Publications by authors named "Shristi Shrestha"

24 Publications

  • Page 1 of 1

Skin Tumors among Biopsy Samples in Patients Attending Dermatological Out Patient Department in a Tertiary Care Hospital of Nepal: A Descriptive Cross-sectional Study.

JNMA J Nepal Med Assoc 2021 Sep 11;59(241):886-891. Epub 2021 Sep 11.

Nepal Medical College and Teaching Hospital, Jorpati, Kathmandu, Nepal.

Introduction: Skin tumors are on the rise in the Nepalese community. The different morphological pattern of skin tumors requires its meticulous categorization for understanding its effect on prognosis and treatment. Our study aimed at studying the prevalence of skin tumors among the skin biopsies performed in the dermatology outpatient department in a tertiary care hospital of Nepal.

Methods: A descriptive cross-sectional study was done from skin biopsy samples from 1st January, 2017 to 31st December, 2019, at a tertiary care center. Ethical clearance was taken from the institutional review committee (IRC), Ref No: 056-077/078. Convenience sampling was done. A self-designed proforma containing questions on the patients' socio-demographic data and clinical details were used, and a biopsy of those clinically suspected to have skin tumors was done. Skin tumors were classified according to the World Health Organization 2018 classification of skin tumors. Data were analyzed using Statistical Package for the Social Sciences Version 16. Point estimate at 95% Confidence Interval was done, and frequency and proportion were calculated.

Results: A total of 671 skin biopsies were done during this study, out of which 125 (18.63%) at 95% Confidence Interval (15.68-21.57) were diagnosed with skin tumors. Among them, 77 (61.6%) were female, and 48 (38.4%) were male. Among the diagnosed cases, 105 (84%) were benign, and 20 (16%) were malignant. Females showed preponderance in both benign and malignant tumors.

Conclusions: The findings from our study show the increasing prevalence of skin tumors, and the results were comparable to other similar studies conducted in various parts of Nepal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31729/jnma.6955DOI Listing
September 2021

Integrated Analysis of the Pancreas and Islets Reveals Unexpected Findings in Human Male With Type 1 Diabetes.

J Endocr Soc 2021 Dec 29;5(12):bvab162. Epub 2021 Oct 29.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Clinical and pathologic heterogeneity in type 1 diabetes is increasingly being recognized. Findings in the islets and pancreas of a 22-year-old male with 8 years of type 1 diabetes were discordant with expected results and clinical history (islet autoantibodies negative, hemoglobin A1c 11.9%) and led to comprehensive investigation to define the functional, molecular, genetic, and architectural features of the islets and pancreas to understand the cause of the donor's diabetes. Examination of the donor's pancreatic tissue found substantial but reduced β-cell mass with some islets devoid of β cells (29.3% of 311 islets) while other islets had many β cells. Surprisingly, isolated islets from the donor pancreas had substantial insulin secretion, which is uncommon for type 1 diabetes of this duration. Targeted and whole-genome sequencing and analysis did not uncover monogenic causes of diabetes but did identify high-risk human leukocyte antigen haplotypes and a genetic risk score suggestive of type 1 diabetes. Further review of pancreatic tissue found islet inflammation and some previously described α-cell molecular features seen in type 1 diabetes. By integrating analysis of isolated islets, histological evaluation of the pancreas, and genetic information, we concluded that the donor's clinical insulin deficiency was most likely the result autoimmune-mediated β-cell loss but that the constellation of findings was not typical for type 1 diabetes. This report highlights the pathologic and functional heterogeneity that can be present in type 1 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvab162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633619PMC
December 2021

Prevalence of Misuse of Topical Corticosteroid among Dermatology Outpatients.

JNMA J Nepal Med Assoc 2020 Nov 22;58(231):834-838. Epub 2020 Nov 22.

Department of Dermatology, Nepal Medical College and Teaching Hospital, Attarkhel, Kathmandu, Nepal.

Introduction: Topical corticosteroids misuse has become one of the burning issues in many countries across the globe. They are known to cause a myriad of adverse effects which include local effects commonly and systemic effects rarely. In dermatology practice, one of the common problems we see these days are steroid-induced and steroid aggravated dermatoses. So, this study was done to find the prevalence of misuse of topical corticosteroid among dermatology outpatients.

Methods: A descriptive cross-sectional study was done in the outpatient department of dermatology at atertiary care hospital for 18 months. Ethical clearance was obtained from the Institutional Review Committee of NMCTH (Reference no. 029-076/077). Convenient sampling was done. Statistical Package for the Social Sciences (SPSS) version 16 was used to tabulate the data and analyze the results. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.

Results: Out of 19464 patients, 614 (3.15%) (2.91%-3.39% at 95% Confidence Interval) gave a history of applying steroid containing creams. Among them, 220 (35.8%) belonged to the age group 21-30 years. Dermatophytoses were the skin disease where TCS was most commonly misused followed by melasma in 425 (69.2%) and 115 (18.7%) respectively. Beclomethasone was the steroid preparation that was misused in the maximum number of patients in 271 (44.1%). Some form of adverse effects was seen in 554 (88.6%) patients.

Conclusions: Non-prescription sale of topical corticosteroids is the major cause of topical corticosteroids abuse in Nepal. Creating awareness among the prescribers as well as the patients is the current need.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.31729/jnma.5271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775011PMC
November 2020

Combinatorial transcription factor profiles predict mature and functional human islet α and β cells.

JCI Insight 2021 09 22;6(18). Epub 2021 Sep 22.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells coexpressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing β cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.151621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492318PMC
September 2021

Clinically Significant Changes in the 17- and 6-Item Hamilton Rating Scales for Depression: A STAR*D Report.

Neuropsychiatr Dis Treat 2021 14;17:2333-2345. Epub 2021 Jul 14.

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Objective: To develop clinically meaningful improvement thresholds in both the 17-item and the 6-item Hamilton Rating Scale for Depression (HRSD) total scores in depressed outpatients.

Methods: The post-hoc analysis included all adult outpatients with non-psychotic major depressive disorder in the STAR*D trial who entered and exited the first treatment step (up to 14 weeks of citalopram) with a complete set of study measures at baseline and exit and at least one post-baseline measure. Within-patient change and linear regression anchor-based analyses were conducted to define meaningful and substantial changes in the HRSD and HRSD using three patient-reported outcomes [Work and Social Adjustment Scale (WSAS), Quality of Life Enjoyment and Satisfaction-Short Form (Q-LES-Q-SF); Mini-Q-LES-Q] obtained at baseline and exit from the first treatment step in STAR*D.

Results: Linear regression analyses identified a meaningful change threshold for the HRSD as 3.9 [3.7-4.1] [lower, upper 95% CI] and a substantial change as 7.8 [7.4-8.3] with the WSAS. Analogous thresholds based on the Q-LES-Q-SF were 5.8 [5.5-6.1] and 11.6 [11.0-12.2], respectively, and 4.9 [4.7-5.2] and 9.9 [9.3-10.4] for the Mini-QLES-Q, respectively. For the HRSD, linear regression analyses with the WSAS identified a meaningful change as 2.2 [2.1-2.4], while a substantial change was 4.5 [4.2-4.7]. Analogous figures based on the Q-LES-Q-SF were 3.2 [3.0-3.4] and 6.4 [6.1-6.8]. Similarly, based on the Mini-QLESQ, results were 2.8 [2.6-2.9] and 5.6 [5.3-5.9]. For both the HRSD and the HRSD, within-patient analyses produced less precise estimates of the same change thresholds with substantial overlap between groups. Based on the WSAS, a clinically meaningful change in the HRSD total score was 9.6 (SD = 6.5), while a substantial change was 15.0 (SD = 6.7). Analogous change thresholds based on the Q-LESQ-SF were 12.9 (SD = 6.2) and 16.8 (SD = 6.4), respectively. For the Mini-Q-LES-Q, thresholds were 10.9 (SD = 6.5) and 16.1 (SD = 6.2).

Conclusion: A 4-6 point change in the HRSD is clinically meaningful; a 7-12 point change is clinically substantial. For the HRSD, analogous estimates were 2-3 and 4-7 point changes, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/NDT.S305331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290193PMC
July 2021

Considering Loxapine Instead of Clozapine: A Case Series and Literature Review.

Cureus 2021 Jan 26;13(1):e12919. Epub 2021 Jan 26.

Psychiatry, Texas Tech University Health Sciences Center, Midland, USA.

This case series highlights the importance of loxapine in psychiatric disorders when clozapine is unable to control agitation and psychotic symptoms due to medication noncompliance, intolerable side effects, or inadequate clinical outcomes. Loxapine is classified as a first-generation typical antipsychotic but displays atypical antipsychotic-like characteristics with structural similarity to clozapine. However, since the inception of second-generation antipsychotic medications, the role of loxapine in modern psychiatric practice has become limited. Loxapine has been underutilized due to concerns of side effects and lack of in-depth research about its safety, tolerability, and efficacy. This report revisits loxapine's clinical utility through two well-studied long-term inpatient cases, where it played a crucial role in controlling psychotic symptoms and achieving better medication compliance by eliminating significant barriers, including monitoring regular differential complete blood counts. We aim to add to the current evidence and literature about the advantage of using loxapine for specific clinical scenarios in psychiatric practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.12919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906363PMC
January 2021

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors.

Transl Psychiatry 2021 02 16;11(1):59. Epub 2021 Feb 16.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-01171-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884786PMC
February 2021

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells.

Cell Metab 2020 12 13;32(6):1028-1040.e4. Epub 2020 Nov 13.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address:

Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into β cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single β cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in β cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects β cells in vivo through ACE2 and TMPRSS2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664344PMC
December 2020

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells.

bioRxiv 2020 Oct 20. Epub 2020 Oct 20.

Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. and transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.08.31.275719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587777PMC
October 2020

Frequency of different types of facial melanoses referring to the Department of Dermatology and Venereology, Nepal Medical College and Teaching Hospital in 2019, and assessment of their effect on health-related quality of life.

BMC Dermatol 2020 08 3;20(1). Epub 2020 Aug 3.

Department of Dermatology and Venereology, Nepal Medical College and Teaching Hospital (NMCTH), Attarkhel, Jorpati, Kathmandu, Nepal.

Background: Abnormalities of facial pigmentation, or facial melanoses, are a common presenting complaint in Nepal and are the result of a diverse range of conditions.

Objectives: The objective of this study was to determine the frequency, underlying cause and impact on quality of life of facial pigmentary disorders among patients visiting the Department of Dermatology and Venereology, Nepal Medical College and Teaching Hospital (NMCTH) over the course of one year.

Methods: This was a cross-sectional study conducted at the Department of Dermatology and Venereology, NMCTH. We recruited patients with facial melanoses above 16 years of age who presented to the outpatient department. Clinical and demographic data were collected and all the enrolled participants completed the validated Nepali version of the Dermatology Life Quality Index (DLQI).

Results: Between January 5, 2019 to January 4, 2020, a total of 485 patients were recruited in the study. The most common diagnoses were melasma (166 patients) and post acne hyperpigmentation (71 patients). Quality of life impairment was highest in patients having melasma with steroid induced rosacea-like dermatitis (DLQI = 13.54 ± 1.30), while it was lowest in participants with ephelides (2.45 ± 1.23).

Conclusion: Facial melanoses are a common presenting complaint and lead to substantial impacts on quality of life. Accurate diagnosis and management can prevent or treat many facial melanoses, including those that lead to substantial loss of quality of life, such as melasma with steroid induced rosacea-like dermatitis. Health care systems in low and middle-income countries should dedicate resources to the identification, prevention and treatment of these conditions to improve quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12895-020-00100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398190PMC
August 2020

Single-cell sperm transcriptomes and variants from fathers of children with and without autism spectrum disorder.

NPJ Genom Med 2020 21;5:14. Epub 2020 Feb 21.

7Rutgers Cancer Institute of New Jersey, New Brunswick, NJ USA.

The human sperm is one of the smallest cells in the body, but also one of the most important, as it serves as the entire paternal genetic contribution to a child. Investigating RNA and mutations in sperm is especially relevant for diseases such as autism spectrum disorders (ASD), which have been correlated with advanced paternal age. Historically, studies have focused on the assessment of bulk sperm, wherein millions of individual sperm are present and only high-frequency variants can be detected. Using 10× Chromium single-cell sequencing technology, we assessed the transcriptome from >65,000 single spermatozoa across six sperm donors (scSperm-RNA-seq), including two who fathered multiple children with ASD and four fathers of neurotypical children. Using RNA-seq methods for differential expression and variant analysis, we found clusters of sperm mutations in each donor that are indicative of the sperm being produced by different stem cell pools. Finally, we have shown that genetic variations can be found in single sperm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-020-0117-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035312PMC
February 2020

A case-control study of trace-element status and lung cancer in Appalachian Kentucky.

PLoS One 2019 27;14(2):e0212340. Epub 2019 Feb 27.

Markey Cancer Center, University of Kentucky, Lexington, KY, United States of America.

Appalachian Kentucky (App KY) leads the nation in lung cancer incidence and mortality. Trace elements, such as As, have been associated with lung cancers in other regions of the country and we hypothesized that a population-based study would reveal higher trace element concentrations in App KY individuals with cancer compared to controls. Using toenail and drinking water trace element concentrations, this study investigated a possible association between lung cancer incidence and trace-element exposure in residents of this region. This population-based case-control study had 520 subjects, and 367 subjects provided toenail samples. Additionally, we explored the relationship between toenail and fingernail trace-element concentrations to determine if fingernails could be used as a surrogate for toenails when patients are unable to provide toenail samples. We found that, contrary to our initial hypothesis, trace element concentrations (Al, As, Cr, Mn, Co, Fe, Ni, Cu, Se, and Pb) were not higher in cancer cases than controls with the exception of Zn where concentrations were slightly higher in cases. In fact, univariate logistic regression models showed that individuals with lower concentrations of several elements (Al, Mn, Cr, and Se) were more likely to have lung cancer, although only Mn was significant in multivariate models which controlled for confounding factors. While drinking water concentrations of Al, Cr and Co were positively related to cancer incidence in univariate models, only Co remained significant in multivariate models. However, since the drinking water concentrations were extremely low and not reflected in the toenail concentrations, the significance of this finding is unclear. We also found that fingernail concentrations were not consistently predictive of toenail concentrations, indicating that fingernails should not be used as surrogates for toenails in future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212340PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392268PMC
November 2019

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

J Clin Invest 2019 01 3;129(1):246-251. Epub 2018 Dec 3.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI121994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307934PMC
January 2019

Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis.

Cell Metab 2019 03 15;29(3):745-754.e4. Epub 2018 Nov 15.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37240, USA; Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare, Nashville, TN 37212, USA. Electronic address:

Identification of cell-surface markers specific to human pancreatic β cells would allow in vivo analysis and imaging. Here we introduce a biomarker, ectonucleoside triphosphate diphosphohydrolase-3 (NTPDase3), that is expressed on the cell surface of essentially all adult human β cells, including those from individuals with type 1 or type 2 diabetes. NTPDase3 is expressed dynamically during postnatal human pancreas development, appearing first in acinar cells at birth, but several months later its expression declines in acinar cells while concurrently emerging in islet β cells. Given its specificity and membrane localization, we utilized an NTPDase3 antibody for purification of live human β cells as confirmed by transcriptional profiling, and, in addition, for in vivo imaging of transplanted human β cells. Thus, NTPDase3 is a cell-surface biomarker of adult human β cells, and the antibody directed to this protein should be a useful new reagent for β cell sorting, in vivo imaging, and targeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402969PMC
March 2019

Carglumic Acid Treatment of a Patient with Recurrent Valproic Acid-induced Hyperammonemia: A Rare Case Report.

Cureus 2018 Sep 12;10(9):e3292. Epub 2018 Sep 12.

Medical Student, American University of Integrative Sciences, Bridgewater, BRB.

Valproic acid, first manufactured as an anticonvulsant, is commonly used to treat both neurological and psychiatric conditions. A rare and deadly side effect of this medication is hyperammonemia, presenting as lethargy, confusion, seizure, and, ultimately, coma. In rare circumstances, hyperammonemia can be recurrent and devastating, especially in patients with an underlying N-acetyl glutamate synthase (NAGS) deficiency, as the valproic acid can enhance this enzyme deficiency and inhibit the conversion of ammonia into urea in the liver. For these subtypes of patients, the United States Food and Drug Administration (US FDA) has recently approved carglumic acid, a medication that can act as a scavenger by effectively increasing the levels of NAGS, ultimately enhancing the conversion of ammonia to urea. In our case report, we have mentioned a patient with treatment-resistant bipolar disorder, who presented with elevated ammonia levels secondary to valproic acid treatment. Valproic acid was the only drug that was effective in his case, so we initiated therapy to reduce his elevated ammonia levels. After a thorough evaluation, we found the patient had a genetic NAGS deficiency. Carglumic acid was initiated and proved efficacious in our patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.3292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235635PMC
September 2018

Comorbidities and Consequences in Hospitalized Heart Failure Patients with Depression.

Cureus 2018 Aug 23;10(8):e3193. Epub 2018 Aug 23.

Internal Medicine, Blake Medical Center, Bradenton, USA.

Objective To evaluate the demographic predictors of major depressive disorder (MDD) in hospitalized congestive heart failure (CHF) patients and measure the differences in hospital stay and cost per comorbidities and the associated risk of in-hospital mortality. Methods This retrospective cross-sectional study used nationwide inpatient data from the healthcare cost and utilization project (HCUP). We identified patients with CHF as the primary diagnosis and MDD as the secondary diagnosis using ICD-9-CM codes and compared with the CHF patient without MDD. The differences in comorbidities were quantified using chi-square tests and the logistic regression model was used to evaluate mortality risk among comorbidities using odds ratio (OR). Results Elder CHF patients, 36-50-year-old (OR: 1.324) and whites (OR: 1.673), have a higher likelihood of a co-diagnosis of MDD. Females with heart failure have two-fold higher odds of MDD (OR: 2.332). Majority of the medical comorbidities were seen in a higher proportion of CHF patients without MDD. Hypothyroidism (10.2%) and drug abuse (15.2%) were seen more in depressed patients comparatively. Among substance use disorder, patients with drug abuse stayed longer and had a higher hospitalization total cost ($51,828). And, hypothyroidism was associated with longer inpatient stay (5.6 days) and cost ($64,726), and four-fold higher odds of in-hospital mortality (OR: 4.405). Though alcohol abuse was seen only in 7.4% of CHF patients with MDD, it was associated with the three-fold higher likelihood of deaths during hospitalization (OR: 3.195). Conclusion A middle-aged, white female with comorbid depression has a higher risk of hospitalization for heart failure. Depressed CHF patients with comorbid hypothyroidism were hospitalized for a longer duration with higher inpatient cost and four times higher risk of mortality during hospitalization stay. Further studies are required to evaluate the underlying cause of worse hospital outcomes in depressed CHF patients with alcohol abuse and hypothyroidism. An integrated healthcare model is required for early diagnosis and treatment of depression and associated comorbidities in CHF patients to reduce mortality and improve post-CHF outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.3193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200440PMC
August 2018

Comorbidities and Consequences in Hospitalized Heart Failure Patients with Depression.

Cureus 2018 Aug 23;10(8):e3193. Epub 2018 Aug 23.

Internal Medicine, Blake Medical Center, Bradenton, USA.

Objective To evaluate the demographic predictors of major depressive disorder (MDD) in hospitalized congestive heart failure (CHF) patients and measure the differences in hospital stay and cost per comorbidities and the associated risk of in-hospital mortality. Methods This retrospective cross-sectional study used nationwide inpatient data from the healthcare cost and utilization project (HCUP). We identified patients with CHF as the primary diagnosis and MDD as the secondary diagnosis using ICD-9-CM codes and compared with the CHF patient without MDD. The differences in comorbidities were quantified using chi-square tests and the logistic regression model was used to evaluate mortality risk among comorbidities using odds ratio (OR). Results Elder CHF patients, 36-50-year-old (OR: 1.324) and whites (OR: 1.673), have a higher likelihood of a co-diagnosis of MDD. Females with heart failure have two-fold higher odds of MDD (OR: 2.332). Majority of the medical comorbidities were seen in a higher proportion of CHF patients without MDD. Hypothyroidism (10.2%) and drug abuse (15.2%) were seen more in depressed patients comparatively. Among substance use disorder, patients with drug abuse stayed longer and had a higher hospitalization total cost ($51,828). And, hypothyroidism was associated with longer inpatient stay (5.6 days) and cost ($64,726), and four-fold higher odds of in-hospital mortality (OR: 4.405). Though alcohol abuse was seen only in 7.4% of CHF patients with MDD, it was associated with the three-fold higher likelihood of deaths during hospitalization (OR: 3.195). Conclusion A middle-aged, white female with comorbid depression has a higher risk of hospitalization for heart failure. Depressed CHF patients with comorbid hypothyroidism were hospitalized for a longer duration with higher inpatient cost and four times higher risk of mortality during hospitalization stay. Further studies are required to evaluate the underlying cause of worse hospital outcomes in depressed CHF patients with alcohol abuse and hypothyroidism. An integrated healthcare model is required for early diagnosis and treatment of depression and associated comorbidities in CHF patients to reduce mortality and improve post-CHF outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.3193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200440PMC
August 2018

Spaceflight Modifies Gene Expression in Response to Antibiotic Exposure and Reveals Role of Oxidative Stress Response.

Front Microbiol 2018 16;9:310. Epub 2018 Mar 16.

Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, United States.

Bacteria grown in space experiments under microgravity conditions have been found to undergo unique physiological responses, ranging from modified cell morphology and growth dynamics to a putative increased tolerance to antibiotics. A common theory for this behavior is the loss of gravity-driven convection processes in the orbital environment, resulting in both reduction of extracellular nutrient availability and the accumulation of bacterial byproducts near the cell. To further characterize the responses, this study investigated the transcriptomic response of to both microgravity and antibiotic concentration. was grown aboard International Space Station in the presence of increasing concentrations of the antibiotic gentamicin with identical ground controls conducted on Earth. Here we show that within 49 h of being cultured, adapted to grow at higher antibiotic concentrations in space compared to Earth, and demonstrated consistent changes in expression of 63 genes in response to an increase in drug concentration in both environments, including specific responses related to oxidative stress and starvation response. Additionally, we find 50 stress-response genes upregulated in response to the microgravity when compared directly to the equivalent concentration in the ground control. We conclude that the increased antibiotic tolerance in microgravity may be attributed not only to diminished transport processes, but also to a resultant antibiotic cross-resistance response conferred by an overlapping effect of stress response genes. Our data suggest that direct stresses of nutrient starvation and acid-shock conveyed by the microgravity environment can incidentally upregulate stress response pathways related to antibiotic stress and in doing so contribute to the increased antibiotic stress tolerance observed for bacteria in space experiments. These results provide insights into the ability of bacteria to adapt under extreme stress conditions and potential strategies to prevent antimicrobial-resistance in space and on Earth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2018.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865062PMC
March 2018

α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.

Cell Rep 2018 03;22(10):2667-2676

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. Electronic address:

Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368357PMC
March 2018

A high-throughput molecular data resource for cutaneous neurofibromas.

Sci Data 2017 04 11;4:170045. Epub 2017 Apr 11.

Children's Tumour Foundation, New York, New York 10005, USA.

Neurofibromatosis type 1 (NF1) is a genetic disorder with a range of clinical manifestations such as widespread growth of benign tumours called neurofibromas, pain, learning disorders, bone deformities, vascular abnormalities and even malignant tumours. With the establishment of the Children's Tumour Foundation biobank, neurofibroma samples can now be collected directly from patients to be analysed by the larger scientific community. This work describes a pilot study to characterize one class of neurofibroma, cutaneous neurofibromas, by molecularly profiling of ~40 cutaneous neurofibromas collected from 11 individual patients. Data collected from each tumour includes (1) SNP Arrays, (2) Whole genome sequencing (WGS) and (3) RNA-Sequencing. These data are now freely available for further analysis at http://www.synapse.org/cutaneousNF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sdata.2017.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387919PMC
April 2017

The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity.

Sci Rep 2016 12 1;6:38063. Epub 2016 Dec 1.

Department of Chemical Engineering, University of Florida, Bldg. 723, Gainesville, FL 32611, USA.

Mechanical integration of the nucleus with the extracellular matrix (ECM) is established by linkage between the cytoskeleton and the nucleus. This integration is hypothesized to mediate sensing of ECM rigidity, but parsing the function of nucleus-cytoskeleton linkage from other mechanisms has remained a central challenge. Here we took advantage of the fact that the LINC (linker of nucleoskeleton and cytoskeleton) complex is a known molecular linker of the nucleus to the cytoskeleton, and asked how it regulates the sensitivity of genome-wide transcription to substratum rigidity. We show that gene mechanosensitivity is preserved after LINC disruption, but reversed in direction. Combined with myosin inhibition studies, we identify genes that depend on nuclear tension for their regulation. We also show that LINC disruption does not attenuate nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex facilitates mechano-regulation of expression across the genome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep38063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131312PMC
December 2016

A Molecular Genetic Basis Explaining Altered Bacterial Behavior in Space.

PLoS One 2016 2;11(11):e0164359. Epub 2016 Nov 2.

BioServe Space Technologies, Aerospace Engineering Sciences Dept., University of Colorado, Boulder, CO, United States of America.

Bacteria behave differently in space, as indicated by reports of reduced lag phase, higher final cell counts, enhanced biofilm formation, increased virulence, and reduced susceptibility to antibiotics. These phenomena are theorized, at least in part, to result from reduced mass transport in the local extracellular environment, where movement of molecules consumed and excreted by the cell is limited to diffusion in the absence of gravity-dependent convection. However, to date neither empirical nor computational approaches have been able to provide sufficient evidence to confirm this explanation. Molecular genetic analysis findings, conducted as part of a recent spaceflight investigation, support the proposed model. This investigation indicated an overexpression of genes associated with starvation, the search for alternative energy sources, increased metabolism, enhanced acetate production, and other systematic responses to acidity-all of which can be associated with reduced extracellular mass transport.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091764PMC
June 2017

Biodegradation of Toluene Under Seasonal and Diurnal Fluctuations of Soil-Water Temperature.

Water Air Soil Pollut 2012 Sep 12;223(7):3579-3588. Epub 2012 May 12.

An increasing interest in bioremediation of hydrocarbon polluted sites raises the question of the influence of seasonal and diurnal changes on soil-water temperature on biodegradation of BTEX, a widespread group of (sub)-surface contaminants. Therefore, we investigated the impact of a wide range of varying soil-water temperature on biodegradation of toluene under aerobic conditions. To see the seasonal impact of temperature, three sets of batch experiments were conducted at three different constant temperatures: 10°C, 21°C, and 30°C. These conditions were considered to represent (1) winter, (2) spring and/or autumn, and (3) summer seasons, respectively, at many polluted sites. Three additional sets of batch experiments were performed under fluctuating soil-water temperature cases (21<>10°C, 30<>21°C, and 10<>30°C) to mimic the day-night temperature patterns expected during the year. The batches were put at two different temperatures alternatively to represent the day (high-temperature) and night (low-temperature) times. The results of constant- and fluctuating-temperature experiments show that toluene degradation is strongly dependent on soil-water temperature level. An almost two-fold increase in toluene degradation time was observed for every 10°C decrease in temperature for constant-temperature cases. Under fluctuating-temperature conditions, toluene degraders were able to overcome the temperature stress and continued thriving during all considered weather scenarios. However, a slightly longer time was taken compared to the corresponding time at daily mean temperature conditions. The findings of this study are directly useful for bioremediation of hydrocarbon-polluted sites having significant diurnal and seasonal variations of soil-water temperature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11270-011-1052-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409364PMC
September 2012

Relevance of patch testing in patients with nummular dermatitis.

Indian J Dermatol Venereol Leprol 2005 Nov-Dec;71(6):406-8

Department of Dermatology, Manipal Hospital, Bangalore, Karnataka, India.

Background: A chronic dermatosis like nummular dermatitis may be complicated by contact dermatitis due to an impaired cutaneous barrier. This study is aimed at evaluating secondary contact dermatitis in patients with nummular dermatitis.

Methods: Patch testing with the Indian Standard Series was performed in 50 of 78 patients with a clinical diagnosis of nummular eczema. Significant reactions were graded as per ICDRG criteria.

Results: Significant reactions were noted in 23 of 50 tested patients. The most frequent sensitizers were colophony, nitrofurazone, neomycin sulfate and nickel sulfate (7.14% each). Reactions to antigens in topical medications, cosmetics and toiletries constituted 64.28% of all the reactions.

Conclusions: Patients with nummular dermatitis are at significant risk of developing secondary allergic contact dermatitis, which contributes to the severity and chronicity of their dermatitis. Patch testing has the potential to improve the quality of life in these patients. Hence, patients with chronic recalcitrant nummular dermatitis must be patch tested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0378-6323.18945DOI Listing
March 2006
-->