Physical inactivity and knee osteoarthritis in guinea pigs.

OBJECTIVE: To investigate whether and how a sedentary lifestyle contributes to knee osteoarthritis (OA) incidence and severity. DESIGN: An experiment was conducted using Hartley guinea pigs, an established idiopathic knee OA model. To simulate a sedentary lifestyle, growing animals (n = 18) were housed for 22 weeks in small cages that restricted their mobility, while another group of animals (n = 17) received daily treadmill exercise to simulate moderate physical activity. After the experiment, histological assessments, biochemical assays, and mechanical testing were conducted to compare tibial articular cartilage structure, strength, and degree of OA degeneration between sedentary and physically active animals. Groups were also compared based on body weight and composition, as well as gut microbial community composition assessed using fecal 16S rRNA gene sequencing. RESULTS: Prevalence of knee OA was similar between sedentary and physically active animals, but severity of the disease (cartilage lesion depth) was substantially greater in the sedentary group (P = 0.02). In addition, during the experiment, sedentary animals developed cartilage with lower aggrecan quantity (P = 0.03) and accumulated more body weight (P = 0.005) and visceral adiposity (P = 0.007). Groups did not differ greatly, however, in terms of cartilage thickness, collagen quantity, or stiffness, nor in terms of muscle weight, subcutaneous adiposity, or gut microbial community composition. CONCLUSIONS: Our findings indicate that a sedentary lifestyle promotes the development of knee OA, particularly by enhancing disease severity rather than risk of onset, and this potentially occurs through multiple pathways including by engendering growth of functionally deficient joint tissues and the accumulation of excess body weight and adiposity.

Worldwide variation in hip fracture incidence weakly aligns with genetic divergence between populations.

UNLABELLED: This study investigates the influence of genetic differentiation in determining worldwide heterogeneity in osteoporosis-related hip fracture rates. The results indicate that global variation in fracture incidence exceeds that expected on the basis of random genetic variance. INTRODUCTION: Worldwide, the incidence of osteoporotic hip fractures varies considerably. This variability is believed to relate mainly to non-genetic factors. It is conceivable, however, that genetic susceptibility indeed differs across populations. Here, we present the first quantitative assessment of the effects of genetic differentiation on global variability in hip fracture rates. METHODS: We investigate the observed variance in publically reported age-standardized rates of hip fracture among 28 populations from around the world relative to the expected variance given the phylogenetic relatedness of these populations. The extent to which these variances are similar constitutes a "phylogenetic signal," which was measured using the K statistic. Population genetic divergence was calculated using a robust array of genome-wide single nucleotide polymorphisms. RESULTS: While phylogenetic signal is maximized when K > 1, a K value of only 0.103 was detected in the combined-sex fracture rate pattern across the 28 populations, indicating that fracture rates vary more than expected based on phylogenetic relationships. When fracture rates for the sexes were analyzed separately, the degree of phylogenetic signal was also found to be small (females: K = 0.102; males: K = 0.081). CONCLUSIONS: The lack of a strong phylogenetic signal underscores the importance of factors other than stochastic genetic diversity in shaping worldwide heterogeneity in hip fracture incidence.

Age-related variation in limb bone diaphyseal structure among Inuit foragers from Point Hope, northern Alaska.

UNLABELLED: Age-related deterioration of limb bone diaphyseal structure is documented among precontact Inuit foragers from northern Alaska. These findings challenge the concept that bone loss and fracture susceptibility among modern Inuit stem from their transition away from a physically demanding traditional lifestyle toward a more sedentary Western lifestyle. INTRODUCTION: Skeletal fragility is rare among foragers and other traditional-living societies, likely due to their high physical activity levels. Among modern Inuit, however, severe bone loss and fractures are apparently common. This is possibly because of recent Western influences and increasing sedentism. To determine whether compromised bone structure and strength among the Inuit are indeed aberrant for a traditional-living group, data were collected on age-related variation in limb bone diaphyseal structure from a group predating Western influences. METHODS: Skeletons of 184 adults were analyzed from the Point Hope archaeological site. Mid-diaphyseal structure was measured in the humerus, radius, ulna, femur, and tibia using CT. Structural differences were assessed between young, middle-aged, and old individuals. RESULTS: In all bones examined, both females and males exhibited significant age-related reductions in bone quantity. With few exceptions, total bone (periosteal) area did not significantly increase between young and old age in either sex, nor did geometric components of bending rigidity (second moments of area). CONCLUSIONS: While the physically demanding lifestyles of certain traditional-living groups may protect against bone loss and fracture susceptibility, this is not the case among the Inuit. It remains possible, however, that Western characteristics of the modern Inuit lifestyle exacerbate age-related skeletal deterioration.

Physical activity engendering loads from diverse directions augments the growing skeleton.

OBJECTIVE: An experiment was conducted to determine if modifying habitual activities to involve mechanical loading from more diverse directions can enhance the growing skeleton. METHODS: Growing female C57BL/6J mice were housed individually for 3 months in enclosures designed to accentuate either non-linear locomotion (diverse-orientation loading) or linear locomotion (stereotypic-orientation loading) (n=10/cage type). Behavioral assessments were performed daily to quantify cage activity level. Following the experiment, trabecular and cortical bone structure in the humeral head and distal femoral metaphysis were analyzed with µCT. RESULTS: Throughout the experiment, groups did not differ in cage activity level. Yet, following the experiment, the proximal humeri of mice that experienced increased diverse-orientation loading had significantly greater trabecular bone volume fraction (p=0.004), greater cortical bone area (p=0.005), greater cortical area fraction (p=0.0007), and thicker cortices (p=0.002). No significant group differences were detected in the distal femoral metaphysis. CONCLUSIONS: Diverting habitual activities to entail loading from more diverse orientations can augment the growing mouse skeleton. This study suggests that low-intensity activities that produce loads from diverse directions may represent a viable alternative to vigorous, high-impact exercise as a means of benefiting skeletal health during growth.

Comparison between creatine kinase brain isoenzyme (CKBB) activity and Sarnat score for prediction of adverse outcome following perinatal asphyxia.

AIM: To assess whether plasma creatine kinase brain isoenzyme (CKBB) levels or Sarnat scores are more accurate for prediction of poor neurological outcome in babies with suspected birth asphyxia. METHODS: In a retrospective study of 97 babies CKBB levels were compared to the presence of severe hypoxic ischaemic encephalopathy (HIE) as a predictive test for these outcomes: developmental delay, cerebral palsy, visual problems, deafness or death from perinatal asphyxia. The tests were compared using positive predictive values (PPV) and likelihood ratios (LR) with confidence intervals (CI). RESULTS: 3 babies had died from perinatal asphyxia and 14 survivors were found to have neurological or developmental problems. CKBB was elevated in babies with severe HIE (p = 0.0004). A receiver operator characteristic (ROC) curve showed the optimal discriminating value for CKBB to be 21 IU/L but the CKBB was a poor predictive test. For prediction of adverse outcome: CKBB > 21 sensitivity 76%, specificity 40%, PPV 21% and LR 1.3 (95% CI 0.8-1.7). Severe HIE sensitivity 53%, specificity 95%, PPV 69% and LR 10.6 (95% CI 3.8-29.2). CONCLUSION: CKBB is elevated following birth asphyxia but is a poor predictor of adverse neurological outcome.

Measles virus infection and replication in undifferentiated and differentiated human neuronal cells in culture.

Measles virus (MV) infection of the human central nervous system (CNS) typically involves widespread infection of neurons. However, little is known about how they become infected, how defective virus arises and accumulates, or how virus spreads among the cells of the CNS. In vitro studies of viral interactions with human neuronal cells may contribute to the resolution of such issues. In mixed cultures containing differentiated human neuronal (hNT2) cells and neuroepithelial cells, immunofluorescence studies show that the neurons, unlike both their NT2 progenitors and the neuroepithelial cells, are not initially susceptible to MV infection. This is possibly due to their lack of expression of CD46, a known cell surface receptor for MV. Later in the course of infection, however, both MV proteins and genomic RNA become detectable in their processes, where they contact infected, fully permissive neuroepithelial cells. Such a mechanism of virus transfer may be involved in the initiation and spread of persistent MV infection in diseases such as subacute sclerosing panencephalitis. Furthermore, mutated defective virus may readily accumulate and spread without the need, at any stage, for viral maturation and budding.

The biochemical diagnosis of lysosomal storage diseases--a review of five years experience.

The inherited lysosomal storage diseases are a distinct group of inborn errors of metabolism characterised by deficiencies in specific lysosomal enzymes. As many as 40 such disorders have now been described in man. We have measured the activities of up to 16 lysosomal acid hydrolases in plasma and/or extracts of leucocytes and cultured skin fibroblasts from 198 patients referred from throughout Ireland. These 16 assays allowed the biochemical diagnosis of 20 lysosomal storage diseases. Activities were compared with reference ranges to determine homozygotes and heterozygotes. Of the 44 patients with positive results, 15 were diagnosed as being homozygous for a specific lysosomal enzyme deficiency, 4 were identified as having multiple enzyme deficiencies (mucolipidosis Type II/I-cell disease) and 25 had heterozygote (carrier) enzyme levels. Of the latter, 24 were either parents (obligate heterozygotes) or siblings of homozygotes and one was a heterozygote for the X-linked recessively inherited Fabry's disease.