Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity.

To migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to 'listen' to receptor inputs and respond to directional reprogramming.

SUMO fosters assembly and functionality of the MutSγ complex to facilitate meiotic crossing over.

Crossing over is essential for chromosome segregation during meiosis. Protein modification by SUMO is implicated in crossover control, but pertinent targets have remained elusive. Here we identify Msh4 as a target of SUMO-mediated crossover regulation. Msh4 and Msh5 constitute the MutSγ complex, which stabilizes joint-molecule (JM) recombination intermediates and facilitates their resolution into crossovers. Msh4 SUMOylation enhances these processes to ensure that each chromosome pair acquires at least one crossover. Msh4 is directly targeted by E2 conjugase Ubc9, initially becoming mono-SUMOylated in response to DNA double-strand breaks, then multi/poly-SUMOylated forms arise as homologs fully engage. Mechanistically, SUMOylation fosters interaction between Msh4 and Msh5. We infer that initial SUMOylation of Msh4 enhances assembly of MutSγ in anticipation of JM formation, while secondary SUMOylation may promote downstream functions. Regulation of Msh4 by SUMO is distinct and independent of its previously described stabilization by phosphorylation, defining MutSγ as a hub for crossover control.

Hiccups and hyponatremia: Unusual co-presentation in COVID-19.

Coronavirus disease (COVID-19) is the newly discovered infectious disease, affecting millions worldwide. Majority of the patients present with mild respiratory syndrome. Some neurological symptoms are reported like anosmia & dysgeusia. We are presenting a case with hiccups as an unusual symptom. An elderly male patient presented to Bapuji teaching hospital attached to JJM medical college, Davangere on 24th July 2020 with intractable hiccups in the last 5 days. There were no other symptoms. Patient's saturation was initially 98% at room air which then dropped to 90%. Based on clinical knowhow, SARS-Cov-2 RNA qualitative RT-PCR test was sent, and the results came positive. Patient improved symptomatically in 2 days and was kept in ward for observation for a total of 7 days. This extremely rare case report brings to light new atypical symptom of COVID-19 are being presented every other day, which shows how the importance being aware of the same.

Prognosis of COVID-19: Red Cell Distribution Width, Platelet Distribution Width, and C-Reactive Protein.

Introduction Cytokine storm is central in the pathobiology of Coronavirus disease 2019 (COVID-19). The pro-inflammatory state and hypoxia disrupt erythropoiesis leading to alterations in red cell distribution width (RDW) and hematocrit. Platelet production increases alongside its destruction, inviting newly formed immature platelets into the circulation. Thus, the platelet distribution width (PDW) and mean platelet volume (MPV) are also affected. The study's objective is to analyze these indices and C-reactive protein (CRP) to elucidate prognostic insights in COVID-19 patients at the time of admission. Methodology This study was a retrospective cross-sectional study conducted at Chigateri General Hospital, attached to JJM Medical College, Davangere, over two months, July and August of 2020. Patients falling under categories B and C according to the interim guidelines issued by the Ministry of Health and Family Welfare, Government of India were enrolled in this study. Patients requiring mechanical ventilation and those with a prior diagnosis of malignancy were excepted from the study. Results The study population comprised a total of hundred patients. Seventy-five patients survived the disease and were discharged; twenty-five patients succumbed to the viral illness. The mean age of survivors (43.0 +/- 13.6 years) was significantly lesser than that of non-survivors (59.1 +/- 11.5 years) (p <0.001). RDW was significantly different among survivors (p=0.002); PDW and CRP were lower among the deceased (p=0.05 and p=0.10, respectively). Cut off values for RDW as 15%, CRP as 67 mg/l, and PDW as 17% were significantly associated with mortality. Hematocrit and MPV were not significantly associated with mortality. RDW has a sensitivity of 92% and a negative predictive value of 95% in predicting mortality. Discussion RDW showed a significant association with increased mortality. Impaired cell-mediated immunity at the onset of infection is responsible for rapid progression to moderate or even severe COVID disease. Since the investigations in our study were ordered at the time of admission, it may lead us to believe that higher RDW is associated with a better patient outcome. Lower C-reactive protein levels are associated with higher mortality. CRP is a non-specific marker for inflammation. Raised CRP is customarily an indicator of acute inflammation. Notwithstanding, the raised CRP may be an indicator of baseline immune response in early COVID infection. High PDW shows a significant association with increased mortality. The pathobiology of change in platelet indices in COVID-19 patients is presumably multifactorial: infection of the bone marrow; autoimmune platelet destruction; platelet sequestration.  Conclusion Red cell distribution width, platelet distribution width, and C-reactive protein are useful early predictive markers of mortality in COVID-19. Although serial investigations would provide a better picture, these indices at admission can gauge the clinical outcome early in the disease. As there is still a lot to be understood about the natural history of COVID-19, our study aims to propose relatively inexpensive indices of mortality that can aid efficient management.

Neutrophil-to-Lymphocyte, Lymphocyte-to-Monocyte, and Platelet-to-Lymphocyte Ratios: Prognostic Significance in COVID-19.

Background and objective Neutrophils are primarily responsible for activating the immune system, and systemic inflammation destroys CD4+ T lymphocytes and increases suppressor CD8+ T lymphocytes, thereby leading to an increased neutrophil-to-lymphocyte ratio (NLR). An increase in the apoptosis of lymphocytes leads to lymphopenia and elevated thrombopoietin (THPO) promotes megakaryocyte production. The reflections of these inflammatory changes can be vital in gauging the progression of the disease. This study aimed at examining the prognostic value of normal and derived neutrophil-to-lymphocyte, lymphocyte-to-monocyte, platelet-to-lymphocyte, and mean platelet volume (MPV)-to-platelet count ratios in patients with coronavirus disease 2019 (COVID-19). Methodology This was a retrospective cross-sectional study conducted in the wards of Chigateri General Hospital, Davangere for a period of two months. Complete blood count was ordered for all patients at the time of admission along with confirmation of the disease by reverse transcription-polymerase chain reaction (RT-PCR). Results The final study population consisted of 100 patients. The mean age of patients who survived (43 years) was significantly lower than the mean age of non-survivors (59.1 years), with a p-value of <0.001. NLR was raised in 60% of the population and was significantly higher in patients who survived the disease, with a p-value of 0.004. The platelet-to-lymphocyte ratio (PLR) also followed a similar trend with a p-value of 0.017. Even though the lymphocyte-to-monocyte ratio (LMR) also mimicked the trend, the statistical association was not significant (p-value: 0.09). The derived NLR and MPV-to-platelets ratios were not found to be significantly associated with mortality in this study. Discussion Younger patients had better clinical outcomes in our study population compared to the geriatric age group. A significant correlation between LMR and mortality was observed when a cut-off of 2.5 was considered as a differentiating benchmark. Conflicting trends were observed in NLR and PLR in our study; however, LMR was in accordance with most other studies. The phase that a patient is in with regard to the natural history of the disease also influences the blood cell ratios. Nonetheless, all three ratios can be used as crucial screening and prognostic tools as they are readily available with the help of a complete hemogram. This is an investigation modality that is widely accessible even in remote areas and resource-limited settings. Conclusion These hematological ratios can facilitate in categorizing the disease severity and progression in patients, thereby enabling us to make appropriate and informed clinical decisions. Since the second wave of the novel coronavirus is on the verge of arrival, it is imperative to channel resources for the patients early in their disease course to ultimately prevent complications and reduce mortality.

Hepatitis A: A refreshing perspective through a rare symptom in a teaching hospital in south India.

Hepatitis A virus is a common cause of acute viral hepatitis in India, due to lack of clean water and sanitation. Usual presentations include gastroenteritis or a viral respiratory infection. Hepatitis A has a variety of extra-hepatic manifestations which, if failed to be recognized, evades diagnosis. A 28-year-old lady presented with pain abdomen for 1 week, fever with rashes for 1 day. Patient was febrile at the time of examination. Rash was maculopapular with irregular edges, tender. On examining abdomen, tenderness noted in right hypochondrium and epigastrium with hepatomegaly. Patient was then admitted. Working diagnosis was Viral hepatitis for evaluation. Hepatitis A serology was sent which came positive for Ig M. Patient was treated with IV fluids, bile acid sequestrants, IV PPI, IV and oral antibiotics, antihistamines and 3 doses of injection Vit K. Calamine lotion was also given for skin care. Patient improved symptomatically in 2 days and was discharged after 3 days of hospital stay. In our case, the maculopapular rash spreading to the whole body was the major presenting symptom. The presentation of Hepatitis A with rashes maybe seen in around 10% of patients with extrahepatic manifestations along with arthralgia. Differential diagnosis in this case should be erythema multiforme which is the most common maculopapular eruptive rash. Other viral hepatitis causing agents (Hepatitis B&E) have been documented to present with rashes. SLE and Kawasaki disease rarely present with fever with rash with nonspecific multisystemic involvement. Borrelia, Leptospira also have icterus in their presentations. Early diagnosis and management in this case prevented complication such as autoimmune hepatitis, pleural effusion, ascites acute kidney injury. This case presentation urges the need to consider Hepatitis A to be an important differential diagnosis of fever with rash especially in tropical/sub-tropical countries with poor sanitation.