Neuroendocrine signaling modulates specific neural networks relevant to migraine

Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10 U·kg(− 1)), glucagon (100 μg·200 μl(− 1)) and leptin (0.3, 1 and 3 mg·kg(− 1)) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (p < 0.001) and leptin (p < 0.01) whereas glucagon had the opposite effect (p < 0.001). Dural-evoked neuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (p < 0.001), glucagon (p < 0.05) and leptin (p < 0.01). Trigeminocervical-complex pERK1/2 cell expression was significantly decreased by insulin and leptin (both p < 0.001), and increased by glucagon (p < 0.001), when compared to vehicle control. However, only leptin affected pERK1/2 expression in the hypothalamus, significantly decreasing pERK1/2 immunoreactive cell expression in the arcuate nucleus (p < 0.05). These findings demonstrate that insulin, glucagon and leptin can alter the transmission of trigeminal nociceptive inputs. A potential neurobiological link between migraine and impaired metabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction

Success of high tibial osteotomy in the United States military

The article of record as published may be located at https://doi.org/10.1177/232596711557467Background: Historically, high tibial osteotomy (HTO) has been performed to treat isolated medial gonarthrosis with varus deformity. Purpose:To evaluate the occupational outcomes of HTO in a high-demand military cohort. Study Design: Case-control study; Level of evidence, 3. Methods: A retrospective analysis of active duty service members undergoing HTO for coronal plane malalignment and/or intra-articular pathology was performed using the Military Health System between 2003 and 2011. Demographic parameters and surgical variables, including rates of perioperative complications, secondary surgery, activity limitations, and medical discharge, were extracted from electronic medical records. For the current study, cumulative failure was defined as conversion to knee arthroplasty or postoperative medical discharge for persistent knee dysfunction. Univariate and multivariate analyses were performed to identify statistical associations with cumulative failure after HTO. Results:A total of 181 service members (202 HTOs) were identified at an average follow-up of 47.5 months (range, 24-96 months). Mean age was 35.7 years (range, 19-55 years), and the majority were men (93%) and of enlisted rank (78%). All index procedures utilized a valgus-producing, opening wedge technique. Concomitant or staged procedures were performed in 87 patients (48%), including 40 ligamentous, 48 meniscal, and 48 chondral procedures. Complications occurred in 19.3% of knees (n = 39), with unplanned reoperation in 26 knees (12.8%). Fifty-three patients (40.7%) had minor activity limitations during military duty postoperatively. Eleven knees (5.4%) underwent conversion to total knee arthroplasty. The cumulative failure rate was 28.2% (n = 51) at 2- to 8-year follow-up. Patient age younger than 30 years at the time of surgery was associated with an independently higher risk of failure, whereas sex, concomitant/staged procedures, and perioperative complications were not significantly associated with subsequent failure. Conclusion: At short- to midterm follow-up, nearly 72% of all service members undergoing HTO returned to military duty and were free from conversion knee arthroplasty

Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts.

ObjectiveTo compare faecal microbial composition in patients with systemic sclerosis (SSc) from 2 independent cohorts with controls and to determine whether certain genera are associated with SSc-gastrointestinal tract (GIT) symptoms.DesignAdult patients with SSc from the University of California, Los Angeles (UCLA) and Oslo University Hospital (OUH) and healthy controls participated in this study (1:1:1). All participants provided stool specimens for 16S rRNA sequencing. Linear discriminant analysis effect size demonstrated genera with differential expression in SSc. Differential expression analysis for sequence count data identified specific genera associated with GIT symptoms as assessed by the GIT 2.0 questionnaire.ResultsThe UCLA-SSc and OUH-SSc cohorts were similar in age (52.1 and 60.5 years, respectively), disease duration (median (IQR): 6.6 (2.5-16.4) and 7.0 (1.0-19.2) years, respectively), gender distribution (88% and 71%, respectively), and GIT symptoms (mean (SD) total GIT 2.0 scores of 0.7 (0.6) and 0.6 (0.5), respectively). Principal coordinate analysis illustrated significant microbial community differences between SSc and controls (UCLA: p=0.001; OUH: p=0.002). Patients with SSc had significantly lower levels of commensal genera deemed to protect against inflammation, such as Bacteroides (UCLA and OUH), Faecalibacterium (UCLA), Clostridium (OUH); and significantly higher levels of pathobiont genera, such as Fusobacterium (UCLA), compared with controls. Increased abundance of Clostridium was associated with less severe GIT symptoms in both cohorts.ConclusionsThe present analysis detected specific aberrations in the lower GIT microbiota of patients with SSc from 2 geographically and ethnically distinct cohorts. These findings suggest that GIT dysbiosis may be a pathological feature of the SSc disease state

Low temperature thermal conductivity in a d-wave superconductor with coexisting charge order: Effect of self-consistent disorder and vertex corrections

Given the experimental evidence of charge order in the underdoped cuprate superconductors, we consider the effect of coexisting charge order on low-temperature thermal transport in a d-wave superconductor. Using a phenomenological Hamiltonian that describes a two-dimensional system in the presence of a Q=(\pi,0) charge density wave and d-wave superconducting order, and including the effects of weak impurity scattering, we compute the self-energy of the quasiparticles within the self-consistent Born approximation, and calculate the zero-temperature thermal conductivity using linear response formalism. We find that vertex corrections within the ladder approximation do not significantly modify the bare-bubble result that was previously calculated. However, self-consistent treatment of the disorder does modify the charge-order-dependence of the thermal conductivity tensor, in that the magnitude of charge order required for the system to become effectively gapped is renormalized, generally to a smaller value.Comment: 19 pages, 15 figure

Remotely sensed and modelled pasture biomass, land condition and the potential to improve grazing-management decision tools across the Australian rangelands

This report assesses the potential for expanding on current capacity to monitor land condition using remotely sensed fractional cover products to improve biomass estimation, animal productivity, pasture growth models and grazing decision tools (e.g. safe carrying capacity) across the Australian rangelands. We focus on northern Australia and include relevant research and implementation from southern Australia where appropriate

Adaptive Optics Nulling Interferometric Constraints on the Mid-Infrared Exozodiacal Dust Emission around Vega

We present the results of mid-infrared nulling interferometric observations of the main-sequence star alpha Lyr (Vega) using the 6.5 m MMT with its adaptive secondary mirror. From the observations at 10.6 microns, we find that there is no resolved emission from the circumstellar environment (at separations greater than 0.8 AU) above 2.1% (3 sigma limit) of the level of the stellar photospheric emission. Thus, we are able to place an upper limit on the density of dust in the inner system of 650 times that of our own solar system's zodiacal cloud. This limit is roughly 2.8 times better than those determined with photometric excess observations such as those by IRAS. Comparison with far-infrared observations by IRAS shows that the density of warm dust in the inner system (< 30 AU) is significantly lower than cold dust at larger separations. We consider two scenarios for grain removal, the sublimation of ice grains and the presence of a planetary mass "sweeper." We find that if sublimation of ice grains is the only removal process, a large fraction (> 80%) of the material in the outer system is ice.Comment: 11 pages, 1 figure, Accepted to The Astrophysical Journal Letter

S100A4 downregulates filopodia formation through increased dynamic instability

Cell migration requires the initial formation of cell protrusions, lamellipodia and/or filopodia, the attachment of the leading lamella to extracellular cues and the formation and efficient recycling of focal contacts at the leading edge. The small calcium binding EF-hand protein S100A4 has been shown to promote cell motility but the direct molecular mechanisms responsible remain to be elucidated. In this work, we provide new evidences indicating that elevated levels of S100A4 affect the stability of filopodia and prevent the maturation of focal complexes. Increasing the levels of S100A4 in a rat mammary benign tumor derived cell line results in acquired cellular migration on the wound healing scratch assay. At the cellular levels, we found that high levels of S100A4 induce the formation of many nascent filopodia, but that only a very small and limited number of those can stably adhere and mature, as opposed to control cells, which generate fewer protrusions but are able to maintain these into more mature projections. This observation was paralleled by the fact that S100A4 overexpressing cells were unable to establish stable focal adhesions. Using different truncated forms of the S100A4 proteins that are unable to bind to myosin IIA, our data suggests that this newly identified functions of S100A4 is myosin-dependent, providing new understanding on the regulatory functions of S100A4 on cellular migration

A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.National Institutes of Health (U.S.) (Grant DK095045)National Institutes of Health (U.S.) (Grant DK099465)National Institutes of Health (U.S.) (Grant DK103658)National Institutes of Health (U.S.) (Grant DK083511)National Institutes of Health (U.S.) (Grant DK093746