Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone disorder characterized by fragile osteopenic bone and muscle weakness. We have previously shown that the soluble activin receptor type IIB decoy (sActRIIB) molecule increases muscle mass and improves bone strength in the mild to moderate G610C mouse model of OI. The sActRIIB molecule binds multiple transforming growth factor-β (TGF-β) ligands, including myostatin and activin A. Here, we investigate the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both myostatin and activin A in wild-type (Wt) and heterozygous G610C (+/G610C) mice using specific monoclonal antibodies. Male and female Wt and +/G610C mice were treated twice weekly with intraperitoneal injections of monoclonal control antibody (Ctrl-Ab, Regn1945), anti-activin A antibody (ActA-Ab, Regn2476), anti-myostatin antibody (Mstn-Ab, Regn647), or both ActA-Ab and Mstn-Ab (Combo, Regn2476, and Regn647) from 5 to 16 weeks of age. Prior to euthanasia, whole body composition, metabolism and muscle force generation assessments were performed. Post euthanasia, hindlimb muscles were evaluated for mass, and femurs were evaluated for changes in microarchitecture and biomechanical strength using micro–computed tomography (μCT) and three-point bend analyses. ActA-Ab treatment minimally impacted the +/G610C musculoskeleton, and was detrimental to bone strength in male +/G610C mice. Mstn-Ab treatment, as previously reported, resulted in substantial increases in hindlimb muscle weights and overall body weights in Wt and male +/G610C mice, but had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment outperformed ActA-Ab alone or Mstn-Ab alone, consistently increasing hindlimb muscle and body weights regardless of sex or genotype and improving bone microarchitecture and strength in both male and female +/G610C and Wt mice. Combinatorial inhibition of activin A and myostatin more potently increased muscle mass and bone microarchitecture and strength than either antibody alone, recapturing most of the observed benefits of sActRIIB treatment in +/G610C mice. © 2022 American Society for Bone and Mineral Research (ASBMR).     

McArdle's disease with myoadenylate deaminase deficiency: observations in a combined enzyme deficiency

Exercise and work potential of a patient with coexistent myophosphorylase and myoadenylate deaminase (AMPDA) deficiency was compared with that of three patients with myophosphorylase deficiency alone. The patient with the combined defect failed to produce an abnormal rise in serum ammonia or hypoxanthine as seen in the other patients after forearm exercise. Maximum oxygen consumption and work rates during cycle ergometer testing were similar in all patients, but well below controls. The occurrence of two defects involving short-term energy metabolism in muscle presents an opportunity to define further the metabolic role of AMPDA.     

Oilseed rape and seasonal symptoms: epidemiological and environmental studies.

BACKGROUND--There is widespread concern that the cultivation of oilseed rape leads to seasonal epidemics of respiratory symptoms in populations living in the neighbourhood, and it has been suggested that the plant is a potent allergen. A study was therefore undertaken to determine the prevalence of seasonal symptoms in rural populations close to and far from areas of oilseed rape cultivation, and to measure the levels of allergen and other potentially harmful substances released by the crop. METHODS--Random samples of 1000 adults from the general practice populations of two villages surrounded by oilseed rape fields, and 1000 adults from one village far from such cultivation, were taken. The subjects completed a previously validated questionnaire on respiratory and other symptoms, including questions on symptom seasonality, occupation, and smoking habits. Pollen and fungal spore counts were made around fields of oilseed rape and in the villages. The chemicals released by oilseed rape were measured in the field. RESULTS--Overall, 86.8% of the subjects completed the questionnaires and the populations of the two samples were generally comparable. Spring and summer exacerbations of symptoms occurred equally in the two areas in approximately 25% of the population. There were small but significant excesses of cough, wheeze, and headaches in spring in the oilseed rape area (2.3% v 1.1%, 6.8% v 4.6%, and 4.8% v 2.8%, respectively), and cough, wheeze, and itchy skin were more prevalent in smokers. Counts of oilseed rape pollen were generally low except adjacent to fields, and counts of fungal spores were mostly higher in the rape than the non-rape areas. Oilseed rape was shown to give off terpenes and these were detected close to fields. CONCLUSIONS--While it is likely that a proportion of the spring symptoms occurring in people living in close proximity to oilseed rape is caused by the plant, the excess of such symptoms is small. This, together with the low levels of pollen in the area, suggests that allergy to oilseed rape pollen is uncommon. The general prevalence of seasonal symptoms in rural areas is of interest, and a proportion of these cases is likely to be caused by factors other than allergy. Release of chemicals by plants and natural rises in summer ozone levels may be contributors.     

Australian Research on Ageing and Social Support

This paper draws on primary publications in Austalian gerontology to review knowledge on ageing and support While there is a well-established literature on family care, social networks studies of the 1980s provided more comprehensive views of expressive and instrumental support across a range of relationships. Notwithstanding stereotypes to the contrary, older people contribute as well as receive support. A new generation of qualitive, interpretative shudies are reporting on the meanings and processes of social support as experienced by older people themselves. Policy-related studies examine social support as a cornerstone for community services, and epidemiological investigations examine social influence on health and well-being. The field could be advanced considerably by longiturdinal surveys and qualitative enquiris exploring the diversity of older people in a variety of social settings.     

Relationship between respiratory symptoms and cough receptor sensitivity.

The relationship was studied between preschool and current respiratory symptoms and cough receptor sensitivity in children. Forty six white children aged 7 years were investigated. They were divided into three groups: (i) healthy children; (ii) children with a history of idiopathic cough; and (iii) children with a history of wheezing. Cough receptor sensitivity was assessed by the inhalation of serially increasing concentrations of nebulised citric acid. The concentration which first induced a cough was the cough threshold and was taken as a measure of cough receptor sensitivity. The cough threshold was unrelated to respiratory symptoms, bronchial responsiveness, parental smoking, and atopic status. A wide variation in cough threshold was seen. Although these results suggest that idiopathic cough is unrelated to cough receptor sensitivity as assessed by the citric acid cough threshold, it is unclear whether threshold measurements are an accurate reflection of receptor sensitivity.