Hyperoxia evokes pericyte-mediated capillary constriction

Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF. Here, we used bright-field imaging of cerebral capillaries and modeling of CBF to show that hyperoxia (95% superfused O₂) led to an increase in intracellular calcium level in pericytes and a significant capillary constriction, sufficient to cause an estimated 25% decrease in CBF. Although hyperoxia is reported to cause vascular smooth muscle cell contraction via generation of reactive oxygen species (ROS), endothelin-1 and 20-HETE, we found that increased cytosolic and mitochondrial ROS levels and endothelin release were not involved in the pericyte-mediated capillary constriction. However, a 20-HETE synthesis blocker greatly reduced the hyperoxia-evoked capillary constriction. Our findings establish pericytes as regulators of CBF in hyperoxia and 20-HETE synthesis as an oxygen sensor in CBF regulation. The results also provide a mechanism by which clinically administered oxygen can lead to a worse neurological outcome.     

Suppression of the USP10/CCND1 axis induces glioblastoma cell apoptosis

Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs.     

Levels and determinants of malnutrition among India's urban poor women: An analysis of Demographic Health Surveys 2006 and 2016

A quarter of 400 million urban Indian residents are poor. Urban poor women are as undernourished as or worse than rural women but urban averages mask this disparity. We present the spectrum of malnutrition and their determinants for more than 26,000 urban women who gave birth within 5 years from the last two rounds of Demographic Health Survey 2006 and 2016. Among urban mothers in the lowest quartile by wealth index (urban poor), 12.8% (95% CI [11.3%, 14.5%]) were short or with height < 145 cm; 20.6% (95% CI [19%, 22.3%]) were thin or with body mass index < 18.5 kg/m²; 57.4% (95% CI [55.5%, 59.3%]) had any anaemia (haemoglobin < 12 g/dL), whereas 32.4% (95% CI [30.5%, 34.3%]) had moderate to severe anaemia; and 21.1% (95% CI [19.3%, 23%]) were obese (body mass index ≥ 25 kg/m²). Decadal gains were significant for thinness reduction (17p.p.) but obesity increased by 12 p.p. Belonging to a tribal household increased odds of thinness by 1.5 (95% CI [1.06, 2.18]) times among urban poor mothers compared with other socially vulnerable groups. Secondary education reduced odds of thinness (0.61; 95% CI [0.48, 0.77]) and higher education of short stature (0.41; 95% CI [0.18, 0.940]). Consuming milk/milk products, pulses/beans/eggs/meats, and dark green leafy vegetables daily reduced the odds of short stature (0.52; 95% CI [0.35, 0.78]) and thinness (0.72; 95% CI [0.54, 0.98]). Urban poor mothers should be screened for nutritional risks due to the high prevalence of all forms of malnutrition and counselled or treated as per risk.     

Iatrogenic coronary artery stenosis following aortic valve replacement.

Until recnetly, coronary arterial perfusion was one of the best methods to protect myocardium during aortic valve replacement. However, the insertion of perfusion cannulas may produce immediate traumatic lesions and late stenosis of the coronary arteries, with grave consequences. Two patients with normal coronary arteries prior to operation developed obstruction of the maximal left main coronary artery following aortic replacement. One of these patients represents the first case of iatrogenic coronary arterial stenosis in which the aortic valve was replaced with a porcine bioprosthesis. Accelerating angina pectoris and ventricular arrhythmias were the presenting clinical manifestations. Aorta-coronary bypass grafting to the left anterior descending and circumflex coronary arteries was successfully performed in one patient, while the other patient died before investigative procedures could be undertaken. Any patient whose aortic valve has been replaced and who develops angina pectoris a few months after operation should be suspected of having developed stenosis of the proximal coronary artery. Coronary angiography should be perfomed promptly. Once the lesion is recognized, the operaiton should be performed posthaste because these lesions are life threatening owing to their proximal location and rapid evolution.     

DIY artificial pancreas: A narrative of the first patient and the physicians’ experiences from India

Background aimsFrustrated with the slow-pace of innovations in diabetes technologies, the type 1 diabetes community have started closing the loop by themselves to automate insulin delivery. While the regulatory and ethical concerns over the systems are still high, these have contributed to enhanced glycemic control characterized by improved estimated HbA1c and time-in-range above 90% as for many users. Our objective is to provide the real-world experience of the first successful patient from India on the Do-It-Yourself Artificial Pancreas (DIYAP) and the perspective of her physicians.MethodsA narrative recounting of a personal experience on DIYAP. The patient completed a Hypoglycemia Fear Survey II and Diabetes Quality of Life instrument before and after looping.ResultsThe patient emphasized the personal/social benefits and the concerns of using the system. Looping has produced a clinically meaningful difference in the quality of life, better sleep patterns, and reduced the disease management burden. We also highlighted the relevant perspectives of the physicians to give deeper insights into the aspect.ConclusionThe patient highlighted better time-in-range, negligible time spent in hypoglycemia, and superior Quality of Life. Globally, more and more patients are adopting this technology; therefore, real-life patient stories will enlighten the medical community.