Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group

BACKGROUND: The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. METHODS: We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. RESULTS: The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups). In a multivariate Cox analysis, the genotype and the QT interval corrected for heart rate were significant independent predictors of a first cardiac event. The cumulative mortality through the age of 40 among members of the three groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher (P<0.001) among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent). CONCLUSIONS: The genotype of the long-QT syndrome influences the clinical course. The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus.     

Purification and characterization of a guanine nucleotide-exchange protein for ADP-ribosylation factor from spleen cytosol

ADP-ribosylation factors (ARFs) are 20-kDa guanine nucleotide-binding proteins and are active in the GTP-bound state and inactive with GDP bound. ARF-GTP has a critical role in vesicular transport in several cellular compartments. Conversion of ARF-GDP to ARF-GTP is promoted by a guanine nucleotide-exchange protein (GEP). We earlier reported the isolation from bovine brain cytosol of a 700-kDa protein complex containing GEP activity that was inhibited by brefeldin A (BFA). Partial purification yielded an approximately 60-kDa BFA-insensitive GEP that enhanced binding of ARF1 and ARF3 to Golgi membranes. GEP has now been purified extensively from rat spleen cytosol in a BFA-insensitive, approximately 55-kDa form. It activated class I ARFs (ARFs 1 and 3) that were N-terminally myristoylated, but not nonmyristoylated ARFs from class-I, II, or III. GEP activity required MgCl2. In the presence of 0.6-0.8 mM MgCl2 and 1 mM EDTA, binding of guanosine 5'-[gamma[35S]thio]triphosphate ([35S]GTP gamma S) by ARF1 and ARF3 was equally high without and with GEP. At higher Mg2+ concentrations, binding without GEP was much lower; with 2-5 mM MgCl2, GEP-stimulated binding was maximal. The rate of GDP binding was much less than that of GTP gamma S with and without GEP. Phospholipids were necessary for GEP activity; phosphatidylinositol was more effective than phosphatidylserine, and phosphatidic acid was less so. Other phospholipids tested were ineffective. Maximal effects required approximately 200 microM phospholipid, with half-maximal activation at 15-20 microM. Release of bound [35S]GTP gamma S from ARF3 required the presence of both GEP and unlabeled GTP or GTP gamma S; GDP was much less effective. This characterization of the striking effects of Mg2+ concentration and specific phospholipids on the purified BFA-insensitive ARF GEP should facilitate experiments to define its function in vesicular transport.     

Patterns of viral replication correlate with outcome in simian immunodeficiency virus (SIV)-infected macaques: effect of prior immunization with a trivalent SIV vaccine in modified vaccinia virus Ankara

The dynamics of plasma viremia were explored in a group of 12 simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) that had received prior immunization with either nonrecombinant or trivalent (gag-pol, env) SIV-recombinant vaccinia viruses. Three distinct patterns of viral replication observed during and following primary viremia accounted for significant differences in survival times. High-level primary plasma viremia with subsequently increasing viremia was associated with rapid progression to AIDS (n = 2). A high-level primary plasma virus load with a transient decline and subsequent progressive increase in viremia in the post-acute phase of infection was associated with progression to AIDS within a year (n = 6). Low levels of primary plasma viremia followed by sustained restriction of virus replication were associated with maintenance of normal lymphocyte subsets and intact lymphoid architecture (n = 4), reminiscent of the profile observed in human immunodeficiency virus type 1-infected long-term nonprogressors. Three of four macaques that showed this pattern had been immunized with an SIV recombinant derived from the attenuated vaccinia virus, modified vaccinia virus Ankara. These data link the dynamics and extent of virus replication to disease course and suggest that sustained suppression of virus promotes long-term, asymptomatic survival of SIV-infected macaques. These findings also suggest that vaccine modulation of host immunity may have profound beneficial effects on the subsequent disease course, even if sterilizing immunity is not achieved.     

Controlled external lumbar drain as treatment for therapy resistant intracranial hypertension--case report

The study investigated the psychological health level and related psychosocial factors of nurses. Through cluster sampling, 650 clinical nurses, who come from 5 city hospitals in Changsha, were interviewed with the Symptom Check List-90 (SCL-90), The Life Event Scale, Type A Behavior Questionnaire, and The Social Support Rating Scale. The results indicated that subjects' average symptom score and most factor scores of SCL-90 were significantly higher than that of the chinese norm. Somatization, depression, and obsession are common psychological problems of the clinical nurses, and the psychological health level of middle age group was significantly lower than that of other groups. Regression analysis (both single factor and multiple factors) suggested that TH and CH scores on Type A Questionnaire as well as life event score on the life event score were negatively related to psychological health level while social support score was positively related to it. The influences of psychosocial factors on psychological health level of clinical nurses were discussed.     

The use of atmospheric pressure MOVPE for the growth of high performance uncooled 1300 nm DFB lasers

Manufacture of high performance uncooled 1300 nm distributed feed-back (DFB) lasers operating single mode over the −40 to +85°C range requires control of the wavelength variation across a 2″ wafer to less than 10nm and preservation of grating definition during processing and regrowth. We have used atmospheric pressure metalorganic vapor phase epitaxy, without substrate rotation to achieve the necessary uniformity. Material was assessed using photoluminescence, x-ray diffraction, transmission electron microscopy, electrochemical current/voltage profiling, and secondary ion mass spectroscopy. The devices are based on a strained quantum well structure with an n-type grating layer to provide gain coupling. The best result gave a wavelength spread across 32×32 mm center square of a 2″ InP wafer of 3 nm. Buried heterostructure DFBs manufactured with high yield in this way operate from −40 to +85°C, with thresholds at 85°C as low as 18 mA.     

Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party

Guidelines on the conduct of clinical trials of antibacterial agents produced by the US Food and Drug Administration, the British Society for Antimicrobial Chemotherapy, the Infectious Diseases Society of America and a European Working Party have been reviewed. Although very informative, these guidelines provide limited practical guidance on the design and statistical aspects of phase III studies of antimicrobial agents. This paper describes the differences between antibacterial trials and clinical studies in other therapeutic areas with regard to subjective endpoints, dual clinical and bacteriological endpoints, frequent protocol violations and difficulty of using placebo controls. The importance of a detailed protocol and planned analysis strategy is emphasized. The choice of comparator agents, practical issues with the blinding of trial materials and the documentation of patients excluded from study entry are discussed. The use of different patient groups and different endpoints in analyses are described. The principles of equivalence and their application to trials of antibacterial agents are discussed, together with an approach to calculating sample size. A variety of statistical analyses of results are compared for different situations indicating some of the problems that can arise. Different methods of presentation of study data are included with emphasis on regulatory submissions rather than scientific publications. Some graphical presentations are recommended and issues regarding data across different studies are discussed.     

Ectasia of the vertebral artery as a cause of isolated pyramidal tract signs: case report and a review of the literature

A rare presentation of vertebral artery ectasia is reported with magnetic resonance imaging and angiographic correlation. The unusually low level of the abnormality had previously resulted in an incorrect diagnosis of primary pyramidal degeneration. One similar case has been reported in the world literature.     

Roles of gonadotropins and releasing hormones in hypothalamic control of lordotic behavior in ovariectomized, estrogen-primed rats.

Intrahypothalamic effects of gonadotropins (luteinizing hormone and follicle-stimulating hormone, LH and FSH, respectively), thyrotropin-releasing hormone (TRH), and luteinizing-hormone-releasing hormone (LRH) on lordotic behavior were evaluated in 63 Wistar ovariectomized (OVX) rats maintained at different receptivity levels. Under low receptivity, in which LRH has been shown to enhance mating behavior, medial preoptic area (MPOA) infusions of LH caused significant depressions in the lordotic response, whereas LH infusions into arcuate ventromedial area (ARC-VM) had no significant effect. FSH infusions into either area did not alter the response. In Exp II, in which OVX Ss were primed with higher doses of estrone to maintain high preinfusion receptivity, MPOA or ARC-VM infusions of either LH or TRH depressed lordotic behavior significantly, whereas neither LRH nor FSH inhibited the response. Exp III evaluated the effects of LH, FSH, and TRH on LRH-facilitated mating behavior with 50 Sprague-Dawley male rats. Infusions of LRH into either MPOA or ARC-VM significantly enhanced mating behavior, whereas addition of TRH or LH to the LRH infusates abolished this response. The antagonistic effects of LH and TRH on LRH-facilitated mating were correlated with previous observations of antagonistic effects on hypothalamic unit activity and monoamine metabolism. The antagonistic interrelation between LRH and LH may represent a mechanism for activation and coordination of sexual receptivity with ovulation. (55 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison between free space and in-waveguide power measurement standards at 94 GHz

The results of a comparison between a photoacoustic determination of power propagating in free space and the UK primary standard of microwave power in waveguide at 94 GHz show that the two methods give concurrent results at the 2% level for powers of 1.5 mW.<>