Publications by authors named "Peter D"

168 Publications

Clinical profile of hereditary angioedema from a tertiary care centre in India.

Indian J Med Microbiol 2021 Apr 29. Epub 2021 Apr 29.

Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India.

Introduction: Hereditary angioedema (HAE) is a clinical condition which could be fatal if not identified and managed appropriately. Knowledge of this condition is mostly confined to individual case reports and literature reviews in India. In this retrospective study we describe HAE cases which presented to a tertiary care centre in India over a period of three and half years.

Materials And Methods: Clinical case records of forty-two HAE patients diagnosed based on clinical and laboratory features were accessed after due approval from the Ethics committee. C1 esterase inhibitor (C1 INH) and C4 levels were measured using nephelometry. All relevant data was entered into Microsoft EXCEL worksheet and analysed using simple statistical tools.

Results: Among the 42 patients diagnosed as having HAE, 37 had low C1INH levels and were diagnosed to have type 1 HAE. The remaining 5 had normal C1 INH levels and were considered probable HAE based on family history and response to HAE specific treatment. The median age of onset of symptoms was 15 years (range 5-49) and median age at diagnosis, 27.5 years (range 5-55). The median delay in diagnosis was 10 years (range 1-27 years). Family history of HAE was observed in 52.6% and 29% reported deaths in the family with HAE like disease. Low dose androgens or tranexamic acid or both were prescribed in 64.2% of the patients. Orofacial edema was the commonest clinical presentation (76%) followed by edema of the extremities (38%), GI tract symptoms (19%) and genital involvement (11.9%).

Conclusion: Many cases of HAE may be going undetected in India. There is a need for clinical awareness and laboratory means to accurately identify and administer appropriate treatment.
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http://dx.doi.org/10.1016/j.ijmmb.2021.03.021DOI Listing
April 2021

Rhinofacial conidiobolomycosis: Clinical and microbiological characterisation and shift in the management of a rare disease.

Mycoses 2021 Apr 29. Epub 2021 Apr 29.

Department of Infectious Diseases, Christian Medical College, Vellore, India.

Background: Conidiobolomycosis is a rare tropical rhinofacial fungal infection which has not been well characterised. The available evidence in its management is sparse due to lack of clinical studies and the limited data on antifungal susceptibility patterns.

Objective: To analyse the clinical manifestations, antifungal treatment and outcomes of patients with conidiobolomycosis and to determine antifungal susceptibility profiles of the isolates.

Patients/methods: Retrospective analysis of data of all patients with a diagnosis of conidiobolomycosis confirmed by histopathology and culture at a tertiary care hospital from 2012 to 2019 was done.

Results: There were 22 patients, 21 males and one female, with a mean age of 37.1 years. Most common presenting symptom was nasal obstruction, found in 20 (90.90%) patients. Patients who presented within 12 months had a better cure rate (85%) compared to those who presented late (67%). Among the 19 patients who had a follow-up, good outcome was seen in 15 of the 17 (88.24%) patients who were on itraconazole or potassium iodide containing regimen. Of the six patients who received additional trimethoprim-sulphamethoxazole (co-trimoxazole), 67% showed good outcome with two patients showing complete cure and two patients still on treatment with significant improvement. High minimum inhibitory concentration (MIC) values were noted for azoles and amphotericin B, whereas co-trimoxazole showed lowest MIC ranges.

Conclusion: Itraconazole and potassium iodide are reasonable first-line options for the treatment of conidiobolomycosis. Good clinical response to KI and comparatively lower MIC of co-trimoxazole are promising. Further studies are required for developing clinical breakpoints that can predict therapeutic outcomes.
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http://dx.doi.org/10.1111/myc.13294DOI Listing
April 2021

Pulmonary thromboembolism post-COVID convalescent plasma therapy: adding fuel to a smoldering fire!

Adv Respir Med 2021 Apr 21. Epub 2021 Apr 21.

Army Institute of Cardiothoracic Science, Armed Forces Medical College, Pune, India.

The current SARS-CoV-2 pandemic has affected millions worldwide and is still undergoing. The severe form of involvement constitutes ARDS and these patients are prone to develop Pulmonary thromboembolism. COVID Convalescent Plasma is presently used widely in treatment but this comes with an additional risk of Pulmonary thromboembolism which should be considered and appropriate measures should be taken to avoid it. This has rarely been reported in the literature.
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http://dx.doi.org/10.5603/ARM.a2021.0022DOI Listing
April 2021

Erroneous reduction of HbA1c levels in patients with type 2 diabetes mellitus on dapsone treatment for Hansen's disease - a single-center retrospective cohort study.

Indian J Dermatol Venereol Leprol 2021 Mar 12:1-4. Epub 2021 Mar 12.

Department of Endocrinology, Diabetes and Metabolism Christian Medical College, Vellore, Tamil Nadu, India.

Background: Dapsone treatment may reduce HbA1c levels in patients with diabetes.

Aims: To assess the prevalence and characteristics of dapsone associated reduction of HbA1c in patients with Hansen's disease.

Methods: A retrospective data review of outpatient and inpatient charts of consecutive patients with Hansen's disease and type 2 diabetes mellitus was conducted over two years from January 2014 to January 2016 at the Department of Dermatology, CMC Vellore, India.

Results: Of the 245 patients with a confirmed diagnosis of Hansen's disease who were on oral dapsone 100 mg/day as part of their treatment regimen, 49 patients had diabetes and were eligible for the study as per predetermined inclusion criteria. Of these, 35 subjects (71%) had an HbA1c discordantly lower than the corresponding mean plasma glucose levels. Patients with discordant HbA1c levels were more likely to be male and to have a higher RBC mean corpuscular volume (MCV). A greater reduction in HbA1c levels was seen during the initial 3 months of therapy of dapsone treatment.

Limitations: The small sample size and retrospective design were limitations of this study. Also, we did not analyze the role of methemoglobinemia or the utility of alternative measures of glycemic control in these patients.

Conclusion: We describe a high prevalence of dapsone associated inappropriate HbA1c lowering in type 2 diabetes mellitus patients. This may have serious implications for the management of diabetes in patients on therapy with dapsone.
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http://dx.doi.org/10.25259/IJDVL_527_18DOI Listing
March 2021

PSENEN Mutation in Coexistent Hidradenitis Suppurativa and Dowling-Degos Disease.

Indian Dermatol Online J 2021 Jan-Feb;12(1):147-149. Epub 2020 Sep 28.

Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India.

Hidradenitis suppurativa is a chronic relapsing disease with multiple abscesses, nodules, and scars in the apocrine bearing areas. Dowling-Degos is a rare autosomal dominant genodermatosis characterized by multiple hyperpigmented macules or papules in reticulate pattern, affecting mainly the flexures. We report a case of coexisting hidradenitis suppurativa and Dowling-Degos disease in a 31-year-old male in whom mutation analysis revealed a splice site mutation c.62-1G>T.
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http://dx.doi.org/10.4103/idoj.IDOJ_218_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982026PMC
September 2020

Clinico-etiological characteristics of organizing pneumonia: A retrospective study.

Lung India 2021 Mar-Apr;38(2):144-148

Department of Anesthesia, AFMC, Pune, Maharashtra, India.

Introduction: Organizing pneumonia (OP) is an idiopathic interstitial pneumonia characterized radiologically by the patchy peripheral areas of ground-glass opacities and consolidation. It is commonly associated with a variety of conditions such as connective tissue diseases (CTD), drugs, infections, malignancy, radiation exposure, post-transplant, and other interstitial pneumonia. There are no specific clinical manifestations unless there is an underlying etiology. We present a series of such cases.

Aims And Objectives: The aim of the study was to identify the clinical characteristics and etiological spectrum of patients manifesting radiologically with OP pattern.

Materials And Methods: This was a retrospective analysis of clinico-radiological profile and etiological diagnosis of 23 patients, who had a radiological diagnosis of OP during the period of January 2017-September 2019.

Results: Our patients presented with nonspecific symptoms of cough, fever, breathlessness, and occasionally with hemoptysis. The various etiologies identified were CTD (n = 4), infection (n = 2), drugs (n = 4), radiation (n = 1), chronic aspiration syndrome (n = 1), malignancy (n = 2), hypersensitivity pneumonitis (n = 1), and chronic heart failure (n = 2), and in majority (n = 7), no underlying etiology was evident and were labeled as cryptogenic organizing pneumonia.

Conclusion: OP is an underdiagnosed entity and is associated with numerous diseases varying from pulmonary tuberculosis to malignancy. Identification of the underlying disease process is of paramount importance as it enables the treating physician to implement necessary therapeutic interventions.
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http://dx.doi.org/10.4103/lungindia.lungindia_105_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098885PMC
March 2021

Early experience with anti-interleukin-6 therapy in COVID-19 hyperinflammation.

Lung India 2021 Mar;38(Supplement):S119-S121

Department of Pulmonary, Critical Care and Sleep Medicine, Army Institute of Cardiothoracic Sciences, Pune, Maharashtra, India.

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http://dx.doi.org/10.4103/lungindia.lungindia_568_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104342PMC
March 2021

IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice.

Commun Biol 2021 Feb 8;4(1):172. Epub 2021 Feb 8.

Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
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http://dx.doi.org/10.1038/s42003-021-01703-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870940PMC
February 2021

Testing the efficacy and comparability of ZooMS protocols on archaeological bone.

J Proteomics 2021 02 15;233:104078. Epub 2020 Dec 15.

Department of Archaeology, Max Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Straße 10, 07745 Jena, Germany. Electronic address:

Collagen peptide mass fingerprinting, best known as Zooarchaeology by Mass Spectrometry (or ZooMS) when applied to archaeology, has become invaluable for the taxonomic identification of archaeological collagenous materials, in particular fragmentary and modified bone remains. Prior to MALDI-based spectrometric analysis, collagen needs to be extracted from the bone's inorganic matrix, isolated and purified. Several protocols are currently employed for ZooMS analysis, however their efficacy and comparability has not been directly tested. Here, we use four different ZooMS protocols to analyze 400 bone samples from seven archaeological sites, dating to between ~500,000-2000 years ago. One of them, single-pot solid-phase-enhance sample preparation (SP3), is used for the first time as a ZooMS protocol. Our results indicate that the least-destructive ZooMS protocol which uses an ammonium bicarbonate buffer as a means of extracting collagen is most suitable for bones with good collagen preservation, whereas the acid-based methodologies can improve success rates for bones with low-to-medium collagen preservation. Since preservation of biomolecules in archaeological bones is highly variable due to age and environmental conditions, we use the percent nitrogen by weight (%N) value as an independent semi-quantitative proxy for assessing collagen content and for predicting which bones will likely result in a successful ZooMS-based identification. We find that 0.26%N as a threshold for screening material could optimize the number of spectra which produce identifications using ZooMS. SIGNIFICANCE STATEMENT: We present a direct comparison of three previously published ZooMS protocols for the analyses of archaeological bones, and the first use of an SP3-based approach to ZooMS analysis. Our results show that the acid-based ZooMS protocols increase the success rate for bones with low-medium collagen preservation. We identify 0.26%N as a threshold for optimizing the number of samples with enough collagen for successful peptide mass fingerprinting.
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http://dx.doi.org/10.1016/j.jprot.2020.104078DOI Listing
February 2021

Preferences for family planning education among men and women in rural, highly religious Tanzanian communities: a discrete choice experiment.

Sex Reprod Health Matters 2020 Dec;28(1):1850198

Research Training and Program Manager, Center for Global Health, Weill Cornell Medical College, New York, NY, USA.

Unmet need for family planning (FP) remains prevalent worldwide. In Tanzania, 21.7% of women desire to delay pregnancy, but do not use modern contraception despite its free availability at local clinics. Our prior data suggest that this is related to complex gender and religious dynamics in rural communities. To understand how education about FP could be improved, we developed a discrete choice experiment (DCE) to rank preferences of six attributes of FP education. Results were stratified by gender. Sixty-eight women and 76 men completed interview-assisted DCEs. Participants significantly preferred education by a clinician (men = 0.62,  < .001; women = 0.38,  < .001) and education in mixed-gender groups (men = 0.55,  < .001; women = 0.26,  < .001). Women also significantly preferred education by a religious leader (0.26,  = .012), in a clinic versus church, mosque, or community centre (0.31,  = .002), and by a female educator (0.12,  = .019). Men significantly preferred a male educator (0.17,  = .015), whom they had never met (0.25,  < .001), and educating married and unmarried people separately (0.22,  = .002). Qualitative data indicate women who had not previously used contraception preferred education led by a religious leader in a church or mosque. FP education tailored to these preferences may reach a broader audience, dispel misconceptions about FP and ultimately decrease unmet need.
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http://dx.doi.org/10.1080/26410397.2020.1850198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888062PMC
December 2020

Agonist-independent Gα activity negatively regulates β-cell compensation in a diet-induced obesity model of type 2 diabetes.

J Biol Chem 2020 Nov 10. Epub 2020 Nov 10.

University of Wisconsin-Madison, United States.

The inhibitory G protein alpha subunit, Gαz, is an important modulator of beta-cell function. Full-body Gαz-null mice are protected from hyperglycemia and glucose intolerance after long-term high-fat diet (HFD) feeding. In this study, at a time point in the feeding regimen where wild-type mice are only mildly glucose intolerant, transcriptomics analyses reveal islets from HFD-fed Gαz KO mice have a dramatically altered gene expression pattern as compared to WT HFD-fed mice, with entire gene pathways not only being more strongly up- or down-regulated vs. control-diet fed groups, but actually reversed in direction. Genes involved in the "Pancreatic Secretion" pathway are the most strongly differentially regulated: a finding that correlates with enhanced islet insulin secretion and decreased glucagon secretion at study end. The protection of Gαz-null mice from HFD-induced diabetes is β-cell autonomous, as β-cell-specific Gαz-null (βKO) mice phenocopy the full-body knockouts. The glucose-stimulated and incretin-potentiated insulin secretion response of islets from HFD-fed βKO mice is significantly improved as compared to islets from HFD-fed wild-type controls, which, along with no impact of Gαz loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass supports a secretion-specific mechanism. Gαz is coupled to the Prostaglandin EP3 receptor in pancreatic beta-cells. We confirm the EP3γ splice variant has both constitutive and agonist-sensitive activity to inhibit cyclic AMP production and downstream β-cell function, with both activities being dependent on the presence of beta-cell Gαz.
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http://dx.doi.org/10.1074/jbc.RA120.015585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948463PMC
November 2020

Detergent and Water Recovery from Laundry Wastewater Using Tilted Panel Membrane Filtration System.

Membranes (Basel) 2020 Sep 27;10(10). Epub 2020 Sep 27.

Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, Skudai 81310, Johor Bahru, Malaysia.

Increasing global concern on clean water scarcity and environmental sustainability drive invention in water reclamation technology. Laundry wastewater reclamation via membrane technology faces the challenge of membrane fouling. This paper assesses a tilting-the-filtration-panel filtration system for the treatment of real laundry wastewater filtration aimed for water and detergent reuse. Results showed that the panel tilting significantly improved fouling control and enhanced permeability due to enhanced contact of air bubbles with the membrane surface, which induced continuous detachment of foulant from the membrane surface. The combination of aeration rate and tilting angle resulted in up to 83% permeability enhancement from 109 to 221.4 ± 10.8 (L/m·h·bar). The system also offers 32% detergent recovery. Overall findings suggest that the system offers an attractive approach for both fouling management and detergent recovery and can potentially be applied under a simple setup in which filtration can be driven by gravity/hydrostatic pressure.
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http://dx.doi.org/10.3390/membranes10100260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599933PMC
September 2020

The relationship between the follow-up to discharge ratio and length of stay.

Am J Manag Care 2020 09;26(9):396-399

Cleveland Clinic Indian River Hospital, 1000 36th St, Vero Beach, FL 32960. Email:

Objectives: Average length of stay (ALOS) is used as a measure of the effectiveness of care delivery and therefore is an important operational measure when evaluating both the hospitalist group and individual hospitalist performance. No metric within the control of the individual hospitalist has been identified to support the individual hospitalist's contribution to the hospitalist group's ALOS goals. This study's objective was to evaluate the correlation between the follow-up to discharge ratio (F:D ratio) and ALOS and assess the relationship between F:D ratio and hospitalist experience.

Study Design: We systematically evaluated the relationship between hospitalist-level billing data for daily inpatient follow-up encounters and discharge visits (F:D ratio) and the attributed ALOS across consecutive hospitalist encounters at a tertiary care center.

Results: Over the study period of 10 quarters from 2017 to 2019, there were 103,080 follow-up or discharge inpatient encounters. The mean (SD) provider F:D ratio and ALOS were 3.94 (0.36) and 4.45 (0.24) days, respectively. The mean (SD) case mix index (CMI) was 1.68 (0.04). There was a strong linear relationship between the F:D ratio and both ALOS and CMI-adjusted ALOS (r = 0.807; P = .014; and r = 0.814; P = .001, respectively). The mean (SD) F:D ratio for hospitalists with 1 year or less of experience compared with those with more than 1 year of experience was 4.23 (0.80) vs 3.88 (0.39), respectively (P = .012).

Conclusions: A strong linear relationship exists between the F:D ratio and ALOS. Additionally, the F:D ratio improves with experience. Provider-level billing data applied as the F:D ratio can be used as a hospitalist management and assessment tool.
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http://dx.doi.org/10.37765/ajmc.2020.88490DOI Listing
September 2020

Batch Mode Active Learning on the Riemannian Manifold for Automated Scoring of Nuclear Pleomorphism in Breast Cancer.

Artif Intell Med 2020 03 25;103:101805. Epub 2020 Jan 25.

Artificial Intelligence & Computer Vision Lab, Department of Computer Science, Cochin University of Science and Technology, Kochi, 682022, Kerala, India.

Breast cancer is the most prevalent invasive type of cancer among women. The mortality rate of the disease can be reduced considerably through timely prognosis and felicitous treatment planning, by utilizing the computer aided detection and diagnosis techniques. With the advent of whole slide image (WSI) scanners for digitizing the histopathological tissue samples, there is a drastic increase in the availability of digital histopathological images. However, these samples are often unlabeled and hence they need labeling to be done through manual annotations by domain experts and experienced pathologists. But this annotation process required for acquiring high quality large labeled training set for nuclear atypia scoring is a tedious, expensive and time consuming job. Active learning techniques have achieved widespread acceptance in reducing this human effort in annotating the data samples. In this paper, we explore the possibilities of active learning on nuclear pleomorphism scoring over a non-Euclidean framework, the Riemannian manifold. Active learning technique adopted for the cancer grading is in the batch-mode framework, that adaptively identifies the apt batch size along with the batch of instances to be queried, following a submodular optimization framework. Samples for annotation are selected considering the diversity and redundancy between the pair of samples, based on the kernelized Riemannian distance measures such as log-Euclidean metrics and the two Bregman divergences - Stein and Jeffrey divergences. Results of the adaptive Batch Mode Active Learning on the Riemannian metric show a superior performance when compared with the state-of-the-art techniques for breast cancer nuclear pleomorphism scoring, as it makes use of the information from the unlabeled samples.
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http://dx.doi.org/10.1016/j.artmed.2020.101805DOI Listing
March 2020

Proliferation of C6 glioma cells requires the phospholipid remodeling enzyme tafazzin independent of cardiolipin composition.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 03 26;1865(3):158596. Epub 2019 Dec 26.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, University of Greifswald, Ferdinand-Sauerbruch-Str., D-17475 Greifswald, Germany. Electronic address:

The mitochondrial phospholipid (CL) has been linked to mitochondrial and cellular functions. It has been postulated that the composition of CL is of impact for mitochondrial energy metabolism and cell proliferation. Although a correlation between CL composition and proliferation could be demonstrated for several cell types, evidence for a causal relationship remains obscure. Here, we applied two independent approaches, i) supplementation of fatty acids and ii) knock-out of the phospholipid remodeling enzyme tafazzin, to manipulate CL composition and analyzed the response on proliferation of C6 glioma cells. Both strategies caused substantial changes in the distribution of cellular fatty acids as well as in the distribution of fatty acids incorporated in CL that were accompanied by changes of the composition of molecular CL species. These changes did not correlate with cell proliferation. However, knock-out of tafazzin caused dramatic reduction in proliferation of C6 glioma cells independent of CL composition. The mechanism of tafazzin-dependent restriction of proliferation remains unclear. Among the various fatty acids administered only palmitic acid restricted cell proliferation by induction of cell death.
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http://dx.doi.org/10.1016/j.bbalip.2019.158596DOI Listing
March 2020

Activated clotting factor X mediates mitochondrial alterations and inflammatory responses via protease-activated receptor signaling in alveolar epithelial cells.

Eur J Pharmacol 2020 Feb 23;869:172875. Epub 2019 Dec 23.

Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Germany; St. Vincenz-Hospital, Cardiology and Intensive Care Medicine, Paderborn, Germany.

There is growing evidence for the contribution of the activated coagulation factor X (FXa) in the development of chronic inflammatory lung diseases. Therefore, we aimed to investigate effects of exogenous FXa on mitochondrial and metabolic function as well as the induction of inflammatory molecules in type II alveolar epithelial cells. Effects of FXa on epithelial cells were investigated in A549 cell line. Activation of extracellular signal-regulated kinase (ERK) and induction of inflammatory molecules were examined by immunoblot and gene expression analysis. Mitochondrial function was assessed by the measurement of oxygen consumption during maximal oxidative phosphorylation and quantitative determination of cardiolipin oxidation. Apoptosis was tested using a caspase 3 antibody. Metabolic activity and lactate dehydrogenase assay were applied for the detection of cellular viability. FXa activated ERK1/2 and induced an increase in the expression of pro-inflammatory cytokines, which was prevented by an inhibitor of FXa, edoxaban, or an inhibitor of protease-activated receptor 1, vorapaxar. Exposure to FXa caused mitochondrial alteration with restricted capacity for ATP generation, which was effectively prevented by edoxaban, vorapaxar and GB83 (inhibitor of protease-activated receptor 2). Of note, exposure to FXa did not initiate apoptosis in epithelial cells. FXa-dependent pro-inflammatory state and impairment of mitochondria did not reach the level of significance in lung epithelial cells. However, these effects might limit regenerative potency of lung epithelial cells, particular under clinical circumstances where lung injury causes exposure to clotting factors.
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http://dx.doi.org/10.1016/j.ejphar.2019.172875DOI Listing
February 2020

Vitamin B6 deficiency in new born rats affects hepatic cardiolipin composition and oxidative phosphorylation.

Exp Biol Med (Maywood) 2019 12 21;244(18):1619-1628. Epub 2019 Nov 21.

Department of Pathological Biochemistry, Otto-von-Guericke University Magdeburg, Magdeburg D-39120, Germany.

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http://dx.doi.org/10.1177/1535370219889880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963376PMC
December 2019

Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion.

Circ Cardiovasc Qual Outcomes 2019 11 11;12(11):e006073. Epub 2019 Nov 11.

Program On Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School in Boston, MA (Z.L., F.A.T., A.S.K.).

Background: Recent court decisions have thrown into question the Food and Drug Administration's rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians' beliefs about drug efficacy.

Methods And Results: In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%, <0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, -6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, -24% to 7%]).

Conclusions: Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers' knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.119.006073DOI Listing
November 2019

Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.

Genes Dev 2019 10 22;33(19-20):1355-1360. Epub 2019 Aug 22.

Department of Biochemistry, Max Planck Institute for Developmental Biology, D-72076 Tübingen, Germany.

GIGYF (Grb10-interacting GYF [glycine-tyrosine-phenylalanine domain]) proteins coordinate with 4EHP (eIF4E [eukaryotic initiation factor 4E] homologous protein), the DEAD (Asp-Glu-Ala-Asp)-box helicase Me31B/DDX6, and mRNA-binding proteins to elicit transcript-specific repression. However, the underlying molecular mechanism remains unclear. Here, we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6. A 2.4 Å crystal structure of the GIGYF-Me31B complex reveals that this motif arranges into a coil connected to a β hairpin on binding to conserved hydrophobic patches on the Me31B RecA2 domain. Structure-guided mutants indicate that 4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated down-regulation of an AU-rich mRNA, thus revealing the molecular principles of translational repression.
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http://dx.doi.org/10.1101/gad.329219.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771390PMC
October 2019

Use of silicon nanoparticle surface coating in infection control: Experience in a tropical healthcare setting.

Infect Dis Health 2019 11 16;24(4):201-207. Epub 2019 Jul 16.

Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka.

Background: A nano-scale surface coating containing silicon nanoparticles (Bacterlon®) creates a hydrophobic surface which prevents the growth of bacteria. Study objective was to evaluate the performance of this silicon nano-coating in Sri Lankan healthcare setting.

Methods: This prospective study was conducted from September 2015 to December 2015 in an Intensive Care Unit and a medical ward in Base Hospital Homagama and a bacteriology laboratory in Medical Research Institute, Colombo, Sri Lanka. Silicon nanoparticle coating was applied to 19 high touch surfaces from those three sites. During the follow-up period, these test sites and non-coated control sites were used for routine work and were cleaned routinely as per institute protocol. Swabbing was done for coated and non-coated sites once a week for 12 weeks at unannounced times. Surfaces were categorized in to low (≤10 CFU/cm) and high (>10-99 CFU/cm) contamination by Aerobic Bacterial Count (ABC) in non-coated sites at any given time.

Results: In low and high contaminated surfaces, an improvement in the mean percentage bioburden reduction from 36.18% to 50.16% was observed from 4th week to 12th week with silicon nanoparticles and a significant reduction (p < 0.05) was seen in ABC in each of the coated surface compared with their non-coated counterpart by the 12th week. The frequency of isolation of Acinetobacter spp. on coated surfaces had a significant reduction (p < 0.01).

Conclusion: Silicon nanoparticle coating demonstrates a significant reduction of the bacterial bioburden in low and high contaminated surfaces for 12 weeks in a tropical healthcare setting.
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http://dx.doi.org/10.1016/j.idh.2019.06.006DOI Listing
November 2019

Awakening the Sleeping Carboxylase Function of Enzymes: Engineering the Natural CO-Binding Potential of Reductases.

J Am Chem Soc 2019 06 14;141(25):9778-9782. Epub 2019 Jun 14.

Department of Biochemistry and Synthetic Metabolism , Max Planck Institute for Terrestrial Microbiology , Karl-von-Frisch-Straße 10 , D-35043 Marburg , Germany.

Developing new carbon dioxide (CO) fixing enzymes is a prerequisite to create new biocatalysts for diverse applications in chemistry, biotechnology and synthetic biology. Here we used bioinformatics to identify a "sleeping carboxylase function" in the superfamily of medium-chain dehydrogenases/reductases (MDR), i.e. enzymes that possess a low carboxylation side activity next to their original enzyme reaction. We show that propionyl-CoA synthase from Erythrobacter sp. NAP1, as well as an acrylyl-CoA reductase from Nitrosopumilus maritimus possess carboxylation yields of 3 ± 1 and 4.5 ± 0.9%. We use rational design to engineer these enzymes further into carboxylases by increasing interactions of the proteins with CO and suppressing diffusion of water to the active site. The engineered carboxylases show improved CO-binding and kinetic parameters comparable to naturally existing CO-fixing enzymes. Our results provide a strategy to develop novel CO-fixing enzymes and shed light on the emergence of natural carboxylases during evolution.
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http://dx.doi.org/10.1021/jacs.9b03431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650136PMC
June 2019

Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression.

Nucleic Acids Res 2019 07;47(13):7035-7048

Department of Biochemistry, Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, D-72076 Tübingen, Germany.

The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5'-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila melanogaster (Dm) GIGYF protein in post-transcriptional mRNA regulation. We show that, when in complex with 4EHP, Dm GIGYF not only elicits translational repression but also promotes target mRNA decay via the recruitment of additional effector proteins. We identified the RNA helicase Me31B/DDX6, the decapping activator HPat and the CCR4-NOT deadenylase complex as binding partners of GIGYF proteins. Recruitment of Me31B and HPat via discrete binding motifs conserved among metazoan GIGYF proteins is required for downregulation of mRNA expression by the 4EHP-GIGYF complex. Our findings are consistent with a model in which GIGYF proteins additionally recruit decapping and deadenylation complexes to 4EHP-containing RNPs to induce translational repression and degradation of mRNA targets.
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http://dx.doi.org/10.1093/nar/gkz429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648886PMC
July 2019

U.S. Internists' Perspectives on Discussing Cost of Care With Patients: Structured Interviews and a Survey.

Ann Intern Med 2019 05;170(9_Suppl):S39-S45

American College of Physicians, Philadelphia, Pennsylvania (A.W., S.R., C.D.S., W.N.).

Background: Rising out-of-pocket costs are creating a need for cost conversations between patients and physicians.

Objective: To understand the factors that influence physicians to discuss and consider cost during a patient encounter.

Design: Mixed-methods study using semistructured interviews and a survey.

Setting: United States.

Participants: 20 internal medicine physicians were interviewed; 621 internal medicine physician members of the American College of Physicians completed the survey.

Measurements: Interviews were analyzed by using thematic analysis, and surveys were analyzed by using descriptive statistics.

Results: From the interviews, 4 themes were identified: Physicians are 1) aware that patients are struggling to afford medical care; 2) relying on clues from patients that hint at their cost sensitivity; 3) relying on experience to anticipate potentially high-cost treatments; and 4) aware that patients are making financial trade-offs to afford their care. Three quarters (n = 466) of survey respondents stated that they consider out-of-pocket costs when making most clinical decisions. For 31% (n = 191) of participants, there were times in the past year that they wanted to discuss out-of-pocket prescription drug costs with patients but did not. The most influential factors for ordering a test are the desire to be as thorough as possible (71% [n = 422]) and insurance coverage for the test (68% [n = 422]).

Limitation: Findings are self-reported, the sample is limited to a single specialty, the survey response rate was low, information on the patient population was limited, and the survey instrument is not validated.

Conclusion: Physicians are attuned to the burden of health care costs and are willing to consider alternative options based on a patient's cost sensitivity.

Primary Funding Source: Robert Wood Johnson Foundation.
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http://dx.doi.org/10.7326/M18-2136DOI Listing
May 2019

Bathing Suit Variant of Autosomal Recessive Congenital Ichthyosis (ARCI) in Two Indian Patients.

Case Rep Dermatol Med 2018 30;2018:3140473. Epub 2018 Dec 30.

Department of Dermatology, University Hospital Muenster, Muenster, Germany.

Bathing suit ichthyosis (BSI) is a rare variant of autosomal recessive congenital ichthyosis (ARCI) due to transglutaminase-1 gene () mutations leading to a temperature sensitive phenotype. It is characterized by dark-grey or brownish scaling restricted to the "bathing suit" areas. We report two Indian girls with bathing suit ichthyosis and mutations in (patient 1: homozygous for c.1147G>A; patient 2: compound heterozygous for c.832G>A, c.919C>G).
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http://dx.doi.org/10.1155/2018/3140473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332984PMC
December 2018

Age-Dependent Protection of Insulin Secretion in Diet Induced Obese Mice.

Sci Rep 2018 12 13;8(1):17814. Epub 2018 Dec 13.

Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, and the William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Type 2 diabetes is an age-and-obesity associated disease driven by impairments in glucose homeostasis that ultimately result in defective insulin secretion from pancreatic β-cells. To deconvolve the effects of age and obesity in an experimental model of prediabetes, we fed young and aged mice either chow or a short-term high-fat/high-sucrose Western diet (WD) and examined how weight, glucose tolerance, and β-cell function were affected. Although WD induced a similar degree of weight gain in young and aged mice, a high degree of heterogeneity was found exclusively in aged mice. Weight gain in WD-fed aged mice was well-correlated with glucose intolerance, fasting insulin, and in vivo glucose-stimulated insulin secretion, relationships that were not observed in young animals. Although β-cell mass expansion in the WD-fed aged mice was only three-quarters of that observed in young mice, the islets from aged mice were resistant to the sharp WD-induced decline in ex vivo insulin secretion observed in young mice. Our findings demonstrate that age is associated with the protection of islet function in diet-induced obese mice, and furthermore, that WD challenge exposes variability in the resilience of the insulin secretory pathway in aged mice.
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http://dx.doi.org/10.1038/s41598-018-36289-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292902PMC
December 2018

Barriers to Earlier Hospital Discharge: What Matters Most?

J Hosp Med 2018 12;13(12):872-874

Associate Professor of Medicine, Cleveland Clinic Lerner School of Medicine at Case Western Reserve University, Cleveland, Ohio, USA.

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http://dx.doi.org/10.12788/jhm.3094DOI Listing
December 2018

The multicatalytic compartment of propionyl-CoA synthase sequesters a toxic metabolite.

Nat Chem Biol 2018 12 29;14(12):1127-1132. Epub 2018 Oct 29.

Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.

Cells must cope with toxic or reactive intermediates formed during metabolism. One coping strategy is to sequester reactions that produce such intermediates within specialized compartments or tunnels connecting different active sites. Here, we show that propionyl-CoA synthase (PCS), an ∼ 400-kDa homodimer, three-domain fusion protein and the key enzyme of the 3-hydroxypropionate bi-cycle for CO fixation, sequesters its reactive intermediate acrylyl-CoA. Structural analysis showed that PCS forms a multicatalytic reaction chamber. Kinetic analysis suggested that access to the reaction chamber and catalysis are synchronized by interdomain communication. The reaction chamber of PCS features three active sites and has a volume of only 33 nm. As one of the smallest multireaction chambers described in biology, PCS may inspire the engineering of a new class of dynamically regulated nanoreactors.
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http://dx.doi.org/10.1038/s41589-018-0153-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499725PMC
December 2018

Chemical diversity and anti-proliferative activity of marine algae.

Nat Prod Res 2019 Jul 25;33(14):2120-2124. Epub 2018 Sep 25.

b Department of Environmental Biotechnology , Bharathidasan University , Tiruchirappalli , India.

The chemical diversity of three macroalgae ( sp) were determined using the GC-MS method with principal component analysis (PCA) and their potential efficacy against human pathogens and cervical carcinoma cells evaluated using MTT bioassay method. Our results showed that >30 metabolites were detected in three seaweeds, among these, steroids and fatty acids are the most dominant chemical group that highly contributes to discriminate this species. The PCA of GC-MS mass spectral variables showed a clear discrimination between three different species based on the phytochemical diversity of seaweeds. The extracts of exhibited anti-microbial activity with (6.00 mm) and showed potential anti-proliferative activity against the HeLa cells (IC 37 µmol/L) at concentration 1-50 µM treatment. Results of this study concluded that PCA analysis of mass spectral variables could be utilized as a reliable tool for species discrimination and chemotaxonomic classification of seaweeds.
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http://dx.doi.org/10.1080/14786419.2018.1488701DOI Listing
July 2019

Setting sun pattern in dermoscopy of a scalp nodule.

Australas J Dermatol 2019 Feb 3;60(1):71-72. Epub 2018 Sep 3.

Department of Pathology, Christian Medical College, Vellore, India.

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http://dx.doi.org/10.1111/ajd.12912DOI Listing
February 2019

Skin fragility, woolly hair syndrome with a desmoplakin mutation - a case from India.

Int J Dermatol 2018 09 25;57(9):e73-e75. Epub 2018 Jun 25.

Pachyonychia Congenita Project, Holladay, UT, USA.

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http://dx.doi.org/10.1111/ijd.14096DOI Listing
September 2018