Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle

BACKGROUND: The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings. METHODS AND RESULTS: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure. CONCLUSIONS: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.     

Reviewing the world's edible mushroom species: A new evidence-based classification system

Wild mushrooms are a vital source of income and nutrition for many poor communities and of value to recreational foragers. Literature relating to the edibility of mushroom species continues to expand, driven by an increasing demand for wild mushrooms, a wider interest in foraging, and the study of traditional foods. Although numerous case reports have been published on edible mushrooms, doubt and confusion persist regarding which species are safe and suitable to consume. Case reports often differ, and the evidence supporting the stated properties of mushrooms can be incomplete or ambiguous. The need for greater clarity on edible species is further underlined by increases in mushroom-related poisonings. We propose a system for categorizing mushroom species and assigning a final edibility status. Using this system, we reviewed 2,786 mushroom species from 99 countries, accessing 9,783 case reports, from over 1,100 sources. We identified 2,189 edible species, of which 2,006 can be consumed safely, and a further 183 species which required some form of pretreatment prior to safe consumption or were associated with allergic reactions by some. We identified 471 species of uncertain edibility because of missing or incomplete evidence of consumption, and 76 unconfirmed species because of unresolved, differing opinions on edibility and toxicity. This is the most comprehensive list of edible mushrooms available to date, demonstrating the huge number of mushrooms species consumed. Our review highlights the need for further information on uncertain and clash species, and the need to present evidence in a clear, unambiguous, and consistent manner.     

Can an immunologically, nonreactive potential allograft recipient undergo transplantation without a donor-specific crossmatch?

Performance of the pretransplant crossmatch requires 4 or more hours . Delays in the crossmatch might alter operating room availability and thereby increase donor organ cold ischemia time that might then result in increased risk of delayed graft function. To avoid these problems, recipients could be identified who would be expected to display negative donor crossmatches and who could be transplanted with a concurrent or retrospective rather than a pretransplant crossmatch. We, therefore, evaluated the percent reactive antibodies and donor IgG-antihuman globulin (AHG) crossmatch results of 1165 sera from 220 potential allograft recipients. Twenty-five (11%) of 220 recipients consistently displayed a 0% PRA and, with only one exception, their sera (n= 156) tested IgG-AHG crossmatch-negative against potential cadaveric donors (a 0.6% IgG-AHG positive crossmatch risk). These data suggest that the timing of the pretransplant serum crossmatch could be altered for a highly selected group of immunologically nonreactive recipients.     

Neutrophil accumulation is reduced during partial liquid ventilation

OBJECTIVE: This study evaluates the ability of perflubron to inhibit pulmonary neutrophil accumulation during partial liquid ventilation (PLV) in the setting of acute lung injury. DESIGN: Randomized, controlled, nonblinded study. SETTING: Research laboratory at a university. SUBJECTS: Male, Sprague-Dawley rats (n = 120, 506 +/- 42 g). INTERVENTIONS: Animals were divided into eight groups (n = 15 in each group, of which n = 12 for myeloperoxidase content and n = 3 for histologic neutrophil counting): a) GV-CVF group, animals received gas ventilation (GV) with the induction of lung injury using cobra venom factor (CVF); b) PLV-CVF group, animals received partial liquid ventilation before the induction of lung injury; c) PEEP-CVF group, animals received positive end-expiratory pressure (PEEP) before the administration of cobra venom factor; d) CVF-PLV group, animals received partial liquid ventilation after cobra venom factor; e) CVF-PEEP group, animals received PEEP after cobra venom factor; f) PLV only group, animals received partial liquid ventilation only; g) GV only group, animals received gas ventilation only; and h) NVSBA group, nonventilated spontaneous breathing animals. MEASUREMENTS AND MAIN RESULTS: After the experimental period, total lung myeloperoxidase content was significantly decreased in the PLV-CVF (0.29 +/- 0.08, p = .02) and PEEP-CVF (0.34 +/- 0.04, p = .01) groups when compared with the GV-CVF group (0.62 +/- 0.07). When compared with the GV-CVF group, a trend toward a reduction in myeloperoxidase was observed in the CVF-PLV (0.42 +/- 0.05, p = .07) and the CVF-PEEP (0.39 +/- 0.06, p = .07) groups. When compared with the cobra venom factor only group (GV-CVF 47 +/- 2 neutrophils/high-power field), reductions in neutrophil count were observed in all groups (neutrophils/high-power field): PLV-CVF (20 +/- 2, p = .009); PEEP-CVF (24 +/- 1, p = .01); CVF-PLV (30 +/- 2, p = .03); and CVF-PEEP (37 +/- 1, p = .04). CONCLUSION: These data suggest that both partial liquid ventilation and PEEP result in a reduction in neutrophil accumulation in the setting of acute lung injury.     

Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an approximately 50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCepsilon expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCepsilon expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.     

How good is the quality of health care in the United States?

Studies over the past decade show that some people are receiving more care than they need, and some are receiving less. Simple averages from a number of studies indicate that 50 percent of people received recommended preventive care; 70 percent, recommended acute care; 30 percent, contraindicated acute care; 60 percent, recommended chronic care; and 20 percent, contraindicated chronic care. These studies strongly suggest that the care delivered in the United States often does not meet professional standards. Efforts to measure quality and report routinely on the results to the public at large would allow more definitive assessments of the status of the nation's health care and would enable us to single out the areas in need of improvement.     

Free radicals generated in yeast by the Salmonella test-negative carcinogens benzene, urethane, thiourea and auramine O

Under pathophysiological conditions, like myocardial ischemia and reperfusion, cardiac phospholipid homeostasis is severely disturbed, resulting in a net degradation of phospholipids and the accumulation of degradation products, such as lysophospholipids and (non-esterified) fatty acids. The derangements in phospholipid metabolism are thought to be involved in the sequence of events leading to irreversible myocardial injury. The net degradation of phospholipids as observed during myocardial ischemia may result from increased hydrolysis and/or reduced resynthesis, while during reperfusion hydrolysis is likely to prevail in this net degradation. Several studies indicate that the activation of phospholipases A2 plays an important role in the hydrolysis of phospholipids. In this review current knowledge regarding the potential role of the different types of phospholipases A2 in ischemia and reperfusion-induced damage is being evaluated. Furthermore, it is indicated how recent advances in molecular biological techniques could be helpful in determining whether disturbances in phospholipid metabolism indeed play a crucial role in the transition from reversible to irreversible myocardial ischemia and reperfusion-induced injury, the knowledge of which could be of great therapeutic relevance.     

An experimental investigation of the safe distance for internal orbital dissection

Six 3-dialkylaminomethyl-1-azaanthraquinones and five 4-dialkylaminomethyl-1-azaanthraquinones were synthesized and evaluated in vitro cytotoxicity against four human cancer cell lines. The compounds retained much of their cytotoxic activity against the multi-drug-resistant cell line (KB-V-1) as shown by resistance index.