Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly

Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha (LXRA, rs12221497), and the solute carrier organic anion transporter (SLCO1B1, rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid sequence of the SLCO1B1 gene product. No effect of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, -37.0%; heterozygotes, 25.8% of the population, -36.0%; and homozygotes, 2.7% of the population, -31.8%, p=0.003 at 6 months, and p=0.022 at 12 months). Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus can significantly decrease the pravastatin induced LDL cholesterol lowering response.     

Alternaria IgG precipitins and adverse reactions.

Late reactions consisting of fever, malaise, and swelling at the site, 4 to 6 hr after injections of Alternaria extract occurred in several patients receiving immunotherapy with Alternaria. These patients had in common serum IgG precipitins and exquisite leukocyte histamine release sensitivity to Alternaria. Such precipitins were 3 times more frequent in patients receiving Alternaria immunotherapy than a control group of patients receiving immunotherapy with other antigens. A prospective study revealed that 5 of 23 Alternaria-sensitive persons had precipitins before immunotherapy and another 6 developed precipitins during therapy. Only one of the 23 experienced a late Alternaria reaction. Thus, precipitins to Alternaria are common and do not seem to be the basis for the late reactions we observed. The finding of precipitins does not contraindicate immunotherapy.     

A preliminary investigation into the long-term injury consequences reported by retired baseball players

Seventy-five retired baseball players participated in a survey (37.8% response rate) in order to establish the long-term consequences of injuries sustained during their playing careers. Respondents had a mean age of 55.8 (+/-11.4) years with a mean age of 41.3 (+/-11.4) years at retirement from play. The mean overall rate of injury suffered per player/playing career was 5.6 (+/-7.1). 54.7% of respondents experienced a major injury (i.e. injury resulting in 5 or more consecutive weeks absence from training and play) with a mean major injury per player/playing career of 1.5 (+/-2.2). The rate for significant injuries (i.e. injury resulting in more than 1 week but less than 5 weeks absence from training and play) was 4.1 (+/-6.5) per player/playing career. Catchers had significantly less injuries than all other positions (p=0.027). 18.7% of all respondents reported suffering from arthritis, 24% from restricted joint mobility and 4% from chronically stiff fingers; all of these conditions were associated with their participation in baseball based on medical examination by their GP or medical specialist. 29.3% of respondents indicated that they had incurred additional medical costs and 12% reported significant loss of income associated with their injuries. Some injuries were severe enough that they resulted in extended stays in hospital producing costs carried by the health care system.     

Archaeal nucleosomes

Archaea contain histones that have primary sequences in common with eukaryal nucleosome core histones and a three-dimensional structure that is essentially only the histone fold. Here we report the results of experiments that document that archaeal histones compact DNA in vivo into structures similar to the structure formed by the histone (H3+H4)₂ tetramer at the center of the eukaryal nucleosome. After formaldehyde cross-linking in vivo, these archaeal nucleosomes have been isolated from Methanobacterium thermoautotrophicum and Methanothermus fervidus, visualized by electron microscopy on plasmid and genomic DNAs, and shown by immunogold labeling, SDS/PAGE, and immunoblotting to contain archaeal histones, cross-linked into tetramers. Archaeal nucleosomes protect ≈60 bp of DNA and multiples of ≈60 bp from micrococcal nuclease digestion, and immunoprecipitation has demonstrated that most, but not all, M. fervidus genomic DNA sequences are associated in vivo with archaeal histones.     

“Dog ear” formation after double-stapled low anterior resection as a risk factor for anastomotic disruption

PURPOSE: The aim of this study was to investigate the possible deleterious effect of the lateral intersecting margins (so-called dog ears) on anastomotic disruption after experimentally performed double-stapled anastomoses. METHODS: Two groups of double-stapled side-to-end anastomoses were performed using pig small intestines. Group A consisted of 35 circular anastomoses and Group B of 32 double-stapled anastomoses with a bilateral dog ear. In both groups bursting pressures were tested using a water-filled, pressure-controlled automatic pumping system (Hamou Endomat®), and special attention was paid to the location(s) in the anastomoses were the disruption(s) occurred. RESULTS: In Group A bursting pressures were significantly higher than in Group B (median pressure, 90vs. 60 mmHg;P<0.001, Mann-WhitneyU test). Remarkably, in Group B in 13 cases (42 percent) the first disruption occurred at the corner of a dog ear. CONCLUSIONS: We conclude that the lateral intersections of double-stapled anastomoses are a structural weak spot and that the currently most often applied double-stapled anastomosis is a less effective type of anastomosis than a complete circular one. Resolving this technical problem might help to reduce the number of anastomotic disruptions after low anterior resections.Equipment supplied by Ethicon Endosurgery-Johnson & Johnson, the Netherlands.Presented at the meeting of the Dutch Surgical Society, Leiden, the Netherlands, November 27, 1998.     

Bestimmung des Bereichs intensiver Dauerleistungsfähigkeit bei Patienten mit koronarer Herzkrankheit

Zusammenfassung K?rperliches Training mit hoher Intensit?t kann bei Patienten mit KHK anhaltend die Funktion des Myokards und das Risikoprofil verbessern. Neben einer hohen Trainingseffektivit?t haben intensive Belastungen ein kardiales Gef?hrdungspotential im Sinne einer geringen therapeutischen Breite. Es wird ein Untersuchungsverfahren auf der Basis der Laktat-In- und -Evasionskinetik vorgestellt, das die individuell maximal vertretbare therapeutische Ausdauertrainingsintensit?t ermittelt. Im Rahmen einer erweiterten Routinediagnostik wurden in zwei Kollektiven jeweils 30 KHK-Patienten untersucht. Zwei aufeinanderfolgende Stufentests mit einer dazwischenliegenden 7 minütigen Pause wurden auf dem Fahrradergometer gefahren. In Stufentest 1 wird durch die Ausbelastung ein „intrinsischer” Laktatbolus gesetzt. In Stufentest 2 findet zun?chst bei leichter und mittlerer Belastung ein überwiegender Laktatabbau mit entsprechendem Abfall der Blutlaktatkonzentration statt. Bei zunehmend intensiver Belastung kommt es zu einem Gleichgewicht von Blutlaktat- In- und -evasion, der Laktatsenke, bei weiter ansteigender Intensit?t dann zu einem überwiegen der Laktat-Invasion mit entsprechendem Laktatkurvenanstieg. In zwei gleich gro?en Kollektiven wurden die Patienten in zwei Dauertesten mit der Intensit?t an der Laktatsenke und mit einer um 10% h?heren Intensit?t über 30 min randomisiert untersucht. In den Dauertests mit der Senkenintensit?t stellte sich ein Steady-State von Laktat und Herzfrequenz ein. Bei den Dauertests mit einer um 10% h?heren Intensit?t brachen 50% der Patienten den Dauertest wegen Ersch?pfung vorzeitig ab. Herzfrequenz und Laktat stiegen bis zum Belastungsabbruch signifikant an als Zeichen dafür, dass hier gerade die Ausdauerleistungsgrenze überschritten wurde. Die Laktatsenke, ermittelt im doppelten Stufentestverfahren, erlaubt eine exakte Festlegung der individuellen Ausdauerdauerleistungsgrenze. Eine nur geringfügig erh?hte Intensit?t sollte als Trainingsvorgabe für Dauerbelastungen vermieden werden. Eingegangen: 11. Oktober 2000 Akzeptiert: 23. M?rz 2001     

Impact of genetic variations in the WRN gene on age related pathologies and mortality

Mutations in the WRN gene lead to the Werner syndrome (WS), which resembles premature aging. Here, we hypothesize that genetic variations in the WRN gene may also influence aging-trajectories in the population at large. To test this hypothesis, we assessed the impact of the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene on the occurrence of cardiovascular pathologies, on cognitive performance and on the risks of all-cause, cardiovascular and cancer mortalities in the population-based Leiden 85-plus Study. This prospective follow-up study includes 1,245 participants aged 85 years and older, with a total follow-up of 5,164 person-years. At baseline the risks of myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke dependent on the i1-C/T, L1074F and C1367R polymorphisms, did not vary between the different genotypes. Also no differences in cognitive functioning were observed, except for attention, where carriers of the 1367R allele performed worse compared to the 1367C homozygotes (94.2 (4.35) versus 84.8 (1.84), p=0.04). Mortality risks, calculated separately for all SNPs, were similar between the different genotype carriers of the i1-C/T, L1074F and C1367R polymorphisms, showing no evidence of altered survival. In conclusion, the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene do not influence the aging-trajectories and survival in the population at large.     

Is intrinsic asthma synonymous with infection?

Rackemann described the 'intrinsic asthma' population over 50 years ago as a unique subgroup that was characterized by onset of progressive loss of lung function beginning later in life, possibly after a respiratory infection. It has also been associated with a female predominance, aspirin-sensitive bronchospasm, and nasal polyposis. While the aetiology is not understood, we propose that persistent respiratory infections play a central role in the development of intrinsic asthma.