Regulation of osteoblast differentiation by Pasteurella multocida toxin (PMT): a role for Rho GTPase in bone formation.

The role of the Rho-Rho kinase signaling pathway on osteoblast differentiation was investigated using primary mouse calvarial cells. The bacterial toxin PMT inhibited, whereas Rho-ROK inhibitors stimulated, osteoblast differentiation and bone nodule formation. These effects correlated with altered BMP-2 and -4 expression. These data show the importance of Rho-ROK signaling in osteoblast differentiation and bone formation. INTRODUCTION: The signal transduction pathways controlling osteoblast differentiation are not well understood. In this study, we used Pasteurella multocida toxin (PMT), a unique bacterial toxin that activates the small GTPase Rho, and specific Rho inhibitors to investigate the role of Rho in osteoblast differentiation and bone formation in vitro. MATERIALS AND METHODS: Primary mouse calvarial osteoblast cultures were used to investigate the effects of recombinant PMT and Rho-Rho kinase (ROK) inhibitors on osteoblast differentiation and bone nodule formation. Osteoblast gene expression was analyzed using Northern blot and RT-PCR, and actin rearrangements were visualized after phalloidin staining and confocal microscopy. RESULTS: PMT stimulated the proliferation of primary mouse calvarial cells and markedly inhibited the differentiation of osteoblast precursors to bone nodules with a concomitant inhibition of osteoblastic marker gene expression. There was no apparent causal relationship between the stimulation of proliferation and inhibition of differentiation. PMT caused cytoskeletal rearrangements because of activation of Rho, and the inhibition of bone nodules was completely reversed by the Rho inhibitor C3 transferase and partly reversed by inhibitors of the Rho effector, ROK. Interestingly, Rho and ROK inhibitors alone potently stimulated osteoblast differentiation, gene expression, and bone nodule formation. Finally, PMT inhibited, whereas ROK inhibitors stimulated, bone morphogenetic protein (BMP)-2 and -4 mRNA expression, providing a possible mechanism for their effects on bone nodule formation. CONCLUSIONS: These results show that PMT inhibits osteoblast differentiation through a mechanism involving the Rho-ROK pathway and that this pathway is an important negative regulator of osteoblast differentiation. Conversely, ROK inhibitors stimulate osteoblast differentiation and may be potentially useful as anabolic agents for bone.     

Immunosuppression in liver transplantation: beyond calcineurin inhibitors.

Although calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression in liver transplantation (LTX), their long-term toxicity significantly contributes to morbidity and mortality. The elucidation of mechanisms of alloimmunity and leukocyte migration have provided novel targets for immunosuppression development. The toxicities of these agents differ from that of the CNI and act additively or synergistically. CNI avoidance protocols in LTX have not been achieved routinely; however, pilot trials have begun to delineate the limitations and promises of such approaches. CNI-sparing protocols appear to be much more promising in balancing the early need for minimizing rejection while tapering doses and minimizing long-term toxicity.     

Relationship Between Body Composition and Death in Patients with COVID-19 Differs Based on the Presence of Gastrointestinal Symptoms

Digestive Diseases and Sciences - Patients with SARS-CoV-2 who present with gastrointestinal symptoms have a milder clinical course than those who do not. Risk factors for severe COVID-19 disease...     

Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly

CONTEXT: GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution. OBJECTIVES: Our objective was to test the hypothesis that in acromegaly whole-body AT mass is less and to examine for the first time the relationship between GH/IGF-I excess and intermuscular AT (IMAT), an AT depot associated with insulin resistance in other populations. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study in 24 adults with active acromegaly compared with predicted models developed in 315 healthy non-acromegaly subjects. OUTCOME MEASURES: Mass of AT in the visceral AT (VAT), sc AT (SAT), and IMAT compartments from whole-body magnetic resonance imaging and serum levels of GH, IGF-I, insulin, and glucose were measured. RESULTS: VAT and SAT were less in active acromegaly (P < 0.0001); these were 68.2 +/- 27% and 79.5 +/- 15% of predicted values, respectively. By contrast, IMAT was greater (P = 0.0052) by 185.6 +/- 84% of predicted. VAT/trunk AT ratios were inversely related to IGF-I levels (r = 0.544; P = 0.0054). Acromegaly subjects were insulin resistant. CONCLUSIONS: VAT and SAT, most markedly VAT, are less in acromegaly. The proportion of trunk AT that is VAT is less with greater disease activity. IMAT is greater in acromegaly, a novel finding, which suggests that increased AT in muscle could be associated with GH-induced insulin resistance. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.     

Validity of Bioelectrical Impedance Analysis for Measuring Changes in Body Water and Percent Fat After Bariatric Surgery

Background

Few studies have validated bioelectrical impedance analysis (BIA) following bariatric surgery.

Methods

We examined agreement of BIA (Tanita 310) measures of total body water (TBW) and percent body fat (%fat) before (T0) and 12 months (T12) after bariatric surgery, and change between T0 and T12 with reference measures: deuterium oxide dilution for TBW and three-compartment model (3C) for %fat in a subset of participants (n?=?50) of the Longitudinal Assessment of Bariatric Surgery-2.

Results

T0 to T12 median (IQR) change in deuterium TBW and 3C %fat was ?6.4 L (6.4 L) and ?14.8 % (13.4 %), respectively. There were no statistically significant differences between deuterium and BIA determined TBW [median (IQR) difference: T0 ?0.1 L (7.1 L), p?=?0.75; T12 0.2 L (5.7 L), p?=?0.35; Δ 0.35 L(6.3 L), p?=?1.0]. Compared with 3C, BIA underestimated %fat at T0 and T12 [T0 ?3.3 (5.6), p?<?0.001; T12 ?1.7 (5.2), p?=?0.04] but not change [0.7 (8.2), p?=?0.38]. Except for %fat change, Bland-Altman plots indicated no proportional bias. However, 95 % limits of agreement were wide (TBW 15–22 L, %fat 19–20 %).

Conclusions

BIA may be appropriate for evaluating group level response among severely obese adults. However, clinically meaningful differences in the accuracy of BIA between individuals exist.     

Automatic indexing and retrieval of encounter-specific evidence for point-of-care support

Evidence-based medicine relies on repositories of empirical research evidence that can be used to support clinical decision making for improved patient care. However, retrieving evidence from such repositories at local sites presents many challenges. This paper describes a methodological framework for automatically indexing and retrieving empirical research evidence in the form of the systematic reviews and associated studies from The Cochrane Library, where retrieved documents are specific to a patient–physician encounter and thus can be used to support evidence-based decision making at the point of care. Such an encounter is defined by three pertinent groups of concepts – diagnosis, treatment, and patient, and the framework relies on these three groups to steer indexing and retrieval of reviews and associated studies. An evaluation of the indexing and retrieval components of the proposed framework was performed using documents relevant for the pediatric asthma domain. Precision and recall values for automatic indexing of systematic reviews and associated studies were 0.93 and 0.87, and 0.81 and 0.56, respectively. Moreover, precision and recall for the retrieval of relevant systematic reviews and associated studies were 0.89 and 0.81, and 0.92 and 0.89, respectively. With minor modifications, the proposed methodological framework can be customized for other evidence repositories.     

Combining Ontologies and Open Standards to Derive a Middle Layer Information Model for Interoperability of Personal and Electronic Health Records

The aim of our study was to enable better interoperability between Personal Health Record (PHR) and Electronic Health Record (EHR) systems and vice versa. A multi-layer architectural model that resides between a PHR and EHR system has been developed. The model consists of an ontology-driven information model and a set of transformation rules that work in conjunction to process data exported from a PHR or EHR system and prepare it accordingly for the receiving system. The model was evaluated by executing a set of case study scenarios containing data from both a PHR and an EHR system. This allowed various challenges to emerge and revealed gaps in current standards in use. The proposed information model offers a number of advantages. Altering only the information model can incorporate modifications to either a PHR or EHR system. The model uses classes and attributes to define how data is captured which allows greater flexibility in how data can be manipulated by receiving systems.     

Independent association of insulin resistance with larger amounts of intermuscular adipose tissue and a greater acute insulin response to glucose in African American than in white nondiabetic women

BACKGROUND: African Americans (AAs) have a higher prevalence of obesity and type 2 diabetes than do whites. Higher insulin resistance and hyperinsulinemia have been reported in adult AAs than in whites. Differences in adipose tissue and its distribution may account for these findings. OBJECTIVE: The objective was to ascertain whether differences between AA and white women in adipose tissue (AT) and skeletal muscle (SM) volumes account for ethnic differences in insulin resistance. DESIGN: We used whole-body magnetic resonance imaging to measure AT and SM volumes and used the intravenous-glucose-tolerance test to measure insulin resistance. RESULTS: AAs (n = 32) were 29-42% more insulin resistant than were whites (n = 28) after adjustment for weight and height or any AT volumes (P < 0.05). After adjustment for SM volume, the difference decreased to 19% and became nonsignificant. AAs had a 163% greater acute insulin response to glucose than did whites; this difference was significant even after adjustment for insulin sensivitity index, weight, height, and any magnetic resonance imaging measures. With respect to regional AT volumes, an association independent of race, weight, height, and SM volume was found only between increased intermuscular AT and lower insulin sensitivity index. CONCLUSIONS: Premenopausal AA women had significantly higher insulin resistance and acute insulin response to glucose than did their white counterparts. Whereas the difference in insulin resistance was partially accounted for by a greater SM volume in the AAs than in the whites, the difference in the acute insulin response to glucose was independent of any AT and SM measures and was disproportionately larger than expected according to the difference in insulin resistance. In addition, whole-body intermuscular AT was an important independent correlate of insulin resistance.     

Diabetes mellitus and serum carotenoids: findings of a population-based study in Queensland, Australia

BACKGROUND: Epidemiologic evidence suggests that serum carotenoids are potent antioxidants and may play a protective role in the development of chronic diseases including cancers, cardiovascular disease, and inflammatory diseases. The role of these antioxidants in the pathogenesis of diabetes mellitus remains unclear. OBJECTIVE: This study examined data from a cross-sectional survey to investigate the association between serum carotenoids and type 2 diabetes. DESIGN: Study participants were adults aged > or = 25 y (n = 1597) from 6 randomly selected cities and towns in Queensland, Australia. Study examinations conducted between October and December 2000 included fasting plasma glucose, an oral-glucose-tolerance test, and measurement of the serum concentrations of 5 carotenoid compounds. RESULTS: Mean 2-h postload plasma glucose and fasting insulin concentrations decreased significantly with increasing quintiles of the 5 serum carotenoids--alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene. Geometric mean concentrations for all serum carotenoids decreased (all decreases were significant except that of lycopene) with declining glucose tolerance status. Beta-carotene had the greatest decrease, to geometric means of 0.59, 0.50, and 0.42 micromol/L in persons with normal glucose tolerance, impaired glucose metabolism, and type 2 diabetes, respectively (P < 0.01 for linear trend), after control for potential confounders. CONCLUSIONS: Serum carotenoids are inversely associated with type 2 diabetes and impaired glucose metabolism. Randomized trials of diets high in carotenoid-rich vegetables and fruit are needed to confirm these results and those from other observational studies. Such evidence would have very important implications for the prevention of diabetes.     

Adipose tissue in muscle: a novel depot similar in size to visceral adipose tissue

BACKGROUND: The manner in which fat depot volumes and distributions, particularly the adipose tissue (AT) between the muscles, vary by race is unknown. OBJECTIVE: The objective was to quantify a previously unstudied and novel intermuscular AT (IMAT) depot and subcutaneous AT, visceral AT (VAT), and total-body skeletal muscle mass in healthy sedentary African American (AA), Asian, and white adults by whole-body magnetic resonance imaging. IMAT is the AT between muscles and within the boundary of the muscle fascia. DESIGN: Analyses were conducted on 227 women [AA (n = 79): body mass index (BMI; in kg/m(2)), 29.0 +/- 5.5; age, 45.7 +/- 16.9 y; Asian (n = 38): BMI, 21.7 +/- 2.9; age, 47.2 +/- 19.9 y; whites (n = 110): BMI, 24.9 +/- 5.4; age, 43.7 +/- 16.2 y]) and 111 men [AA (n = 39): BMI, 25.6 +/- 3.2; age, 45.5 +/- 18.8 y; Asian (n = 13): BMI, 24.9 +/- 2.5; age, 45.6 +/- 25.0 y; white (n = 59): BMI, 25.8 +/- 3.8; age 44.5 +/- 16.3 y]. RESULTS: IMAT depots were not significantly different in size between race groups at low levels of adiposity; however, with increasing adiposity, AAs had a significantly greater increment in the proportion of total AT (TAT) than did the whites and Asians (58, 46, and 44 g IMAT/kg TAT, respectively; P = 0.001). VAT depots were not significantly different in size at low levels of adiposity but, with increasing adiposity, VAT accumulation was greater than IMAT accumulation in the Asians and whites; no significant differences were observed in AAs. CONCLUSION: Race differences in AT distribution extend to IMAT, a depot that may influence race-ethnicity differences in dysglycemia.