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).     

Influence of Short‐term Confinement and Exercise on Tibia Development in Growing Pigs

The influence of short‐term confinement and moderate exercise on tibia development was investigated in growing pigs (36–41 kg, 10 weeks at the beginning of the study). Animals were kept for 2 weeks either in individual crates of 0.8 m² (‘confinement’, n = 4) or kept in groups of four animals in large crates of 5.6 m² without (‘control’) or with additional exercise (30 min walking at 5 days/week; ‘exercise’). Bone density and morphological parameters were evaluated by computer tomography (CT). Periosteal apposition and longitudinal growth were determined after polychrome sequential labelling in weekly intervals. Cortical areas of the cross sections at the mid‐shaft and at 75% of the length of the bone measured distal to the carpus by CT were significantly correlated to each other (r = 0.70) and revealed a significant reduction in confined animals. This difference was explained by lower periosteal apposition rates in these animals compared with exercised and group‐housed pigs. Similarly longitudinal growth and the formation and calcification of spongiosa of the tibiae were inhibited by confinement. Thus, 2 weeks of confinement led to significant differences in bone growth and metabolism in young growing piglets when compared with animals with moderate activity.     

Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome.

BACKGROUND: There are limited studies of large cohorts of patients with specific polysaccharide antibody deficiency (SPAD) syndrome. OBJECTIVE: To study the clinical and laboratory characteristics of patients with specific polysaccharide antibody deficiency syndrome. METHODS: We retrospectively studied 75 patients with total IgG levels of at least 500 mg/dL and fewer than 9 of 12 responses to vaccination with pneumococcal vaccine polyvalent. Exclusion criteria included an IgG level less than 500 mg/dL, established immunodeficiency syndrome, and secondary immunodeficiency. RESULTS: The most common clinical presentation was frequent infections (n = 69; 92%), including sinusitis (n = 53; 77%), pneumonia (n = 29; 42%), ear infections (n = 18; 26%), and bronchitis (n = 19; 28%). Other presentations were systemic infections (n = 5; 7%), autoimmune or rheumatic diseases (n = 6; 8%), and chronic diarrhea (n = 4; 5%). The median IgG2 level of patients with no response to pneumococcal vaccine polyvalent tended to be lower than that of patients with at least 1 response (150 vs 193 mg/dL, respectively; P = .06). There was no association between total IgG level (categorized as 500-600 or > or = 600 mg/dL) and frequency of infection (P = .43). Patients with fewer responses to pneumococcal vaccine polyvalent and a higher frequency of infections were more likely to receive intravenous immunoglobulin (IVIG) therapy (P = .01 and .003, respectively). Treatment with IVIG significantly reduced the number of infections (P < .001). CONCLUSION: Patients with no response to pneumococcal vaccine polyvalent tended to have lower IgG2 levels; those with fewer responses were more likely to receive IVIG therapy.     

Optimized and combined T1 and B1 mapping technique for fast and accurate T1 quantification in contrast-enhanced abdominal MRI.

Fast T(1) mapping techniques are a valuable means of quantitatively assessing the distribution and dynamics of intravenously or orally applied paramagnetic contrast agents (CAs) by noninvasive imaging. In this study a fast T(1) mapping technique based on the variable flip angle (VFA) approach was optimized for accurate T(1) quantification in abdominal contrast-enhanced (CE) MRI. Optimization methods were developed to maximize the signal-to-noise ratio (SNR) and ensure effective RF and gradient spoiling, as well as a steady state, for a defined T(1) range of 100-800 ms and a limited acquisition time. We corrected B(1) field inhomogeneities by performing an additional measurement using an optimized fast B(1) mapping technique. High-precision in vitro and abdominal in vivo T(1) maps were successfully generated at a voxel size of 2.8 x 2.8 x 15 mm(3) and a temporal resolution of 2.3 s per T(1) map on 1.5T and 3T MRI systems. The application of the proposed fast T(1) mapping technique in abdominal CE-MRI enables noninvasive quantification of abdominal tissue perfusion and vascular permeability, and offers the possibility of quantitatively assessing dilution, distribution, and mixing processes of labeled solutions or drugs in the gastrointestinal tract.     

A statewide preventive health care program for the aged

Because of the rising percentage of elderly in the population and the cost of health care expenditures, interest has increased in preventive health care services for the aging. Although the effectiveness of such programs is still being discussed by policy makers, the number of preventive health programs for the elderly is increasing. One of the oldest and largest preventive health programs for the elderly in the United States, the California Preventive Health Care for the Aging Program (PHCAP) is analyzed. The typical PHCAP participant was white, female, between 70 and 79 years of age, and living in an urban area. More than half (59 percent) of the PHCAP participants had some kind of private medical insurance in addition to Medicare coverage. Seventy-seven percent of the participants had seen a physician within the previous year. The most frequently reported chronic conditions were arthritis (31 percent), hypertension (24 percent), cardiovascular problems (13 percent), and vision and hearing problems (18 and 11 percent). Twenty-seven percent of the population were hypertensive; 7 percent of these had moderate to severe hypertension. Eighty percent of the participants were identified as having at least one problem; 40 percent were referred to a physician. Frequently, public health programs need to be evaluated without the benefit of a controlled trial design. This analysis of a statewide preventive health care program for the aging, PHCAP, shows the program's effectiveness in detecting a large number of health problems and making extensive referrals to other health professionals, particularly physicians. These findings should be useful to health practitioners and policy makers developing similar statewide programs for the elderly.     

Revisionsersatz des vorderen Kreuzbandes

With increasing numbers of primary anterior cruciate ligament reconstruction, the incidence of unsatisfactory results and graft failures will increase. The goals of revision reconstruction are similar to those of primary reconstruction and include stabilization of the knee, prevention of secondary degenerative changes, and recovery of knee function. Besides the recurrent tear there are specific technical failures, such as tunnel malplacement and unrecognized associated ligamentous pathologies, which might lead to graft failure. Thus, preoperative planning includes a detailed analysis of failure mechanisms by thorough preoperative history taking, comprehensive physical examination, and appropriate radiographic evaluation. The treatment algorithm addresses issues of hardware removal, need for a staged procedure or concomitant surgery, graft source, tunnel placement, and graft fixation. Correct placement of tunnels and graft fixation are the essential surgical steps, which might also influence graft selection. Successful revision ACL surgery requires a motivated and compliant patient and an experienced surgeon who is proficient in a variety of different surgical techniques. However, since clinical outcome is reported to be inferior in revision compared to primary ACL reconstruction the importance of counseling the patient preoperatively regarding less satisfactory results than in most primary ACL reconstructions must be emphasized. This article describes indications, analysis and surgical procedures for revision anterior cruciate ligament reconstruction.     

The immune-enhancing effect of perioperative thymopentin administration in elderly patients undergoing major surgery

The effects of perioperative administration of thymopentin (TP-5) on in vivo and in vitro measurements of cell-mediated immunity in elderly patients undergoing major surgery were investigated. A placebo-controlled study was conducted in 25 patients (mean age, 67 years) with congenital or acquired heart disease undergoing surgery with cardiopulmonary bypass. Patients were divided into three groups: Group 1 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively. Group 2 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively and 48 hours postoperatively. Group 3 patients were given placebo at corresponding times. Cell-mediated immunity measurements were the in vivo delayed-type hypersensitivity (DTH) response on day 0 and on day 7 to an antigen skin test battery. The in vitro studies included antigen cocktail-induced lymphocyte proliferation of peripheral blood mononuclear cells. The DTH response on day 7 after surgery was significantly suppressed in group 3 patients compared with the preoperative baseline value, while it remained unaltered in group 1 and 2 patients. There was a considerable difference of DTH measurements (number of positive antigen responses and sum of their mean diameters) between group 2 and 3 patients. Antigen cocktail-induced lymphocyte proliferation, following initial suppression in the majority of patients, was significantly different between the placebo group and patients in group 2 on day 7 after surgery. The data indicate that perioperative administration of TP-5 might be of considerable clinical utility in preventing a defective cellular immune response.     

Developing an integrated public health information system for Missouri.

The Missouri Department of Health realized it had a problem with 67 different information systems that ran on different platforms and could not communicate with one another. A new, integrated information system, the Missouri Health Strategic Architectures and Information Cooperative (MOHSAIC) is being developed based on information engineering (IE). This article describes IE, the process of developing MOHSAIC, and some key lessons learned in developing the system. Some of the lessons learned include the importance of executive sponsorship, tension between efficiency and program accountability, importance of confidentiality, and difficulties of funding an integrated system. The article stresses how integrated information systems will be important for the viability of public health under health care reform.