A retrospective study on the clinical picture of COVID-19 patients associated with type 2 diabetes mellitus in India

Background: The clinical characterization of COVID varies from mild to severe. In the initial phases of the disease, symptoms like fever, cough, and dyspnea can occur. The severity and outcome of COVID vary with preexisting conditions, particularly type 2 diabetes mellitus (T2DM). Objective of current study was to assess the clinical presentation and laboratory derangements of COVID-19 patients associated with T2DM.Methods: The present retrospective study was started after the approval of the Institutional Ethics Committee. Various clinical (Sp02, final diagnosis, co-morbidity, and outcome) and biochemical parameters (CBC, LFT, RFT, LDH, Trop I, CK-MB D-dimer, CRP, ferritin levels, RBS, HbA1c) of Covid-19 patients were collected from Central Laboratory and & Medical Record Department of our institution. Patient names were anonymized and data were analyzed. The results are expressed in percentages.Results: A total of 24 COVID-19 patients (with T2DM) details were collected from the medical record department and central laboratory. Out of 24 patients, 16 (66.6%) were male, and the remaining 08 (33.3%) were female. Out of 24, 05 patients had mild covid, 02 were moderate and the remaining 17 suffered from severe COVID. The mean values of oxygen saturation, LDH, D-dimer, Troponin-I, CRP, Ferritin, Procalcitonin, and CK-MB were 76%, 797.3 U/l, 1614.2 ng/ml, 6.93 ng/ml, 72.6 mg/dl, 521.2 µg/l, 2.33 µg/l and 40.59 ng/ml respectively. The average random blood sugar level and glycosylated hemoglobin were 308.8 mg/dl and HbA1c 10.22%. Mean values of 42.5 mg/dl and 1.54 mg/dl were recorded for blood urea and S. creatinine. Regarding liver function test, mean values of 0.87 mg/dl, 0.37 mg/dl, 0.49mg/dl, 344.8U/l, 115.6U/l,108U/l respectively noted for total bilirubin, direct, indirect, SGOT, SGPT and ALP. Regarding patient outcome, 09 (37.5%) patients recovered and 15 (62.5%) died due to COVID. The values of glycosylated Hb and random blood sugar among the 15 patients who died due to covid infection suggested uncontrolled diabetes Mellitus in 7 of them with associated hypertension and died due to septic shock. Conclusions: Though the laboratory mean values of the liver function test and renal function test shows moderate variations the mean values of CRP, LDH, Procalcitonin, and Ferritin which are the acute inflammatory markers are highly disrupted when compared to normal ranges. 

Modeling vesicle traffic reveals unexpected consequences for Cdc42p-mediated polarity establishment

SummaryBackgroundPolarization in yeast has been proposed to involve a positive feedback loop whereby the polarity regulator Cdc42p orients actin cables, which deliver vesicles carrying Cdc42p to the polarization site. Previous mathematical models treating Cdc42p traffic as a membrane-free flux suggested that directed traffic would polarize Cdc42p, but it remained unclear whether Cdc42p would become polarized without the membrane-free simplifying assumption.ResultsWe present mathematical models that explicitly consider stochastic vesicle traffic via exocytosis and endocytosis, providing several new insights. Our findings suggest that endocytic cargo influences the timing of vesicle internalization in yeast. Moreover, our models provide quantitative support for the view that integral membrane cargo proteins would become polarized by directed vesicle traffic given the experimentally determined rates of vesicle traffic and diffusion. However, such traffic cannot effectively polarize the more rapidly diffusing Cdc42p in the model without making additional assumptions that seem implausible and lack experimental support.ConclusionsOur findings suggest that actin-directed vesicle traffic would perturb, rather than reinforce, polarization in yeast

“How can our children learn from us about our way of life or understand who they are?”:Residential schools and their impact on the wellbeing of Indigenous youth in Attapadi, South India

Residential schools are commonly used in India to provide education for Indigenous youth, which requires young people to stay for long periods at distance from their families and communities. Internationally, there is clear evidence for the deleterious effects of residential schools on the mental health and social and community outcomes of Indigenous children, however little is known about the Indian Indigenous experience. This study examined the impact of residential schooling on Indigenous children's wellbeing and that of their communities, using data from an ethnographic research project in Attapadi, Kerala, including interviews, focus group discussions and participant observation with Indigenous communities. Key outcomes from residential schooling reported by the participants include the fear of losing Indigenous identity, shame of being Indigenous, change in the attitude of young people when they returned from schools, and feelings of confusion and stress that young Indigenous participants felt trying to fit into their communities on their return. Findings suggest that these Indigenous youth felt disconnected from several factors that are known to promote resilience for Indigenous communities including a strong cultural identity, connection to the land and ancestors, thereby making them more vulnerable to poor mental health and negative impacts on their overall wellbeing. Addressing these concerns requires a detailed understanding of the specific factors influencing outcomes for Indigenous youth within the Indian residential schooling system, and designing and implementing data-informed conceptual, structural and policy change including the provision of culturally safe mental health services.</p

A PROSPECTIVE STUDY ON GASTRIC BLEEDING AND DRUG INTERACTIONS ASSOCIATED WITH ANTICOAGULANT THERAPY AT CARDIOLOGY DEPARTMENT OF A TERTIARY CARE HOSPITAL

Background: Anticoagulants are the class of drugs that are used to prevent thrombus extension and embolic complications by reducing the rate of fibrin formation. They do not dissolve already formed clot but prevent recurrences. Method: A total of 200 patients were included in these prospective, uni-centric, observational studies who were suffering from Cardiovascular Diseases, from the cardiology inpatient department at a tertiary care hospital in Bangalore. Results: It was observed that out of 200 patients included in the study, 122 (61%) patients were treated with anticoagulants and antiplatelets, 75(37.5%) were treated with anticoagulants only. Out of 200 prescriptions encountered, 198 (99%) prescriptions have rational use of anticoagulants and only 2 (1%) were irrational. It was also observed that only 0.5% was present with GI bleeding whereas 2% of the total population was present with other side effects like nasal bleeding, haematuria, etc. Among 200 prescriptions, 251 drug interactions were found with anticoagulants. where Heparin and Aspirin was the most frequently encountered (23.1%) interaction, The least (0.4%) seen drug interactions were Aspirin & Warfarin, Heparin & Eptifibatide, Enoxaparin & Eptifibatide, Heparin & Tirofiban, Heparin & Enoxaparin, Warfarin & Tramadol, Warfarin & Amoxicillin & Glipizide and Heparin. Keywords: GI Bleeding, Anticoagulant

Akt and SHIP Modulate Francisella Escape from the Phagosome and Induction of the Fas-Mediated Death Pathway

Francisella tularensis infects macrophages and escapes phago-lysosomal fusion to replicate within the host cytosol, resulting in host cell apoptosis. Here we show that the Fas-mediated death pathway is activated in infected cells and correlates with escape of the bacterium from the phagosome and the bacterial burden. Our studies also demonstrate that constitutive activation of Akt, or deletion of SHIP, promotes phago-lysosomal fusion and limits bacterial burden in the host cytosol, and the subsequent induction of Fas expression and cell death. Finally, we show that phagosomal escape/intracellular bacterial burden regulate activation of the transcription factors sp1/sp3, leading to Fas expression and cell death. These data identify for the first time host cell signaling pathways that regulate the phagosomal escape of Francisella, leading to the induction of Fas and subsequent host cell death

Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP

Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida–induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida–induced cytokine production through the inhibition of NFκB. Consistently, macrophages lacking SHIP displayed enhanced NFκB-driven gene transcription, whereas overexpression of SHIP led to decreased NFκB activation. Thus, we propose that SHIP negatively regulates F. novicida–induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFκB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia

Molecular Mechanisms of Bortezomib Resistant Adenocarcinoma Cells

Bortezomib (Velcade™) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ∼30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response

MiR-155 Induction by F. novicida but Not the Virulent F. tularensis Results in SHIP Down-Regulation and Enhanced Pro-Inflammatory Cytokine Response

The intracellular Gram-negative bacterium Francisella tularensis causes the disease tularemia and is known for its ability to subvert host immune responses. Previous work from our laboratory identified the PI3K/Akt pathway and SHIP as critical modulators of host resistance to Francisella. Here, we show that SHIP expression is strongly down-regulated in monocytes and macrophages following infection with F. tularensis novicida (F.n.). To account for this negative regulation we explored the possibility that microRNAs (miRs) that target SHIP may be induced during infection. There is one miR that is predicted to target SHIP, miR-155. We tested for induction and found that F.n. induced miR-155 both in primary monocytes/macrophages and in vivo. Using luciferase reporter assays we confirmed that miR-155 led to down-regulation of SHIP, showing that it specifically targets the SHIP 3′UTR. Further experiments showed that miR-155 and BIC, the gene that encodes miR-155, were induced as early as four hours post-infection in primary human monocytes. This expression was dependent on TLR2/MyD88 and did not require inflammasome activation. Importantly, miR-155 positively regulated pro-inflammatory cytokine release in human monocytes infected with Francisella. In sharp contrast, we found that the highly virulent type A SCHU S4 strain of Francisella tularensis (F.t.) led to a significantly lower miR-155 response than the less virulent F.n. Hence, F.n. induces miR-155 expression and leads to down-regulation of SHIP, resulting in enhanced pro-inflammatory responses. However, impaired miR-155 induction by SCHU S4 may help explain the lack of both SHIP down-regulation and pro-inflammatory response and may account for the virulence of Type A Francisella