Gender Differences in the Heritability of Musculoskeletal and Body Composition Parameters in Mother-Daughter and Mother-Son Pairs

Bone mass and body composition traits are genetically programmed, but the timing and gender and site specificities of their heritability are unclear. Mother-child correlations of bone mineral density (BMD) and bone mineral content, lean mass, and fat mass were studied in 169 premenopausal mothers and their 239 children. Heritability estimates of lean mass, fat mass, BMD, and area were derived for each gender and pubertal stage. There were significant correlations for most densitometry-derived variables at the spine, hip, femoral neck (FN), and total body (r = 0.192–0.388) in mother-postmenarcheal daughter pairs, for bone areas at all sites in early puberty (r = 0.229–0.508) and for volumetric-derived density at FN and spine (r = 0.238–0.368) in mother-son pairs. Fat mass correlations were significant in both genders after puberty (r = 0.299–0.324) and lean mass in postmenarcheal girls only (r = 0.299). Heritability estimates varied between 21% and 37% for mother-daughter and 18% and 35% for mother-son pairs for density-derived variables and between 26% and 40% for body composition variables. Maternal inheritance of bone traits is expressed in early-pubertal boys for several skeletal site traits but consistently involves most site traits in girls and boys by late puberty. Body composition inheritance is more variable.     

Tracer kinetic modeling of [11C]AFM,a new PET imaging agent for the serotonin transporter

[¹¹C]AFM, or [¹¹C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [¹¹C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [¹¹C]AFM binding potential (BP_ND) matched well with the known regional SERT densities. For routine use of [¹¹C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [¹¹C]AFM is a suitable PET radioligand to image and quantify SERT in humans.     

The impact of preventive health behaviour and social factors on visits to the doctor

Background

The aim of this study is to examine the joint impact of preventive health behavior (PHB) and social and demographic factors on the utilization of primary and secondary medical care under a universal health care system, as measured by visits to the doctor, who were categorized as either a General Practitioner (GP) or Specialist Doctor (SD).

Methods

An ordered probit model was utilized to analyze data obtained from the 2009 Israeli National Health Survey. The problem of endogeneity between PHB factors and visits to GP was approached using the two-stage residuals inclusion and instrumental variables method.

Results

We found a positive effect of PHB on visits to the doctor while the addition of the PHB factors to the independent variables resulted in important changes in explaining visits to GP (in values of the estimates, in their sign, and in their statistical significance), and only in slight changes for visits to SD. A 1% increase in PHB factors results in increasing the probability to visit General Practitioner in the last year in 0.6%. The following variables were identified as significant in explaining frequency of visits to the doctor: PHB, socio-economic status (pro-poor for visits to GP, pro-rich for visits to SD), location (for visits to SD), gender, age (age 60 or greater being a negative factor for visits to GP and a positive factor for visits to SD), chronic diseases, and marital status (being married was a negative factor for visits to GP and a positive factor for visits to SD).

Conclusions

There is a need for allowing for endogeneity in examining the impact of PHB, social and demographic factors on visits to GP in a population under universal health insurance.For disadvantaged populations with low SES and those living in peripheral districts, the value of IndPrev is lower than for populations with high SES and living in the center of the country. Examining the impact of these factors, significant differences in the importance and sometimes even in the sign of their influence on visits to different categories of doctors - GP and SD, are found.

     

Hypoglycemia as a predictor of mortality in hospitalized elderly patients

BACKGROUND: Hypoglycemia during hospitalization occurs in patients with and without diabetes. The aims of this study were to determine the incidence, associated risk factors, and short- and long-term outcome of hypoglycemia among hospitalized elderly patients. METHODS: This is a case-control study conducted at geriatric and medicine departments. All patients 70 years or older with documented hypoglycemia hospitalized within 1 year (n = 281) were compared with a nonhypoglycemic group of 281 elderly, randomly selected patients from the same hospitalized population. RESULTS: Among 5404 patients 70 years or older, 281 (5.2%) had documented hypoglycemia. Compared with the nonhypoglycemic group, we found the following characteristics to be true in the hypoglycemic group: there were more women than men (58% vs 44%, P =.001); sepsis was 10 times more common (P<.001); malignancy was 2.8 times more common (P =.04); the mean serum albumin level was lower (2.8 g/dL vs 3.4 g/dL, P<.001); and the mean serum creatinine and alkaline phosphatase levels were higher (P<.001 for both). Diabetes was known in 42% of the hypoglycemic group and in 31% of the nonhypoglycemic group (P =.03); 70 patients in the hypoglycemic group were taking sulfonylureas or insulin. Multivariate logistic analysis showed that sepsis, albumin level, malignancy, sulfonyurea and insulin treatment, alkaline phosphatase level, female sex, and creatinine level were all independent predictors of developing hypoglycemia. In-hospital mortality and 3-month mortality were about twice as high in the hypoglycemic group (P<.001). Multivariate analysis of mortality found that sepsis, low albumin level, and malignancy were independent predictors, while hypoglycmia was not. CONCLUSIONS: Hypoglycemia was common in elderly hospitalized patients and predicted increased in-hospital 3- and 6-month cumulative mortality. However, in a multivariate analysis, hypoglycemia was not an independent predictor for mortality, implying that it is only a marker.     

CD169+ macrophages in lymph node and spleen critically depend on dual RANK and LTbetaR signaling

CD169⁺ macrophages reside in lymph node (LN) and spleen and play an important role in the immune defense against pathogens. As resident macrophages, they are responsive to environmental cues to shape their tissue-specific identity. We have previously shown that LN CD169⁺ macrophages require RANKL for formation of their niche and their differentiation. Here, we demonstrate that they are also dependent on direct lymphotoxin beta (LTβ) receptor (R) signaling. In the absence or the reduced expression of either RANK or LTβR, their differentiation is perturbed, generating myeloid cells expressing SIGN-R1 in LNs. Conditions of combined haploinsufficiencies of RANK and LTβR revealed that both receptors contribute equally to LN CD169⁺ macrophage differentiation. In the spleen, the Cd169-directed ablation of either receptor results in a selective loss of marginal metallophilic macrophages (MMMs). Using a RANKL reporter mouse, we identify splenic marginal zone stromal cells as a source of RANKL and demonstrate that it participates in MMM differentiation. The loss of MMMs had no effect on the splenic B cell compartments but compromised viral capture and the expansion of virus-specific CD8⁺ T cells. Taken together, the data provide evidence that CD169⁺ macrophage differentiation in LN and spleen requires dual signals from LTβR and RANK with implications for the immune response.

CD169⁺ macrophages are strategically localized at the lymphatic sinuses of lymph nodes (LNs) and the marginal zone of the spleen, where they capture lymph- and blood-borne antigens, respectively (1). These macrophages reside close to B cells and mesenchymal stromal cells. B cells are a constitutive source of lymphotoxin (LT) α and LTβ that bind to the LTβ receptor (R) as LTα₁β₂ heterotrimer (2). Lack of B cells and unconditional or B cell–specific ablation of LTα or LTβ lead to loss of CD169⁺ macrophages in LNs and the spleen (3–6). Conversely, B cell–specific overexpression of LTαβ results in an increase of their numbers (7). Furthermore, administration of the decoy fusion protein LTβR-Fc or LTβR inactivation negatively affects their presence in both organs (3, 8, 9). However, although the myeloid cell lineage has been shown to express LTβR (10–12), it remains unclear whether the dependency on LTβR signaling is direct or implies an intermediate cell partner such as the adjacent stromal cells (9, 13, 14).We have recently shown that receptor activator of NF-κB ligand (RANKL) from marginal zone reticular cells (MRCs) regulates the differentiation of CD169⁺ macrophages in the LN (15). Like LTα and LTβ, RANKL is a member of the TNF superfamily and binds to the signaling receptor RANK (16). Stromal RANKL activates the lymphatic endothelial cells to form a cellular niche for macrophages and directly stimulates their differentiation into the CD169⁺ macrophages of the subcapsular sinus (subcapsular sinus macrophages, SSMs). However, a role of stromal RANKL for the splenic CD169⁺ macrophages has not been addressed. LTαβ and RANKL share many similarities in their biological functions. They are both indispensable for the organogenesis of secondary lymphoid organs (17, 18), are involved in the organogenesis of the thymus (19), and contribute to the formation of the intestinal microfold cells (20). However, RANKL stands out for its role in osteoclastogenesis (16), while LTαβ regulates the production of homeostatic chemokines and the differentiation of follicular dendritic cells (2).In the context of partially overlapping functions, we scrutinized the implication of the RANK–RANKL and LTβR–LTαβ axes in the differentiation of LN and splenic CD169⁺ macrophages. Using Cd169-directed conditional deficiency of RANK or LTβR, we report that direct RANK and LTβR signals are required for their differentiation in the LN and the spleen. In the absence of the receptors, LN CD169⁺ macrophages were replaced by myeloid cells phenotypically similar to the SIGN-R1⁺ medullary sinus macrophages. Deficiency of one copy of either Rank or Ltbr alleles sufficed for a prominent decrease in macrophage numbers, but the heterozygous deletion of both genes had a compound effect. Altered macrophage differentiation had a negative impact on lymph-borne antigen transport to B cells. In the spleen, Cd169-directed RANK or LTβR deficiency elicited a selective loss of the CD169⁺ MMMs. By the use of a RANKL reporter mouse together with RT-qPCR of sorted splenic stromal subsets, we identified CCL19⁺ splenic MRCs as a source of RANKL and demonstrated in Ccl19-cre RANKL-deficient mice that stromal RANKL participates in MMM differentiation. Their specific loss had no effect on the marginal zone B cell compartment but compromised viral capture and the formation of the virus-specific CD8⁺ T cell response. Taken together, the data provide evidence that CD169⁺ macrophage differentiation is dependent on the dual signals emanating from LTβR and RANK, with implications for the immune response to lymph- and blood-borne pathogens.     

Effectiveness of education in evidence-based healthcare: the current state of outcome assessments and a framework for future evaluations

Background A discipline which critically looks at the evidence for practice should itself be critically examined. Credible evidence for the effectiveness of training in evidence-based healthcare (EBHC) is essential. We attempted to summarise the current knowledge on evaluating the effectiveness of training in EBHC while identifying the gaps. Methods A working group of EBHC teachers developed a conceptual framework of key areas of EBHC teaching and practice in need of evidence mapped to appropriate methods and outcomes. A literature search was conducted to review the current state of research in these key areas. Studies of training interventions that evaluated effectiveness by considering learner, patient or health system outcomes in terms of knowledge, skills, attitude, judgement, competence, decision-making, patient satisfaction, quality of life, clinical indicators or cost were included. There was no language restriction. Results Of 55 articles reviewed, 15 met the inclusion criteria: six systematic reviews, three randomised controlled trials and six before-after studies. We found weak indications that undergraduate training in EBHC improves knowledge but not skills, and that clinically integrated postgraduate teaching improves both knowledge and skills. Two randomised controlled trials reported no impact on attitudes or behaviour. One before-after study found a positive impact on decision-making, while another suggested change in learners' behaviour and improved patient outcome. We found no studies assessing the impact of EBHC training on patient satisfaction, health-related quality of life, cost or population-level indicators of health. Conclusions Literature evaluating the effectiveness of training in EBHC has focused on short-term acquisition of knowledge and skills. Evaluation designs were methodologically weak, controlled trials appeared inadequately powered and systematic reviews could not provide conclusive evidence owing to weakness of study designs.