PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels

Two-pore (2-P) domain potassium channels are implicated in the control of the resting membrane potential, hormonal secretion, and the amplitude, frequency and duration of the action potential. These channels are strongly regulated by hormones and neurotransmitters. Little is known, however, about the mechanism underlying their regulation. Here we show that phosphatidylinositol 4,5-bisphosphate (PIP₂) gating underlies several aspects of 2-P channel regulation. Our results demonstrate that all four 2-P channels tested, TASK1, TASK3, TREK1 and TRAAK are activated by PIP₂. We show that mechanical stimulation may promote PIP₂ activation of TRAAK channels. For TREK1, TASK1 and TASK3 channels, PIP₂ hydrolysis underlies inhibition by several agonists. The kinetics of inhibition by the PIP₂ scavenger polylysine, and the inhibition by the phosphatidylinositol 4-kinase inhibitor wortmannin correlated with the level of agonist-induced inhibition. This finding suggests that the strength of channel PIP₂ interactions determines the extent of PLC-induced inhibition. Finally, we show that PIP₂ hydrolysis modulates voltage dependence of TREK1 channels and the unrelated voltage-dependent KCNQ1 channels. Our results suggest that PIP₂ is a common gating molecule for K⁺ channel families despite their distinct structures and physiological properties.     

Articulation of Asthma and Its Care Among Low-Income Emergency Care Recipients

Low-income minority patients from East St. Louis, Illinois, a depressed midwestern urban city, who had visited acute care settings with asthma symptoms, participated in a focus group. Questions were constructed around the Health Belief Model to characterize participants' experiences in receiving asthma care, their confidence in long-term asthma self-management, barriers they perceived to managing their asthma, and recommendations they would make for improving asthma care in their community. Analysis of comments suggests an appreciable understanding of asthma triggers, limited coping behaviors for asthma symptoms, very limited practice of active asthma management, perception of the health care system as frequently insensitive to their needs or their knowledge of their own care, exchange of well-articulated information regarding how to deal with the system, and an apparent lack of awareness of any potential contribution of patient education or support system.     

Transitional progressive multiple sclerosis: MRI and MTI findings

Transitional progressive multiple sclerosis (MS) is quite an unusual form of presentation and course of the disease. A case with this progressive form is presented and brain MRI and MTI findings are discussed in relation to the possible insight they may provide for understanding the mechanisms that determine progressive disability in MS.     

Inhibition of leukocyte chemotaxis by serum factor in diabetes mellitus: selective depression of cell responses mediated by complement-derived chemoattractants

Rat neutrophil chemotactic responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene (LT) B4, and lipopolysaccharide-activated serum (LPS-AS) were quantitatively assessed using the micropore filter system. Cells were suspended in either normal or diabetic rat serum for testing. Diabetic donor serum did not affect migration of neutrophils in a concentration gradient of the synthetic chemotactic agents. In contrast, the migratory responses to LPS-AS were significantly less than normal in this circumstance. Summation of effects was observed when FMLP and LPS-AS, or LTB4 and LPS-AS were simultaneously added to the test chamber, with cells suspended in normal serum. Suspended in diabetic rat serum neutrophils responded normally to the synthetic chemoattractants but the response to the activated serum was blocked. Cells previously incubated in the presence of diabetic donor serum then transferred to a culture medium for testing, presented reduced migratory responses to LPS-AS. Supramaximal, inhibitory concentrations of FMLP and LTB4, did not influence the response of neutrophils to LPS-AS. In vivo, suppression of cellular emigration to an inflamed area was observed from the early stages of the diabetic state. The inhibitory activity of chemotaxis in diabetes mellitus was previously reported to be associated with a protein factor in plasma of the animals. It is suggested that the inhibitory factor of chemotaxis in diabetes mellitus interacts with neutrophil receptors for complement-derived chemoattractants to induce blockade of cell-oriented locomotion either in vitro or in vivo.     

Umbilical vs peripheral vein catheterization for parenteral nutrition in sick premature neonates.

The efficacy and safety of using umbilical venous catheters vs. peripheral venous catheters for the delivery of parenteral nutrition was studied in 129 critically ill premature infants who were treated in a neonatal intensive care unit for the first 3 weeks of life. Infants who received parenteral nutrition by umbilical venous catheter had greater parenteral caloric intake, lower physiologic weight loss and greater weight gain during the study as compared to infants who received parenteral nutrition by peripheral vein. While the overall incidence of sepsis was comparable in both groups (19% vs 19.7%), benign and transient episodes of hyperglycemia were seen more commonly in infants receiving parenteral nutrition by umbilical catheters. None of the hyperglycemic infants, however, required insulin therapy. The incidence of other metabolic complication was comparable in both groups. At follow up, no evidence of portal hypertension was detected in any of the infants up to 66 months of age treated with umbilical venous catheters. We conclude that the use of umbilical venous catheter allows for a comparably safe and a more appropriate parenteral nutrition support than peripheral catheters in critically ill premature neonates.     

Bile acid profile as early indicator of allograft function during orthotopic liver transplantation

Orthotopic liver transplantation was performed in 20 pigs. Serum total bile acids (STBA) were determined and their profile compared with standard early function parameters: total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactic acid. In phase I, the STBA level was 32.89 +/- 1.29 mumol/l. In phase II, STBA accumulated to 84.46 +/- 15.25 mumol/l (p less than 0.01), followed by hepatic clearance in phase III (63.61 +/- 9.71 mumol/1; NS). Between phase III and 6- and 12-hour samples, STBA decreased progressively, reaching values of 33.63 +/- 7.05 mumol/l at 24 h. AST was elevated in phases I, II, III, and at 6, 12 and 24 h (p less than 0.001), as was ALT (but with insignificant differences). Thus, STBA and their profile appear to be earlier and more specific indicators of early graft function than conventional parameters.     

美国研究发现流产不会增加乳腺癌患病风险

美国一项大规模的前瞻性研究已经发现，人工流产和自然流产均不增加乳腺癌的患病风险。