Boards, Advisory Committees, Professional Organizations
Associate Editor, ESC Heart Failure (2020 - Present)
Michael Snyder, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
Longitudinal host-microbial omics profiling and wearables-based monitoring to understand Autism Spectrum Disorder (ASD), its heterogeneity, and predictors of the diverse symptoms that ASD individuals experience.
Wearable Devices: Implications for Precision Medicine and the Future of Health Care.
Annual review of medicine
Wearable devices are integrated analytical units equipped with sensitive physical, chemical, and biological sensors capable of noninvasive and continuous monitoring of vital physiological parameters. Recent advances in disciplines including electronics, computation, and material science have resulted in affordable and highly sensitive wearable devices that are routinely used for tracking and managing health and well-being. Combined with longitudinal monitoring of physiological parameters, wearables are poised to transform the early detection, diagnosis, and treatment/management of a range of clinical conditions. Smartwatches are the most commonly used wearable devices and have already demonstrated valuable biomedical potential in detecting clinical conditions such as arrhythmias, Lyme disease, inflammation, and, more recently, COVID-19 infection. Despite significant clinical promise shown in research settings, there remain major hurdles in translating the medical uses of wearables to the clinic. There is a clear need for more effective collaboration among stakeholders, including users, data scientists, clinicians, payers, and governments, to improve device security, user privacy, data standardization, regulatory approval, and clinical validity. This review examines the potential of wearables to offer affordable and reliable measures of physiological status that are on par with FDA-approved specialized medical devices. We briefly examine studies where wearables proved critical for the early detection of acute and chronic clinical conditions with a particular focus on cardiovascular disease, viral infections, and mental health. Finally, we discuss current obstacles to the clinical implementation of wearables and provide perspectives on their potential to deliver increasingly personalized proactive health care across a wide variety of conditions. Expected final online publication date for the Annual Review of Medicine, Volume 75 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View details for DOI 10.1146/annurev-med-052422-020437
View details for PubMedID 37983384
Multi-omics profiling for health.
Molecular & cellular proteomics : MCP
The world has witnessed a steady rise in both non-infectious and infectious chronic diseases, prompting a cross-disciplinary approach to understand and treat disease. Current medical care focuses on treating people after they become patients rather than to preventing illness, leading to high costs in treating chronic and late-stage diseases. Additionally, a 'one-size-fits all' approach to healthcare does not take into account individual differences in genetics, environment, or lifestyle factors, decreasing the number of people benefiting from interventions. Rapid advances in omics technologies and progress in computational capabilities have led to the development of multi-omics deep phenotyping, which profiles the interaction of multiple levels of biology over time and empowers precision health approaches. This review highlights current and emerging multi-omics modalities for precision health and discusses applications in the following areas: genetic variation, cardio-metabolic diseases, cancer, infectious diseases, organ transplantation, pregnancy, and longevity/aging. We will briefly discuss the potential of multi-omics approaches in disentangling host-microbe and host-environmental interactions. We will touch on emerging areas of electronic health record and clinical imaging integration with muti-omics for precision health. Finally, we will briefly discuss the challenges in clinical implementation of multi-omics and their future prospects.
View details for DOI 10.1016/j.mcpro.2023.100561
View details for PubMedID 37119971
ApoA-I Nanotherapy Rescues Postischemic Vascular Maladaptation by Modulating Endothelial Cell and Macrophage Phenotypes in Type 2 Diabetic Mice
Arteriosclerosis, Thrombosis, and Vascular Biology
View details for DOI 10.1161/ATVBAHA.122.318196
DNA methylation processes in atheosclerotic plaque
2019; 281: 168-179
Underlying mechanisms of cardiovascular diseases (CVD) have been investigated for over 100 years and novel molecular level mechanisms in the pathophysiology are still continuously being discovered. Genetic polymorphisms (SNPs = single nucleotide polymorphisms) have explained about one tenth of the CVD risk, but polymorphisms fail to account for gene-environment interactions i.e. explain the dynamics of epigenome modifications in CVD. Accumulating evidence suggests that epigenetic modifications are actively reshaping pathological processes (e.g. dedifferentiation of smooth muscle cells, accumulation of senescent cells) in CVD. Senescence of vascular cells in ageing arteries not only counteracts regenerative processes but also exacerbates atherogenesis. Epigenome modifications include changes in DNA methylation, histone code and expression of non-coding RNAs. DNA methylation is a major epigenetic regulator modulating cell-type specific gene expression in mural cells, but there is some controversy regarding how to interpret the role of DNA hyper- and hypomethylation in CVD pathology. DNA hypomethylation (loss of methyl cytosines) appears to predominate in atherosclerosis, while a few genes become more methylated (i.e. hypermethylated) as the disease progresses in medium-sized and large arteries. The actual time-course of atherosclerosis-linked changes in genomic DNA methylation is still poorly studied. This review highlights recent novel findings which link alterations in DNA methylation to atherogenesis and points out new potential approaches for novel treatments.
View details for DOI 10.1016/j.atherosclerosis.2018.12.006
View details for Web of Science ID 000459973200023
View details for PubMedID 30591183
A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
2018; 67 (7): 1414-1427
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
View details for DOI 10.2337/db17-0914
View details for Web of Science ID 000435927000019
View details for PubMedID 29703844
View details for PubMedCentralID PMC6014557
Aggravated Postinfarct Heart Failure in Type 2 Diabetes Is Associated with Impaired Mitophagy and Exaggerated Inflammasome Activation
AMERICAN JOURNAL OF PATHOLOGY
2017; 187 (12): 2659-2673
Type 2 diabetes mellitus (T2DM) is a major risk factor for heart disease. Mortality rates after myocardial infarction (MI) are significantly increased in T2DM patients because of dysfunctional left ventricle (LV). However, molecular pathways underlying accelerated heart failure (HF) after MI in T2DM remain unclear. We investigated the underlying mechanisms by inducing MI in a well-established model of T2DM and control mice. Cardiac imaging revealed a significantly decreased global left ventricular ejection fraction in parallel with increased mortality after MI in T2DM mice compared with control mice. Genome-wide mRNA sequencing, immunoblot, electron microscopy, together with immunofluorescence staining for LC3 and p62 indicated an impaired mitophagy in peri-infarct regions of LV in T2DM mice compared with control mice. Furthermore, defective mitophagy was associated with an increased release of mitochondrial DNA, resulting in Aim2 and NLRC4 inflammasome and caspase-I hyperactivation in cardiomyocytes and cardiac macrophages in peri-infarct regions of LV in T2DM mice. Consistent with inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-18 secretion were increased in T2DM mice. Our results indicate that T2DM aggravates HF after MI through defective mitophagy, associated exaggerated inflammasome activation, cell death, and IL-18 secretion, suggesting that restoring mitophagy and inhibiting inflammasome activation may serve as novel targets for the prevention and treatment of HF in T2DM.
View details for DOI 10.1016/j.ajpath.2017.08.023
View details for Web of Science ID 000417009100005
View details for PubMedID 28935571
Differential Promoter Methylation of Macrophage Genes Is Associated With Impaired Vascular Growth in Ischemic Muscles of Hyperlipidemic and Type 2 Diabetic Mice Genome-Wide Promoter Methylation Study
2015; 117 (3): 289-299
Hyperlipidemia and type 2 diabetes mellitus (T2DM) severely impair adaptive vascular growth responses in ischemic muscles. This is largely attributed to dysregulated gene expression, although details of the changes are unknown.To define the role of promoter methylation in adaptive vascular growth in hyperlipidemia (LDLR(-/-)ApoB(100/100)) and T2DM (IGF-II/LDLR(-/-)ApoB(100/100)) mouse models of hindlimb ischemia.Unilateral hindlimb ischemia was induced by ligating femoral artery. Perfusion was assessed using ultrasound, and capillary and arteriole parameters were assessed using immunohistochemistry. Genome-wide methylated DNA sequencing was performed with DNA isolated from ischemic muscle, tissue macrophages (Mϕs), and endothelial cells. Compared with the controls, hyperlipidemia and T2DM mice showed impaired perfusion recovery, which was associated with impaired angiogenesis and arteriogenesis. Genome-wide proximal promoter DNA methylation analysis suggested differential patterns of methylation in Mϕ genes in ischemic muscles. Classically activated M1-Mϕ gene promoters, including Cfb, Serping1, and Tnfsf15, were significantly hypomethylated, whereas alternatively activated M2-Mϕ gene promoters, including Nrp1, Cxcr4, Plxnd1, Arg1, Cdk18, and Fes, were significantly hypermethylated in Mϕs isolated from hyperlipidemia and T2DM ischemic muscles compared with controls. These results combined with mRNA expression and immunohistochemistry showed the predominance of proinflammatory M1-Mϕs, compared with anti-inflammatory and proangiogenic M2-Mϕs in hyperlipidemia and T2DM ischemic muscles.We found significant promoter hypomethylation of genes typical for proinflammatory M1-Mϕs and hypermethylation of anti-inflammatory, proangiogenic M2-Mϕ genes in hyperlipidemia and T2DM ischemic muscles. Epigenetic alterations modify Mϕ phenotype toward proinflammatory M1 as opposed to anti-inflammatory, proangiogenic, and tissue repair M2 phenotype, which may contribute to the impaired adaptive vascular growth under these pathological conditions.
View details for DOI 10.1161/CIRCRESAHA.115.306424
View details for Web of Science ID 000358045300010
View details for PubMedID 26085133
Adventitial gene transfer of VEGFR-2 specific VEGF-E chimera induces MCP-1 expression in vascular smooth muscle cells and enhances neointimal formation
2011; 219 (1): 84-91
The role of vascular endothelial growth factors (VEGFs) in neointimal formation has been controversial. VEGF receptor (R)-2 signaling pathway is crucial in bringing about the effects of VEGFs including vasodilatation, endothelial cell migration and proliferation. In this study we have used an established adventitial gene transfer technique, in vitro studies and a novel VEGF-E/PlGF chimera that binds specifically to VEGFR-2, to investigate the role of VEGFR-2 in neointimal formation.Intimal hyperplasia was induced in the carotid arteries of cholesterol fed male New Zealand White rabbits using a silastic collar. Adenoviral vectors encoding VEGF-E chimera (1×10(9) pfu/ml) were transferred to the adventitia of the carotid arteries either alone or together with adenoviruses encoding soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were sacrificed 7 days after the gene transfer.Significant increases in neointimal formation, proliferating cells, inflammatory responses and adventitial angiogenesis were observed in the VEGF-E chimera transduced arteries. The number of medial smooth muscle cells expressing VEGFR-2 was significantly (p<0.001) higher. MCP-1 mRNA levels were significantly (p<0.01) increased in the VEGF-E chimera transduced arteries and transduced rabbit aortic smooth muscle cells (p<0.05). Soluble VEGFR-2 (sVEGFR-2) significantly inhibited VEGF-E chimera induced neointimal formation (p<0.01), cellular proliferation (p<0.01), inflammatory responses (p<0.01) and adventitial angiogenesis (p<0.01).The results indicate that VEGFR-2 mediated signaling could aggravate neointimal formation and suggest a potential therapeutic role of sVEGFR-2 in inhibiting neointimal formation and adventitial angiogenesis.
View details for DOI 10.1016/j.atherosclerosis.2011.07.103
View details for Web of Science ID 000296587200015
View details for PubMedID 21862016
VEGF-DNC mediated angiogenesis in skeletal muscles of diabetic WHHL rabbits
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
2010; 40 (5): 422-432
Arterial occlusive disease is often associated with diabetes mellitus and hypercholesterolaemia which may reduce angiogenic potential of several growth factors. Accordingly, the usefulness of therapeutic angiogenesis in the presence of diabetes and hypercholesterolaemia has remained unclear. We evaluated angiogenic effects of the mature form of vascular endothelial growth factor-D (VEGF-D(deltaNdeltaC)) in skeletal muscles in the presence of severe diabetes and hypercholesterolaemia.Intra muscular injections of adenoviruses encoding human VEGF-D(deltaNdeltaC) (AdVEGF-D(deltaNdeltaC)) were given in the hind limbs of a group of diabetic hypercholesterolaemic rabbits and adenoviruses encoding LacZ (AdLacZ) were used as a control. All animals were killed 6 days after the gene transfer.Capillary count, capillary area, capillary permeability and perfusion were significantly higher in the AdVEGF-D(deltaNdeltaC) transduced muscles compared with the AdLacZ controls. Expressions of endothelial nitric oxide synthase (eNOS) and VEGF receptor(R)-2 were also significantly increased in the VEGF-D(deltaNdeltaC) transduced muscles, along with an increased expression of angiopoietins (Angs) and neuropilin-2 (NP-2). Furthermore, VEGF-D(deltaNdeltaC) gene transfer to the skeletal muscles increased localized recruitment of cells with endothelial progenitor-like characteristics.VEGF-D(deltaNdeltaC) gene transfer can induce efficient angiogenesis in the presence of severe diabetes and hypercholesterolaemia by upregulating eNOS and VEGFR-2 expression. VEGF-D(deltaNdeltaC) appears to be a promising agent for inducing therapeutic angiogenesis even in cases with severe diabetes and hypercholesterolaemia.
View details for DOI 10.1111/j.1365-2362.2010.02285.x
View details for Web of Science ID 000276924300007
View details for PubMedID 20534064
Intravitreal Adenoviral 15-Lipoxygenase-1 Gene Transfer Prevents Vascular Endothelial Growth Factor A-Induced Neovascularization in Rabbit Eyes
HUMAN GENE THERAPY
2009; 20 (12): 1679-1686
Excessive angiogenesis mediated by vascular endothelial growth factor (VEGF) plays an important role in angioproliferative ocular diseases. We have previously developed a large animal model for these diseases by intravitreal adenoviral gene transfer of VEGF-A(165). 15-Lipoxygenase-1 (15-LO-1), an oxidizing enzyme producing reactive lipid hydroperoxides, has been shown to induce aberrant angiogenesis in cancer models of transgenic mice overexpressing human 15-LO-1. Our purpose was to study the effects of 15-LO-1 on VEGF-A(165)-induced angiogenesis in New Zealand White rabbit eyes, using intravitreal adenovirus-mediated gene transfers. AdCMV and Adh15-LO-1 alone served as controls. As determined by immunohistochemistry, VEGF-A(165) significantly increased the number and size of the capillaries in various compartments of the eyes. 15-LO-1 efficiently inhibited VEGF-A(165)-induced neovascularization and pathological changes by reducing VEGF-A(165) mRNA and protein expression, determined by RT-PCR, ELISA, and immunohistochemistry. 15-LO-1, which produces endogenous ligands for peroxisome proliferator-activated receptor-gamma (PPARgamma), also prevented VEGF-A(165)-induced expression of PPARgamma and VEGF receptor-2, as measured by quantitative RT-PCR. In conclusion, our findings show that 15-LO-1 prevents VEGF-A(165)-induced angiogenesis and consequent pathology in the eyes, suggesting that intravitreal 15-LO-1 gene transfer could be a potential new strategy for the treatment of neovascular complications in the eyes.
View details for DOI 10.1089/hum.2009.069
View details for Web of Science ID 000272633400018
View details for PubMedID 19694557
VEGF-E chimera gene transfer to periadventitial space induces neointimal formation
MARY ANN LIEBERT INC. 2009: 1450
View details for Web of Science ID 000271441000293
ROLE OF VASCULAR GROWTH FACTORS IN DIABETIC NEPHROPATHY
SPRINGER TOKYO. 2009: 438
View details for Web of Science ID 000271023103071
15-lipoxygenase-1 prevents vascular endothelial growth factor A- and placental growth factor-induced angiogenic effects in rabbit skeletal muscles via reduction in growth factor mRNA levels, NO bioactivity, and downregulation of VEGF receptor 2 expression
2008; 102 (2): 177-184
Human 15-lipoxygenase-1 (15-LO-1) is an oxidizing enzyme capable of producing reactive lipid hydroperoxides. 15-LO-1 and its products have been suggested to be involved in many pathological conditions, such as inflammation, atherogenesis, and carcinogenesis. We used adenovirus-mediated gene transfers to study the effects of 15-LO-1 on vascular endothelial growth factor (VEGF)-A165- and placental growth factor (PlGF)-induced angiogenesis in rabbit skeletal muscles. 15-LO-1 significantly decreased all angiogenic effects induced by these growth factors, including capillary perfusion, vascular permeability, vasodilatation, and an increase in capillary number. The effects are attributable to the reduction in the amount of VEGF-A165 and PlGF transcripts by 15-LO-1, resulting in reduced protein expression. The most likely mediator of the VEGF family-induced capillary vasodilatation is nitric oxide (NO), which is produced by NO synthases. Endothelial NO synthase protein expression and NO synthase activity were significantly induced by VEGF-A165, and these inductions were reduced by 15-LO-1. VEGF-A165 induces its angiogenic effects primarily via vascular endothelial growth factor receptor (VEGFR)2, and also PlGF mediates angiogenic signaling via VEGFR2, even though it binds to VEGFR1. VEGFR2 expression is induced by peroxisome proliferator-activating receptor . We showed by quantitative RT-PCR and immunohistochemistry that expression of endogenous rabbit peroxisome proliferator-activating receptor and VEGFR2 were significantly increased in the growth factor-transduced muscles, but these inductions were efficiently prevented by 15-LO-1. In conclusion, the results suggest that expression of 15-LO-1 has an efficient antiangiogenic effect in vivo via reduction in growth factor mRNA levels, NO bioactivity, and VEGFR2 expression.
View details for DOI 10.1161/CIRCRESAHA.107.155556
View details for Web of Science ID 000252825600010
View details for PubMedID 17991885
Screening for human cationic trypsinogen (PRSS1) and trypsinogen inhibitor gene (SPINK1) mutations in a Finnish family with hereditary pancreatitis
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY
2007; 42 (8): 1000-1005
Mutations in the cationic trypsinogen gene (PRSS1) have been linked with hereditary pancreatitis (HP). A change in R122H in the third exon is one of the mutations most frequently associated with HP. A mutation N34S in the serine protease inhibitor Kazal type 1 gene has also been shown to be linked with HP. The purpose of this study was to report on the incidence of PRSS1 and SPINK1 mutations in a Finnish family with HP and to correlate the findings to the clinical symptoms.The study included 36 individuals from one Finnish family with HP (21 M, 15 F, median age 38 years). All individuals underwent abdominal ultrasound and laboratory tests (glucose, faecal elastase-1 test). Blood samples were taken for mutational analysis of PRSS1 (R122H, N29I and A16V) and SPINK1 (N34S).Ten (28%) individuals were affected by mutations: the most frequent mutation was R122H, affecting 8 (22%) individuals; 2 (6%) individuals were affected by the N34S mutation and none by the other tested mutations (N29I and A16V). Four out of eight (50%) R122H-positive individuals had a diagnosis of chronic pancreatitis without other known aetiologies. Four out of five (80%) male individuals with the R122H mutation also had clinical pancreatitis, whereas none of the three mutation-positive females had any signs or symptoms of chronic pancreatitis. The two individuals with the N34S mutation did not have any signs of chronic pancreatitis.In the investigated Finnish pedigree with HP, the PRSS1 mutation R122H is linked with chronic disease. Although the SPINK1 mutation (N34S) was also observed in two individuals, it was not linked with the disease.
View details for DOI 10.1080/00365520701206738
View details for Web of Science ID 000247778700015
View details for PubMedID 17613931
VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-kappa B, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits
2006; 20 (12): 2159-+
Plaque angiogenesis may be associated with the development of unstable and vulnerable plaques. Vascular endothelial growth factors (VEGFs) are potent angiogenic factors that can affect plaque neovascularization. Our objective was to determine the effect of diabetes on atherosclerosis and on the expression of angiogenesis-related genes in atherosclerotic lesions. Alloxan was used to induce diabetes in male Watanabe heritable hyperlipidemic (WHHL) rabbits that were sacrificed 2 and 6 months after the induction of diabetes. Nondiabetic WHHL rabbits served as controls. Blood glucose (Glc), serum-free fatty acids (FFA), and serum triglyceride levels were significantly higher in diabetic rabbits. Accelerated atherogenesis was observed in the diabetic WHHL rabbits together with increased intramyocellular lipids (IMCL), as determined by 1H-NMR spectroscopy. Atherosclerotic lesions in the diabetic rabbits had an increased content of macrophages and showed significant increases in immunostainings for vascular endothelial growth factor (VEGF)-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, RAGE, and NF-kappaB. VEGF-A165 and VEGFR-2 mRNA levels were significantly increased in aortas of the diabetic rabbits, where a trend toward increased plaque vascularization was also observed. These results suggest that diabetes accelerates atherogenesis, up-regulates VEGF-A, VEGF-D, and VEGF receptor-2 expression, and increases NF-kappaB, RAGE, and inflammatory responses in atherosclerotic lesions in WHHL rabbits.
View details for DOI 10.1096/fj.05-5029fje
View details for Web of Science ID 000241156900051
View details for PubMedID 16935942
Adenovirus-mediated gene transfer of placental growth factor to perivascular tissue induces angiogenesis via upregulation of the expression of endogenous vascular endothelial growth factor-A
HUMAN GENE THERAPY
2005; 16 (12): 1422-1428
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that binds specifically to VEGF receptor (VEGFR)-1. However, the mechanism of PlGF- and VEGFR-1-mediated angiogenesis has remained unclear and some in vitro studies suggest that VEGF-A/VEGFR-2 signaling may also play a role in PlGF-mediated angiogenesis. To clarify these issues we evaluated angiogenic responses in a well-characterized periadventitial angiogenesis model using adenovirus-mediated PlGF-2 (AdvPlGF-2) gene transfer. We also investigated the roles of VEGFR-1 and VEGFR-2 in PlGF-2-mediated angiogenesis. Using a periadventitial collar technique, AdvPlGF-2 (1 x 10(9) plaque-forming units/ml) was transferred to the adventitia of New Zealand White rabbits alone or together with adenoviruses encoding soluble VEGFR-1 (sVEGFR-1) or soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were killed 7 days after gene transfer. Increased neo-vessel formation, upregulation of endogenous VEGF-A expression, and a significant inflammatory response were seen in AdvPlGF-2-transduced arteries. The neo-vessels were large and well perfused. sVEGFR-1 and sVEGFR-2 suppressed the angiogenic response of PlGF-2 by 80 and 71.7%, respectively. We conclude that adenovirus-mediated PlGF-2 gene transfer to vascular tissue increases endogenous VEGF-A expression and produces significant angiogenesis. Both sVEGFR-1 and sVEGFR-2 can inhibit PlGF-2-mediated angiogenesis. PlGF-2 is a potentially useful candidate for the induction of therapeutic angiogenesis in vivo.
View details for DOI 10.1089/hum.2005.16.1422
View details for Web of Science ID 000234253000007
View details for PubMedID 16390273
Effect of total colectomy and PYY infusion on food intake and body weight in rats
2005; 131 (1-3): 29-33
PYY (3-36) is postulated to act as a satiety factor in the gut-hypothalamic pathway to inhibit food intake and body weight gain in humans and rodent models. We determined the effect of 14-day continuous intravenous infusion of PYY (3-36) (175 microg/kg/day) on food intake and body weight gain in colectomized male Wistar rats. Colectomy caused an increase in plasma PYY levels at 7 days which was reduced at 14 days but still significantly elevated compared to basal preoperative values. Animals treated with continuous PYY (3-36) infusion had significantly elevated PYY levels compared to the control group throughout the whole experiment, but showed a similar pattern of food intake and body weight gain. In conclusion, although continuous intravenous infusion is the most physiologically relevant method to mimic high postprandial PYY levels, we did not observe any significant effect on food intake and body weight gain in non-food deprived colectomized animals. This suggests that PYY has, if at all, only a minor role in food intake in rats.
View details for DOI 10.1016/j.regpep.2005.06.004
View details for Web of Science ID 000232709100005
View details for PubMedID 15996768
Genetic analysis of a four generation Indian family with Usher syndrome: a novel insertion mutation in MYO7A
2004; 10 (109): 910-916
Usher syndrome (USH) is a rare autosomal recessive disorder characterized by deafness and retinitis pigmentosa. The purpose of this study was to determine the genetic cause of USH in a four generation Indian family.Peripheral blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to known USH loci, microsatellite markers were selected from the candidate regions of known loci and used to genotype the family. Exon specific intronic primers for the MYO7A gene were used to amplify DNA samples from one affected individual from the family. PCR products were subsequently sequenced to detect mutation. PCR-SSCP analysis was used to determine if the mutation segregated with the disease in the family and was not present in 50 control individuals.All affected individuals had a classic USH type I (USH1) phenotype which included deafness, vestibular dysfunction and retinitis pigmentosa. Pedigree analysis suggested an autosomal recessive mode of inheritance of USH in the family. Haplotype analysis suggested linkage of this family to the USH1B locus on chromosome 11q. DNA sequence analysis of the entire coding region of the MYO7A gene showed a novel insertion mutation c.2663_2664insA in a homozygous state in all affected individuals, resulting in truncation of MYO7A protein.This is the first study from India which reports a novel MYO7A insertion mutation in a four generation USH family. The mutation is predicted to produce a truncated MYO7A protein. With the novel mutation reported here, the total number of USH causing mutations in the MYO7A gene described to date reaches to 75.
View details for Web of Science ID 000225599200001
View details for PubMedID 15592175
Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations
2004; 66 (4): 341-348
Patients with primary microcephaly, an autosomal recessive trait, have mild to severe mental retardation without any other neurological deficits. It is a genetically heterogeneous disorder with six known loci: MCPH1 to MCPH6. Only the genes for MCPH1 and MCPH5 have been identified so far. We have ascertained nine consanguineous families with primary microcephaly from India. To establish linkage of these nine families to known MCPH loci, microsatellite markers were selected from the candidate regions of each of the six known MCPH loci and used to genotype the families. The results were suggestive of linkage of three families to the MCPH5 locus and one family to the MCPH2 locus. The remaining five families were not linked to any of the known loci. DNA-sequence analysis identified one known (Arg117X) and two novel (Trp1326X and Gln3060X) mutations in the three MCPH5-linked families in a homozygous state. Three novel normal population variants (i.e., c.7605G > A, c.4449G > A, and c.5961 A > G) were also detected in the ASPM gene.
View details for DOI 10.1111/j.1399-0004.2004.00304.x
View details for Web of Science ID 000223757800013
View details for PubMedID 15355437
Genetic analysis of a five generation Indian family with BPES: A novel missense mutation (p.Y215C)
2004; 10 (56): 445-449
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare eye genetic disorder caused by mutations in the FOXL2 gene located at chromosome 3q23. The purpose of the present study was to carry out genetic analysis of BPES in a five-generation Indian family.Peripheral blood samples were obtained from individuals for genomic DNA isolation. To determine the linkage of this family to the FOXL2 locus, haplotype analysis was carried out using microsatellite markers from the BPES candidate region. Five overlapping sets of primers were used to amplify the entire coding region of the FOXL2 gene for mutation detection. Allele-specific oligonucleotide hybridization (ASOH) analysis was carried out to determine segregation of the mutation in the family and to also determine if the mutation was present in 100 ethnically matched normal control chromosomes.Pedigree analysis suggested that BPES segregated in this family as an autosomal dominant trait. Cytogenetic analysis in one patient did not reveal any rearrangement. Haplotype analysis suggested that this family was linked to the FOXL2 locus on chromosome 3q23. DNA sequence analysis showed that the BPES phenotype in this family was caused by a novel missense mutation, c.881A->G (p.Y215C).This study reports for the first time a novel missense mutation in a five-generation Indian family with BPES. A review of the literature showed that the total number of mutations in the FOXL2 gene described to date is 42.
View details for Web of Science ID 000222692600001
View details for PubMedID 15257268