or she is concerned with the whole person. This enhances the patientphysician relationship and is likely to increase the therapeutic impact of interventions. Doctors, health care professionals and mental health clinicians should be required to learn about the ways in which religion and culture can influence patients’ needs and recovery.

Wilding [27] qualitative study found that in the past 10- 20 years there has been increasing interest in the relationship between spirituality and health. he interviewed six patients from community mental health centers, using a phenomenological approach to explore how concepts of spirituality, occupation and mental illness/mental health are related. Four main themes were identified: Spirituality is a phenomenon that provides meaning to life. Spirituality can help a person cope with mental illness. Spiritual beliefs can make everyday occupations more meaningful and health-enhancing. Some people find it valuable to engage in shared occupations that focus on spirituality. Spirituality is an important and relevant issue to be discussed between patients and health practitioners, provided that practitioners can exercise sensitivity, caution, tolerance and acceptance of values that may differ from their own”.

Therefore, Winslow and Wehtje-Winslow [28] mentioned that “in an age that features technologically sophisticated medical interventions, patients still desire spiritually nurturing health care. Attention to patients’ spiritual needs and resources in the clinical setting may raise a number of ethical questions. Five ethical guidelines are offered as illustrations of norms that respect patients’ preferences and preserve health care professionals’ integrity”.

The study conducted by Gioiella, Berkman and Robinson [29] support the inclusion of spirituality as part of routine patient assessment and intervention. Clinical intervention that would increase a patient’s level of spiritual awareness and his or her level of comfort associated with a personal perspective on death could help decrease the patient’s level of psychosocial distress. Despite the medical establishment’s bias to the contrary, religion and spirituality are positively associated with both physical and mental health and may be particularly significant to terminally ill patients. The curricula of medical, nursing, and other health schools should be redesigned appropriately.

Koslander, da Silva, et al. [30] illuminated how existential needs and spiritual needs are related to health care ethics and individuals’ mental health and well-being. The term existential needs is defined as the necessity of experiencing life as meaningful, whereas the term spiritual needs is defined as the need of deliverance from despair, guilt and/or sin, and of pastoral care. It discusses whether or not patients’ needs are holistically addressed in Western health care systems that neglect patients’ existential and spiritual needs, because of their biomedical view of Man which recognizes only patients’ physical needs. It excludes a holistic health care which considers all needs, expressed by patients in treatment of mental illness. Addressing all needs is important for patients’ improvement and recovery. For some patients, this is the only way to regain their mental health and well-being.

Spiritual intelligence and pain symptom management

In 1998, the results of study conducted by McNeill et al, found that an inverse relationship between current pain intensity and general level of pain with overall satisfaction with pain management. Oral pain medications, prayer, intravenous and intramuscular injections were the top-ranked methods. Yates et al [31] mentioned that religion seems to be an important source of support for many patients. In addition to patients with advanced cancer who found comfort from their religious and spiritual beliefs were more satisfied, happier, and had less pain. Kaldjian, Jekel, and Friedland [9] found that spiritual beliefs and religious practices appeared to play a role in end-of-life decisions among patients with HIV. Thus Health-care providers need to recognize patients’ spiritual beliefs and incorporate them into discussions about terminal care. The study of Cohen et al [32] found that there was a significantly relationship between meaningful existence subscale and a single item scale rating overall quality of life. In the same direction the results of the study conducted by Brady et al [8] found a significant correlation between spirituality and quality of life.

All these findings illustrate that spiritual intelligence play a role in coping with illness, and in turn its reliefs the symptoms pain. Thus, if we need to recover the homeostasis of patients, it is necessary to include the treatment plan developing the spiritual skills and meaning of life of these patients.

This is confirmed by the findings of a study conducted by Harris et al [34] that provided empirical evidence that recipients with strong beliefs who participated in religious activities had better physical and emotional well-being, fewer health worries, and better medical compliance by the final 12-month assessment. These findings suggest the development of specific nursing, social-service, or pastoral-involvement strategies, continuing staff education about the role of religion in patient care.

Spiritual intelligence helps patients to recover their physical and psychological, especially patients with chronic pain, high blood pressure, headaches, and irritable bowel syndrome. Ehman et al [35] found that 45% of participants reported that religious beliefs would influence their medical decisions if they become gravely ill. Ninety-four percent of individuals with such beliefs agreed or strongly agreed that physicians should ask them whether they have such beliefs if they become gravely ill. Forty-five percent of the respondents who denied having such beliefs also agreed that physicians should ask about them. Altogether, two thirds of the respondents indicated that they would welcome the study question in a medical history, whereas 16% reported that they would not. Only 15% of the study group recalled having been asked whether spiritual or religious beliefs would influence their medical decisions.

Keramati and Gutkin [36] said that survival requires living organisms to maintain their physiological integrity within the environment, which means they must preserve homeostasis. In this sense, efficient behavioral decisions depend on two brain circuits working in concert: the hypothalamic homeostatic regulation (HR) system, and the cortico-basal ganglia reinforcement learning (RL) mechanism.

Shapiro [19] argued that “our biological systems are designed with both positive and negative feedback loops that respond to the impact of the world around us. Negative feedback loops promote homeostasis, keeping things more or less as they are. We notice something is sharp (negative) and we pull back from it so we are not cut. Positive feedback loops promote novelty and growth. We notice that exercise makes us feel healthy (positive) and we begin to take regular walks. Both feedback loops are in continuous operation. Both are necessary. And she mentioned homeostasis is critical to survival. If our bodies do not maintain themselves within certain tolerances (temperature being one example) we cannot function. Growing through creative change is also critical. If we cannot adapt to shifts in our environment, we cannot function either. Ignoring the presence of change may give us a temporary sense of stability, but it is an illusion.

Cannon [37] referred that the adrenal medulla releases the hormone epinephrine into the blood when individual response to a perceived threat. Adrenal has a coordinating role involving many different body systems. In his theory for stress, Selye [38] pointed out that when homeostasis was challenged to the point of failure, the “thermostat of defense” needs to be raised to a higher level, by defensive mechanisms that stimulate the physiologic adaptive mechanisms.

Selye has been shown that continuous exposure to stress leads to disturbances in different parts of the body, leading to the emergence of the purposes called the general symptoms of dysplasia and this is happening in three stages: warning, resistance, exhaustion.

The first phase: alarm

At this stage, the body will call all its defensive forces to face the danger it is exposed to as a result of the sudden exposure to stimuli that was not prepared for it. It is a group of organic chemical changes. The blood sugar rises, the pulse accelerates, and the arterial pressure rises, thus the body is alert in order to adapt to the threatening actor.

The second phase: resistance stage

This phase includes the physical symptoms caused by the constant exposure to the stimuli and stress positions that the organism has acquired the ability to adapt to. This stage is important in the origin of the purposes of adaptation or the socalled cycosomatic purposes This occurs especially when the human ability to cope with situations cannot be met by adaptive reaction, and continuous exposure to pressure leads to an internal disturbance, resulting in more hormonal secretions causing organ disturbances.

The third stage: exhaustion

Exhaustion is likely to occur If the individual is exposed to multiple pressures for a longer period, he will reach a point unable to continue the resistance and enter the stage of exhaustion and becomes unable to fully adapt at this stage collapse hormonal payments and reduce the resistance of the body and damage many nerve devices and the patient goes to death at a rapid pace many adaptive responses that help the individual to protect themselves whenever exposed to changes and stressful situations are stopped. Low or increased temperature, hunger, thirst, excessive muscle activity and emotional stress all result in changes in the organism due to stress state.

Fletcher [39] mentioned that “Cannon originated the term homeostasis to describe the tendency of organisms to maintain stability or uniformity in their body states. By an extension of the principle, it might be used to describe the already demonstrated tendency to maintain status at the mental level of behavior, even in anticipation of the disturbing conditions. Instances of the usefulness of the term are drawn from such fields as perception (constancy), habit formation, learning, reasoning, work level (level of aspiration), and personality adjustment, to explain such mechanisms as rationalization and compensation” (p.80).

Through this view, biological homeostasis achieves the mental and psychological homeostasis of the individual, as well as the individual possessing the skills of spiritual intelligence achieves the physiological homeostasis and allostatic processes in the various functions of the body.

Thus Shapiro argued that “how do we develop our capacity to be open to the possibilities around us, to loosen our fear of impermanence? The first step is simply to acknowledge that we are working with the balance between homeostasis and creative change - that we need both. The second step is to pay attention - not label, not judge, not push away, not grab - just pay attention to what is happening within us and around us right now. Seems simple enough, but actually it’s not. Paying attention takes practice. Possibilities arise around us in every moment. We miss them because we are not paying attention, because we have labeled things before, we take the time to discover what they are. Someone looks different or speaks in a way we don’t understand and, without noticing, we instantly give them a label (“old”, “young”, “beautiful”, “unkind”, “dangerous”) and think we know something about them and what they bring to our lives. But we don’t. Until we actually pay attention to what or who is in front of us, we really have no idea what gifts this experience may bring”.

From the above view of Shapiro, we can say that Spiritual intelligence led to homeostasis, because all of this steps that develop our capacity to be open to the possibilities around us; working with the balance between homeostasis and pay attention to what is happening within us and around us right now, are include spiritual intelligence skills. This is consistent with Shapiro [40] said that as we train our attention, we can turn that basic curiosity to everything, rather than making judgments, we can simply become aware of what life is bringing us on all levels. And we can cultivate an appreciative awareness of the balance in our lives between homeostasis and creative change. Cannon considered homeostasis as part of the “wisdom of the body.” Which is released by the integrity of body, mind, soul and spirit all together. As mentioned in Lambert these illustrations from Bernard and Cannon, attest to the body’s wisdom for maintaining homeostasis-that is, a constant internal environment. The maintenance of homeostasis depends on a negative feedback system, a self-correcting process that reduces the discrepancy between a desired state and an actual state. Lambert mentioned a desired state is a condition crucial for life, comfort, or safety. The actual state of the system is compared to the set point, and if a discrepancy is detected, a self-correcting process is initiated. The process ends when the discrepancy reaches zero.

Future Directions in the use of Spiritual Intelligence

At present, with the proliferation of physical competition in the world, the speed of changes has increased, issues such as intelligence appeared more serious, especially the subject of spiritual intelligence as the infrastructure of individual beliefs, its capital of an important role in many areas, especially in mental and psychological health.

The development of interest in spiritual methods in psychotherapy is an appropriate attitude, and spiritual subjects have significant and significant effects on changes in mental health, Spiritual and religious values may facilitate the process of therapeutic progress. Spiritual intelligence is a key element in the achievement of the individual aims. The individual’s possession of high spiritual intelligence is indicative of the individual’s possession of other intelligences, and a clear indication of the individual’s enjoyment of mental health and psychological homeostasis.

Todres, et al. [41] revealed that unique clinical pastoral education program provides the clinician with knowledge, language, and understanding to explore and support spiritual and religious issues confronting critically ill patients and their families. Thus, they emphasized that incorporating spiritual care of the patient and family into clinical practice is an important step in addressing the goal of caring for the whole person.

Vaughan [42] emphasized that spiritual intelligence is associated with mental health in general, although some forms of spirituality may be dysfunctional or sick. When spiritual beliefs promote denial and rejection and lead to fear and conflict, they can be destructive and seriously problematic. Seybold and Hill [38] suggested that spiritual beliefs, practices and commitments are associated with positive outcomes, such as mental and physical health; marital satisfaction and stability; positive interaction with individuals; and a better quality of life. While Emmons [7] argued that one of the factors contributing to such positive outcomes may be that having a spiritual orientation to life protects people from undesirable and non-adaptive behaviors such as destructive, social or even personal behavior.

As for the importance of emotional intelligence in the health of individuals, the studies showed that high emotional intelligence was associated with high physical and mental health, high satisfaction with life, and emotional intelligence plays an important role in regulating health care. Spiritual intelligence plays an important role in human physical and psychological health. Studies have shown that spirituality has been positively correlated with adaptive ability in individuals with physical health problems and has also been associated with effective positive coping methods in cancer patients. Kirby et al. [43] study found that spirituality also reduces the negative effects of older people. And Fry study revealed that the sense of value and life was associated with increased physical and mental health in the elderly. King [44] emphasized that spiritual intelligence plays an important role in all the steps of health care, especially its management, treatment and healing, as it leads to appropriate results which other abilities / intelligences cannot do. Health is a general word that reflects not only the body, mind and spirit, not pain and happiness, only the whole human existence and the universal view of man.

Thus, the results of previous studies confirm the importance of spiritual intelligence to the physical and psychological health of the individual so that his quality of life can be realized. Howard [45] pointed out that spiritual intelligence enables the individual to confront and solve life problems, and the individual has the qualities of compassion, humility, gratitude, and wisdom. Atkinson [46] argues that harnessing the power of spiritual intelligence is the key to purity, prosperity and happiness, and to creating paradise on earth, because the self alone is not enough to make a more merciful and stable future. Spiritual intelligence is the solution, which is simply the intelligent energy that creates life and the strong desire to exist and to make everything new [47-52].

Conclusion

From all mentioned above, by spiritual intelligence interventions and understand homeostatic mechanism we can achieve a homeostasis in the secretion of hormones, neurotransmitters, heart attacks, blood pressure can be changed by the autonomic nervous system and cell and organ functions becomes better after a defect has been caused by the problems and stress experienced by the individual in his lifespan. Cannon [37] defined homeostasis as physiological mechanisms that maintain relatively constant the variables related to the internal milieu of the organism. Thus the Biopsychosocial-Spiritual Model of Care is a vital for applied if we are need to help the patients in reducing their physical and psychological suffering and achieving a better life for them. We need to plan counseling and psychotherapy programs to development spiritual intelligence for all individual to be happier and well-being, and to release quality of life for all healthy and patients’ individuals across different stages of growth.

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Eosinophilia and Neutrophilia Associated with Anti- PD-1 use in Metastatic Non-Small Cell Lung Cancer – A Case Report-Iris Publishers

Authored by Yasir Khan*

Abstract

The use of immunotherapy has dramatically changed the way many cancers are treated with several studies having looked at the relationship between eosinophils and immunotherapy. This case study reports nivolumab induced eosinophilia and neutrophilia with no other systemic adverse effects in a patient with metastatic non-small cell lung cancer. A 61-year-old woman with Eastern Cooperative Oncology Group performance status 1 was diagnosed with metastatic non-small cell lung cancer without any driver mutations and was commenced on nivolumab after progressing on platinum doublet therapy. She had mild eosinophilia and neutrophilia at baseline in the context of a lower respiratory tract infection which became more pronounced with the introduction of nivolumab. Nivolumab was ceased at week-26 due to significant eosinophilia and reached peak levels at week-35. She developed postural hypotension during the course of her disease and prednisolone was commenced to treat possible adrenal insufficiency from metastasis. The introduction of steroids led to the improvement in eosinophilia and neutrophilia. She had stable disease for 8 months after commencement of immunotherapy before progression of disease leading to clinical deterioration and death. Asymptomatic eosinophilia and neutrophilia is an extremely rare toxicity of immune checkpoint inhibitors. Its significance as prognostic and predictive marker needs to be researched further.

Keywords: Immunotherapy induced eosinophilia; Neutrophilia; Nivolumab.

Introduction

Immune checkpoint inhibitors (ICI) targeting PD-1, PD-L1 and CTLA-4 are routinely used in clinical practice in multiple tumour types. These drugs are very effective especially for solid organ malignancies with high mutational load but carry a wide spectrum of toxicities driven by over stimulation of immune system. Immunerelated adverse events (irAEs) range from low grade toxicities to severe toxicities which can potentially be life threatening in some cases. Among some of the uncommon side effects, immunotherapy induced eosinophilia is a rare toxicity with only a few documented cases and mostly associated with eosinophilia related systemic manifestations or with additional toxicities. There are well established guidelines for treating common irAEs but little is known about the optimal management of rarer toxicities like asymptomatic eosinophilia. This case study reports nivolumab induced eosinophilia and neutrophilia with no other systemic adverse events in a patient with metastatic non-small cell lung cancer.

Case Report

A 61-year-old woman was admitted with the diagnosis of lower respiratory tract infection with investigations leading to a diagnosis of stage IV adenocarcinoma of the lung without targetable mutations. She had a left lung mass, hilar nodes enlargement, malignant ipsilateral pleural effusion and liver metastases. PDL1 status was not obtained as there were no standard treatments based on PD-L1 levels at that time. She was a smoker and had Eastern Cooperative Oncology Group (ECOG) performance status 1.

Due to prescribing restrictions applicable at that time, she was initially commenced on carboplatin and gemcitabine chemotherapy before progression of disease. Second line pemetrexed was given but it failed to provide any clinical benefit. She was then commenced on nivolumab monotherapy. Initial interval scan suggested worsening of disease, however given there was no clinical deterioration, she was given the benefit of doubt and nivolumab was continued on the assumption of pseudo progression. Her baseline neutrophils and eosinophils count were mildly elevated (Table 1). Of note this was in the setting of lower respiratory tract infection. The elevated eosinophil counts were persistent but still mild at the commencement of nivolumab. Both neutrophilia and eosinophilia were more pronounced at 14 weeks post-nivolumab and reached peak levels at 35 weeks (Figure 1) (Table 1).

Table 1:Serial full blood counts (FBC).

Nivolumab was stopped after 13 cycles due to worsening of eosinophilia and neutrophilia in the context of stable disease on imaging. Patient did not have any other systemic features at the time when nivolumab was stopped. Possible differential diagnosis at that stage included paraneoplastic phenomenon, immune mediated toxicity, and myeloproliferative disorder. She started to deteriorate clinically with recurrent falls. Adrenal insufficiency was considered to be the most likely diagnosis based on the clinical features of postural hypotension, hyponatremia, hyperkalemia and finding of left adrenal metastasis on repeat imaging. This diagnosis was further confirmed by inadequate response of adrenal glands to short synacthen test. She was commenced on prednisolone to correct adrenal insufficiency which also led to the improvement in neutrophilia and eosinophilia. Eventually disease progression was recorded soon afterwards along with clinical deterioration predominantly from progression in the lungs causing respiratory failure and death. She had 14 months of survival since diagnosis of the cancer. Progression free survival on immunotherapy was 8 months with stable disease being the best response.

Discussion

A well-known cause of hyper eosinophilia is the DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome. Common features of DRESS include blood eosinophilia, fever, skin changes, facial oedema, visceral involvement, and atypical lymphocytes [1]. DRESS has been reported to be associated with immunotherapy. Mirza et al presented a case of patient who developed DRESS after combination ipilimumab and nivolumab for melanoma and successfully treated with steroids [2]. Voskens et al also presented a case of DRESS syndrome following ipilimumab for melanoma which responded to steroids [3]. Furthermore, there have been other case reports documenting relationship between immunotherapy and eosinophilia with uncommon systemic manifestations. Khoja et al. presented a case of a patient who developed eosinophilic fasciitis and cerebral vasculitis one month after completing an 18-month course of pembrolizumab for metastatic melanoma [4]. Okano et al presented a case of a patient with hypophysitis with associated eosinophilia following nivolumab for metastatic lung cancer [5]. To our knowledge, there are only two case series published in literature in regard to nivolumab induced eosinophilia, however a majority of those patients also experienced other irAEs of various grades [6,7]. In addition to this, there have been five published case reports of nivolumab induced eosinophilia to date [2,8-11]. Our report documents a case with isolated hematological abnormalities including eosinophilia and neutrophilia without systemic features in a patient treated with nivolumab for metastatic non-small cell lung cancer (NSCLC) which is a rare toxicity of anti-PD-1 antibodies.

The role of eosinophils in tissue homeostasis is not fully understood. Nevertheless, certain conditions have a well-known association with eosinophilia such as allergic diseases, infectious diseases (especially parasitic infections), autoimmune diseases (especially adrenal insufficiency) and haematological disorders. Eosinophilia has also been described as a paraneoplastic phenomenon of many solid organ malignancies and is most associated with an advanced stage and poor prognosis [12]. Eosinophils can also play a role in pathogenesis through depositing granules which can have both direct toxic effects and recruit as well as activate other inflammatory cells [13]. A hypereosinophilic syndrome (HES) in which there are symptoms from a high eosinophil count in blood or tissue has been described with the underlying cause often never found despite extensive investigation [12,13]. There are various mechanisms reported in the literature to explain pathophysiology of eosinophilia. Immune proteins and cytokines like interleukin-3 (IL-3) and interleukin-5 (IL-5) have been associated to play a role in elevated eosinophil counts [14,15]. Our patient also had neutrophilia in addition to eosinophilia. Neutrophilia is induced by granulocyte macrophage colony stimulating factor (GM-CSF). Interaction and interplay of immune proteins like GM-CSF, IL-3 and IL-5 leads to activation of multiple cell lines. The role of eosinophils in tumour microenvironment is not well known and may possess anti-tumour effects in some cases while promoting tumorigenesis in others [16]. Its value as prognostic and predictor factor is also unclear. Eosinophilia at diagnosis of the cancer has been linked with poor prognosis in some advanced malignancies [17,18]. On the other hand, some pre-clinical studies indicate immunotherapy induced eosinophilia may be a predictor of response to treatment. In our case, when immunotherapy was stopped after 13 cycles the best response achieved with immunotherapy was stable disease only. As eosinophilia pre-dated the start of immunotherapy, at least in our case, it does not seem to be associated with treatment response or effectiveness.

Conclusion

Asymptomatic eosinophilia and neutrophilia is an extremely rare toxicity of ICI. Development of eosinophilia in the setting of immunotherapy use needs to be studied further to delineate its role as both prognostic and predictive marker.