Effects of age on parathyroid hormone signaling in human marrow stromal cells

Human bone marrow stromal cells (hMSCs) have the potential to differentiate into osteoblasts; there are age‐related decreases in their proliferation and differentiation to osteoblasts. Parathyroid hormone (PTH), when applied intermittently in vivo, has osteoanabolic effects in a variety of systems. In this study, we compared PTH signaling and osteoanabolic effects in hMSCs from young and old subjects. There were age‐related decreases in expression of PTH/PTHrP receptor type 1 (PTHR1) gene (P = 0.049, n = 19) and in PTH activation of CREB (P = 0.029, n = 7) and PTH stabilization of β‐catenin (P = 0.018, n = 7). Three human PTH peptides, PTH1‐34, PTH1‐31C (Ostabolin‐C, Leu²⁷, Cyclo[Glu²²‐Lys²⁶]‐hPTH1‐31), and PTH1‐84 (10 nm ), stimulated osteoblast differentiation with hMSCs. Treatment with PTH1‐34 resulted in a significant 67% increase in alkaline phosphatase activity in hMSCs obtained from younger subjects (<50 years old, n = 5), compared with an 18% increase in hMSCs from elders (>55 years old, n = 7). Both knockdown of CREB and treatment with a protein kinase A inhibitor H‐89 blocked PTH stimulation of osteoblast differentiation in hMSCs from young subjects. The PTH peptides significantly stimulated proliferation of hMSCs. Treatment with PTH1‐34 resulted in an average of twice as many cells in cultures of hMSCs from young subjects (n = 4), but had no effect with hMSCs from elders (n = 7). Upregulation of PTHR1 by 24‐h pretreatment with 100 nm dexamethasone rescued PTH stimulation of proliferation in hMSCS from elders. In conclusion, age‐related intrinsic alterations in signaling responses to osteoanabolic agents like PTH may contribute to cellular and tissue aging of the human skeleton.     

Human body temperature is inversely correlated with body mass

Forty-two women and 18 men of mean age 54 years had their sub-lingual oral temperature measured hourly from 0700 h to 2300 h. Mean oral temperature (averaged over the 17 readings) was inversely correlated with body mass in the group as a whole (r = -0.44, df = 58, p = 0.0003). The women had significantly higher mean oral temperatures than the men, but the inverse relationship between mean oral temperature and body mass was still significant when the data from the women were analyzed separately (r = -0.37, df = 40, p = 0.013). The results suggest that in humans, mean body temperature is inversely related to body mass, irrespective of gender.     

Injections of leptin into rat ventromedial hypothalamus increase adipocyte apoptosis in peripheral fat and in bone marrow

The accumulation of fat cells (adipocytes) in bone marrow is now thought to be a factor contributing to age-related bone loss. Women with osteoporosis have higher numbers of marrow adipocytes than women with healthy bone, and bone formation rate is inversely correlated with adipocyte number in bone tissue biopsies from both men and women. Adipogenic differentiation of bone marrow stromal cells increases with age, but the factors regulating populations of mature adipocytes are not well understood. Leptin is thought to regulate adipose tissue mass via its receptors in the ventromedial hypothalamus (VMH). We have therefore tested the hypothesis that stimulation of leptin receptors in the VMH regulates adipocyte number in bone marrow. Results indicate that unilateral twice-daily injections of leptin into the rat VMH for only 4 or 5 days cause a significant reduction in the number of adipocytes in peripheral fat pads and bone marrow and indeed eliminate adipocytes almost entirely from bone marrow of the proximal tibia. Osteoblast surface is not affected with leptin treatment. Apoptosis assays performed on bone marrow samples from control and treated rats have revealed a significant increase in protein concentration of the apoptosis marker caspase-3 with leptin treatment. We conclude that stimulation of leptin receptors in the VMH significantly decreases the adipocyte population in bone marrow, primarily through apoptosis of marrow adipocytes. Elimination of marrow adipocytes via this central pathway may represent a useful strategy for the treatment and prevention of osteoporosis.     

Age-related decline in osteoblastogenesis and 1α-hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

With aging, there is a decline in bone mass and in osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro. Osteoblastogenesis can be stimulated with 1,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] and, in some hMSCs, by the precursor 25‐hydroxyvitamin D₃ (25OHD₃). CYP27B1/1α‐hydroxylase activates 25OHD₃ and, to a variable degree, hMSCs express CYP27B1. In this study, we tested the hypotheses (i) that age affects responsiveness to 25OHD₃ and expression/activity of CYP27B1 in hMSCs and (ii) that parathyroid hormone (PTH) upregulates CYP27B1 in hMSCs, as it does in renal cells. There were age‐related declines in osteoblastogenesis (n = 8, P = 0.0286) and in CYP27B1 gene expression (n = 27, r = ?0.498; P = 0.008) in hMSCs. Unlike hMSCs from young subjects (≤50 years), hMSCs from older subjects (≥55 years) were resistant to 25OHD₃ stimulation of osteoblastogenesis. PTH1‐34 (100 nm ) provided hMSCs with responsiveness to 25OHD₃ (P = 0.0313, Wilcoxon matched pairs test) and with two episodes of increased 1,25(OH)₂D₃ synthesis, of cAMP response element binding protein (CREB) activation, and of CYP27B1 upregulation. Both increases in CYP27B1 expression by PTH were obliterated by CREB‐siRNA or KG‐501 (which specifically inhibits the downstream binding of activated CREB). Only the second period of CREB signaling was diminished by AG1024, an inhibitor of insulin‐like growth factor‐I receptor kinase. Thus, PTH stimulated hMSCs from elders with responsiveness to 25OHD₃ by upregulating expression/activity of CYP27B1 and did so through CREB and IGF‐I pathways.     

Polyethylenimine‐mediated gene delivery into human bone marrow mesenchymal stem cells from patients

Transplantation of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for post‐infarction left ventricular (LV) dysfunction. However, age‐related functional decline of stem cells has restricted their clinical benefits after transplantation into the infarcted myocardium. The limitations imposed on patient cells could be addressed by genetic modification of stem cells. This study was designed to improve our understanding of genetic modification of human bone marrow derived mesenchymal stem cells (hMSCs) by polyethylenimine (PEI, branched with Mw 25 kD), one of non‐viral vectors that show promise in stem cell genetic modification, in the context of cardiac regeneration for patients. We optimized the PEI‐mediated reporter gene transfection into hMSCs, evaluated whether transfection efficiency is associated with gender or age of the cell donors, analysed the influence of cell cycle on transfection and investigated the transfer of therapeutic vascular endothelial growth factor gene (VEGF). hMSCs were isolated from patients with cardiovascular disease aged from 41 to 85 years. Optimization of gene delivery to hMSCs was carried out based on the particle size of the PEI/DNA complexes, N/P ratio of complexes, DNA dosage and cell viability. The highest efficiency with the cell viability near 60% was achieved at N/P ratio 2 and 6.0 μg DNA/cm². The average transfection efficiency for all tested samples, middle‐age group (<65 years), old‐age group (>65 years), female group and male group was 4.32%, 3.85%, 4.52%, 4.14% and 4.38%, respectively. The transfection efficiency did not show any correlation either with the age or the gender of the donors. Statistically, there were two subpopulations in the donors; and transfection efficiency in each subpopulation was linearly related to the cell percentage in S phase. No significant phenotypic differences were observed between these two subpopulations. Furthermore, PEI‐mediated therapeutic gene VEGF transfer could significantly enhance the expression level.     

Expression of wingless type (WNT) genes and their antagonists at mRNA levels in equine endometrium during the estrous cycle and early pregnancy

WNT signaling pathway plays important roles in reproductive events. Aims were to (1) determine presence of WNT genes and their antagonists in equine endometrium; and (2) to evaluate their expression profiles during early pregnancy. Endometrial biopsies were obtained from mares on day of ovulation (d0, n=4) and on days of 14 (P14, n=4), 18 (P18, n=4), 22 (P22, n=4) of early pregnancy. Biopsies were also collected from cyclic mares during late diestrus (LD, on day of 13.5-14, n=4) and after luteolysis in estrus phase (AL, on day of 17.5-18, n=4) of the cycle. PCR was used to detect expression of genes studied and then relative expression levels were quantified using real-time PCR analysis. A mixed model was fitted on the normalized data and least significant difference test (α=0.05) was employed. Eleven WNT genes (WNT2, WNT2B, WNT4, WNT5A, WNT5B, WNT7A, WNT8A, WNT9B, WNT10B, WNT11 and WNT16) and their antagonists (SFRP1, SFRP2, SFRP5, DKK1, DKK2 and WIF-1) were detected in equine endometrium. Compared to d0, WNT2, WNT5B, WNT7A and SFRP1 expressions were downregulated by the pregnancy while DKK1 was upregulated. WNT5A, WNT11 and WIF-1 were upregulated on P14 and P18, but WNT2B increased only on P14. When LD and P14 were compared, level of WNT8A decreased on P14 while increase in WNT4 level on P14 was slightly significant (P<0.06). Levels of WNT7A and SFRP1 decreased while DKK1 and WIF-1 increased by the pregnancy on P18 compared to AL. Moreover, WNT2B, WNT5A, WNT9B, WNT10B, WNT11, WNT16 DKK1 and WIF-1 were upregulated on LD compared to AL whereas WNT4, WNT7A, SFRP1 were downregulated. In conclusion, the results demonstrate that WNT genes and their antagonists appear to be regulated during early pregnancy in equine endometrium possibly due to embryonic factors and/or maternal progesterone.     

Sleep duration and BMI in a sample of young adults

We examined the association between sleep duration and BMI in young adults, and, specifically, in possible gender differences. The population-based sample included 955 young men and 1051 young women (mean age = 25.3 years, s.d. = 1.7) who participated in Project EAT-III (Eating and Activity in Teens and Young Adults)-III. In 2008-2009, study participants completed a survey, on which they reported their weight, height, and typical bed and awakening times. Gender-specific regression models estimated cross-sectional associations between sleep duration and weight status, adjusting for age, race, SES, family structure, depressive symptoms, physical activity, and sedentary and dietary behaviors. In multivariable-adjusted linear regression models, an hour increase in sleep was associated with a -0.38 (-0.70, -0.048) BMI in men. Men who slept <7 h had a 1.4 unit higher mean BMI (27.9; 95% confidence interval (CI): 26.9, 28.9) than men who slept 7-9 h/day (26.5; 95% CI: 26.1, 27.0). Prevalence estimates of overweight (BMI ≥ 25) and obesity (BMI ≥ 30) were also inversely associated with sleep duration among men. Sleep duration was not associated with BMI, overweight, or obesity in women. Among women, but not men, there was a statistically significant positive association between trouble falling or staying asleep and mean BMI. Sleep may be an important modifiable risk factor for obesity, particularly in young adult men.     

Comparison of thermoregulatory responses between men and women immersed in cold water.

Eleven women (age = 24.4 +/- 6.3 yr, mass = 65.0 +/- 7.8 kg, height = 167 +/- 8 cm, body fatness = 22.4 +/- 5.9%, mean +/- SD) were immersed to neck level in 18 degrees C water for up to 90 min for comparison of their thermal responses with those of men (n = 14) in a previous similarly conducted protocol. Metabolic rate increased about three times resting levels in men and women, whereas the rate of rectal temperature cooling (DeltaT(re)/Deltat) in women (0.47 degrees C/h) was about one-half that in men. With use of all data, DeltaT(re)/Deltat correlates with the ratio of body surface area to size and the metabolic rate of shivering correlates inversely to the square root of body fatness. No significant gender differences in total metabolic heat production normalized for body mass or surface area were found among subjects who completed 90 min of immersion (9 women and 7 men). Nor was there a gender difference in the overall percent contribution ( approximately 60%) of fat oxidation to total heat production. Blood concentrations of free fatty acids, glycerol, beta-hydroxybutyrate, and lactate increased significantly during the 90-min immersion, whereas muscle glycogen sampled from the right quadriceps femoris vastus lateralis decreased (free fatty acids, glycerol, and beta-hydroxybutyrate were higher in women). When the subjects were subgrouped according to similar body fatness and 60 min of immersion (6 women and 5 men), no significant gender differences emerged in DeltaT(re)/Deltat, energy metabolism, and percent fat oxidation. These findings suggest that no gender adjustments are necessary for prediction models of cold response if body fatness and the ratio of body surface area to size are taken into account and that a potential gender advantage with regard to carbohydrate sparing during cold water immersion is not supported.     

Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment

Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O(2)) than under 20% O(2) and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our (13)C NMR spectroscopic measurements indicate that (13)C-lactate is converted to (13)C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.     

Human mesenchymal stem cells support megakaryocyte and pro-platelet formation from CD34(+) hematopoietic progenitor cells

Megakaryocytopoiesis and thrombocytopoiesis result from the interactions between hematopoietic progenitor cells, humoral factors, and marrow stromal cells derived from mesenchymal stem cells (MSCs) or MSCs directly. MSCs are self-renewing marrow cells that provide progenitors for osteoblasts, adipocytes, chondrocytes, myocytes, and marrow stromal cells. MSCs are isolated from bone marrow aspirates and are expanded in adherent cell culture using an optimized media preparation. Culture-expanded human MSCs (hMSCs) express a variety of hematopoietic cytokines and growth factors and maintain long-term culture-initiating cells in long-term marrow culture with CD34(+) hematopoietic progenitor cells. Two lines of evidence suggest that hMSCs function in megakaryocyte development. First, hMSCs express messenger RNA for thrombopoietin, a primary regulator for megakaryocytopoiesis and thrombocytopoiesis. Second, adherent hMSC colonies in primary culture are often associated with hematopoietic cell clusters containing CD41(+) megakaryocytes. The physical association between hMSCs and megakaryocytes in marrow was confirmed by experiments in which hMSCs were copurified by immunoselection using an anti-CD41 antibody. To determine whether hMSCs can support megakaryocyte and platelet formation in vitro, we established a coculture system of hMSCs and CD34(+) cells in serum-free media without exogenous cytokines. These cocultures produced clusters of hematopoietic cells atop adherent MSCs. After 7 days, CD41(+) megakaryocyte clusters and pro-platelet networks were observed with pro-platelets increasing in the next 2 weeks. CD41(+) platelets were found in culture medium and expressed CD62P after thrombin treatment. These results suggest that MSCs residing within the megakaryocytic microenvironment in bone marrow provide key signals to stimulate megakaryocyte and platelet production from CD34(+) hematopoietic cells.     

Gender dimorphism in skeletal muscle leptin receptors, serum leptin and insulin sensitivity

To determine if there is a gender dimorphism in the expression of leptin receptors (OB-R170, OB-R128 and OB-R98) and the protein suppressor of cytokine signaling 3 (SOCS3) in human skeletal muscle, the protein expression of OB-R, perilipin A, SOCS3 and alpha-tubulin was assessed by Western blot in muscle biopsies obtained from the m. vastus lateralis in thirty-four men (age = 27.1+/-6.8 yr) and thirty-three women (age = 26.7+/-6.7 yr). Basal serum insulin concentration and HOMA were similar in both genders. Serum leptin concentration was 3.4 times higher in women compared to men (P<0.05) and this difference remained significant after accounting for the differences in percentage of body fat or soluble leptin receptor. OB-R protein was 41% (OB-R170, P<0.05) and 163% (OB-R128, P<0.05) greater in women than men. There was no relationship between OB-R expression and the serum concentrations of leptin or 17beta-estradiol. In men, muscle OB-R128 protein was inversely related to serum free testosterone. In women, OB-R98 and OB-R128 were inversely related to total serum testosterone concentration, and OB-R128 to serum free testosterone concentration. SOCS3 protein expression was similar in men and women and was not related to OB-R. In women, there was an inverse relationship between the logarithm of free testosterone and SCOS3 protein content in skeletal muscle (r = -0.46, P<0.05). In summary, there is a gender dimorphism in skeletal muscle leptin receptors expression, which can be partly explained by the influence of testosterone. SOCS3 expression in skeletal muscle is not up-regulated in women, despite very high serum leptin concentrations compared to men. The circulating form of the leptin receptor can not be used as a surrogate measure of the amount of leptin receptors expressed in skeletal muscles.     

Senescent B lymphopoiesis is balanced in suppressive homeostasis: decrease in interleukin-7 and transforming growth factor-beta levels in stromal cells of senescence-accelerated mice

The suppression of the B cell population during senescence has been considered to be due to the suppression of interleukin-7 (IL-7) production and responsiveness to IL-7; however, the upregulation of transforming growth factor-beta (TGF-beta) was found to contribute to B cell suppression.To investigate the mechanism of this suppression based on the interrelationship between IL-7 and TGF-beta during senescence, senescence-accelerated mice (SAMs), the mouse model of aging, were used in this study to elucidate the mechanisms of B lymphopoietic suppression during aging. Similar to regular senescent mice, SAMs showed a decrease in the number of IL-7-responding B cell progenitors (i.e., colony-forming unit pre-B [CFU-pre-B] cells in the femoral bone marrow [BM]). A co-culture system of B lymphocytes and stromal cells that the authors established showed a significantly lower number of CFU-pre-B cells harvested when BM cells were co-cultured with senescent stromal cells than when they were co-cultured with young stromal cells. Interestingly, cells harvested from a senescent stroma and those from the control culture without stromal cells were higher in number than those harvested from a young stroma, thereby implying that an altered senescent stromal cell is unable to maintain self-renewal of the stem cell compartment. Because TGF-beta is supposed to suppress the proliferative capacity of pro-B/pre-B cells, we added a neutralizing anti-TGF-beta antibody to the co-culture system with a pro-B/pre-B cell-rich population to determine whether such suppression may be rescued. However, unexpectedly, any rescue was not observed and the number of CFU-pre-B cells remained unchanged when BM cells were co-cultured with senescent stromal cells compared with the co-culture with young stromal cells, which essentially showed an increase in the number of CFU-pre-B cells (P < 0.001 in 5 microg/ml). Furthermore, TGF-beta protein level in the supernatant of cultured senescent stroma cells was evaluated by enzyme-linked immunoabsorbent assay, but surprisingly, it was found that TGF-beta concentration was significantly lower than that of cultured young stromal cells. Thus, TGF-beta activity was assumed to decline particularly in a senescent stroma, which means a distinct difference between the senescent suppression of B lymphopoiesis and secondary B lymphocytopenia. Concerning proliferative signaling, on the other hand, the level of IL-7 gene expression in cells from freshly isolated BM decreased significantly with age. Therefore, the acceleration of proliferative signaling and the deceleration of suppressive signaling may both be altered and weakened in a senescent stroma (i.e., homeosuppression).     

Collagen type XV and the ‘osteogenic status’

We have previously demonstrated that collagen type XV (ColXV) is a novel bone extracellular matrix (ECM) protein. It is well known that the complex mixture of multiple components present in ECM can help both to maintain stemness or to promote differentiation of stromal cells following change in qualitative characteristics or concentrations. We investigated the possible correlation between ColXV expression and mineral matrix deposition by human mesenchymal stromal cells (hMSCs) with different osteogenic potential and by osteoblasts (hOBs) that are able to grow in culture medium with or without calcium. Analysing the osteogenic process, we have shown that ColXV basal levels are lower in cells less prone to osteo‐induction such as hMSCs from Wharton Jelly (hWJMSCs), compared to hMSCs that are prone to osteo‐induction such as those from the bone marrow (hBMMSCs). In the group of samples identified as ‘mineralized MSCs’, during successful osteogenic induction, ColXV protein continued to be detected at substantial levels until early stage of differentiation, but it significantly decreased and then disappeared at the end of culture when the matrix formed was completely calcified. The possibility to grow hOBs in culture medium without calcium corroborated the results obtained with hMSCs demonstrating that calcium deposits organized in a calcified matrix, and not calcium ‘per se’, negatively affected ColXV expression. As a whole, our data suggest that ColXV may participate in ECM organization in the early‐phases of the osteogenic process and that this is a prerequisite to promote the subsequent deposition of mineral matrix.     

Expression of proinflammatory cytokines by human mesenchymal stem cells in response to cyclic tensile strain

Mesenchymal stem cells produce proinflammatory cytokines during their normal growth. Direct or indirect regulation of bone resorption by these cytokines has been reported. However, the effects of osteogenic conditions—chemical and/or mechanical—utilized during in vitro bone tissue engineering on expression of cytokines by hMSCs have not been studied. In this study, we investigated the effects of cyclic tensile strain, culture medium (with and without dexamethasone), and culture duration on the expression of tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and interleukin‐8 (IL‐8) by bone marrow derived human mesenchymal stem cells (hMSCs). Human MSCs seeded in three‐dimensional Type I collagen matrices were subjected to 0%, 10%, and 12% uniaxial cyclic tensile strains at 1 Hz for 4 h/day for 7 and 14 days in complete growth or dexamethasone‐containing osteogenic medium. Viability of hMSCs was maintained irrespective of strain level and media conditions. Expression of either TNF‐α or IL‐1β was not observed in hMSCs under any of the conditions investigated in this study. Expression of IL‐6 was dependent on culture medium. An increase in IL‐6 expression was caused by both 10% and 12% strain levels. Both 10% and 12% strain levels caused an increase in IL‐8 production by hMSCs that was dependent on the presence of dexamethasone. IL‐6 and IL‐8 expressions by hMSCs were induced by cyclic tensile strain and osteogenic differentiating media, indicating that IL‐6 and IL‐8 may be functioning as autocrine signals during osteogenic differentiation of hMSCs. J. Cell. Physiol. 219: 77–83, 2009. © 2008 Wiley‐Liss, Inc.     

Associations between Cognition,Gender and Monocyte Activation among HIV Infected Individuals in Nigeria

The potential role of gender in the occurrence of HIV-related neurocognitive impairment (NCI) and associations with markers of HIV-related immune activity has not been previously examined. In this study 149 antiretroviral-naïve seropositive subjects in Nigeria (SP, 92 women and 57 men) and 58 seronegative (SN, 38 women and 20 men) were administered neuropsychological testing that assessed 7 ability domains. From the neuropsychological test scores was calculated a global deficit score (GDS), a measure of overall NCI. Percentages of circulating monocytes and plasma HIV RNA, soluble CD163 and soluble CD14 levels were also assessed. HIV SP women were found to be younger, more educated and had higher CD4+ T cell counts and borderline higher viral load measures than SP men. On the neuropsychological testing, SP women were more impaired in speed of information processing and verbal fluency and had a higher mean GDS than SN women. Compared to SP men, SP women were also more impaired in speed of information processing and verbal fluency as well as on tests of learning and memory. Numbers of circulating monocytes and plasma sCD14 and sCD163 levels were significantly higher for all SP versus all SN individuals and were also higher for SP women and for SP men versus their SN counterparts. Among SP women, soluble CD14 levels were slightly higher than for SP men, and SP women had higher viral load measurements and were more likely to have detectable virus than SP men. Higher sCD14 levels among SP women correlated with more severe global impairment, and higher viral load measurements correlated with higher monocyte numbers and sCD14 and sCD14 levels, associations that were not observed for SP men. These studies suggest that the risk of developing NCI differ for HIV infected women and men in Nigeria and, for women, may be linked to effects from higher plasma levels of HIV driving activation of circulating monocytes.     

Does Childhood Sexual Abuse Predict Young Adult's BMI? A Birth Cohort Study

Objective: The objective was to identify the extent to which childhood sexual abuse (CSA) is associated with BMI and overweight status in young adulthood and to examine whether any associations differ by gender. Research Methods and Procedures: The Mater‐University of Queensland Study of Pregnancy is a prospective birth cohort from a population‐based sample involving 7223 singletons whose mothers were enrolled in the 1980s at the first antenatal visit. The present cohort consisted of a subgroup of 2461 young adults who had both self‐reported CSA data and measured BMI at 21 years. Results: Of 1273 men, 10.5% reported non‐penetrative and 7.5% reported penetrative CSA before age 16 years. Of 1305 women, 20.6% reported non‐penetrative and 7.9% reported penetrative CSA by age 16 years. We found young women's BMI and the prevalence of overweight at age 21 were greater in those who experienced penetrative CSA. This association was robust to adjustment for a variety of potential confounders. However, there was no association between non‐penetrative CSA and BMI in women and no association between either category of CSA and BMI in men. There was statistical evidence for a gender difference in the association of CSA with mean BMI at age 21 (p value for statistical interaction <0.01 in all models). Discussion: These findings suggest that among women, penetrative CSA is associated with greater BMI and increased odds of being overweight in later life, whereas in men, this association does not hold. This gender difference may reflect differences between women and men in the relationship between psychological trauma and body image or may be a chance subgroup finding.     

In aged mice,low surrogate light chain promotes pro‐B‐cell apoptotic resistance,compromises the PreBCR checkpoint,and favors generation of autoreactive,phosphorylcholine‐specific B cells

In aged mice, new B‐cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B‐cell precursors with higher levels of the surrogate light chain (SLC) proteins (λ5/VpreB) and (ii) λ5^low B‐cell precursors generate new B cells which show increased reactivity to the self‐antigen/bacterial antigen phosphorylcholine (PC). Pro‐B cells in old bone marrow as well as pro‐B cells from young adult λ5‐deficient mice are resistant to cytokine‐induced apoptosis (TNFα; TGFβ), indicating that low λ5 expression in pro‐B cells is sufficient to cause increased survival. Transfer of TNFα‐producing ‘age‐associated B cells’ (ABC; CD21/35^? CD23^?) or follicular (FO) B cells from aged mice into RAG‐2 KO recipients led to preferential loss of λ5^high pro‐B cells, but retention of λ5^low, apoptosis‐resistant pro‐B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of λ5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNFα‐producing B cells, results in preferential loss of SLC^high pro‐B cells within the bone marrow. Further B‐cell development then occurs via an ‘SLC^low’ pathway that not only impairs B‐cell generation, but promotes autoreactivity within the naïve antibody repertoires in the bone marrow and periphery.     

Influence of gender on post-tetanic potentiation in human dorsiflexors

Twitch contractions of the ankle dorsiflexors were evoked before and after 7 s of tetanic stimulation at 100 Hz in young women and men. Torque decreased more in men (18%) than in women (12%) during the tetanus. There was no gender difference in twitch peak torque potentiation over the 5-min post-tetanus. Potentiation was 42% (women) and 45% (men) at 5 s post-tetanus, and still present at 5 min (women 24%, men 25%). The immediate (5 s) shortening of twitch rise time was similar in women (14%) and men (13%), but during the 5-min men's rise time came to exceed whereas women's only approached pretetanus values (e.g., +9% vs. -1% at 5 min). The immediate decrease in half-relaxation time was also similar in women (24%) and men (22%); however, women's but not men's values remained less than pretetanus values for most of the 5-min period. Twitch rate of torque development increased similarly (75%) in women and men at 5 s, with no gender difference over 5 min. In contrast, rate of torque relaxation increased significantly only in men. Rate of torque development normalized to peak torque was similar in women and men pretetanus and increased similarly 5 s post-tetanus, but women had greater values through most of the 5-min post-tetanus. Normalized rate of torque relaxation was similar in women and men and not affected by tetanus. In the dorsiflexor muscles, young women and men show a similar amount and pattern of twitch force potentiation, but there are gender differences in time-related twitch contractile properties in the first 5 min after tetanus.