To investigate the epidemiological and clinical features of patients with COVID-19 in Anhui province of China. Method: In this descriptive study, we obtained epidemiological, demographic, manifestations, laboratory data and radiological findings of patients confirmed by real-time RT-PCR in the NO.2 People's Hospital of Fuyang City from Jan 20 to Feb 9, 2020. Clinical outcomes were followed up to Feb 18, 2020. Results: Of 125 patients infected SARS-CoV-2, the mean age was 38.76 years (SD, 13.799) and 71(56.8%) were male. Common symptoms include fever [116 (92.8%)], cough [102(81.6%)], and shortness of breath [57(45.6%)]. Lymphocytopenia developed in 48(38.4%) patients. 100(80.0%) patients showed bilateral pneumonia, 26(20.8%) patients showed multiple mottling and ground-glass opacity. All patients were given antiviral therapy. 19(15.2%) patients were transferred to the intensive care unit. By February 18, 47 (37.6%) patients were discharged and none of patients died. Among the discharged patients, the median time of length of stay was 14.8 days (SD 4.16). Conclusion:In this single-center, retrospective, descriptive study, fever is the most common symptom. Old age, chronic underlying diseases and smoking history may be risk factors to worse condition. Certain laboratory inspection may contribute to the judgment of the severity of illness.

The nodal regulatory properties of microRNAs (miRNA) in metastatic cancer may offer new targets for therapeutic control. Here, we report that upregulation of miR-483-5p is correlated with the progression of human lung adenocarcinoma. miR-483-5p promotes the epithelial-mesenchymal transition (EMT) accompanied by invasive and metastatic properties of lung adenocarcinoma. Mechanistically, miR-483-5p is activated by the WNT/b-catenin signaling pathway and exerts its prometastatic function by directly targeting the Rho GDP dissociation inhibitor alpha (RhoGDI1) and activated leukocyte cell adhesion molecule (ALCAM), two putative metastasis suppressors. Furthermore, we found that downregulation of RhoGDI1 enhances expression of Snail, thereby promoting EMT. Importantly, miR-483-5p levels are positively correlated with b-catenin expression, but are negatively correlated with the levels of RhoGDI1 and ALCAM in human lung adenocarcinoma. Our findings reveal that miR-483-5p is a critical b-catenin-activated prometastatic miRNA and a negative regulator of the metastasis suppressors RhoGDI1 and ALCAM. Cancer Res; 74(11); 3031-42. Ó2014 AACR.

It has been postulated that specialized glucose-sensing neurons in the ventromedial hypothalamus (VMH) are able to detect falling blood glucose and trigger the release of counterregulatory hormones during hypoglycemia. The molecular mechanisms used by glucose-sensing neurons are uncertain but may involve cell surface ATP-sensitive K ؉ channels (K ATP channels) analogous to those of the pancreatic ␤-cell. We examined whether the delivery of sulfonylureas directly into the brain to close K ATP channels would modulate counterregulatory hormone responses to either brain glucopenia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically catheterized rats. The closure of brain K ATP channels by global intracerebroventricular perfusion of sulfonylurea (120 ng/min glibenclamide or 2.7 g/min tolbutamide) suppressed counterregulatory (epinephrine and glucagon) responses to brain glucopenia and/or systemic hypoglycemia (2.8 mmol/l glucose clamp). Local VMH microinjection of a small dose of glibenclamide (0.1% of the intracerebroventricular dose) also suppressed hormonal responses to systemic hypoglycemia. We conclude that hypothalamic K ATP channel activity plays an important role in modulating the hormonal counterregulatory responses triggered by decreases in blood glucose. Our data suggest that closing of K ATP channels in the VMH (much like the ␤-cell) impairs defense mechanisms against glucose deprivation and therefore could contribute to defects in glucose counterregulation.

OBJECTIVE-To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia.RESEARCH DESIGN AND METHODS-Using gene silencing technology to selectively downregulate AMPK in the VMH, a key hypothalamic glucose-sensing region, we demonstrate a key role for AMPK in the detection of hypoglycemia. In vivo hyperinsulinemic-hypoglycemic (50 mg dl Ϫ1 ) clamp studies were performed in awake, chronically catheterized Sprague-Dawley rats that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPK␣. (ϳ60%) and epinephrine (ϳ40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation also required more exogenous glucose to maintain the hypoglycemia plateau and showed significant reductions in endogenous glucose production and wholebody glucose uptake. RESULTS-In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon CONCLUSIONS-We

Defective counterregulatory responses (CRRs) to hypoglycemia are associated with a marked increase in the risk of severe hypoglycemia. The mechanisms leading to the development of defective CRRs remain largely unknown, although they are associated with antecedent hypoglycemia. Activation of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) amplifies the counterregulatory increase in glucose production during acute hypoglycemia. To examine whether activation of AMPK in the VMH restores defective CRR, controlled hypoglycemia (ϳ2.8 mmol/l) was induced in a group of 24 Sprague-Dawley rats, all of which had undergone a 3-day model of recurrent hypoglycemia before the clamp study. Before the acute study, rats were microinjected to the VMH with either 5-aminoimidazole-4-carboxamide (AICAR; n ‫؍‬ 12), to activate AMPK, or saline (n ‫؍‬ 12). In a subset of rats, an infusion of H 3 -glucose was additionally started to calculate glucose turnover. Stimulation of AMPK within the VMH was found to amplify hormonal CRR and increase endogenous glucose production. In addition, analysis of tissue from both whole hypothalamus and VMH showed that recurrent hypoglycemia induces an increase in the gene expression of AMPK ␣ 1 and ␣ 2 . These findings suggest that the development of novel drugs designed to selectively activate AMPK in the VMH offer a future therapeutic potential for individuals with type 1 diabetes who have defective CRRs to hypoglycemia. Diabetes 55:1755-1760, 2006 S ingle or recurrent episodes of acute hypoglycemia in nondiabetic or type 1 diabetic (1-3) individuals are known to impair hormonal counterregulatory responses (CRRs) to a subsequent episode of hypoglycemia. Defective hormonal counterregulation to hypoglycemia is closely associated with both altered glucose thresholds for activation of the CRR and reduced symptomatic awareness of hypoglycemia, a combination of clinical syndromes that collectively have been termed hypoglycemia-associated autonomic failure (4). Defective hormonal CRR is in itself associated with a markedly increased risk of severe hypoglycemia (5).The mechanism through which recurrent hypoglycemia per se induces defective hormonal CRR remains largely unknown. Potential candidate mechanisms include alterations in key steps in the glucose-sensing pathway in the brain (6,7), increased glucose and/or alternate fuel uptake by the brain (8 -11), increases in the brain glycogen pool (12), and an effect of hypothalamopituitary axis activation (13,14). In addition, we have recently demonstrated that pharmacological activation of the serine/threonine kinase AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH), a key central glucose-sensing region (15), amplifies the glucose CRR to acute hypoglycemia. In that study AMPK activation in the VMH during acute hypoglycemia resulted in a marked increase in endogenous glucose production (R a ), with a corresponding reduction in the requirement for exogenous glucose, in the absence of a change in the hormonal CRR (1...

The mechanisms by which specialized glucose-sensing neurons within the hypothalamus are able to detect a falling blood glucose remain largely unknown but may be linked to some gauge of neuronal energy status. We sought to test the hypothesis that AMP-activated protein kinase (AMPK), an intracellular kinase purported to act as a fuel sensor, plays a role in hypoglycemia sensing in the ventromedial hypothalamus (VMH) of the Sprague-Dawley rat by chemically activating AMPK in vivo through bilateral microinjection, before performing hyperinsulinemic-hypoglycemic or hyperinsulinemic-euglycemic clamp studies. In a subgroup of rats, H3-glucose was infused to determine glucose kinetics. The additional chemical activation by AICAR of AMPK in the VMH during hypoglycemia markedly reduced the amount of exogenous glucose required to maintain plasma glucose during hypoglycemia, an effect that was almost completely accounted for by a three-to fourfold increase in hepatic glucose production in comparison to controls. In contrast, no differences were seen between groups in hypoglycemia-induced rises in the principal counterregulatory hormones. In conclusion, activation of AMPK within the VMH may play an important role in hypoglycemia sensing. The combination of hypoglycemiaand AICAR-induced AMPK activity appears to result in a marked stimulus to hepatic glucose counterregulation.

No abstract

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic ␤-cell, ATP-sensitive K ؉ channels (K ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K ATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (ϳ2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU ⅐ kg ؊1 ⅐ min ؊1 ) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation. Diabetes 54:3169 -3174, 2005