Miracle-dz/UniFAR-FTUs huggingface dataset:
[Effects of 24 h -6 degrees head-down tilt bed-rest on cardiovascular function and response to orthostatic stress].

Objective. To investigate the effects of 24 h -6 degrees head-down tilt bed-rest (HDT) on cardiovascular function and response to orthostatic stress. Method. -6 degrees head-down tilt bed rest for 24 h in 6 healthy males, aged 22-23, were observed. The changes of cardiac function were observed by electrical impedance instrument before and at 0th, 6th, 12th, 18th and 24th hour of HDT, and blood pressure were recorded and urine were collected. The changes of cardiovascular response to head up tilt (HUT 90 degrees, 10 min) before and post HDT were recorded. Result. During HDT, HR reduced significantly than that of pre-HDT (standing). HR at 6th, 12th, and 18th hour of HDT reduced significantly than that at 0th hour of HDT. Stroke output (SO) and stroke index (SI) [correction of CI] at 0th, 6th, 12th, and 24th hour of HDT were higher than pre-HDT value. Cardiac output (CO) and cardiac index (CI) at 18th hour of HDT were significantly lower than those at 0 h of HDT. Total peripheral resistance (TPR) at 18th hour of HDT were higher than that at 0th of HDT. During HUT before and post HDT, HR, MBP, TPR were significantly increased, SO, [correction of SV] SI, CO and CI were significantly reduced. DBP were significantly increased and PP were reduced significantly during HUT post-HDT. Hourly average value of urine during 0-4 h were higher than those during 4-12 h and 12-24 h. Conclusion. 24 h -6 degrees head-down tilt bed rest has significant effects on cardiovascular function and response to HUT in humans.
Lipid Profiling of In Vitro Cell Models of Adipogenic Differentiation: Relationships With Mouse Adipose Tissues

Our objective was to characterize lipid profiles in cell models of adipocyte differentiation in comparison to mouse adipose tissues in vivo. A novel lipid extraction strategy was combined with global lipid profiling using direct infusion and sequential precursor ion fragmentation, termed MS/MSALL. Perirenal and inguinal white adipose tissue and interscapular brown adipose tissues from adult C57BL/6J mice were analyzed. 3T3‐L1 preadipocytes, ear mesenchymal progenitor cells, and brown adipose‐derived BAT‐C1 cells were also characterized. Over 3000 unique lipid species were quantified. Principal component analysis showed that perirenal versus inguinal white adipose tissues varied in lipid composition of triacyl‐ and diacylglycerols, sphingomyelins, glycerophospholipids and, notably, cardiolipin CL 72:3. In contrast, hexosylceramides and sphingomyelins distinguished brown from white adipose. Adipocyte differentiation models showed broad differences in lipid composition among themselves, upon adipogenic differentiation, and with adipose tissues. Palmitoyl triacylglycerides predominate in 3T3‐L1 differentiation models, whereas cardiolipin CL 72:1 and SM 45:4 were abundant in brown adipose‐derived cell differentiation models, respectively. MS/MSALL data suggest new lipid biomarkers for tissue‐specific lipid contributions to adipogenesis, thus providing a foundation for using in vitro models of adipogenesis to reflect potential changes in adipose tissues in vivo. J. Cell. Biochem. 117: 2182–2193, 2016. © 2016 Wiley Periodicals, Inc.
Endogenous oestradiol and cardiovascular disease in healthy men: a systematic review and meta-analysis of prospective studies

Context The literature provides no clear answer as to whether total oestradiol (E2) concentrations increase the risk of incident cardiovascular disease (CVD) in healthy men. Objective The authors conducted a systematic review and meta-analysis to estimate the predictive value of E2 for CVD, and to identify study features explaining conflicting results. Data sources Articles were identified by a Medline and Embase search and citation tracking. Study selection Eligible articles were prospective population-based cohorts and nested case-control studies on E2 and incident cardiovascular disease (CVD), including myocardial infarction, stroke or death from coronary heart disease. Data-extraction Independent researchers re-expressed associations of E2 and incident CVD in a uniform manner to be used in meta-regression analyses for identification of study features explaining conflicting results, and to estimate the predictive value of E2 for CVD. Results and conclusions 14 studies out of 128 electronically identified articles were eligible. Data to be used for meta-analysis could be calculated in seven cases, and in the remaining seven cases, data of three more became available by contacting those authors. Overall, a non-significant association was found with an estimated summary RR of 0.98 for a change of >75th versus <25th percentile in E2 (95% CI 0.74 to 1.31). Mean body mass index (BMI) of the study population (βs −0.8, p<0.004), and quality of E2 assay (βs −0.6, p<0.08) may have modified the relationship between E2 and incident CVD. The present systematic review does not provide evidence for a pronounced harmful or beneficial effect of E2 on risk for incident CVD in healthy men. If present, an effect of E2 on risk for CVD might be modulated by BMI.
Rasburicase for the Treatment and Prevention of Hyperuricemia

OBJECTIVE: To review the information currently available on rasburicase for treatment and prevention of hyperuricemia. DATA SOURCES: MEDLINE (1966–August 2002) was searched for primary and review articles. STUDY SELECTION/DATA EXTRACTION: Studies evaluating rasburicase, including abstracts and proceedings, were considered for inclusion. English-language literature was evaluated for the pharmacology, pharmacodynamics, pharmacokinetics, therapeutic use, and adverse effects of rasburicase. DATA SYNTHESIS: Rasburicase, a recombinant urate oxidase, has been shown to be effective in lowering uric acid and preventing uric acid accumulation in patients with hematologic malignancies who had hyperuricemia or who were at high risk for developing hyperuricemia. It has been approved for pediatric use in the US. CONCLUSIONS: In addition to allopurinol, hydration, and urinary alkalinization, rasburicase is a new alternative for the treatment and prevention of hyperuricemia in patients with hematologic malignancies. Its rapid onset of action and the ability to lower preexisting elevated uric acid levels are the advantages of rasburicase compared with allopurinol. It may allow the patient to receive chemotherapy treatment without delay.
Regulation of opioid gene expression: a model to understand neural plasticity.

The recent finding that neurotransmitters and drugs that affect neurotransmission have important influences on gene expression suggests that drug-induced alterations in gene expression may underlie many long-term effects of addictive drugs, for example, dependence and drug-seeking behaviors. These long-term adaptive responses to opiate drugs have been particularly difficult to understand at a mechanistic level. Data presented here indicate that the gene encoding the opioid precursor proenkephalin is highly regulated by neural activity, second-messenger pathways, and PKA. These observations raise the possibility that drugs of abuse (e.g., opiates acting through opiate receptors) may act at the genetic level to modulate the expression of endogenous opiates and that these effects may underlie one component of the brain's long-term adaptive response to exogenous opiates. The transgenic animals described above can be used to investigate opiate drug-induced changes in proenkephalin gene expression, allowing rapid analysis of changes in proenkephalin gene expression in highly restricted populations of neurons in a fashion previously impossible. In addition, by analyzing the effects of specific enhancer mutations on tissue-specific and transsynaptic regulation of proenkephalin expression, transgenic models will permit mechanistic investigations within the intact nervous system that cannot otherwise be undertaken. Investigation of mechanisms underlying this process requires the analysis of intracellular signaling pathways, responsive DNA regulatory elements, and the transcription factors transducing synaptic signals into gene regulation. In the studies described herein, we demonstrate that AP-1 complexes consisting of different Jun proteins differentially regulate proenkephalin transcription at the CRE-2 element. c-Jun constitutively activates proenkephalin transcription, whereas JunD activates in a fashion completely dependent on the activation of second-messenger pathways and the cAMP-dependent PKA. JunB alone has no effect on proenkephalin gene expression, yet this molecule effectively blocks activation mediated by JunD and, hence, may act as a repressor. These data are consistent with a model (figure 4) in which preexisting JunD mediates the rapid cAMP-dependent activation of the proenkephalin enhancer, whereas IEGs such as JunB or c-Fos mediate the protein synthesis-dependent inactivation. Because c-Jun activates proenkephalin transcription constitutively, induction of c-Jun may lead to a further and prolonged activation of proenkephalin gene expression. Hence, the ratio of c-Jun to JunB induction may determine whether proenkephalin is repressed or further activated.
Intensive risk-adjusted follow-up with the CEA, TPA, CA19.9, and CA72.4 tumor marker panel and abdominal ultrasonography to diagnose operable colorectal cancer recurrences: effect on survival.

HYPOTHESIS Intensive risk-adjusted follow-up leads to improved resectability of tumor recurrences and better overall survival among patients who have undergone surgery for colorectal cancer. DESIGN Long-term observational single-center study. SETTING University of Pisa, Pisa, Italy. PATIENTS One hundred eight disease-free patients who had undergone surgery for colorectal cancer were submitted to long-term follow-up with the serum CEA, TPA, CA19.9, and CA72.4 tumor marker (TM) panel and abdominal ultrasonography. MAIN OUTCOME MEASURES Sensitivities and specificities of TMs, abdominal ultrasonography, and abdominal and chest computed tomography (CT); the median survival among patients operated on and those not operated on and the cumulative 5-year overall survival among the entire group. RESULTS Twenty-two patients with asymptomatic colorectal cancer recurred 32 times. The CEA, TPA, CA19.9, CA72.4, and TM panel sensitivities were 46.9%, 34.4%, 9.4%, 9.4%, and 81.0%, respectively, and the mean (SD) lead times before confirmation of recurrence were 4.3 (4.8), 4.1 (4.7), 8.3 (10.9), 5.0 (7.0), and 5.3 (5.8) months, respectively. Abdominal and chest CT sensitivities were 100.0%. Among 86 patients without recurrence, specificities of the TM panel and all panel markers were 100.0%, while specificities of abdominal ultrasonography, abdominal CT, and skeletal CT were 99.9%, 99.0%, and 100.0%, respectively. The median survival after first recurrence was 16 months (range, 3-48 months) for 8 patients with recurrence who did not undergo second-line surgery. Among 14 remaining patients who underwent metastasectomy, the median survival after first recurrence was 37 months (range, 12-187 months; P = .03). Among the entire group of 108 patients, the cumulative 5-year overall survival was 88.7%. CONCLUSIONS Long-term intensive risk-adjusted monitoring using the CEA, TPA, CA19.9, and CA72.4 TM panel and abdominal ultrasonography allows early detection of most recurrences. Patients can then undergo radical metastasectomy, with potentially improved overall survival.
Safety and efficacy of once daily ledipasvir/sofosbuvir fixed-dose combination in patients with chronic hepatitis C

ABSTRACT Introduction: During the past couple of years, the regulatory authorities have approved seven new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C (CHC). In 2014, the US FDA approved the fixed dose combination of ledipasvir (LDV) plus sofosbuvir (SOF) for the treatment of genotype (GT) 1 HCV and the European Commission Granted its marketing authorization to treat patients with GT1 and 4. This regimen showed outstanding rates of virologic response along with a favorable safety profile with a very low rate of both virologic failure and treatment discontinuation. Areas covered: In this review, we sought to review the pharmacokinetics, clinical efficacy and safety profile pertaining to LDV/SOF combination in treatment of CHC with special emphasis on phase III clinical trials. Expert opinion: In all phase III trials, the 12-week course of this new interferon (IFN)-sparing regimen has delivered high virologic cure rates among patient with GT1 and 4 both treatment-naïve and – experienced Data about its effectiveness in patients under 18 years of age, end-stage renal disease and patients with significant other organ involvement are eagerly awaited.
Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking

Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine‐Sottas syndrome (DSS) and in the corresponding mouse model (P0null‐mice). In the mammalian CNS, the tetraspan‐membrane protein PLP is the major structural myelin constituent and required for the long‐term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type‐2) and the relevant mouse model (Plpnull‐mice). The Plp‐gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0null‐mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0null*Plpnull‐double‐mutant mice. Compared with either single‐mutant, P0null*Plpnull‐mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non‐myelinated but in a one‐to‐one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0null*Plpnull‐mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell‐dependent support of peripheral axons and the oligodendrocyte‐dependent support of central axons. GLIA 2016;64:155–174
Corticotropin‐releasing Factor in the Caudal Pontine Reticular Nucleus Mediates the Expression of Fear‐potentiated Startle in the Rat

The fear‐potentiated startle paradigm is a valuable model for the investigation of the neuronal basis of fear. Previous studies have demonstrated that the neuropeptide corticotropin‐releasing factor (CRF) plays an important role in fear‐related processes, notably in the potentiation of the acoustic startle response. The present study investigated the role in fear‐potentiated startle of CRF in the caudal pontine reticular nucleus, a brain nucleus that mediates the acoustic startle response. First, we showed that the central nucleus of the amygdala gives rise to a CRFergic projection to the caudal pontine reticular nucleus. In the second experiment, we iontophoretically applied CRF to caudal pontine reticular nucleus neurons and extracellularly recorded the activity of these neurons. CRF had a mainly excitatory effect on the tone‐evoked activity of the neurons. In our third experiment, we injected the CRF antagonist α‐helical CRF into the caudal pontine reticular nucleus of awake rats. Here, α‐helical CRF dose‐dependently blocked fear‐potentiated startle, but had no effect on the baseline startle amplitude. The present results show that CRF‐containing neurons which project from the central nucleus to the caudal pontine reticular nucleus are important for the enhancement of startle by fear, and further characterize the hypothetical neuronal circuitry underlying the expression of fear‐potentiated startle.
On Being New to an Insurance Plan: Health Care Use Associated With the First Years in a Health Insurance Plan

BACKGROUND We wanted to compare health care utilization and costs in the first year of being in a health insurance plan with those of subsequent years. METHODS We used claims data from an independent practitioner association (IPA)-style managed care organization in the Rochester, NY, metropolitan area from 1996 through 1999. Cross-sectional and panel analyses of up to 4 years of claims data were conducted, involving 335,547 adult patients assigned to the panels of 687 primary care physicians (internists and family physicians). Multivariate analyses, adjusting for age, sex, case mix, and socioeconomic status derived from ZIP codes, examined the relationship between the first year of health insurance and Papanicolaou tests, mammograms in women older than 40 years, physician use, avoidable hospitalization, and expenditures. RESULTS After multivariate adjustment, the first year of insurance was associated with a higher risk of not getting a mammogram, a higher risk of avoidable hospitalization, greater likelihood of visiting a physician, and higher expenditures, especially for testing. There was no relationship, however, between Papanicolaou test compliance and year of enrollment. CONCLUSIONS The findings suggest there might be adverse clinical and financial implications associated with changing insurance.
Mineralogy and Petrology of Comet 81P/Wild 2 Nucleus Samples

The bulk of the comet 81P/Wild 2 (hereafter Wild 2) samples returned to Earth by the Stardust spacecraft appear to be weakly constructed mixtures of nanometer-scale grains, with occasional much larger (over 1 micrometer) ferromagnesian silicates, Fe-Ni sulfides, Fe-Ni metal, and accessory phases. The very wide range of olivine and low-Ca pyroxene compositions in comet Wild 2 requires a wide range of formation conditions, probably reflecting very different formation locations in the protoplanetary disk. The restricted compositional ranges of Fe-Ni sulfides, the wide range for silicates, and the absence of hydrous phases indicate that comet Wild 2 experienced little or no aqueous alteration. Less abundant Wild 2 materials include a refractory particle, whose presence appears to require radial transport in the early protoplanetary disk.
Functional characterisation of genetic variants associated with malignant hyperthermia

Mutations in the skeletal muscle sarcoplasmic reticulum calcium release channel (RYR1) have been identified in association with malignant hyperthermia(MH)and exertional heat stroke(EHS). MH is a pharmacogenetic disorder in which hypermetabolism is triggered upon exposure to volatile anaesthetics. MH has long been linked with EHS, a life threatening increase in body temperature caused by strenuous exercise in warm climates with both conditions being caused by a deregulation of skeletal muscle calcium homeostasis. The availability of genetic testing in MH is limited to variants that have been proven to alter calcium handling in vitro. In this thesis, data on the functional consequences of seven RYR1 variants found in association with MH are presented, one of which has also been identified in an EHS patient. Site-directed mutagenesis was used to introduce the variants into a human RYR1 cDNA clone before expressing wild type and mutant constructs in HEK293 cells. Six of the variants, including the EHS mutation, were found to have an increased sensitivity to caffeine as evidenced through a significant decrease in EC50 as well as exaggerated calcium release at low doses of caffeine as compared to wild type controls. For one variant, p.D3986E, an increase in RYR1 expression was required before the phenotype resembled the other RYR1 variants, hinting at a more complicated role in MH for this variant. The functional data presented in this thesis is supportive of the addition of six RYR1 variants onto the genetic diagnostic panel for MH, increasing the availability of initial genetic testing by 19%. Furthermore, the work presented further supports the link between MH and EHS through the presence of a common RYR1 variant proven to alter calcium handling. Finally, data obtained for the p.D3986E variant lays the foundation for future studies aiming to identify genetic modifiers of the MH phenotype.
Non‐junctional human desmoglein 3 acts as an upstream regulator of Src in E‐cadherin adhesion, a pathway possibly involved in the pathogenesis of pemphigus vulgaris

E‐cadherin, a classical cadherin, is an adhesion receptor in adherens junctions and has important functions in cell–cell adhesion and cell signalling. Recently we reported that a desmosomal cadherin, desmoglein 3 (Dsg3), an autoantigen in pemphigus vulgaris (PV), associates with E‐cadherin and activates Src, which results in tyrosine phosphorylation of adherens junction proteins. However, the nature of such an interaction and its role in cell–cell adhesion remain unclear. In this report, we provide direct evidence that it is the detergent‐soluble, non‐desmosomal Dsg3 that regulates the activity of Src and its association with E‐cadherin in adherens junction formation. Modulation of Dsg3 levels, either by Dsg3 silencing or over‐expression, alters Src activity and its association with E‐cadherin. Dsg3 silencing caused retardation of calcium‐induced E‐cadherin junction assembly and a reduction of desmosomal protein expression. Furthermore, we provide evidence that this signalling pathway is involved, at least in part, in the pathophysiology of pemphigus. Along with the reduced expression of Dsg3, loss and disruption of E‐cadherin and a concomitant decreased pSrc signalling was identified in the basal keratinocytes surrounding the blisters in PV. These findings suggest a novel function for Dsg3 in the control of E‐cadherin–Src signalling and cell–cell adhesion. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.