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1.  Response to Ayurvedic therapy in the treatment of migraine without aura 
Migraine patients who do not respond to conventional therapy, develop unacceptable side-effects, or are reluctant to take medicines resort to complementary and alternative medicines (CAM). Globally, patients have been seeking various non-conventional modes of therapy for the management of their headaches. An Ayurvedic Treatment Protocol (AyTP) comprising five Ayurvedic medicines, namely Narikel Lavan, Sootshekhar Rasa, Sitopaladi Churna, Rason Vati and Godanti Mishran along with regulated diet and lifestyle modifications such as minimum 8 h sleep, 30-60 min morning or evening walk and abstention from smoking/drinking, was tried for migraine treatment. The duration of the therapy was 90 days. Out of 406 migraine patients who were offered this AyTP, 204 patients completed 90 days of treatment. Complete disappearance of headache and associated symptoms at completion of AyTP was observed in 72 (35.2%); mild episode of headache without need of any conventional medicines in 72 (35.2%); low intensity of pain along with conventional medicines in 50 (24.5%); no improvement in seven (3.4%) and worst pain was noted in three (1.4%) patients, respectively. In 144 (70.5%) of patients marked reduction of migraine frequency and pain intensity observed may be because of the AyTP. Though the uncontrolled open-label design of this study does not allow us to draw a definite conclusion, from this observational study we can make a preliminary assessment regarding the effectiveness of this ayurvedic treatment protocol.
doi:10.4103/0974-7788.59941
PMCID: PMC2876931  PMID: 20532095
Alternative therapy; Ayurveda; CAM; migraine
2.  SPONTANEOUS OR INDUCED REGRESSION OF CANCER A NOVEL RESEARCH STRATEGY FOR AYURVIDYA 
Ancient Science of Life  2003;22(3):75-83.
Regression of cancer has been an interiguiny factor for medicinal science. This article is bringing out some interesting data on this issue with a view to generate in the Ayurvedic researchers to see the possibilities of Ayurveda in induced regression of cancer.
PMCID: PMC3331012  PMID: 22557089
3.  A Protein Complex Network of Drosophila melanogaster 
Cell  2011;147(3):690-703.
SUMMARY
Determining the composition of protein complexes is an essential step towards understanding the cell as an integrated system. Using co-affinity purification coupled to mass spectrometry analysis, we examined protein associations involving nearly five thousand individual, FLAG-HA epitope-tagged Drosophila proteins. Stringent analysis of these data, based on a novel statistical framework to define individual protein-protein interactions, led to the generation of a Drosophila Protein interaction Map (DPiM) encompassing 556 protein complexes. The high quality of DPiM and its usefulness as a paradigm for metazoan proteomes is apparent from the recovery of many known complexes, significant enrichment for shared functional attributes and validation in human cells. DPiM defines potential novel members for several important protein complexes and assigns functional links to 586 protein-coding genes lacking previous experimental annotation. DPiM represents, to our knowledge, the largest metazoan protein complex map and provides a valuable resource for analysis of protein complex evolution.
doi:10.1016/j.cell.2011.08.047
PMCID: PMC3319048  PMID: 22036573
Drosophila; proteome; protein complex map; interactome
4.  Spontaneous gas gangrene in a patient with Crohn’s disease 
Summary
Background:
Spontaneous gas gangrene is necrosis of muscles in the absence of trauma, causing an acutely painful and potentially fatal condition. However, the occurrence of this condition in Crohn’s disease has been very rarely documented.
Case Report:
In this extremely rare case we describe an occurrence of spontaneous gas gangrene, in a known case of Crohn’s disease. The patient presented with fever and pain in the left arm and abdomen. After admission and initial management with antibiotics, the patient developed crepitus in the arm and myonecrosis necessitating a fasciotomy and later an emergency amputation of his left upper limb.
The pathogenesis of gas gangrene in inflammatory bowel disease is not fully understood. Management includes aggressive antibiotic administration followed by amputation of the non-salvageable limb.
Conclusions:
A high index of suspicion of such rare complications is a must and surgical intervention is life saving; however, the efficacy of anti-gas gangrene serum is controversial. We recommend use of a multipronged approach in such cases with high mortality rates.
doi:10.12659/AJCR.883493
PMCID: PMC3616112  PMID: 23569538
spontaneous gas gangrene; Crohns disease; fasciotomy
5.  Establishing a health demographic surveillance site in Bhaktapur district, Nepal: initial experiences and findings 
BMC Research Notes  2012;5:489.
Background
A health demographic surveillance system (HDSS) provides longitudinal data regarding health and demography in countries with coverage error and poor quality data on vital registration systems due to lack of public awareness, inadequate legal basis and limited use of data in health planning. The health system in Nepal, a low-income country, does not focus primarily on health registration, and does not conduct regular health data collection. This study aimed to initiate and establish the first HDSS in Nepal.
Results
We conducted a baseline survey in Jhaukhel and Duwakot, two villages in Bhaktapur district. The study surveyed 2,712 households comprising a total population of 13,669. The sex ratio in the study area was 101 males per 100 females and the average household size was 5. The crude birth and death rates were 9.7 and 3.9/1,000 population/year, respectively. About 11% of births occurred at home, and we found no mortality in infants and children less than 5 years of age. Various health problems were found commonly and some of them include respiratory problems (41.9%); headache, vertigo and dizziness (16.7%); bone and joint pain (14.4%); gastrointestinal problems (13.9%); heart disease, including hypertension (8.8%); accidents and injuries (2.9%); and diabetes mellitus (2.6%). The prevalence of non-communicable disease (NCD) was 4.3% (95% CI: 3.83; 4.86) among individuals older than 30 years. Age-adjusted odds ratios showed that risk factors, such as sex, ethnic group, occupation and education, associated with NCD.
Conclusion
Our baseline survey demonstrated that it is possible to collect accurate and reliable data in a village setting in Nepal, and this study successfully established an HDSS site. We determined that both maternal and child health are better in the surveillance site compared to the entire country. Risk factors associated with NCDs dominated morbidity and mortality patterns.
doi:10.1186/1756-0500-5-489
PMCID: PMC3494612  PMID: 22950751
6.  Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in healthy volunteers 
Ashwagandha (Withania somnifera) (WS), a “rasayana” drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30) were enrolled. After baseline investigations, they received WS capsules (Rx) (aqueous extract, 8:1) daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day ×10 days, 1 000 mg/day × 10 days, 1 250 mg/day × 10 days). Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar's test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia.
doi:10.4103/0975-9476.100168
PMCID: PMC3487234  PMID: 23125505
Ayurvedic plant drug; exercise tolerance; muscle activity; muscle strength; Rasayana drug; Withania somnifera
8.  A study of standardized extracts of Picrorhiza kurroa Royle ex Benth in experimental nonalcoholic fatty liver disease 
As a major organ of intermediary metabolism, the liver is exposed to a variety of metabolic insults due to diseases and xenobiotics viz., insulin resistance (IR) drugs, toxins, microbial products, etc. One of the consequences of these metabolic insults including obesity and type 2 diabetes mellitus is the development of non-alcoholic fatty liver disease (NAFLD). The recent alarming increase in the prevalence of NAFLD compels the need to develop an appropriate animal model of the disease so as to evolve effective interventions. In this study, we have developed, in the rat, a new model of NAFLD showing several key features akin to the disease in humans. Male Wistar rats were challenged with 30% high fat diet (HFD) – butter, for 2 weeks to induce NAFLD. A hydroalcoholic extract of Picrorhiza kurroa was administered to study the possible reversal of fatty changes in the liver. The extract was given in two doses viz., 200mg/kg and 400 mg/kg b.i.d., p.o. for a period of 4 weeks. There were three control groups (n = 6/group) – vehicle with a regular diet, vehicle with HFD, and HFD with silymarin – a known hepatoprotective.
Histopathology showed that the P. kurroa extract brought about a reversal of the fatty infiltration of the liver (mg/g) and a lowering of the quantity of hepatic lipids (mg/g) compared to that in the HFD control group (38.33 ± 5.35 for 200mg/kg; 29.44 ± 8.49 for 400mg/kg of P. kurroa vs.130.07 ± 6.36mg/g of liver tissue in the HFD control group; P<0.001). Compared to the standard dose of the known hepatoprotective silymarin, P. kurroa reduced the lipid content (mg/g) of the liver more significantly at the dose of 400mg/kg (57.71 ± 12.45mg/kg vs. 29.44 ± 8.49 for the silymarin group vs. 400mg/kg of P. kurroa, P<0.001). In view of the increasing prevalence of metabolic syndrome and NAFLD, P. kurroa should be investigated by the reverse pharmacology path as a potential drug for the treatment of NAFLD, and essential safety studies and preformulation research for concentration of the putative actives should be carried out.
doi:10.4103/0975-9476.72622
PMCID: PMC3087357  PMID: 21547049
Hepatoprotective; high fat diet; insulin resistance; metabolic syndrome; non-alcoholic fatty liver; Picrorhiza kurroa reverse pharmacology
9.  Maternal Health, Supraja (Eugenics) and Ayurveda 
Ancient Science of Life  2008;28(1):44-48.
Mother and child care has been described in great detail in Ayurveda. All basic principles of Ayurveda need to be applied to deal with the problems of maternal and foetal mortality. Rules of Ahara (diet), Vihara (lifestyle), Sadavrutta (moral conduct), along with varied therapies are used in tackling the various problems. There is need to take an in depth view at causes. Major changes in lifestyle may be required. Uses of various Ayurvedic formulations like various ghrtas and tailas (ghees and oils) have given wonderful results. Ayurveda aims at producing “Supraja” or healthy progeny. Ayurveda provides answers to some of the most worrying problems facing doctors today.
PMCID: PMC3336340  PMID: 22557298
11.  Association of Parity with Carotid Diameter and Distensibility: Multi-Ethnic Study of Atherosclerosis 
Hypertension  2014;64(2):253-258.
Pregnancy and childbirth are associated with hemodynamic changes and vascular remodeling. It is not known whether parity is associated with later adverse vascular properties such as larger arterial diameter, wall thickness and lower distensibility.
We used baseline data from 3283 women free of cardiovascular disease aged 45-84 years enrolled in the population based Multi-Ethnic Study of Atherosclerosis. Participants self-reported parity status. Ultrasound derived carotid artery lumen diameters and brachial artery blood pressures were measured at peak-systole and end-diastole. Common carotid intima media thickness (cIMT) was also measured. Regression models to determine the association of carotid distensibility coefficient, lumen diameter, and cIMT with parity were adjusted for age, race, height, weight, diabetes, current smoking, BP medication use, total and high density lipoprotein cholesterol levels.
The prevalence of nulliparity was 18%. In adjusted models, carotid distensibility coefficient was 0.09 × 10−5Pa−1 lower (p = 0.009) in parous vs. nulliparous women. Among parous women, there was a nonlinear association with the greatest carotid DC seen in women with 2 live births, and significantly lower distensibility seen in primiparas (p=0.04) or with higher parity > 2 (p=0.005). No such pattern of association with parity was found for lumen diameter or cIMT.
Parity is associated with lower carotid artery distensibility, suggesting arterial remodeling that lasts beyond childbirth. These long-term effects on the vasculature may explain the association of parity with cardiovascular events later in life.
doi:10.1161/HYPERTENSIONAHA.114.03285
PMCID: PMC4184976  PMID: 24842921
common carotid artery; arterial stiffness; carotid intima-media thickness; women; pregnancy
12.  Hippocampal HDAC4 Contributes to Postnatal Fluoxetine-Evoked Depression-Like Behavior 
Neuropsychopharmacology  2014;39(9):2221-2232.
Fluoxetine treatment in adulthood evokes antidepressant and anxiolytic responses. Paradoxically, postnatal fluoxetine (PNFlx) induces persistent depression- and anxiety-like behaviors. The mechanistic underpinnings of this paradox remain poorly understood. Here, we examined specific molecular changes in the rat hippocampus that accompany perturbed emotionality observed across life following PNFlx. PNFlx-induced hippocampal gene regulation observed in microarray and quantitative PCR studies indicate functional enrichment of genes involved in response to organic substances, protein kinase pathways, DNA binding, and transcriptional repression. We noted specific transcripts (Hdac4, mammalian target of rapamycin (mTOR), Gnai1, protein kinase C gamma (Prkcc), and hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1)) that were consistently dysregulated across life, and selectively influenced by postnatal, but not adult, fluoxetine. Increased histone deacetylase-4 (HDAC4) recruitment, accompanied by decreased activating histone acetylation marks at the mTOR and Gnai1 promoters, indicate a role for HDAC4 in PNFlx-mediated gene dysregulation. Strikingly, coadministration of the HDAC inhibitor sodium butyrate with PNFlx prevented the dysregulation of Hdac4 and mTOR, and the emergence of depression- and anxiety-like behavior. Importantly, we also find that retreatment of PNFlx animals with fluoxetine in adulthood reversed the increased Hdac4 expression, prevented HDAC4 recruitment to the mTOR and Gnai1 promoters, and attenuated the decline in mTOR and Gnai1 expression, coincident with normalization of PNFlx-evoked depression- and anxiety-like behavior. Further, we show that viral-mediated hippocampal overexpression of Hdac4 was sufficient to induce depression-, but not anxiety-, like behavior in adulthood. Our results highlight the unique nature of molecular signatures evoked by PNFlx, and implicate HDAC4 in the dysregulated gene expression and emergence of perturbed emotionality following fluoxetine exposure in early life.
doi:10.1038/npp.2014.73
PMCID: PMC4104341  PMID: 24663010
antidepressant; depression; anxiety; Prozac; selective serotonin reuptake inhibitor; hippocampus; histone modification; histone deacetylase; mTOR
13.  Pleiotropic genes for metabolic syndrome and inflammation 
Molecular genetics and metabolism  2014;112(4):317-338.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
doi:10.1016/j.ymgme.2014.04.007
PMCID: PMC4122618  PMID: 24981077
14.  Rhabdomyolysis-induced acute kidney injury in a cancer patient exposed to denosumab and abiraterone: a case report 
BMC Nephrology  2015;16:118.
Background
Denosumab and abiraterone were approved by the United States Food and Drug Administration in 2011 for the treatment of metastatic castration-resistant prostate cancer. Neither denosumab nor abiraterone is known to cause rhabdomyolysis.
Case presentation
A 76-year-old Caucasian man with metastatic prostate cancer presented with non-oliguric severe acute kidney injury (AKI) 3 weeks after receiving simultaneous therapy with denosumab and abiraterone. The patient had been on statin therapy for more than 1 year with no recent dose adjustments. His physical exam was unremarkable. Blood work on admission revealed hyperkalemia, mild metabolic acidosis, hypocalcemia, and elevated creatine kinase (CK) at 44,476 IU/L. Kidney biopsy confirmed the diagnosis of rhabdomyolysis-induced AKI. The patient responded well to intravenous isotonic fluids and discontinuation of denosumab, abiraterone, and rosuvastatin, with normalization of CK and recovery of kidney function.
Conclusion
We report the first case of biopsy-proven rhabdomyolysis-induced AKI in a cancer patient acutely exposed to denosumab and abiraterone. Whether one of these drugs individually, or the combination, was the bona fide culprit of muscle breakdown is unknown. Nonetheless, our report is hypothesis-generating for further investigations on the effect of these drugs on muscle cells.
doi:10.1186/s12882-015-0113-6
PMCID: PMC4519001  PMID: 26220655
Denosumab; Abiraterone; Acute kidney injury; Rhabdomyolysis
15.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
16.  PoopMD, a Mobile Health Application, Accurately Identifies Infant Acholic Stools 
PLoS ONE  2015;10(7):e0132270.
Biliary atresia (BA) is the leading cause of pediatric end-stage liver disease in the United States. Education of parents in the perinatal period with stool cards depicting acholic and normal stools has been associated with improved time-to-diagnosis and survival in BA. PoopMD is a mobile application that utilizes a smartphone’s camera and color recognition software to analyze an infant’s stool and determine if additional follow-up is indicated. PoopMD was developed using custom HTML5/CSS3 and wrapped to work on iOS and Android platforms. In order to define the gold standard regarding stool color, seven pediatricians were asked to review 45 photographs of infant stool and rate them as acholic, normal, or indeterminate. Samples for which 6+ pediatricians demonstrated agreement defined the gold standard, and only these samples were included in the analysis. Accuracy of PoopMD was assessed using an iPhone 5s with incandescent lighting. Variability in analysis of stool photographs as acholic versus normal with intermediate rating weighted as 50% agreement (kappa) was compared between three laypeople and one expert user. Variability in output was also assessed between an iPhone 5s and a Samsung Galaxy S4, as well as between incandescent lighting and compact fluorescent lighting. Six-plus pediatricians agreed on 27 normal and 7 acholic photographs; no photographs were defined as indeterminate. The sensitivity was 7/7 (100%). The specificity was 24/27 (89%) with 3/27 labeled as indeterminate; no photos of normal stool were labeled as acholic. The Laplace-smoothed positive likelihood ratio was 6.44 (95% CI 2.52 to 16.48) and the negative likelihood ratio was 0.13 (95% CI 0.02 to 0.83). kappauser was 0.68, kappaphone was 0.88, and kappalight was 0.81. Therefore, in this pilot study, PoopMD accurately differentiates acholic from normal color with substantial agreement across users, and almost perfect agreement across two popular smartphones and ambient light settings. PoopMD may be a valuable tool to help parents identify acholic stools in the perinatal period, and provide guidance as to whether additional evaluation with their pediatrician is indicated. PoopMD may improve outcomes for children with BA.
doi:10.1371/journal.pone.0132270
PMCID: PMC4519295  PMID: 26221719
17.  Nanoparticle Detection of Urinary Markers for Point-of-Care Diagnosis of Kidney Injury 
PLoS ONE  2015;10(7):e0133417.
The high incidence of acute and chronic kidney injury due to various environmental factors such as heavy metals or chemicals has been a major problem in developing countries. However, the diagnosis of kidney injury in these areas can be more challenging due to the lack of highly sensitive and specific techniques that can be applied in point-of-care settings. To address this, we have developed a technique called ‘micro-urine nanoparticle detection (μUNPD)’, that allows the detection of trace amounts of molecular markers in urine. Specifically, this technique utilizes an automated on-chip assay followed by detection with a hand-held device for the read-out. Using the μUNPD technology, the kidney injury markers KIM-1 and Cystatin C were detected down to concentrations of 0.1 ng/ml and 20 ng/ml respectively, which meets the cut-off range required to identify patients with acute or chronic kidney injury. Thus, we show that the μUNPD technology enables point of care and non-invasive detection of kidney injury, and has potential for applications in diagnosing kidney injury with high sensitivity in resource-limited settings.
doi:10.1371/journal.pone.0133417
PMCID: PMC4506142  PMID: 26186708
18.  Platelet Response to Serotonin in Patients with Stable Coronary Heart Disease 
The American journal of cardiology  2014;114(2):181-186.
Patients with heart disease and depression have an increased mortality rate. Both behavioral and biologic factors have been proposed as potential etiologic mechanisms. Given that the pathophysiology of depression is thought to involve disruption in brain serotonergic signaling, we investigated platelet response to serotonin stimulation in patients with stable coronary artery disease (CAD). We enrolled 92 patients with stable CAD. Platelet response to increasing concentrations of serotonin (5HT), epinephrine-augmented 5HT, and ADP was measured by optical aggregation and flow cytometry. As concentrations of 5HT and ADP increased, so did the activation and aggregation of the platelets. However, upon addition of the highest concentration of 5HT (30 uM), a significant decrease in platelet activation (p = 0.005) was detected by flow cytometry. This contrasts the increase in platelet activation seen with the addition of the highest concentration of ADP. In conclusion, we found increased platelet activation and aggregation with increased concentrations of ADP; however, when platelets are stimulated with a high concentration of 5HT (30 uM), there is decreased platelet activation. The data demonstrate unique patterns of platelet activation by 5HT in patients with stable CAD. The cause of this phenomenon is unclear. Our study sheds light on the in-vitro response of platelet function to serotonin in patients with stable CAD which may further the mechanistic understanding of heart disease and depression.
doi:10.1016/j.amjcard.2014.04.023
PMCID: PMC4130397  PMID: 24952926
Platelets; Serotonin; Depression; Heart Disease
20.  Compatibility of Electroanatomical Mapping Systems with a Concurrent Percutaneous Axial Flow Ventricular Assist Device 
Background
Hemodynamic instability hinders activation and entrainment mapping during ventricular tachycardia (VT) ablation. The Impella 2.5 microaxial flow device (MFD) (Abiomed Inc., Danvers, MA, USA) is used to prevent hemodynamic instability during electrophysiologic study. However, electromagnetic interference (EMI) generated by this device can preclude accurate electroanatomic mapping.
Methods
Impella was placed in the left ventricle of 7 canines for circulatory support. Electroanatomic mapping during sinus rhythm, ventricular pacing, and ventricular fibrillation (VF) was performed using magnet- (Carto3, Biosense Webster Inc., Diamond Bar, CA, USA) and impedance- (EnSite Velocity System/EnSite NavX, St. Jude Medical Inc., St. Paul, MN, USA) based systems. Distance from device to points with severe EMI precluding acquisition was compared to points with mild/no EMI. Two methods were used to reduce EMI: 1) titration of MFD performance, and 2) impedance-only mapping combined with manual annotation of activation.
Results
Severe EMI did not occur during impedance-based mapping. Severe EMI was observed using Carto3 at 9.4% of all points attempted at maximum performance level (P8) of device. Severe EMI occurred at points closer to device (40.1 ± 16.8 mm) vs. (55.5 ± 20.0 mm) for mild/no EMI, p<0.0001. Severe EMI using Carto3 was resolved by either 1) reduction of performance from P8 to P6 or 2) impedance-only mapping with manual annotation
Conclusion
Concurrent use of MFD caused EMI to prevent acquisition of points with magnet-based mapping. Predictors for EMI were distance from device and performance level. Temporary reductions to P6 or impedance-only mapping are two methods to resolve EMI.
doi:10.1111/jce.12437
PMCID: PMC4447707  PMID: 24758340
ventricular tachycardia; catheter ablation; Impella; electroanatomical mapping systems; impedance; magnetic
22.  Aggressive fibromatosis (desmoid tumour) of the head and neck: a benign neoplasm with high recurrence 
BMJ Case Reports  2013;2013:bcr2013200156.
A 50-year-old man presented with a 5-month history of swelling over the right side of neck. The swelling was associated with dull aching pain radiating to the forearm without associated weakness of upper extremity or sensory loss. There was no history of trauma. On examination a fixed mass approximately 8×6 cm in size, smooth, firm in consistency, with ill-defined margins was present in the right posterior triangle. MRI scan of the neck revealed well-defined, lobulated, heterogeneously enhancing altered signal intensity mass at the root of neck. Debulking of the tumour was performed in view of its close proximity to the brachial plexus. Histopathology revealed aggressive fibromatosis (AF). AF is a benign fibrous neoplasm arising from fascia, periosteum and musculoaponeurotic structures of the body. AF in the head and neck region tends to be locally aggressive with a nature to invade bone and soft tissue structures.
doi:10.1136/bcr-2013-200156
PMCID: PMC3703068  PMID: 23814230
23.  Ultra-Long Term Stability of Single Units Using Chronically Implanted Multielectrode Arrays 
Recordings from chronically implanted multielectrode arrays have become prevalent in both neuroscience and neural engineering experiments. To date, however, the extent to which populations of single-units remain stable over long periods of time has not been well characterized. In this study, neural activity was recorded from a Utah multielectrode array implanted in the primary motor cortex of a rhesus macaque during 18 recording sessions spanning nine months. We found that 67% of the units were stable through the first 15 days, 31% of units were stable through 47 days, 21% of units were stable through 106 days, and 8% of units were stable over 9 months. Thus not only were units stable over a timescale of several months, but units stable over 2 months were more likely to remain stable in the next 2 months.
doi:10.1109/EMBC.2014.6944715
PMCID: PMC4482221  PMID: 25571083
24.  Rhabdomyosarcoma of spermatic cord in a 65-year-old man presenting as a groin swelling 
BMJ Case Reports  2013;2013:bcr2013010499.
A 65-year-old man presented with a swelling in the right groin of 6 months duration. The swelling was associated with dull aching pain and the patient reported of increase in size of the swelling during lifting of heavy weights. The swelling was 6×5 cm, hard in consistency, mobile and there was no impulse of cough. Ultrasonography showed a solid mass measuring 5.3×1.5×5.2 cm arising from the spermatic cord. High-inguinal orchiectomy was performed. Histopathology revealed rhabdomyosarcoma (RMS) of the spermatic cord. Patient was advised adjuvant chemotherapy but he refused. Spermatic cord RMS is a rare tumour derived from the undifferentiated mesoderm. It is most often observed in children and adolescents. It rarely appears after the second decade of life. It usually manifests as a painless, firm to hard mass in the inguinal canal or scrotum. Radical high-inguinal orchiectomy is the treatment of choice.
doi:10.1136/bcr-2013-010499
PMCID: PMC3703094  PMID: 23814027
25.  The Association of Brachial Artery Diameter with Noncalcified Coronary Plaque Burden in Apparently Healthy Individuals 
Coronary artery disease  2013;24(8):657-662.
Objective
Coronary atherosclerosis has been associated with systemic arterial remodeling even in non-atherosclerotic vessels. However it is not known whether systemic remodeling is differentially associated with the cumulative atherosclerotic process, reflected by putatively quiescent calcified plaque (CP) or with active atherosclerosis consisting of non-calcified plaque (NCP). We thus examined the association of brachial artery diameter (BAD), an artery which does not suffer clinical atherosclerosis, with the presence and the extent of coronary CP and NCP.
Methods
We studied 688 apparently healthy, asymptomatic participants from 350 families with a history of early-onset coronary artery disease (<60 years of age) measuring CAD risk factors and coronary plaque using dual-source CT angiography. Plaque volumes were quantified using a validated automated method. BAD was measured during diastole using B-mode ultrasound. The association of resting BAD with any detectable plaque, and log-transformed CP and NCP volumes if detectable, was tested using Generalized Estimating Equations (GEE) adjusted for age, sex, race, current smoking, diabetes, hypertension, body mass index, non-HDL and HDL-cholesterol.
Results
Higher quintiles of BAD were associated with greater age and male sex (both p <0.001). In fully adjusted analysis, CP volume was not associated with BAD (p=0.65) but 1 ml greater NCP volume was associated with 0.65 mm larger BAD (p=0.027).
Conclusion
Our results suggest that systemic arterial remodeling of non-atherosclerotic arteries is a dynamic process that is correlated with the extent of putatively active atherosclerotic processes in distant beds, but not inactive accumulated plaque burden.
doi:10.1097/MCA.0000000000000034
PMCID: PMC4476290  PMID: 24077324
Brachial Artery; Remodeling; CT Angiography

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