#Mendelian disease diagnosis

[rnewspost]

Effectiveness of exome and genome sequencing to detect undiagnosed syndromes

Recently, next-generation sequencing (NGS) technology has been effectively used for disease management and the formulation of new treatments. Genome sequencing (GS) and exome sequencing (ES) methods, both of which are based on NGS, have radically changed the diagnosis of rare Mendelian diseases.  Despite the development of these innovative techniques, several rare diseases remain undiagnosed. In…

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/weekly-top-scientific-research-review-1742017-2142017/

Weekly Top Scientific Research Review (17/4/2017 – 21/4/2017)

A new week again! What is the progress of your research this week? Anyway, be relax, and read the latest research report with us.

1. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro.

Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in developmental potential. Here, Sarah Ellys Harrison at University of Cambridge, Department of Physiology, Development and Neuroscience in Cambridge, UK and her colleagues combined mouse embryonic stem cells (ESCs) and extraembryonic trophoblast stem cells (TSCs) in a three-dimensional scaffold to generate structures whose morphogenesis is markedly similar to that of natural embryos. By using genetically modified stem cells and specific inhibitors, the team show that embryogenesis of ESC- and TSC-derived embryos—ETS-embryos—depends on cross-talk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extraembryonic border, in response to Wnt and BMP signaling. Their study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell types resemble those of natural embryos.

Read more, please click http://science.sciencemag.org/content/356/6334/eaal1810

2. A murine preclinical syngeneic transplantation model for breast cancer precision medicine.

Lorenzo Federico at Department of Systems Biology, University of Texas MD Anderson Cancer Center in Houston, USA and his colleagues previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. They have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.

Read more, please click http://advances.sciencemag.org/content/3/4/e1600957

3. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice.

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. Yu Zhang at Department of Molecular Biology, University of Texas Southwestern Medical Center in Dallas, USA and his colleagues deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD.

Read more, please click http://advances.sciencemag.org/content/3/4/e1602814

4. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation.

Tumor progression locus 2 (TPL2; also known as MAP3K8) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activate the MAPKs extracellular signal–regulated kinase 1 (ERK1) and ERK2 (ERK1/2) in macrophages stimulated through the interleukin-1 receptor (IL-1R), Toll-like receptors (TLRs), or the tumor necrosis factor receptor (TNFR). Kate Senger at Genentech Research, Genentech Inc. in South San Francisco, USA and his colleagues describe a conserved and critical role for TPL2 in mediating the effector functions of neutrophils through the activation of the p38 MAPK signaling pathway. Gene expression profiling and functional studies of neutrophils and monocytes revealed a MEK1/2-independent branch point downstream of TPL2 in neutrophils. Biochemical analyses identified the MAPK kinases MEK3 and MEK6 and the MAPKs p38α and p38δ as downstream effectors of TPL2 in these cells. Genetic ablation of the catalytic activity of TPL2 or therapeutic intervention with a TPL2-specific inhibitor reduced the production of inflammatory mediators by neutrophils in response to stimulation with the TLR4 agonist lipopolysaccharide (LPS) in vitro, as well as in rodent models of inflammatory disease. Together, these data suggest that TPL2 is a drug target that activates not only MEK1/2-dependent but also MEK3/6-dependent signaling to promote inflammatory responses.

Read more, please click http://stke.sciencemag.org/content/10/475/eaah4273

5. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. Beryl B. Cummings at Analytic and Translational Genetics Unit, Massachusetts General Hospital in Boston, USA and his colleagues explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. The team describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. They demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. They also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. They identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

Read more, please click http://stm.sciencemag.org/content/9/386/eaal5209

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New Post has been published on Biotech Advisers

Interests on http://www.bioadvisers.com/weekly-top-scientific-research-review-1742017-2142017/

Weekly Top Scientific Research Review (17/4/2017 – 21/4/2017)

A new week again! What is the progress of your research this week? Anyway, be relax, and read the latest research report with us. 1. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Mammalian embryogenesis requires intricate interactions between.... Click for moreWeekly Top Scientific Research Review (17/4/2017 – 21/4/2017).

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/weekly-top-scientific-research-review-1742017-2142017/

Weekly Top Scientific Research Review (17/4/2017 – 21/4/2017)

A new week again! What is the progress of your research this week? Anyway, be relax, and read the latest research report with us.

1. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro.

Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in developmental potential. Here, Sarah Ellys Harrison at University of Cambridge, Department of Physiology, Development and Neuroscience in Cambridge, UK and her colleagues combined mouse embryonic stem cells (ESCs) and extraembryonic trophoblast stem cells (TSCs) in a three-dimensional scaffold to generate structures whose morphogenesis is markedly similar to that of natural embryos. By using genetically modified stem cells and specific inhibitors, the team show that embryogenesis of ESC- and TSC-derived embryos—ETS-embryos—depends on cross-talk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extraembryonic border, in response to Wnt and BMP signaling. Their study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell types resemble those of natural embryos.

Read more, please click http://science.sciencemag.org/content/356/6334/eaal1810

2. A murine preclinical syngeneic transplantation model for breast cancer precision medicine.

Lorenzo Federico at Department of Systems Biology, University of Texas MD Anderson Cancer Center in Houston, USA and his colleagues previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. They have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.

Read more, please click http://advances.sciencemag.org/content/3/4/e1600957

3. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice.

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. Yu Zhang at Department of Molecular Biology, University of Texas Southwestern Medical Center in Dallas, USA and his colleagues deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD.

Read more, please click http://advances.sciencemag.org/content/3/4/e1602814

4. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation.

Tumor progression locus 2 (TPL2; also known as MAP3K8) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activate the MAPKs extracellular signal–regulated kinase 1 (ERK1) and ERK2 (ERK1/2) in macrophages stimulated through the interleukin-1 receptor (IL-1R), Toll-like receptors (TLRs), or the tumor necrosis factor receptor (TNFR). Kate Senger at Genentech Research, Genentech Inc. in South San Francisco, USA and his colleagues describe a conserved and critical role for TPL2 in mediating the effector functions of neutrophils through the activation of the p38 MAPK signaling pathway. Gene expression profiling and functional studies of neutrophils and monocytes revealed a MEK1/2-independent branch point downstream of TPL2 in neutrophils. Biochemical analyses identified the MAPK kinases MEK3 and MEK6 and the MAPKs p38α and p38δ as downstream effectors of TPL2 in these cells. Genetic ablation of the catalytic activity of TPL2 or therapeutic intervention with a TPL2-specific inhibitor reduced the production of inflammatory mediators by neutrophils in response to stimulation with the TLR4 agonist lipopolysaccharide (LPS) in vitro, as well as in rodent models of inflammatory disease. Together, these data suggest that TPL2 is a drug target that activates not only MEK1/2-dependent but also MEK3/6-dependent signaling to promote inflammatory responses.

Read more, please click http://stke.sciencemag.org/content/10/475/eaah4273

5. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. Beryl B. Cummings at Analytic and Translational Genetics Unit, Massachusetts General Hospital in Boston, USA and his colleagues explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. The team describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. They demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. They also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. They identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

Read more, please click http://stm.sciencemag.org/content/9/386/eaal5209

[abbkine]

New Post has been published on Biotech Advisers

Weekly Top Scientific Research Review (17/4/2017 – 21/4/2017)

A new week again! What is the progress of your research this week? Anyway, be relax, and read the latest research report with us.

1. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro.

Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in developmental potential. Here, Sarah Ellys Harrison at University of Cambridge, Department of Physiology, Development and Neuroscience in Cambridge, UK and her colleagues combined mouse embryonic stem cells (ESCs) and extraembryonic trophoblast stem cells (TSCs) in a three-dimensional scaffold to generate structures whose morphogenesis is markedly similar to that of natural embryos. By using genetically modified stem cells and specific inhibitors, the team show that embryogenesis of ESC- and TSC-derived embryos—ETS-embryos—depends on cross-talk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extraembryonic border, in response to Wnt and BMP signaling. Their study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell types resemble those of natural embryos.

Read more, please click http://science.sciencemag.org/content/356/6334/eaal1810

2. A murine preclinical syngeneic transplantation model for breast cancer precision medicine.

Lorenzo Federico at Department of Systems Biology, University of Texas MD Anderson Cancer Center in Houston, USA and his colleagues previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. They have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.

Read more, please click http://advances.sciencemag.org/content/3/4/e1600957

3. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice.

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. Yu Zhang at Department of Molecular Biology, University of Texas Southwestern Medical Center in Dallas, USA and his colleagues deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD.

Read more, please click http://advances.sciencemag.org/content/3/4/e1602814

4. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation.

Tumor progression locus 2 (TPL2; also known as MAP3K8) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activate the MAPKs extracellular signal–regulated kinase 1 (ERK1) and ERK2 (ERK1/2) in macrophages stimulated through the interleukin-1 receptor (IL-1R), Toll-like receptors (TLRs), or the tumor necrosis factor receptor (TNFR). Kate Senger at Genentech Research, Genentech Inc. in South San Francisco, USA and his colleagues describe a conserved and critical role for TPL2 in mediating the effector functions of neutrophils through the activation of the p38 MAPK signaling pathway. Gene expression profiling and functional studies of neutrophils and monocytes revealed a MEK1/2-independent branch point downstream of TPL2 in neutrophils. Biochemical analyses identified the MAPK kinases MEK3 and MEK6 and the MAPKs p38α and p38δ as downstream effectors of TPL2 in these cells. Genetic ablation of the catalytic activity of TPL2 or therapeutic intervention with a TPL2-specific inhibitor reduced the production of inflammatory mediators by neutrophils in response to stimulation with the TLR4 agonist lipopolysaccharide (LPS) in vitro, as well as in rodent models of inflammatory disease. Together, these data suggest that TPL2 is a drug target that activates not only MEK1/2-dependent but also MEK3/6-dependent signaling to promote inflammatory responses.

Read more, please click http://stke.sciencemag.org/content/10/475/eaah4273

5. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. Beryl B. Cummings at Analytic and Translational Genetics Unit, Massachusetts General Hospital in Boston, USA and his colleagues explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. The team describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. They demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. They also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. They identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

Read more, please click http://stm.sciencemag.org/content/9/386/eaal5209

[abbkineus]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/weekly-top-scientific-research-review-1742017-2142017/

Weekly Top Scientific Research Review (17/4/2017 – 21/4/2017)

A new week again! What is the progress of your research this week? Anyway, be relax, and read the latest research report with us.

1. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro.

Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in developmental potential. Here, Sarah Ellys Harrison at University of Cambridge, Department of Physiology, Development and Neuroscience in Cambridge, UK and her colleagues combined mouse embryonic stem cells (ESCs) and extraembryonic trophoblast stem cells (TSCs) in a three-dimensional scaffold to generate structures whose morphogenesis is markedly similar to that of natural embryos. By using genetically modified stem cells and specific inhibitors, the team show that embryogenesis of ESC- and TSC-derived embryos—ETS-embryos—depends on cross-talk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extraembryonic border, in response to Wnt and BMP signaling. Their study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell types resemble those of natural embryos.

Read more, please click http://science.sciencemag.org/content/356/6334/eaal1810

2. A murine preclinical syngeneic transplantation model for breast cancer precision medicine.

Lorenzo Federico at Department of Systems Biology, University of Texas MD Anderson Cancer Center in Houston, USA and his colleagues previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. They have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.

Read more, please click http://advances.sciencemag.org/content/3/4/e1600957

3. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice.

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. Yu Zhang at Department of Molecular Biology, University of Texas Southwestern Medical Center in Dallas, USA and his colleagues deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD.

Read more, please click http://advances.sciencemag.org/content/3/4/e1602814

4. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation.

Tumor progression locus 2 (TPL2; also known as MAP3K8) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activate the MAPKs extracellular signal–regulated kinase 1 (ERK1) and ERK2 (ERK1/2) in macrophages stimulated through the interleukin-1 receptor (IL-1R), Toll-like receptors (TLRs), or the tumor necrosis factor receptor (TNFR). Kate Senger at Genentech Research, Genentech Inc. in South San Francisco, USA and his colleagues describe a conserved and critical role for TPL2 in mediating the effector functions of neutrophils through the activation of the p38 MAPK signaling pathway. Gene expression profiling and functional studies of neutrophils and monocytes revealed a MEK1/2-independent branch point downstream of TPL2 in neutrophils. Biochemical analyses identified the MAPK kinases MEK3 and MEK6 and the MAPKs p38α and p38δ as downstream effectors of TPL2 in these cells. Genetic ablation of the catalytic activity of TPL2 or therapeutic intervention with a TPL2-specific inhibitor reduced the production of inflammatory mediators by neutrophils in response to stimulation with the TLR4 agonist lipopolysaccharide (LPS) in vitro, as well as in rodent models of inflammatory disease. Together, these data suggest that TPL2 is a drug target that activates not only MEK1/2-dependent but also MEK3/6-dependent signaling to promote inflammatory responses.

Read more, please click http://stke.sciencemag.org/content/10/475/eaah4273

5. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. Beryl B. Cummings at Analytic and Translational Genetics Unit, Massachusetts General Hospital in Boston, USA and his colleagues explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. The team describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. They demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. They also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. They identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

Read more, please click http://stm.sciencemag.org/content/9/386/eaal5209

[lupine-publishers-lojpcr]

Lupine Publishers | A De-Novo SCN2A Mutation Identified in a Chinese Patient With Epilepsy: A Case Report

Lupine Publishers | LOJ Pharmacology & Clinical Research

Abstract

Objective: To investigate the genetic causes of epilepsy in a 5-year-old Chinese female patient.

Methods: Clinical diagnosis and next-generation sequencing.

Results: The patient carries a de-novo heterozygous missense mutation (c.3686 A>T p.Asp1229Val) in the SCN2A gene. This mutation was evaluated as a pathogenic mutation based on the standards and guidelines of ACMG (American College of Medical Genetics and Genomics) and clinical research publications.

Conclusion: The de-novo heterozygous mutation (c.3686 A>T p.Asp1229Val) in the SCN2A gene is the genetic cause of the epilepsy for the patient. So far, this mutation of SCN2A gene is the first reported in the worldwide overall populations.

Keywords: Chinese; Epilepsy; SCN2A gene

Abbreviations: Whole Exome Sequencing (WES); Sanger sequencing; American College of Medical Genetics and Genomics (ACMG)

Introduction

The SCN2A gene encodes the voltage-gated sodium channel Na(v)1.2, which plays an important role in the initiation and conduction of action potentials. SCN2A is expressed in axon initiation segments and at nodes of Ranvier in myelinated nerve fibers during early development, and is later expressed in unmyelinated axons [1]. Mutations in the SCN2A gene, cause a variety of neuropsychiatric syndromes with different severity ranging from self-limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures [2-4]. So far, more than 700 mutations in SCN2A were reported to be associated with epilepy [5]. The aim of the present study was to detect and report genetic causes of a 5-year-old Chinese female patient with epilepsy. The patient was found to have a de-nove mutation (c.3686 A>T p.Asp1229Val) in the SCN2A gene that has not reported in the previous studies.

Materials and Methods

Clinical diagnosis

A 5-year-old female Chinese patient who was born with no family history of seizures or other types of neurological diseases, has experienced epileptic spasms since she was 1.5 years old. The patient had fallen down while she was walking, and her head contacted the ground, but she did not loss consciousness at the time. On the same day, the patient began to nod her head continuously, with each occurance lasting approximately several seconds in length. Since then, her head nods occurred in clusters daily, and up to 30 to 40 times a day at the worst cases. The patient was carried to the hospital and was diagnosed with infantile spasms. Her symptoms of head nodding was relieved after treatment with intravenous immunoglobulin (pH4), Sodium valproate oral solution and Topiramate. The patient took Sodium valproate oral solution and Topiramate after her discharge from the hospital. However, she still had the head nods which occurred at random intervals. After she turned 2-years-old, the head nods did not occur again, but she began to have epilepsy symptoms such as loss of consciousness, twitching of the limbs, spitting out white foam et al. The epilepsy happened approximately once a month and lasted approximately 1 to 2 minutes in length at each occurence. The patient visited the hospital again and the Clonazepam was added to her medications [6]. Her symptoms of epilepsy were being controlled well and did not happen within a 8 month period. However, in April of 2019, when the patient was 5 years old, her head nods occurred again without any obvious causes. This time, the head nods happened in the early morning, and 4～5 times everyday. The patient was admitted to our hospital (the Second Hospital of Shanxi Medical University). The following tests were performed for the patient: physical examinations, brain MRI, and electroencephalogram.

Molecular test

In order to study the cause of the disease, whole exome sequencing was performed for the patient. Furthermore, Sanger sequencing was used to verify the variant for the patient and her parents. Sequencing data was analyzed by using numerous bioinformatics’ softwares, the pathogenicity of the mutation was evaluated based on the standards and guidelines of ACMG (American College of Medical Genetics and Genomics), Clinvar database, OMIM (Online Mendelian Inheritance in Man), HGMD (Human Gene Mutation Database), and clinical research papers published in scientific journals.

Results and Analysis

Clinical data analysis

The patient was admitted to our hospital in April of 2019. The patient appeared normal under physical examinations. She has a clear mind, but only can pronunce simple words. She had poor orientation, cognition, memory, calculation, and attention span. Brain MRI showed that the symmetrical brain hemispheres on both sides, and the structures of gray and white matter were normal. No other abnormalities were found in the brain parenchyma (Figure 1). The electroencephalogram of the patient showed that the slowwave activity were in the awake period (Figure 2A). Total epileptic discharge during sleep period (Figures 2B & 2C). The patient was given intravenous human immunoglobulin and Dexamethasone for immunotherapy. The medications she has had were also adjusted to Levetiracetam tablets, Clonazepam, Topiramate, and Sodium valproate oral liquid. No recurrence of the head nods after 3 month of the treatment. Figure 2D showed that no obvious abnormal discharge was found in the patient’s return visit on Oct. 2020.

  Molecular biological data analysis

In order to identify the causes of the patient’s seizures, we conducted Whole Exome Sequencing (WES) based on Nextgeneration sequencing for the patient. a heterozygous missense mutation in SCN2A gene (c.3686 A>T p.Asp1229Val) reference transcript, NM_001040143) was detected in the patient. This variant was further confirmed by Sanger Sequencing, and not detected in either of the healthy parents, which indicated that this variant was de novo (Figure 3A). No other pathogenic variants were detected in more than approximately 800 genes that were defined by the OMIM database as related with epilepsy syndromes for this patient (Figures 3B & 3C). The mutation c.3686 A>T (p.Asp1229Val) either not being recorded in any clincial disease-related database (Clinvar and HGMD), nor in Human genome databases (1000 Genome and Genome mutation frequency database). The function prediction databases (SIFT and polyphen, etc.) predicted this mutation to be damaging. This variant was evaluated as a pathogenic mutation based on the standards and guidelines of ACMG.

 Discussion

Pathogenic variants in SCN2A are reported in a spectrum of neurodevelopmental disorders including developmental and epileptic encephalopathies, benign familial neonatal-infantile seizures, episodic ataxia, and autism spectrum disorder and intellectual disability with and without seizures [1]. More than 1000 mutaions of SCN1A gene were reported in the Clinvar database, including deletion, duplication, indel, insertion and single nucleotide types. Around 70% of those variations was evaluated as responsible for the occurences of Benign familial infantile seizures or early infantile epileptic encephalopathy 11. The single nucleotide mutations were the most frequently reported mutations and were 84% in the total mutation types. However, only about 8.5% of the single nucleotide mutations were due to de-nove mutations in the SCN2A gene. Comparing with the 65% of the de-novo rate in the SCN1A gene, the rate of de-novo in the SCN2A gene is significantly lower [6]. We evaluated WES data from 332 Chinese patients with epilepsy and identified the one de-nove missense mutation in the SCN2A in this patient and the mutation was evaluated as the cause of the disease. Generally, the de-novo mutations of SCN2A gene often lead to severe phenotype with developmental delay [3]. The patient in our case reported here is only 5 years old, but she had epilepsy syndromes for more than three years and had more severe symptoms such as poor orientation, cognition, memory, calculation, and attention et al. The mutation of the SCN2A gene we detected (c.3686 A>T p.Asp1229Val) has not been recorded in the Clinvar database as of today [6]. Our report provided further evidence for the cause of epilepsy from a genetic level. We predict the result will be immediately useful for the clinical interpretation of SCN2A variants, and also provides deeper insights for SCN2A mutations associated with the broad clinical spectrum of seizures.

Declarations

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of the Second Hospital of Shanxi Medical University. Written informed consent was obtained from individual or guardian participants. This study was supported in the part by grants from the Epilepsy Research Fund (UCB No. 2014007) from China antiepileptic Association.

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[ashwinichawla4]

Testing Including Whole Exome Sequencing to Know Medical Future

DNA profiling is important because they determine how healthy or unhealthy a person is. The way to do this is to do the Whole-exome sequencing that gives you a complete picture of the protein-coding regions of the genes in a genome. The genes in a genome are the exome. Chromosomal analysis is karyotyping. This analyses the chromosomes for changes such as a missing chromosome or an extra copy of a chromosome.

Exome Sequencing Methods

The first step in the Whole exome sequencing is to select only the subset of DNA that codes the proteins. Humans have 180,000 such regions known as exons. This forms 1% of the human genome. Then, use any high-throughput DNA sequencing technology to sequence the exons. Exome sequencing has application in both academic and clinical diagnosis because the variants of the exomes can cause both common polygenic and Mendelian diseases.

Immediate Identification of Variants

The most important thing about the Whole exome sequencing is that it helps to identify the variants in the genes of an individual. It is possible to identify the rare Mendelian diseases within a short time. These are present in a small number of individuals whereas SNP arrays can only detect genetic variants when the majority of the people share it.

The First Step in the Process

Target enrichment is the first strategy in this process. Though we have many techniques described theoretically, we have extended only a few to capture the entire sequencing of genomes through the Clinical exome sequencing. Array-based capture is simple and effective. Genomic DNA gets sheared to form double strands that undergo end repairs and form blunt edges. Unhybridized fragments get washed away following with PCR to do the amplification.

Marking with beads help in this Clinical exome sequencing. In-solution capture is another technique where they synthesize and hybridize the probes to a fragmented genomic sample.

[kritikarehani]

Leber’s Hereditary Optic Neuropathy (LHON) Market Share & Size, Market Trends and Forecast 2030

Leber’s Hereditary Optic Neuropathy (LHON) is a distinct type of “inherited optic atrophies” or “hereditary optic neuropathies.” It refers to an optic nerve dysfunction due to point mutations in the mitochondrial DNA and is transmitted in non-mendelian pattern.

DelveInsight's "Leber's Hereditary Optic Neuropathy (LHON) - Market Insights, Epidemiology, and Market Forecast-2030" report delivers an in-depth understanding of the Leber's Hereditary Optic Neuropathy (LHON) , historical and forecasted epidemiology as well as the Leber's Hereditary Optic Neuropathy (LHON) market trends in the United States, EU5 (Germany, Spain, Italy, France, and United Kingdom) and Japan.

Geography Covered

·  The United States

·  EU5 (Germany, France, Italy, Spain, and the United Kingdom)

·  Japan

Study Period: 2017-2030

View detailed report @ https://www.delveinsight.com/report-store/lebers-hereditary-optic-neuropathy-lhon-market

Leber's Hereditary Optic Neuropathy (LHON) Disease Understanding and Treatment Algorithm

The primary cell type lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows the mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role.

It is characterized by bilateral subacute loss of central vision due to focal degeneration of the retinal ganglion cell layer and optic nerve. LHON most commonly presents as painless loss of central vision in one eye, followed rapidly by loss of vision in the other eye within a few months. In some cases, both eyes will be affected from the onset. It can have both ophthalmologic and extra-ocular features. Ophthalmologic manifestations can further be subdivided into the acute phase and chronic phase.

LHON is maternally inherited, and both male and female offspring can inherit the mutation, yet 50% of males and only 10% of females experience vision loss. Also, it has been hypothesized that there is a recessive X-linked susceptibility gene that works in concert with the mitochondrial mutation, which could explain the male predominance among carriers who lose vision.

The DelveInsight Leber's Hereditary Optic Neuropathy (LHON) market report gives a thorough understanding of the Leber's Hereditary Optic Neuropathy (LHON) by including details such as disease definition, symptoms, causes, pathophysiology, diagnosis and treatment. 

Leber's Hereditary Optic Neuropathy (LHON) Epidemiology  

The Leber's Hereditary Optic Neuropathy (LHON) epidemiology division provide insights about historical and current Leber's Hereditary Optic Neuropathy (LHON) patient pool and forecasted trend for every seven major countries. It helps to recognize the causes of current and forecasted trends by exploring numerous studies and views of key opinion leaders. This part of the DelveInsight report also provides the diagnosed patient pool and their trends along with assumptions undertaken.  

Key Findings

· The prevalence of LHON is thought to be around 1/50,000 people worldwide.

 · The disease affects approximately 10,000 people in the United States and can lead to legal blindness.

 · The prevalence of LHON has been well established in Northern European populations with figures ranging from 1/30,000 to 1/50,000.

The disease epidemiology covered in the report provides historical as well as forecasted Leber's Hereditary Optic Neuropathy (LHON) epidemiology scenario in the 7MM covering the United States, EU5 countries (Germany, Spain, Italy, France, and the United Kingdom), and Japan from 2017 to 2030. 

Request for sample pages: https://www.delveinsight.com/sample-request/lebers-hereditary-optic-neuropathy-lhon-market

Leber's Hereditary Optic Neuropathy (LHON) Drug Chapters

Key players, such as GenSight, Stealth BioTherapeutics, and others, are in the process of developing potential therapies for the treatment of Leber’s hereditary optic neuropathy (LHON). The launch of emerging therapies, such as GS010 (GenSight), Elamipretide (Stealth BioTherapeutics), and others, are expected to significantly impact the treatment scenario of Leber’s Hereditary Optic Neuropathy (LHON) in the upcoming years.

Drug chapter segment of the Leber's Hereditary Optic Neuropathy (LHON) report encloses the detailed analysis of Leber's Hereditary Optic Neuropathy (LHON) marketed drugs and late stage (Phase-III and Phase-II) pipeline drugs. It also helps to understand the Leber's Hereditary Optic Neuropathy (LHON) clinical trial details, expressive pharmacological action, agreements and collaborations, approval and patent details, advantages and disadvantages of each included drug and the latest news and press releases.

Leber's Hereditary Optic Neuropathy (LHON) Market Outlook

The mainstay of clinical treatment for Leber’s hereditary optic neuropathy (LHON) remains supportive rather than curative. The management of LHON patients includes low vision aids, occupational rehabilitation, and registration with local social services. Those with mitochondrial mutations should be advised to refrain from smoking and binge alcohol drinking. Furthermore, screening for extraocular manifestations should be carried out in the form of an electrocardiogram and complete neurological evaluation.

The Leber's Hereditary Optic Neuropathy (LHON) market outlook of the report helps to build the detailed comprehension of the historic, current, and forecasted Leber's Hereditary Optic Neuropathy (LHON) market trends by analyzing the impact of current therapies on the market, unmet needs, drivers and barriers and demand of better technology. 

According to DelveInsight, Leber's Hereditary Optic Neuropathy (LHON) market in 7MM is expected to change in the study period 2017-2030.

Download sample pages: https://www.delveinsight.com/sample-request/lebers-hereditary-optic-neuropathy-lhon-market

[mariebenz]

Genetic Variations Altering Familial Risk of Prostate Cancer Identified

MedicalResearch.com Interview with:

Dr. Jeffrey Smith Jeffrey R. Smith, MD PhD Department of Medicine, Division of Genetic Medicine Vanderbilt-Ingram Cancer Center, and Vanderbilt Genetics Institute Vanderbilt University Medical Center Medical Research Service Tennessee Valley Healthcare System, Veterans Administration Nashville, TN MedicalResearch.com: What is the background for this study?   Response: Roughly 20% of men with prostate cancer have a family history of the disease, and 5% meet criteria for hereditary prostate cancer. Although prostate cancer has the greatest heritability of all common cancers (twice that of breast cancer), extensive heterogeneity of its inherited causes has presented a considerable obstacle for traditional pedigree-based genetic investigative approaches. Inherited causes across, as well as within families are diverse. This study introduced a new familial case-control study design that uses extent of family history as a proxy for genetic burden. It compared a large number of men with prostate cancer, each from a separate family with a strong history of the disease, to screened men with no personal or family history. The study comprehensively deconstructs how the 8q24 chromosomal region impacts risk of hereditary prostate cancer, introducing several new analytical approaches. The locus had been known to alter risk of prostate, breast, colon, ovarian, and numerous additional cancers. MedicalResearch.com: What are the main findings? Response: Seven distinct ancestral segments of DNA (haplotypes) were inherited among these men that alter risk of prostate cancer. Four haplotypes each carried risks as high as 22-fold, and three were instead protective. Each was distinguished by a large number of individual genetic variants that were associated with prostate cancer. Observations replicated across independent study populations and were at genome-wide significance. Sequencing the near-Mendelian haplotype revealed candidates for the causal mutation. One risk haplotype was associated with an early age of diagnosis, with a mean age that was seven years younger than the US and UK average. Intriguingly, haplotypes that were protective (reducing risk), were also associated with both a later age of diagnosis and less aggressive disease when inherited by a case. MedicalResearch.com: What should readers take away from your report? Response: Overall, the genetic variants discovered in the study account for ~ 9% of prostate cancer heritability. Study of cases with a strong history of the disease enabled the identification of genetic variation with particularly strong risk effects – with clinically predictive ability. The identified 8q24 risk-altering variants are pertinent for familial cancer care. The study introduces approaches that are effective in the setting of complex genetic heterogeneity and that discern risk from protective effects (both impacting a person’s risk).  MedicalResearch.com: What recommendations do you have for future research as a result of this work? Response: The study design and analytical approaches can be applied to other, similarly complex diseases. The authors report no conflicts of interest. Citation: Dupont, W.D., Breyer, J.P., Plummer, W.D. et al. 8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer. Nat Commun 11, 1523 (2020). https://doi.org/10.1038/s41467-020-15122-1   The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.   Read the full article

[siva3155]

300+ TOP TRANSPLANTATION SURGERY Objective Questions and Answers

TRANSPLANTATION SURGERY Multiple Choice Questions :-

1. The “father of experimental surgery” who performed pioneering research, including several transplantation procedures, was: A. Homer, the Greek who described the Chimaera in his Iliad. B. Gasparo Tagliacozzi, the Italian who described a method of reconstructing the nose. C. John Hunter, the Scot who performed autografts and xenografts. D. Emrick Ullmann, the Austrian who performed the first successful renal allograft. E. Alexis Carrel, the Franco-American who described a successful technique for vascular anastomosis. Answer: C 2. Transplantation terminology contains terms to describe the relationship of the graft donor to the graft recipient. Historical terms such as “homograft” and “heterograft” have been replaced by less ambiguous terms. The correct modern terminology for a graft between genetically nonidentical members of the same species is: A. Allogeneic graft. B. Autogeneic graft. C. Isogeneic graft. D. Syngeneic graft. E. Xenogeneic graft. Answer: A 3. The modern era of clinical organ transplantation began with the advent of chemical immunosuppression. The important discovery that produced the initial success of cadaveric transplantation was: A. Cyclophosphamide. B. Azathioprine. C. Cyclosporine. D. Antilymphocyte serum. E. Monoclonal antibody OKT3. Answer: B 4. Which of the following statements correctly characterize the genetic basis of histocompatibility? A. Histocompatibility is determined by a series of genes inherited as a complex and subject to the mendelian rules that characterize recessive traits. B. Histocompatibility depends in part on the inheritance of histocompatibility genes and in part on the inheritance of T-cell receptor genes. C. Major histocompatibility genes are polymorphic. D. Histocompatibility genes are independently segregating and co-dominant. E. Histocompatibility is learned. Answer: CDE 5. The major histocompatibility complex (MHC) includes genes that encode which of the following proteins? A. HLA-A. B. HLA-DR. C. TAP-1. D. 21-Hydroxylase. E. HLA-L. Answer: ABCD 6. Which of the following distinguish MHC class I from MHC class II antigens? A. MHC class I and class II antigens are encoded in different regions of the MHC complex. B. MHC class I antigens are expressed on specialized antigen-presenting cells, whereas MHC class II antigens are expressed on all cells. C. MHC class I and class II are members of different supergene families. D. MHC class I are considered to be the major histocompatibility antigens and MHC class II the minor histocompatibility antigens. E. MHC class I is recognized by the CD8 glycoprotein, whereas MHC class II is recognized by the CD4 glycoprotein. Answer: AE 7. Which of the following characterize the role of the major histocompatibility antigens in immune responses? A. The major histocompatibility antigens are critical in antigen processing and presentation. B. Major histocompatibility antigens contribute to the maturation of T cells in the thymus. C. T cells recognize only foreign antigens that are complexed with major histocompatibility antigens. D. Expression of major histocompatibility antigens is increased in inflammation. E. Recognition of major histocompatibility antigens is critical to the development of tolerance. Answer: ABCDE 8. The unusual intensity of alloimmune responses reflects which of the following characteristics? A. The presence of a peptide-binding groove in the MHC molecule. B. Recognition of the native structure of allogeneic MHC molecules. C. The high frequency of T cells able to recognize directly allogeneic MHC antigens. D. Stimulation of many T-cell receptors during the interaction of a T cell with an antigen-presenting cell. E. The high frequency of antigen-presenting cells able to be recognized by T cells. Answer: BCDE 9. Which of the following statements correctly characterize the role of histocompatibility typing in transplantation? A. Histocompatibility typing must be carried out before transplantation can safely be undertaken. B. The “rules” of histocompatibility were established shortly after the advent of immunosuppressive therapy made transplantation feasible. C. Histocompatibility typing may involve serologic, cellular, and molecular procedures for typing. D. The role of histocompatibility matching in transplantation is controversial. E. The cross-match test is carried out to determine whether a potential graft recipient has antibodies against the donor. Answer: CDE 10. Activation of T cells requires: A. Stimulation of the antigen receptor. B. Stimulation of the MHC antigen. C. Co-stimulation. D. Anergy. E. CD3. Answer: ACE

TRANSPLANTATION SURGERY MCQs 11. Which of the following statements characterize the biology of allotransplantation? A. The rejection response is systemic. B. The rejection response is learned. C. The rejection response involves a constellation of immunologic and environmental factors. D. Allotransplantation evokes a cellular immune response. E. Allotransplantation evokes a humoral immune response. Answer: ABDE 12. Allograft rejection may involve which of the following? A. Helper T cells. B. Veto cells. C. Cytotoxicity. D. Cytokines. E. The Arthus reaction. Answer: ACD 13. Which of the following statements about allograft rejection are true? A. In the absence of immunosuppression, the time and intensity of rejection of transplants between unrelated donors and recipients is highly variable. B. Allograft rejection may be mediated by antibodies or by cells. C. Allograft rejection is thought to be caused by Th2 cells. D. Acute cellular rejection is the major cause for loss of clinical organ transplants. E. An individual with “tolerance” is unable to reject an allograft. Answer: B 14. The presence of donor-reactive lymphocytotoxic antibodies in the serum of a potential kidney transplant recipient: A. Can be detected by in vitro testing with recipient leukocytes and donor serum. B. Is a contraindication to kidney transplantation. C. Can be found in all male patients older than 20 years. Answer: B 15. Utilization of a living related donor instead of a cadaver donor is no longer an advantage in renal transplantation because: A. Public recognition of transplantation as a successful therapy has facilitated obtaining family permission for recovery of transplantable organs. Thus, because sufficient kidneys are available from “brain-dead” accident victims, there is no need to use related donors. B. Cyclosporine therapy after cadaveric renal transplants has improved their outcome, which is now comparable to related-donor transplants. C. Modern preservation techniques can maintain viability of kidneys from cadaver donors for many hours, consistently allowing their early function to be as good as that of kidneys from living donors. D. None of the above. Answer: D 16. Large volumes of urine in the early postoperative course of renal transplant patients: A. Result from osmotic stimuli to diuresis. B. May signify reversible polyuric acute tubular necrosis. C. Should be replaced by administration of equal volumes of crystalloid. D. Facilitate the diagnosis of rejection and obstruction of the renal artery and/or collecting system. Answer: ABCD 17. As compared with the early immunosuppressive (azathioprine, steroids, antilymphocyte serum) some newer agents have the following specific advantages: A. Cyclosporine, which interferes with lymphokine production, exhibits neither bone marrow nor renal toxicity. B. Monoclonal antibody (OKT3) is more available and has greater specificity and fewer side effects than antilymphocyte serum. C. Tacrolimus (FK506) has properties similar to those of cyclosporine but is especially valuable for rescue of grafts that are failing on cyclosporine therapy. D. None of the above. Answer: C 18. Survival rates for patients on dialysis are better than those for patients receiving renal allografts in the following circumstances: A. A living related donor is available. B. A cadaver donor must be used. C. The recipient's renal failure is secondary to diabetes. D. None of the above. Answer: D 19. Posttransplantation hypertension can be caused by: A. Rejection. B. Cyclosporine nephrotoxicity. C. Renal transplant artery stenosis (RTAS). D. Recurrent disease in the allograft. Answer: ABCD 20. Which of the following statements about posttransplantation malignancy is correct? A. Certain immunosuppressive agents increase the incidence of malignancy in transplant recipients, whereas others do not. B. Those malignancies most commonly seen in the general population (breast, colon) are substantially more common in transplant recipients. C. Lymphoproliferative states and B-cell lymphomas are associated with Epstein-Barr virus. D. None of the above. Answer: C 21. One week after receiving a cadaver renal allograft, the recipient remains oliguric and dialysis dependent. Ultrasonography reveals a larger perigraft fluid collection. Your next step in management includes: A. No further investigations (since perigraft collections are fairly common after renal transplantation). B. Aspiration of the perigraft fluid collection and instillation of a fibrosis-inducing agent to obliterate the dead space. C. Angiography for localization of a bleeding site in the renal allograft. D. Aspiration of the perigraft fluid collection for chemical analysis. Answer: D 22. Regarding access for hemodialysis, which of the following statements is/are incorrect? A. Some patients are not candidates for hemodialysis. B. Some complications can lead to exsanguination. C. The best access to place for a patient beginning dialysis is a leg polytetrafluoroethylene (PTFE) graft from the femoral artery to the saphenous vein. D. First of all one should attempt to create a Brescia-Cimino fistula. E. The leading complication of PTFE grafts is infection. Answer: CE 23. Access to the peritoneal cavity for peritoneal dialysis can be gained: A. Percutaneously. B. Surgically. C. Using laparoscopy. D. Only using general anesthesia. Answer: ABC 24. Which of the following are true concerning immunosuppression? A. Current immunosuppressive agents function in a nonspecific manner to suppress rejection. B. The use of immunosuppressive agents is associated with an increased rate of opportunistic infections. C. An increased rate of malignancy is not associated with the use of immunosuppressive agents. D. In almost all cases, the graft is rejected if immunosuppression is discontinued. Answer: ABD 25. Which of the following is true for hyperacute rejection? A. It is mediated by preformed cytotoxic antibody. B. It occurs late in the life of the graft. C. It is usually reversible with a bolus of steroids. D. None of the above. Answer: A 26. The major components of the immune system include which of the following? A. T lymphocytes. B. B lymphocytes. C. Cytokines. D. Macrophages. Answer: ABCD 27. The most common types of immunosuppressive agents used clinically include which of the following? A. Antimetabolites. B. Alkylating agents. C. Inhibitors of helper T-cell activation. D. Irradiation. E. Lymphocyte depletion compounds. Answer: ABCDE 28. Which of the following is/are true of the antiproliferative agents? A. They act by preventing the differentiation and division of the immunocompetent lymphocyte after it encounters antigen. B. The antimetabolites in this group have a structural similarity to cell metabolites and either inhibit enzymes of a metabolic pathway or are incorporated during synthesis to produce faulty molecules. C. The most frequently used antiproliferative agent is azathioprine. Answer: ABC 29. Which of the following is the one true statement about acute rejection. A. Acute rejection is mediated by T lymphocytes. B. Acute rejection is mediated by preformed cytotoxic antibody. C. Acute rejection most frequently occurs over months. Answer: A 30. Which of the following are true of cyclosporine? A. It was the first immunosuppressive agent to be used clinically. B. It acts selectively on T cells to suppress rejection. C. Toxic effects include hirsutism, hypertension, nephrotoxicity, and increased risk of opportunistic infections. Answer: BC 31. Which of the following are true of OKT3? A. It is not a monoclonal antibody. B. It binds to the T-cell receptor and inactivates T-cell function. C. It is the monoclonal antibody most frequently used in clinical transplantation. Answer: BC 32. Hypothermia (0? to 4? C) is a critical component of successful organ cold storage because: A. Oxygen is more soluble in cold solutions and provides a continual supply for energy metabolism. B. There is no way to suppress microbial growth except by cooling and slowing the growth rate. C. Hypothermia diminishes energy requirements and allows the limited energy reserve to keep the organ alive. D. It slows metabolism and the enzymic processes that would destroy the cell. Answer: D 33. Is the following statement true or false? Organs should be preserved only for short periods of time (4 to 8 hours) because longer periods lead to too many complications, and even loss of the organ. Answer: FALSE 34. Which of the following statements about hepatic artery thrombosis following liver transplantation is/are correct? A. Thrombosis of the hepatic artery following liver transplantation is more common in children than in adult patients. B. Thrombosis of the hepatic artery usually occurs several weeks after transplant as a result of arteriosclerosis. C. Thrombosis of the hepatic artery in the early days following transplantation is a serious complication leading to death unless retransplantation can be performed within 36 to 72 hours. D. Late thrombosis of the hepatic artery may present as biliary complication or intrahepatic abscesses. E. Thrombosis of the portal vein is more frequent than hepatic artery thrombosis following liver transplantation. Answer: ACE 35. Which of the following statements about fulminant hepatic failure (FHF) is/are correct? A. Fulminant hepatic failure can occur in the setting of pre-existing chronic liver disease. B. Coagulopathy and coma are important findings in patients with FHF. C. Liver transplant should not be attempted in patients with FHF because of the high mortality rate, regardless of the treatment used. D. The main cause of death in these patients is cerebral edema. E. One of the most important factors in prognosis of FHF is the cause of liver disease. Answer: BDE TRANSPLANTATION SURGERY Objective type Questions with Answers 36. Which of the following statements about immunology in liver transplantation is/are correct? A. Good human leukocyte antigen (HLA) matching between recipient and donor is mandatory for a good outcome for liver transplantation. B. Hyperacute rejection is almost nonexistent following liver transplantation. C. Acute rejection occurs in more than 50% of patients and is reversible in most patients with large doses of steroids. D. Acute rejection is very rare later than 2 months after liver transplantation unless the patient is inadequately immunosuppressed. E. Chronic rejection is different from acute rejection, is usually irreversible, and often requires retransplantation. Answer: BCDE 37. An elevated serum amylase level following pancreas-kidney transplantation may be due to: A. Preservation/procurement injury. B. Rejection. C. Reflux pancreatitis. D. Duodenal segment leak or bladder leak. E. Native pancreatitis. F. Constipation. Answer: ABDEF 38. Complications of a pancreas transplant drained into the bladder include: A. Duodenal segment leak. B. Recurrent urinary tract infections. C. Recurrent hematuria. D. Urethritis. E. Refractory loss of bicarbonate. Answer: ABCDE 39. Patient selection criteria for simultaneous pancreas-kidney transplantation should include: A. Type I diabetes mellitus. B. Type II diabetes mellitus. C. Dialysis dependence. D. Renal dysfunction with a creatinine value greater than 3.0. E. Minimal extrarenal morbidity related to diabetes. Answer: ADE 40. Criteria for a pancreas donor include: A. No history of diabetes. B. No liver donation. C. No replaced hepatic artery vessels arising from the superior mesenteric artery (SMA). D. No previous splenectomy. E. No pancreatitis. Answer: AE 41. For which of the following clinical scenarios would cardiac transplantation be an appropriate therapeutic modality? A. A 50-year-old man with angina pectoris, three-vessel coronary artery disease, and a left ventricular ejection fraction of 25%. B. A 75-year-old woman with irremediable heart failure secondary to critical aortic stenosis. C. A 25-year-old male athlete with insidious onset of heart failure secondary to idiopathic dilated cardiomyopathy. D. A 55-year-old woman who is status post two previous surgeries for coronary artery revascularization, now presenting with heart failure in the absence of angina, left ventricular ejection fraction of 15%, and insufficient target coronary arteries for a third bypass procedure. E. A newborn infant with hypoplastic left heart syndrome and no other congenital anomalies. F. A 30-year-old woman who develops irremediable heart failure due to postpartum cardiomyopathy after giving birth. Answer: CDEF 42. Suitable donors for heart transplantation have which of the following characteristics? A. Normal electrocardiogram (ECG). B. Normal echocardiogram. C. Positive serology for HIV or hepatitis B or C. D. Patient requiring high-dose epinephrine to maintain a systolic blood pressure of 90 mm. Hg. E. Age over 70 years. Answer: AB 43. Heart-lung transplant is currently the therapy of choice for which of the following conditions? A. Primary pulmonary hypertension with reasonably well-preserved right ventricular function. B. Eisenmenger's syndrome due to single ventricle and truncus arteriosus. C. Validated cardiomyopathy in a patient with cystic fibrosis and end-stage lung disease. D. Cystic fibrosis and end-stage lung failure with normal heart function. E. Eisenmenger's syndrome due to an atrial septal defect. F. End-stage lung disease secondary to emphysema. Answer: BC 44. Both single and bilateral lung transplantation are suitable technical alternatives for which of the following conditions? A. Obstructive lung disease (chronic obstructive pulmonary disease, emphysema). B. Restrictive lung disease (pulmonary fibrosis). C. Primary pulmonary hypertension. D. Cystic fibrosis. Answer: ABC 45. Which of the following are contraindications to lung transplantation? A. Age 65 years or older. B. Current corticosteroid therapy. C. History of thoracotomy. D. Ventilator-dependent respiratory failure. Answer: D 46. Which of the following is the single most useful approach for diagnosing acute lung allograft rejection? A. Clinical diagnosis. B. Decline in spirometry and oxygenation. C. Chest radiographic abnormalities. D. Fiberoptic bronchoscopy with transbronchial lung biopsy. Answer: D 47. Advantages of split-thickness skin grafts over full-thickness skin grafts include: A. Split-thickness grafts include only part of the epidermis and none of the dermis. B. Split-thickness grafts offer better pigment matching. C. Split-thickness grafts offer better resistance to contraction. D. Split-thickness grafts offer better resistance to infection. E. Split-thickness grafts survive better on surfaces with compromised blood supply. Answer: DE 48. The most commonly used substitutes for peripheral arteries are: A. Dacron grafts. B. Expanded polytetrafluoroethylene (Gore-Tex) grafts. C. Internal, external, and/or common iliac artery autografts. D. Bovine carotid artery xenografts. E. Saphenous vein autografts. Answer: E 49. Endocrine autografts were among the first successful transplantation procedures. The demonstration by Berkhold in 1849 that autotransplanted testes led to the acquisition of secondary characteristics in castrated cocks marked the beginning of experimental endocrinology. Endocrine autografts used successfully in modern surgical practice include: A. Adrenal medulla to the brain. B. Thyroid to the forearm. C. Parathyroid to the forearm. D. Testicle to the scrotum. E. Pancreatic islets to the liver. Answer: CDE 50. Several types of gastrointestinal autografts have been used to replace the esophagus after extirpation of carcinomas. Successful reconstructions have been achieved most frequently with: A. Stomach. B. Jejunum. C. Ileum. D. Ascending colon. E. Descending colon. Answer: A 51. Which of the following statement(s) is/are true concerning the options for managing the exocrine secretions following pancreatic transplantation? a. Ductal ligation is associated with no adverse effects to pancreatic parenchyma b. Drainage of the pancreatic ductal system into the bladder is useful in the early diagnosis of rejection c. All pancreatic grafts should be placed in a retroperitoneal position d. Complications following enteric drainage of the pancreas (without the duodenum) are primarily associated with anastomatic leakage Answer: b, d 52. The term “tolerance” refers to responses observed which include long-term graft acceptance without the need for chronic immunosuppression. There are a variety of specific ways in which T and B lymphocytes can be tolerant or nonresponsive to antigen. Which of the following is/are mechanisms of tolerance? a. Clonal abortion b. Clonal deletion c. Clonal anergy d. Suppression Answer: a, b, c, d 53. Which of the following statement (s) is/are true concerning currently approved immunosuppressant agents? a. Azathioprine (Imuran) is useful in the treatment of acute ongoing rejection b. Methylprednisolone is particularly useful in immunosuppression as it has lesser toxicity than Prednisone c. Cyclosporine blocks transcription of several early T-cell activation genes d. FK-506 is both more potent and less toxic than cyclosporine e. The monoclonal antibody OKT3 interferes with T-cell antigen recognition function Answer: c, e 54. Which of the following patients would be a candidate for a liver transplant? a. A 48-year-old man with end-stage liver disease secondary to non-A, non-B hepatitis b. A 35-year-old man with both primary sclerosing cholangitis and ulcerative colitis and end-stage liver disease c. A 22-year-old woman with fulminant hepatic failure secondary to acetaminophen overdose d. A 4-year-old child with congenital biliary atresia having failed a previous Kasai procedure e. A 48-year-old patient with alcoholic cirrhosis and a 2.5 cm central unresectable hepatoma Answer: a, b, c, d, e 55. Which of the following statement(s) is/are true concerning changes in physiology following lung transplant? a. In patients with pulmonary hypertension, changes in right ventricular function and pulmonary artery pressure takes weeks to months to resolve b. In single lung transplantation, changes in pulmonary function are seen almost immediately following transplantation c. Patients with double lung transplants have both better pulmonary function studies as well as better exercise capabilities d. After single-lung transplant, ventilation perfusion mismatch persists and carbon dioxide retention is seen Answer: b 56. Current clinical protocols determine a limited number of variables and parameters for matching and allocation of donor organs to potential recipients. Which of the following statement(s) is/are true concerning aspects of immunity important for clinical transplantation? a. HLA matching is important for kidney, pancreas, and liver transplantation b. A cross match assay determines if there are preformed antibodies in the recipient’s serum which will react with antigens on the cell surface of the potential donor’s lymphocytes c. A patient with a history of multiple transfusions or previous transplant will have a high panel reactive antibody (PRA) d. A normal heterozygous individual with a complete donor-recipient match will have a four-antigen match Answer: b, c 57. T-lymphocytes are divided into two main sub-classes: CD4+ and CD8+. Which of the following statement(s) is/are true concerning these classes of T-cells? a. CD4+ T-cells are restricted to recognizing antigens of the class II major histocompatibility complex (MHC) b. CD8+ T-cells perform primarily cytotoxic functions c. CD4+ 8+ double positive cells are well-differentiated mature cells d. CD4+ T-cells also perform suppressor functions Answer: a, b, d 58. Correct statement(s) concerning postoperative complications after hepatic transplantation include: a. Primary nonfunction occurs in 5 to 10% of transplanted livers in the immediate postoperative period b. A biliary leak, although a common complication, is usually of minimal clinical importance c. Portal vein thrombosis occurs much more commonly than hepatic artery thrombosis d. If postoperative bleeding is encountered, immediate return to the operating room is indicated Answer: a 59. Which of the following statement(s) is/are true concerning renal transplantation? a. Living-related donor transplants typically can be expected to have one-year graft survival rates of over 90% b. Preconditioning of the recipient with the use of donor-specific blood transfusions from their living donor improves graft survival and therefore should be used routinely c. Pre-transplant blood transfusions result in improved graft survival following cadaveric renal transplant in the cyclosporine era d. Age of the recipient over 50 years is generally associated with a poorer outcome due to graft rejection Answer: a 60. Which of the following statement(s) is/are true concerning clinical syndromes of rejection? a. Hyperacute rejection occurs with kidney, heart, liver and lung transplants b. The histologic characteristics of acute rejection include lymphocyte infiltration accompanied by plasma cells, eosinophils, or neutrophils c. Vascular atherosclerosis and obliteration are characteristic of chronic rejection d. Transplantation across major ABO incompatibility will result in hyperacute rejection of a renal or cardiac transplant Answer: b, d 61. Which of the following statement(s) is/are true concerning techniques for multiple organ procurement and preservation? a. The liver and pancreas are generally removed en bloc and separated as a bench procedure b. Renal allograft function is improved by the use of machine perfusion c. UW (University of Wisconsin) cold storage solution is the method of choice of most programs for hepatic and pancreatic transplantation d. Cardiac allografts have the shortest limit of cold ischemia Answer: a, c, d 62. Which of the following statement(s) is/are true concerning the outcome of renal transplantation? a. Two-thirds of all graft losses alone (without death) occur from one to six months after transplantation b. The most common cause for graft loss after one year following transplantation is patient death c. Most patient deaths following transplantation are related to immunosuppression d. An acute rejection episode in a renal allograft recipient is the most important clinical event, determining both short-term and long-term graft survival e. The period between the six months and one year following transplantation is the most critical time period following renal transplant Answer: a, b, d 63. Which of the following characteristics or conditions will exclude a patient as a suitable cadaveric organ donor? a. Active systemic bacterial infection b. Primary CNS malignancy c. Age over 65 d. History of prior cholecystectomy for a possible hepatic donor Answer: a 64. Which of the following statement(s) is/are true concerning associated renal and pancreatic transplantation? a. The most important advantage is the use of renal function as an early indicator of pancreatic graft rejection b. After renal transplant, there is no additional risk associated with immunosuppression c. A major disadvantage of simultaneous renal/pancreatic transplant is the potential adverse effect on renal allograft as the result of a pancreatic complication d. A diabetic with a renal transplant continues to be at risk for diabetic nephropathy Answer: a, b, c, d 65. There are numerous toxicities and adverse effects associated with immunosuppression. Which of the following statement(s) is/are true concerning complications of immunosuppression? a. Transplant recipients are susceptible primarily to infections with unusual organisms (fungus, virus, atypical bacteria) b. Immunosuppressive agents may blunt the inflammatory response to infection leading to a late presentation of an infectious process c. The development of malignancy appears primarily due to direct mitogenic effects of the agent d. Lymphomas are the most common malignant tumors developing in the transplant patient e. Graft-vs-host disease is a progressive condition and extremely difficult to treat Answer: b 66. Which of the following statement(s) is/are true concerning the results of lung transplantation? a. One year survival following single lung transplant is significantly better than following bilateral transplant b. The worst survival is seen in patients with pulmonary hypertension c. Patients with cystic fibrosis have a markedly poorer result than do patients with emphysema d. Infection is a common cause of mortality in both the early and late post-transplant period Answer: b, d 67. Categories of patients in which pancreatic transplantation is applicable includes: a. Diabetics with a functioning renal transplant b. Diabetic patients with end-stage renal disease requiring renal transplantation c. Nonuremic diabetics with other complications of their disease d. Well-controlled adult onset diabetics Answer: a, b, c 68. Which of the following statement(s) is/are true concerning the results of cardiac transplantation? a. Overall one-year survival is approximately 80% b. Survival following transplant in the pediatric age group is significantly worse than in adults c. There is no difference in survival when cardiac transplantation is performed in a heterotopic position versus an orthotopic position d. The survival rate for retransplantation is approximately 50% Answer: a, d TRANSPLANTATION SURGERY Questions and Answers pdf Download Read the full article

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Hypomelanosis of Ito with Partial Motor Seizure and Hemimegaloencephaly: Case Report

Authored by  Amal Y. Kentab*

Abstract

The term hypomelanosis of Ito [HI] is applied to individuals with skin hypopigmentation along the lines of Blaschko. Even though originally described as a purely cutaneous disease, subsequent reports have included a 33% to 94% association with multiple extracutaneous manifestations mostly of the central nervous and musculoskeletal systems leading to frequent characterization as a neurocutaneous disorder. A boy with constellation of multiple congenital anomalies including facial dysmorphism, skin hypopigmentation, musculoskeletal, and nervous system abnormalities in the form of hypotonia and mild mental retardation suggestive of [HI] presented with partial motor seizures and found to have hemimegalencephaly [HME] on MRI of the brain.

Keywords: Hypomelanosis ito (HI); Cortical dysplasia; Neurocutaneous syndrome; Cerebral malformation.

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Introduction

Hypomelanosis of I to [HI] or Incontinentia pigmenti achromians [OMIM no. 146150]. Ito first introduced the syndrome 1951 [1]. It is a rare neurocutaneous syndrome that involves mainly skin and nervous system symptoms in 75 % of cases and may be associated with multiple organ systems involvement including the head and face, eyes (microphthalmia, cataracts, optic atrophy, and retinal detachment), teeth, cleft lip and palate, heart (tetralogy of Fallot), kidneys, musculoskeletal (hemihypertrophy), and reproductive systems (precocious puberty) [2-4]. The incidence and prevalence of [HI] has been reported to be1/7540 births and 1/82,000 individuals, respectively [4]. McKusick`s catalogue of inherited diseases lists HI as an autosomal dominant disorder, although evidence for this mode of inheritance, or indeed for any genetic etiology, is inconclusive [2]. Frequency is equal among males and females. It is caused by Nonheritable mutation, and it have been reported frequently in association of various chromosomal abnormalities, including mosaicism for aneuploidy or unblanaced translocations, mosaic trisomy 18, ring chromosome 22, and translocations involving the X chromosome. There is no clear genotype - phenotype correlation [2]. Only a few cases of HI have been reported with partial motor seizures in association with hemimegalencephaly [HME]. In order to highlight on this rare neurocutaneous disorder, this report describes such association in a 10 year old boy with skin hypopigmentation, craniofacial and musculosketetal abnormalities.

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Case Report

A 10 -year-old male, left handed, 6th grade student was evaluated in our tertiary care neurology clinic for afebrile complex partial motor seizure with 2nd generalization, started one month prior to presentation. He had frequent episodes of sudden left-sided eye deviation and facial twitching with secondary left-sided unilateral and generalized tonic-clonic seizures. Each episodes last for less than 3 minutes, preceded by dizziness, pain in the right eye with blurred vision and headache, end spontaneously after an episode of vomiting , headache , and postictal sleep without loss of sphincter control . Seizures were controlled with levetiracetam (Keppra). He was a product uneventful pregnancy delivered by spontaneous vaginal delivery at 36 weeks gestational age, readmitted on 2nd day, and operated for intestinal intussusception. Past history included a slower cognitive and language development in comparison to other siblings, skin hypopigmentation noted at 6 months of age, bronchial asthma, abnormal dentation with frequent dental caries, and tonsillectoy-adenectomy operation for frequent tonsillitis.

His parents were consanguineous and there was a history of seizure disorder in two sons of paternal uncle from twin pregnancy. Microophthalmia in two sisters of paternal ante. Reported multiple infantile deaths of both parental, and maternal side with obscured reasons. His mother had cafe`-au lit spot and hypopigmentation on her thighs. On examination, he had macrocephaly, short stature, dysmorphic features in the form of high prominent forehead, low set and posteriorly rotated prominent ears, orbital hypertelorism, epicanthal fold, depressed nasal bridge, anteverted nostrils, high arched palate, tooth spacing with abnormality in size and shape, micrognathia, broad fingers with archanodactyly, mild clinodatyly of 5th finger, broad nails, a gap between big toe and the second one, syndactly between the 2nd and the 3rd toes on the right foot, mild scoliosis (deviation to the left) with prominent lordosis, joint hyperlaxity and bilateral pes plans , with mild hemi hypertrophy of the right side of the body , involving mainly the face and upper extremity.

Hypopigmented areas (whorl-like and streaks) noted on the anterior and the lateral aspects of both legs extending to involve the left shine anteriorly and another similar one but with small size seen at the right shoulder (Figure 1). His neurological examination revealed poor short-term memory and cognitive delay, especially in terms of general knowledge, the ability to read and mathematical concepts and mild right hemiparesis. His initial basic laboratory work-up was normal apart from mild anemia, and low vitamin D 62 nmol/l (NR 75-120). Full metabolic screen thyroid function test, full chromosomal analysis, microarray CGH showed and Cardiac evaluation by electrocardiogram (ECG), echocardiogram (Echo) and Abdominal ultrasound were unrevealing. Ophthalmological evaluation showed mild sclerocornea, pigmented iris, and bilateral flat retinal astrocytoma with retinal pigmentary changes. Skeletal survey revealed mild osteoporosis and mildscoliosis.

Electroencephalogram (EEG) showed background asymmetry with slow theta wave activity noted on the left hemisphere with occasional sharp waves seen predominately on the left hemisphere. Computed tomographic (CT) scan of the brain showed no space occupying lesion, but left hemimegaloencephaly with dilated left ventricle. Magnetic resonance imaging scan of the brain (MRI) revealed similar findings with small arachnoid cyst at left middle fossa with no evidence of neuronal migration disorders or cortical dysplasia (Figure 2). Magnetic resonance angiography (MRA) was normal with no evidence of vessel stenosis or picture similar to moyamoya disease.

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Discussion

The cutaneous features of HI include multiple hypopigmented streaks or patches that found in 100% of affected individuals and are either present at birth or emerge in infancy. These lesions follow Blaschko lines (skin lines that form specific patterns over the trunk and extremities, such as a V shape over the back and linear lines over the limbs and are best detected under ultraviolet light in light - skinned children. In contrary to incontinentiapigmenti, these lesions, are not preceded by inflammatory or degenerative changes. (Table 1) The extent of the skin lesions do not correlate strongly with neurologic involvement. An important differential diagnosis is Tuberus Sclerosis Complex, where the hypopigmented patch (ash leave spot which is usually oval in shape with regular border) appears during the 1st year of life mainly on trunk or extremities, and as the child approaching puberty other skin manifestations appear like adenoma sebaceum, on the face, shagreen patch on the back and periungual fibroma [3,4].

(Table 1) Neurologic manifestations include intellectual impairment with mild to severe mental deficiency (IQ<70) that is usually seen in 57% while only 20% of patients have an IQ above 85% with reported poor school performance in (40-60%). Seizures that include generalized tonic or tonic-clonic, complex partial, myoclonic seizures or infantile spasm with onset early in the first year of life, with variable response to anticonvulsant drugs . Behavior disorders that include autism, Asperger`s syndrome, self-injurious behavior and severe sleep problems especially in the first 3-5 years of age [3,4]. Macrocephaly or microcephaly may be seen, with the former being more common. Other associated findings include, a non-progressive speech delay, muscular hypotonia or hypertonia, hyperkinesias, nystagmus, ataxia, and neurosensory deafness. MRI in more than half of patients may show either cerebral or cerebellar hypoplasia and various other malformations of cortical development including hemimegalencephaly, lissencephaly, pachygyria, and heterotopia. White matter abnormalities of either cystic like lesions or delayed myelination. Other brain abnormalities include, focal or generalized brain atrophy, basal ganglia lesion, or intracranial vascular abnormalities such as A-V malformation, Moyamoya disease, leptomeningeal angioma [2]. The patient in this report had clinical picture suggestive of HI (skin hypopigmentation, facial dysmorphism, eye and dental abnormalities, joint hypermobility, skeletal abnormalities ie. short stature, scoliosis, osteoporosis, mild learning disability, partial motor seizures), mild right hemiparesis and HME with no other associated neuronal migration disorder on brain MRI which has been previously reported [5-9].

Hemimegalencephaly is a major, but rare congenital hamartomatous malformation of the brain [10], characterized by enlargement of all or parts of a cerebral hemisphere and frequently associated with cortical focal or diffuse neuronal migration defects, such as polymicrogyria, pachygyria, or heterotopias. HEM affects all ethnic groups and both genders equally.

Its etiology remains unknown. It has been suggested that it results from some type of acquired unilateral hemispheric insult in the mid to late second trimester of pregnancy [11] that affect the genetically programmed process that establishes symmetry as well as the development of neuroepithelial lineage and cellular growth occurring at an earlier stage of neuroblast migration [12]. It does not follow a Mendelian pattern of inheritance and usually occurs sporadically. It is widely believed that a single or multiple gene mutations contribute to this process.

It typically presents with a triad of intractable epilepsy, psychomotor delay and hemiparesis. Some patients show entire brain asymmetry, hemifacial hypertrophy, or hemicorporal hypertrophy. Other associated features may include macrocephaly with cranial asymmetry, and behavioral disabilities. Epilepsy is usually of early onset and intractable. Those with later-onset epilepsy are more likely to have mild motor deficit like the patient in this report, or normal motor function. The EEG is abnormal in all cases of HME. In the neonatal period, suppression burst pattern, followed by hypsarrhythmia and later, focal seizure activity may be seen. Functional or anatomical hemispherectomyis recommended for early - onset pharmacoresistant epilepsy as improvement of either the motor function level or intellectual development was seen in most patients post-surgery [13,14].

It is often an isolated disorder, but may be syndromic associated with several diseases or neurocutaneous syndromes, such as epidermal nevus syndrome, tuberous sclerosis complex (TSC), linear sebaceous nevus syndrome, Klippel - Trenaunay syndrome (KTS), Proteus syndrome (PS), hypomelanosis of ito (HI), neurofibromatosis , Sotos syndrome and Alexander [10,15]. It is worthy to mentioned that usually there is no differences in clinical symptoms in regards to the laterality (Right or left) or the type (isolated or syndromic) of hemimegalencephaly [16].

MR Imaging is the investigation of choice for diagnosis, though ultrasound and CT will show the abnormalities. As in our patient, increased size and altered shape of the ventricle is usual. The cortex is broader (dysplastic) than normal, neuroblast migratory anomalies are frequently seen, the most common being heterotopias. [11], as well as white-matter abnormalities (high signal intensity in T2W image) [17]. Since the disease does not follow a Mendelian pattern of inheritance, chances of recurrence are rare and there is usually no family history of other affected individuals. Prenatal diagnosis may be suspected on the basis of fetal ultrasound [18] or MRI (diffusion - weighted images) [19].

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Conclusion

Combination of a triad of intractable epilepsy, psychomotor delay and hemiparesis in the presence of macrocephaly and / or skin hypopigmentation should prompt consideration of HEM . MRI is the imaging of choice for diagnosis of HEM. HEM should prompt a search for other syndromic diagnosis such as HI.

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Acknowledgment

This work was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University.

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A biomarker for diagnosing Celiac disease in people on a gluten-free diet

Celiac disease is a complex condition, routinely treated by means of a strict gluten-free diet. One of the diagnostic challenges of this disease is that patients need to be consuming gluten so that a correct diagnosis by means of endoscopy can be made. Yet nowadays there are more and more people who opt to eliminate gluten from their diets before seeing a specialist, and this makes it tremendously difficult to reliably diagnose the disease. However, as José Ram��n Bilbao and Nora Fernandez-Jimenez, researchers at the UPV/EHU and the Biocruces-Bizkaia Institute of Healthcare Research, pointed out, "the self-diagnosis of gluten intolerance is a growing global phenomenon as it reaches 12-13 % of the general population in European countries such as Italy and the United Kingdom."

In an article published recently in the Human Molecular Genetics journal these researchers report on the discovery of a biomarker that could enable celiac disease to be diagnosed in the blood of people on a gluten-free diet. In this work, though an analysis of applied statistics, the researchers have discovered that the relative expression of the isoforms of the UBE2L3 gene in the blood makes it possible to distinguish with 100 % sensitivity and specificity celiac patients on a gluten-free diet.

From basic research to clinical practice

The UPV/EHU has patented this discovery so that in the future it can be transferred to companies interested in marketing this new diagnostic system. Right now, Dr Fernandez is focussing her efforts on securing funding because "last year the project received an award for best poster at the Congress of the Spanish Celiac Disease Society, but now further funding needs to be secured to validate the biomarker in a larger cohort of people." According to Dr Bilbao, "UBE2L3 is an example of how the transfer from basic Genomics research to clinical practice is possible, and could have a huge impact on the routine diagnosis of celiac disease."

Story Source:

Materials provided by University of the Basque Country. Note: Content may be edited for style and length.

Journal Reference:

Nora Fernandez-Jimenez, Jose Ramon Bilbao. Mendelian Randomization analysis of celiac GWAS reveals a blood expression signature with diagnostic potential in absence of gluten consumption. Human Molecular Genetics, 2019; DOI: 10.1093/hmg/ddz113

Cite This Page:

University of the Basque Country. "A biomarker for diagnosing Celiac disease in people on a gluten-free diet: The UPV/EHU-University of the Basque Country patents a biomarker for diagnosing celiac disease in the blood of people who do not consume any gluten." ScienceDaily. ScienceDaily, 5 June 2019. <www.sciencedaily.com/releases/2019/06/190605100326.htm>.

University of the Basque Country. (2019, June 5). A biomarker for diagnosing Celiac disease in people on a gluten-free diet: The UPV/EHU-University of the Basque Country patents a biomarker for diagnosing celiac disease in the blood of people who do not consume any gluten. ScienceDaily. Retrieved June 5, 2019 from www.sciencedaily.com/releases/2019/06/190605100326.htm

University of the Basque Country. "A biomarker for diagnosing Celiac disease in people on a gluten-free diet: The UPV/EHU-University of the Basque Country patents a biomarker for diagnosing celiac disease in the blood of people who do not consume any gluten." ScienceDaily. www.sciencedaily.com/releases/2019/06/190605100326.htm (accessed June 5, 2019).

Source: https://www.sciencedaily.com/releases/2019/06/190605100326.htm

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6 Avoidable Risk Factors for Asthma

Many of us would agree there’s nothing worse than difficulty breathing, and while there are many conditions out there, I want to talk to you today about asthma. A terrible respiratory condition, it can greatly affect one’s quality of life. If you’re living with asthma, it’s likely you already know your triggers, but there might be some things you weren’t aware of. Perhaps you’ve been newly diagnosed and wish to keep attacks at a minimum. That said, here are 6 avoidable risk factors I want to share with you.

1. Obesity

When a person has a body mass index (BMI) of 30 or higher, that person is termed obese. In a worrying discovery, childhood obesity—or obesity at any age—can also lead to asthma. One recent study even suggested the risk of asthma increased by 55% for every extra unit of BMI. [1]

2. Stress

There are many things that can affect the health of your unborn child, and it seems your stress levels might be one of them. A new study suggests high-stress events could be linked to a greater risk for childhood asthma. [2] Not only were the mothers studied, but the children were also evaluated at ages 6 and 14. The children, at 14, were “twice as likely to have asthma […] if their mothers had been through a single stressful life event.”

3. Household Chemicals

Often used as stabilizing agents, endocrine-disrupting phthalates in household chemicals could also increase the risk for childhood asthma. Scientists studied the phthalate levels of pregnant women, and noted the children of women with higher phthalate levels were almost three times more likely to have an asthma diagnosis. [3]

4. Inadequate Gas Ventilation

Gas stoves without proper ventilation could also be a trigger for childhood asthma, with a new study suggesting a link between gas kitchen stove ventilation and asthma. [4] When used for cooking or heating, these stoves can increase the number of indoor pollutants that trigger an asthma attack. So while the chances for breathing problems are still there, using proper ventilation can cut a kid’s risk by thirty to forty percent.

5. Breathing Dirty Air

A recent study looking to North Carolina as a model suggested air quality has significantly improved since mid-1990s governmental regulations. Many of you with asthma know how pollution can act as a trigger, so, for some, better air quality can lead to a better quality of life. Because of cleaner air, fewer asthma deaths have been reported, with numbers dropping almost by half. [5]

6. Smoking

It seems like smoking and breathing problems could go hand in hand, doesn’t it? Well, a recent study suggested those problems could start well before birth, noting children born to fathers who began smoking at an early age had three times higher risk for asthma. [6] And remember, a child with asthma has a doubled risk of attacks or symptoms if either parent smokes in the home. [7]

One Final Thought

Genetics certainly plays a large role in an asthma diagnosis, so while avoiding these risk factors can help, it isn’t a surefire guarantee you’ll completely dodge the condition. When it comes to helping your child, exposure to allergens in the first year could be critical when a child is building up immunity. In a study of 560 children at high-risk for asthma, “only 17 percent of those exposed to three household allergens during the first year of life had recurrent wheezing,” suggesting timing can be crucial. [8] Remember that sometimes a little dirt can be a good thing! How do you avoid asthma risk factors? Tell us about it in the comments.

by Dr. Edward Group DC, NP, DACBN, DCBCN, DABFM

Source: 6 Avoidable Risk Factors for Asthma

References (8)

Grenell, R. et al. Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study. PLOS Medicine.

Sly, PD. et al. Prenatal adverse life events increase the risk for atopic diseases in children, which is enhanced in the absence of a maternal atopic predisposition. The Journal of Allergy and Clinical Immunology. 134 (1).

Whyatt, R. et al. Asthma in Inner-City Children at 5–11 Years of Age and Prenatal Exposure to Phthalates: The Columbia Center for Children’s Environmental Health Cohort. Environmental Health Perspectives.

Smit, E. et al. A cross-sectional study of the association between ventilation of gas stoves and chronic respiratory illness in U.S. children enrolled in NHANESIII. Environmental Health. 13 (71).

Abernethy, AP. et al. Long-term dynamics of death rates of emphysema, asthma, and pneumonia and improving air quality. International Journal of Chronic Obstructive Pulmonary Disease. 9 (1).

Svanes, C. et al. Parental smoking prior to conception and asthma in offspring. European Respiratory Journal.

Committee on Environmental Health. Environmental Tobacco Smoke: A Hazard to Children. Pediatrics. 99 (4).

Lynch, S. et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. The Journal of Allergy and Clinical Immunology. 134 (3).

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[evoldir]

Conference: Philadelphia.Sept16-17.MolecularEvolution

Deadline is approaching for Early Bird registration for a two-day symposium at Temple University in Philadelphia (September 16-17, 2017) On the first day (Saturday, September 16th, 2017), we will have the "Molecular Evolution informs Medicine" symposium, where we will highlight the impact of molecular evolutionary studies on the understanding, diagnosis, and treatment of disease. There will be sessions on Mendelian (rare) diseases, Complex diseases, Cancers, and Infectious diseases. Invited and contributed presentations will be showcased. You can still apply for presenting posters and talks. On the second day (Sunday, September 17th, 2017), we will have the "Molecular Evolutionary Genetics" event, where we will celebrate academic contributions of Dr. Masatoshi Nei. There will be many talks from Nei students and long-time associates on evolutionary genomics and molecular phylogenetics. More than 30 speakers are already confirmed (see program) Program information is listed at http://bit.ly/2rpl45j To register, click on http://bit.ly/2qr2NqL To present a contributed talk or poster, visit http://bit.ly/2rpl59n For all inquiries, please contact mailto:igemevents@temple.edu Sudhir Kumar Temple University via Gmail

[bisexualspace]

You clearly didn’t watch the video though. She goes into how we see race and what a persons ancestry actually is. She is a black woman with a white father. If she goes into a physicians office, they see her as a black woman and treat her accordingly, even though she has half her genetics from a white man (meaning that she could be at risk for cystic fibrosis, or Crohn's disease). You talk about sickle cell among those of african or mediterranean ancestry, but neglect to notice that those of mediterranean ancestry can be white? As someone with Italian heritage I had to be tested for thalassaemia (somewhat similar to sickle cell, also found in ppl of african and mediterranean descent) when I showed symptoms of anaemia. My doctor didn’t do that test because I was white. She did it because she did a thorough family history. Thats what doctors should be doing. Taking thorough histories and examining risk of disease before testing. Yes people with different genetic backgrounds are more susceptible to varying diseases, BUT their risk of disease can be determined much, much more accurately by doing a family history (and potentially pedigree analysis for mendelian disorders). 

She also talks about how creatinine levels are “corrected” based on race, because black people are assumed to have a larger muscle mass than white people, therefore they must have more creatinine naturally appearing in their urine. Should we not just look at the person and their physique instead of assuming levels based on race? If I have a white body builder coming in (perhaps actually ingesting supplements/protein powder with creatinine), they are going to naturally have a higher creatinine level in their urine than Prof Roberts (who is fairly slim). But if I corrected based on race, I could not only send my white body builder pt for extensive and expensive unnecessary testing, but I will potentially miss a critical diagnosis of kidney problems in Prof Roberts.

Yes genetics plays a key role in disease and disease progression, however, assumptions made on race are inaccurate at best, and incredibly dangerous at worst. Taking a thorough history mitigates the need for these assumptions anyways, and will give you a clearer picture of your patients health. Most of the time, race based assumptions in medicine just give doctors the excuse to skip over a very time consuming part of their job.

TLDR: Race based medicine is a shitty, lazy way of making a diagnosis, and is often wrong and detrimental to your patients overall wellbeing.

 - Sincerely, a medical student who didn’t just pull facts out of their ass/wikipedia like your dumbass did.