Alpha-hydroxybutyrate dehydrogenase activity in sex-linked muscular dystrophy

In two families with severe sex-linked muscular dystrophy, high levels of alpha-hydroxybutyrate dehydrogenase (HBD), lactate dehydrogenase (LD), aspartate transaminase (AspT), aldolase, and creatine phosphokinase (CPK) were found in the sera of three young affected males. In both families the mother had a raised level of HBD activity. Four sisters of the three affected boys had raised serum enzyme levels, and they are regarded as presumptive carriers of the disease. Biopsy specimens of dystrophic muscle had LD and HBD contents which were significantly lower than those of control specimens, while the HBD/LD ratios were markedly greater. Muscle from two unaffected members of the same family also exhibited high ratios, indicating the presence of the electrophoretically fast LD isoenzymes, and this was confirmed by acrylamide-gel electrophoresis.     

Actin cytoskeletal network in aging and cancer

The cytoskeleton is being recognized as an important modulator of metabolic functions of the cell. The actin cytoskeletal network, in particular, is involved in events regulating cell proliferation and differentiation. The state of actin in a variety of cell types is regulated by signals arising from the cell surface through a wide spectrum of interactions. In this review, we explore the role of actin cytoskeletal network in a series of events which are known to influence cell proliferation and differentiation. These include interaction opf actin network with extracellular matrix proteins, cell surface membranes, second messengers, cytoplasmic enzymes and the nucleus. Because of the involvement of the actin network in such diverse interactions, we propose that alterations in the actin cytoskeletal function may be an important aspect of generalized decrease in cellular functions associated with aging. Preliminary data indicate that alterations in the cytoskeletal network do occur in cells obtained from older individuals. Alterations in actin state are also reported during malignant transformation of cells in culture, and in naturally occurring tumors. Taken together, the existing data seem to suggest that changes in the actin cytoskeletal network may be a part of the aging process as well as malignant transformation. Therefore, the study of the actin cytoskeletal network and its regulation has the potential to yield important information regarding cellular senescence and neoplastic transformation.     

Intravaginal contraception with the synthetic progestin, R2323

A Silastic^R intravaginal ring (IVR) containing R2323 (17α-ethinyl-l7β -hydroxy-18-methyl-4,9,11-estrien-3-one) in its center core was tested $\text{in vitro}$ and in four women for one cycle each. Initially 330 micrograms of drug was released per day from the IVR $\text{in vitro}$, and after 150 days the value had declined to about 230 micrograms. Ovulation was inhibited in the four subjects due to the constant release of R2323 as evidenced by the steroid blood levels of 1 to 3 ng/ml. When the IVR was removed, R2323 blood levels quickly fell to zero. All the women had normal withdrawal bleeding, and two subjects followed during a recovery cycle had ovulatory levels of progesterone.     

Clinical trial with subdermal implants of the progestin R-2323

Six 3-cm polydimethylsiloxane capsules containing 30 mg each of R-2323 were implanted subdermally in each of 38 women to assess their effect upon fertility, menstrual pattern, some aspects of metabolism and the incidence of side effects associated with the use of this hormonal contraceptive. There were no pregnancies in a total of 292 months of exposure. The longest duration of use was 12 months and the median was between 8 and 9 months. Amenorrhea and signs of androgenicity such as acne and hyperthricosis were common complaints and a frequent reason for closure. Headache and nervousness also were reported by a high proportion of patients. Blood and urine analyses were normal with the exception of elevated transaminases in 20 out of 27 patients after the third month of treatment. Side effects and elevation of the serum transaminase levels disappeared promptly after removal of the implants in all cases. It is concluded that R-2323 implants at the dose tested are potent inhibitors of fertility in women. The high incidence of treatment-associated adverse reactions impose limitations on their use in Chilean women.     

Genotypes of Mycobacterium tuberculosis in patients at risk of drug resistance in Bolivia

Bolivia ranks among the 10 Latin American countries with the highest rates of tuberculosis (TB) and multidrug resistant (MDR) TB. In view of this, and of the lacking information on the population structure of Mycobacterium tuberculosis in the country, we explored genotype associations with drug resistance and clustering by analyzing isolates collected in 2010 from 100 consecutive TB patients at risk of drug resistance in seven of the nine departments in which Bolivia is divided. Fourteen isolates were MDR, 29 had other drug resistance profiles, and 57 were pansusceptible. Spoligotype family distribution was: Haarlem 39.4%, LAM 26.3%, T 22.2%, S 2.0%, X 1.0%, orphan 9.1%, with very low intra-family diversity and absence of Beijing genotypes. We found 66 different MIRU-VNTR patterns; the most frequent corresponded to Multiple Locus Variable Analysis (MLVA) MtbC15 patterns 860, 372 and 873. Twelve clusters, each with identical MIRU-VNTR and spoligotypes, gathered 35 patients. We found no association of genotype with drug resistant or MDR-TB. Clustering associated with SIT 50 and the H3 subfamily to which it belongs (p < 0.0001). The largest cluster involved isolates from three departments and displayed a genotype (SIT 50/MLVA 860) previously identified in Bolivian migrants into Spain and Argentina suggesting that this genotype is widespread among Bolivian patients. Our study presents a first overview of M. tuberculosis genotypes at risk of drug resistance circulating in Bolivia. However, results should be taken cautiously because the sample is small and includes a particular subset of M. tuberculosis population.     

Editorial Expression of Concern: Water and sodium in heart failure: a spotlight on congestion

Heart Failure Reviews -     

“Simulect” as a model compound for assessing placental transfer of monoclonal antibodies in minipigs

The aim of this study was to directly test and measure in vivo, if placental transfer of monoclonal antibodies takes place in pregnant Göttingen Minipigs to assess their suitability for reproductive assessment of therapeutic monoclonal antibodies.Simulect®, an approved anti CD25 (anti IL-2 receptor alpha) chimeric monoclonal IgG1 antibody, was used as a model monoclonal antibody. Maternal systemic exposure and potential placental transfer of Simulect® to fetuses were investigated following 4 weekly bolus intravenous administration of 5.0 mg/kg from gestation day (GD) 79 or 80 (e.g GD 79, 86, 93 and 100) and with terminal Caesarean section on GD 108 or GD 109 respectively. Results clearly showed exposure in maternal animals, detectable compound in the amniotic fluid from one out of 9 maternal animals, but no exposure in fetuses confirming absence of placental transfer of the selected model antibody Simulect® in minipigs. The absence of Simulect® in the fetuses further supports that the presence of Simulect® in the amniotic fluid in one maternal animal was likely due to contamination with maternal blood during sampling. The demonstrated absence of fetal exposure clearly indicates that, the minipig is not a suitable species for conduct of reproductive toxicity studies with monoclonal antibodies.