A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder caused by mutationally altered dominant-acting sarcomere proteins, exhibits significant clinical heterogeneity. To determine whether genetic background could influence the expression of this disease, we studied a murine model for this human condition. Hypertrophic responses to the Arg403Gln missense mutation in a cardiac myosin heavy chain gene were compared in 129SvEv (inbred; designated 129SvEv- alpha MHC403/+) and Black Swiss (outbred; designated BSw- alpha MHC403/+) strains. At 30-50 weeks of age all 129SvEv- alpha MHC403/+ showed left ventricular hypertrophy, while left ventricular wall thickness was increased in only half of BSw- alpha MHC403/+ mice demonstrating that a polymorphic modifier gene can determine the hypertrophic response to this dominant-acting sarcomere protein mutation. Further analysis suggests that SJL/J mice bear a recessive allele of this modifier gene that prevents a hypertrophic response to the Arg403Gln missense mutation. We conclude that genetic modifiers in mice, and presumably in man, can alter the hypertrophic response to sarcomere protein gene missense mutations.

Comparison of two murine models of familial hypertrophic cardiomyopathy.

Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Mortality and complications associated with laparoscopic cholecystectomy. A meta-analysis.

OBJECTIVE: The purpose of this study was to perform a meta-analysis of large laparoscopic cholecystectomy case-series and compare results concerning complications, particularly bile duct injury, to those reported in open cholecystectomy case-series. SUMMARY BACKGROUND DATA: Since the introduction of laparoscopic cholecystectomy in the United States, hundreds of reports about the technique have been published, many including statements about the advantages of laparoscopic cholecystectomy compared with those of open cholecystectomy. There is an unevenness in scope and quality of the studies. Nevertheless, enough data have accumulated from large series to permit analyses of data regarding some of the most important issues. METHODS: Articles identified via a MEDLINE (the National Library of Medicine's computerized database) search were evaluated according to standard criteria. Data regarding the patient sample, study methods, and outcomes of cholecystectomy were abstracted and summarized across studies. RESULTS: Outcomes of laparoscopic cholecystectomy are examined for 78,747 patients reported on in 98 studies and compared with outcomes of open cholecystectomy for 12,973 patients reported on in 28 studies. Laparoscopic cholecystectomy appears to have a higher common bile duct injury rate and a lower mortality rate. Estimated rates of other types of complications after laparoscopic cholecystectomy generally were low. Most conversions followed operative discoveries (e.g., dense adhesions) and were not the result of injury. CONCLUSIONS: There is wide variability in the amount and type of data reported within any single study, and patient populations may not be comparable across studies. Except for a higher common bile duct injury rate, laparoscopic cholecystectomy appears to be at least as safe a procedure as that of open cholecystectomy.

Abundance and distribution of bacterioplankton in the Gambia River, West Africa.

Four ecological zones of the Gambia River were sampled during four different hydrologic seasons for determination of microbial, nutrient, and physical parameters. A Greco-Latin Square experimental design was used to define the particular transect, station, depth, and tide/time-of-day of samples taken. Ranges of total bacterioplankton densities (10(6) cells/ml) were similar to those of tropical and temperate environments. Numbers of free bacteria were similar temporally, whereas attached bacteria numbers were greater during periods of high stream flows when suspended solids concentrations were higher. Free bacteria were usually twice as numerous in the freshwater zones than in the estuarine zones. Attached bacterial densities were approximately four times greater in the estuarine zones than in the freshwater zones. Uptake of(3)H-glucose on both a sample volume and per-cell basis increased from the early stages of the flood (6.95±SE 1.37 ng/liter/hour and 3.8 pg/hour/10(6) cells, respectively) and reached observed annual maximums during the dry season (21.01±SE 3.05 ng/ liter/hour and 13.0 pg/hour/10(6) cells, respectively). Spatially,(3)H-glucose uptake per sample volume and per cell was highest in the upper river zone and lowest in the lower estuary zone. The lower estuary zone consistently acted out of concert with the other river zones in terms of(3)H-glucose and(14)C-bicarbonate uptake. Analysis of variance (ANOVA) indicated that free and attached bacterioplankton densities were not homogeneous among transects, stations, depths, and tide/time-of-day at the different zones during the four hydrologic seasons. The results suggested that heterotrophy overshadowed autotrophy in the river and that the bacterial abundance, distribution, and glucose uptake activity in this tropical floodplain river were greatly influenced by the annual flood and the presence of extensive mangrove forests in the estuary.

AIDS: definition and guidelines for the health professional.

AIDS is a lethal infectious disease that must certainly be dealt with carefully, but through conscientious application of well-established procedures and techniques, health care professionals may provide the best possible care to the patients suffering the ravages of this disease without undue risk to themselves or their loved ones. There is no reason to believe that caring for the AIDS patient is any more dangerous than caring for a patient with any infectious disease; by utilizing already established safety precautions, we can deal with this situation efficiently and confidently.

Double-blind controlled trial of immunosuppression in the treatment of multiple sclerosis: final report.

In a double-blind controlled trial 43 patients with relapsing-remitting multiple sclerosis were treated either with anti-lymphocyte globulin, prednisolone, and azathioprine, or with placebo preparations. Treatment began with a combination of the three medicaments but after 1 month was continued for another 14 months with azathioprine (3 mg/kg dialy) only. There was a marginally beneficial effect of immunosuppression on the overall relapse rate and clinical progression. However, there were significant effects on in-vitro lymphocyte function and in the visual evoked potentials in favour of the group receiving suppressive treatment. Placebo-treated patients of the HLA A3 tissue type had significantly more relapses than placebo-treated patients who were not of type HLA A3. Nevertheless, HLA-A3-positive patients treated with immunosuppression had significantly fewer relapses than A3-positive placebo-treated patients.