Low temperature decreases bone mass in mice: Implications for humans

ObjectivesHumans exhibit significant ecogeographic variation in bone size and shape. However, it is unclear how significantly environmental temperature influences cortical and trabecular bone, making it difficult to recognize adaptation versus acclimatization in past populations. There is some evidence that cold‐induced bone loss results from sympathetic nervous system activation and can be reduced by nonshivering thermogenesis (NST) via uncoupling protein (UCP1) in brown adipose tissue (BAT). Here we test two hypotheses: (1) low temperature induces impaired cortical and trabecular bone acquisition and (2) UCP1, a marker of NST in BAT, increases in proportion to degree of low‐temperature exposure.MethodsWe housed wildtype C57BL/6J male mice in pairs at 26 °C (thermoneutrality), 22 °C (standard), and 20 °C (cool) from 3 weeks to 6 or 12 weeks of age with access to food and water ad libitum (N = 8/group).ResultsCool housed mice ate more but had lower body fat at 20 °C versus 26 °C. Mice at 20 °C had markedly lower distal femur trabecular bone volume fraction, thickness, and connectivity density and lower midshaft femur cortical bone area fraction versus mice at 26 °C (p < .05 for all). UCP1 expression in BAT was inversely related to temperature.DiscussionThese results support the hypothesis that low temperature was detrimental to bone mass acquisition. Nonshivering thermogenesis in brown adipose tissue increased in proportion to low‐temperature exposure but was insufficient to prevent bone loss. These data show that chronic exposure to low temperature impairs bone architecture, suggesting climate may contribute to phenotypic variation in humans and other hominins.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146428/1/ajpa23684.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146428/2/ajpa23684_am.pd

Do we know more about hypertension in Poland after the May Measurement Month 2017?-Europe

Elevated blood pressure (BP) is a worldwide burden, leading to over 10 million deaths yearly. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed at raising awareness of hypertension and the need for BP screening. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. BP measurement, the definition of hypertension and statistical analysis followed the globally approved MMM17 Study Protocol. In Poland 5834 (98.9%, Caucasian) individuals were screened. After multiple imputation, 2601 (35.3%) had hypertension. Of individuals not receiving anti-hypertensive medication, 976 (20.6%) were hypertensive. Of individuals receiving anti-hypertensive medication, 532 (49.1%) had uncontrolled BP. In the crude screened group, 81.4% declared to not receive any anti-hypertensive treatment, while the remaining 18.6% were on such medications. In overweight and obese patients both systolic and diastolic BP were significantly higher than in normal weight and underweight subjects. In addition, BP measured on Sundays was significantly lower than on Mondays. MMM17 was one of the largest recent BP screening campaigns in Poland. We found that over 1/3 of participants were hypertensive. Almost half of the treated subjects had uncontrolled BP. These results suggest that opportunistic screening can identify substantial numbers with raised BP

Streptozotocin, Type I Diabetes Severity and Bone

As many as 50% of adults with type I (T1) diabetes exhibit bone loss and are at increased risk for fractures. Therapeutic development to prevent bone loss and/or restore lost bone in T1 diabetic patients requires knowledge of the molecular mechanisms accounting for the bone pathology. Because cell culture models alone cannot fully address the systemic/metabolic complexity of T1 diabetes, animal models are critical. A variety of models exist including spontaneous and pharmacologically induced T1 diabetic rodents. In this paper, we discuss the streptozotocin (STZ)-induced T1 diabetic mouse model and examine dose-dependent effects on disease severity and bone. Five daily injections of either 40 or 60 mg/kg STZ induce bone pathologies similar to spontaneously diabetic mouse and rat models and to human T1 diabetic bone pathology. Specifically, bone volume, mineral apposition rate, and osteocalcin serum and tibia messenger RNA levels are decreased. In contrast, bone marrow adiposity and aP2 expression are increased with either dose. However, high-dose STZ caused a more rapid elevation of blood glucose levels and a greater magnitude of change in body mass, fat pad mass, and bone gene expression (osteocalcin, aP2). An increase in cathepsin K and in the ratio of RANKL/OPG was noted in high-dose STZ mice, suggesting the possibility that severe diabetes could increase osteoclast activity, something not seen with lower doses. This may contribute to some of the disparity between existing studies regarding the role of osteoclasts in diabetic bone pathology. Examination of kidney and liver toxicity indicate that the high STZ dose causes some liver inflammation. In summary, the multiple low-dose STZ mouse model exhibits a similar bone phenotype to spontaneous models, has low toxicity, and serves as a useful tool for examining mechanisms of T1 diabetic bone loss

Stochastic Reaction-diffusion Equations Driven by Jump Processes

We establish the existence of weak martingale solutions to a class of second order parabolic stochastic partial differential equations. The equations are driven by multiplicative jump type noise, with a non-Lipschitz multiplicative functional. The drift in the equations contains a dissipative nonlinearity of polynomial growth.Comment: See journal reference for teh final published versio

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Glutathione-Related Antioxidant Defense System in Elderly Patients Treated for Hypertension

The purpose of this study was to analyze glutathione antioxidant defense system in elderly patients treated for hypertension. Studies were carried out in the blood collected from 18 hypertensive and 15 age- and sex-matched controls, all subjects age over 60. Hypertensives were on their usual antihypertensive treatment at the time of blood collection. The concentration of glutathione (GSH) in whole blood and activities of glutathione peroxidase (GPx-1), glutathione transferase (GST), and glutathione reductase (GR) in erythrocytes were measured. The data from patients and controls were compared using independent-samples t test. P value of 0.05 and less was considered statistically significant. We observed increased glutathione-related antioxidant defense in treated hypertensive elderly patients (HT) when compared with healthy controls (C). Mean GSH concentration was significantly higher in HT when compared with C: 3.1 ± 0.29 and 2.6 ± 0.25 mmol/L, respectively, P < 0.001. Mean activity of GR was significantly higher in HT group if compared with C: 83.4 ± 15.25 U/g Hb versus 64.2 ± 8.26 U/g Hb, respectively, P < 0.001. Mean activity of GST was significantly higher in HT group compared with C: 3.0 ± 0.60 mmol CDNB-GSH/mgHb/min and 2.6 ± 0.36 mmol CDNB-GSH/mgHb/min, respectively, P < 0.05. No difference in GPx activity was observed between two groups. These results show that glutathione-related antioxidant defense system was enhanced in elderly hypertensive patients treated for their conditions. This suggests important role of glutathione system in blood pressure regulation. Alterations in concentration and activity of antioxidants observed during antihypertensive medication are likely to be related to the effect of the treatment on NO bioavailability

Clinical autonomic nervous system laboratories in Europe. A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49–251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100–360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4–110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p&nbsp;= 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

Discordant Gene Expression Signatures and Related Phenotypic Differences in Lamin A- and A/C-Related Hutchinson-Gilford Progeria Syndrome (HGPS)

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNAK542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS