Sotalol and metoprolol comparison of their anti-hypertensive effect

Summary 28 patients, aged 35–62 years, with uncomplicated hypertension, entered a double-blind, crossover study, in which the effects of single daily doses of sotalol and metoprolol were compared. Both drugs exerted a clinically useful anti-hypertensive effect as monotherapy, or in combination with a thiazide diuretic. No significant difference in hypotensive effects was noted between the two beta-blocking agents, when the dose was titrated to an optimal clinical effect. Treatment with sotalol and metoprolol was associated with a clinically insignificant increase in serum uric acid concentration. The side-effects observed were few, and in only two cases was therapy discontinued. We regard both sotalol and metoprolol as useful anti-hypertensive drugs.     

Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.     

Women with low-energy fracture should be investigated for osteoporosis

Introduction Treatment of osteoporosis is becoming more effective, but methods to identify patients who are most suitable for investigation and treatment are still being debated. Should any type of fracture have higher priority for investigation of osteoporosis than any other? Is the number of previous fractures useful information?

Material and methods We investigated 303 consecutive women patients between 55 and 75 years of age who had a newly diagnosed low-energy fracture. They answered a questionnaire on previous fractures which also dealt with risk factors. Bone mineral density (BMD) was measured at the hip, lumbar spine, and forearm.

Results The distribution of fracture location was: distal forearm 56%, proximal humerus 12%, vertebra 18%, and hip 13%, all with similar age. Half of the subjects had had at least one previous fracture before the index fracture, 19% had had two previous fractures, and 6% had had three or more previous fractures. Patients with vertebral or hip fracture had lower BMD and had had more previous fractures than patients with forearm or humerus fractures. There was an inverse correlation between number of fractures and BMD. Osteoporosis was present in one-third of patients with forearm fracture, in one-half of those with hip or humerus fracture, and in two-thirds of those with vertebral fracture.

Interpretation Vertebral fractures were the strongest marker of low BMD and forearm fractures the weakest. The number of previous fractures is helpful information for finding the most osteoporotic patient in terms of severity. Investigation of osteoporosis therefore seems warranted in every woman between the ages of 55 and 75 with a recent low-energy fracture, with highest priority being given to those with vertebral, hip, or multiple fractures.     

Prediction of fracture risk in men: a cohort study

FRAX is a tool that identifies individuals with high fracture risk who will benefit from pharmacological treatment of osteoporosis. However, a majority of fractures among elderly occur in people without osteoporosis and most occur after a fall. Our aim was to accurately identify men with a high future risk of fracture, independent of cause. In the population‐based Uppsala Longitudinal Study of Adult Men (ULSAM) and using survival analysis we studied different models' prognostic values (R²) for any fracture and hip fracture within 10 years from age 50 (n = 2322), 60 (n = 1852), 71 (n = 1221), and 82 (n = 526) years. During the total follow‐up period from age 50 years, 897 fractures occurred in 585 individuals. Of these, 281 were hip fractures occurring in 189 individuals. The rates of any fracture were 5.7/1000 person‐years at risk from age 50 years and 25.9/1000 person‐years at risk from age 82 years. Corresponding hip fractures rates were 2.9 and 11.7/1000 person‐years at risk. The FRAX model included all variables in FRAX except bone mineral density. The full model combining FRAX variables, comorbidity, medications, and behavioral factors explained 25% to 45% of all fractures and 80% to 92% of hip fractures, depending on age. The corresponding prognostic values of the FRAX model were 7% to 17% for all fractures and 41% to 60% for hip fractures. Net reclassification improvement (NRI) comparing the full model with the FRAX model ranged between 40% and 53% for any fracture and between 40% and 87% for hip fracture. Within the highest quintile of predicted fracture risk with the full model, one‐third of the men will have a fracture within 10 years after age 71 years and two‐thirds after age 82 years. We conclude that the addition of comorbidity, medication, and behavioral factors to the clinical components of FRAX can substantially improve the ability to identify men at high risk of fracture, especially hip fracture. © 2012 American Society for Bone and Mineral Research.     

Reliability of anthropometric measurements in overweight and lean subjects: consequences for correlations between anthropometric and other variables

OBJECTIVE: To estimate the reliability of anthropometric measurements in overweight and lean subjects, and to examine the influence of this reliability on correlations to other variables, since low reliability leads to underestimation of correlations. DESIGN: Replicate measurements by two observers in 26 overweight and 25 lean subjects measured at two occasions. MEASUREMENTS: Sagittal abdominal diameter (SAD), waist circumference (waist), waist-to-hip ratio (W/H) and skinfold measurements. RESULTS: Intra-class correlation coefficients (ICCs) for SAD and waist were higher than for W/H (0.98 vs. 0.90, P<0.001, and 0.97 vs. 0.90, P = 0.001, respectively). For waist, the ICC was lower for overweight than for lean subjects (0.85 vs 0.95, P=0.030), but the ICC values were comparable for SAD and W/H (0.92 vs. 0.95 and 0.78 vs. 0.83, respectively). Intra-observer variations (IOV) for SAD and waist were lower than for W/H (coefficients of variation; 1.6%, 1.4% and 2.3%, respectively), as were intra-subject variations (ISV) (2.7%, 3.0% and 3.4%, respectively). ICC values ranged from 0.84 to 0.93 and were lower for overweight than for lean subjects for biceps, subscapular and umbilical skinfolds (P=0.031, P<0.001 and P=0.048, respectively). Coefficients of variations for skinfold measurements ranged between 7.3% and 16.0% for IOV and between 14.9% and 20.8% for ISV. CONCLUSIONS: The low ICC values imply that correlations can be underestimated in overweight groups. We propose that, because of their higher reliability, SAD and waist have a higher predictive capacity for cardiovascular risk than W/H. SAD is the only measurement with high reliability in both weight groups and its use is recommended.     

A human monoclonal autoantibody recognizes a neoantigen on glycoprotein IIIa expressed on stored and activated platelets

We prepared a heterohybrid cell line that secretes a human IgM monoclonal autoantibody that recognizes an antigen found on thrombin-activated or stored platelets. The surface expression of the epitope recognized by this autoantibody, 5E5, increases with time as platelets age in vitro, suggesting that it may represent a senescence or activation-specific antigen. 5E5 binds to the purified platelet membrane glycoprotein (GP) IIb-IIIa complex in an enzyme-linked immunosorbent assay (ELISA). In an immunoblot technique, 5E5 binds to a protein with an apparent mol wt of 95,000, which is identical to that of GPIIIa under nonreduced conditions. In crossed immunoelectrophoresis (CIE), the predominant antigen recognized by 5E5 is contained in the GPIIb-IIIa precipitin arc. An additional precipitin arc recognized by 5E5 is often observed only on gels derived from lysates of platelets stored under blood bank conditions for greater than 3 days. These findings illustrate the usefulness of human monoclonal antibodies for the identification of membrane neoantigens expressed as a result of platelet activation or revealed as platelets age in vitro.     

Intronic sequence elements impede exon ligation and trigger a discard pathway that yields functional telomerase RNA in fission yeast

The fission yeast telomerase RNA (TER1) precursor harbors an intron immediately downstream from its mature 3′ end. Unlike most introns, which are removed from precursor RNAs by the spliceosome in two sequential but tightly coupled transesterification reactions, TER1 only undergoes the first cleavage reaction during telomerase RNA maturation. The mechanism underlying spliceosome-mediated 3′ end processing has remained unclear. We now demonstrate that a strong branch site (BS), a long distance to the 3′ splice site (3′ SS), and a weak polypyrimidine (Py) tract act synergistically to attenuate the transition from the first to the second step of splicing. The observation that a strong BS antagonizes the second step of splicing in the context of TER1 suggests that the BS–U2 snRNA interaction is disrupted after the first step and thus much earlier than previously thought. The slow transition from first to second step triggers the Prp22 DExD/H-box helicase-dependent rejection of the cleaved products and Prp43-dependent “discard” of the splicing intermediates. Our findings explain how the spliceosome can function in 3′ end processing and provide new insights into the mechanism of splicing.