Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels.

BACKGROUND Many men older than 50 years have bioavailable testosterone levels below the reference range for young adult men. The impact of the decreased androgen levels on cognition and health perception has received little attention. METHODS Sixty-seven men (mean age 76 +/- 4 years, range 65-87) with bioavailable testosterone levels below 128 ng/dl (lower limit for adult normal range) were randomized to receive transdermal testosterone (2-2.5 mg patches/d) or placebo patches for 1 year. All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones [testosterone, bioavailable testosterone, sex hormone binding globulin (SHBG), estradiol, and estrone], cognitive tests (Digit Symbol, Digit Span, Trailmaking A and B), health perception (Medical Outcome Survey Short-form 36 or SF-36), lower extremity muscle strength and power, and calcium intake. RESULTS Twenty-three men (34%) withdrew from the study; 44 men completed the trial. Bioavailable testosterone levels increased from 93 +/- 34 (SD) to 162 +/- 100 ng/dl (p <.002) at 12 months in the testosterone group (n = 24) while no change occurred in the control group (n = 20). While there was no change in estradiol levels in either group, estrone levels increased in the testosterone group (28 +/- 7 to 32 +/- 9 pg/dl, p =.017). Scores on the Digit Symbol test improved in both the testosterone and placebo groups. Scores on Trailmaking B improved in men treated with testosterone (p <.005), although the changes were not statistically different from the changes seen in the placebo group. Twelve-month scores on Trailmaking B for the entire group were correlated with 12-month testosterone levels (p =.016). Scores for health perception measured by SF-36 did not change significantly, though scores of mental and general health declined in both groups during the 12-month intervention. Twelve-month bioavailable testosterone scores were directly correlated with scores for physical role (p =.022), vitality (p =.036), and the physical composite score (p =.010). CONCLUSIONS Transdermal testosterone treatment in men with low bioavailable testosterone levels does not impair and may improve cognitive function. Treatment did not improve health perception but this may have been due to the side effects of skin irritation suggested by similar reactions in both the testosterone and placebo groups.
SunRiSE – measuring translation elongation at single-cell resolution by means of flow cytometry

ABSTRACT The rate at which ribosomes translate mRNAs regulates protein expression by controlling co-translational protein folding and mRNA stability. Many factors regulate translation elongation, including tRNA levels, codon usage and phosphorylation of eukaryotic elongation factor 2 (eEF2). Current methods to measure translation elongation lack single-cell resolution, require expression of multiple transgenes and have never been successfully applied ex vivo. Here, we show, by using a combination of puromycilation detection and flow cytometry (a method we call ‘SunRiSE’), that translation elongation can be measured accurately in primary cells in pure or heterogenous populations isolated from blood or tissues. This method allows for the simultaneous monitoring of multiple parameters, such as mTOR or S6K1/2 signaling activity, the cell cycle stage and phosphorylation of translation factors in single cells, without elaborated, costly and lengthy purification procedures. We took advantage of SunRiSE to demonstrate that, in mouse embryonic fibroblasts, eEF2 phosphorylation by eEF2 kinase (eEF2K) mostly affects translation engagement, but has a surprisingly small effect on elongation, except after proteotoxic stress induction. This article has an associated First Person interview with the first author of the paper. Highlighted Article: A novel method to measure translation elongation rate and intensity in complex and heterogeneous cell populations by combining puromycilation, translation run-off experiment and flow cytometry detection is presented.
Comparative Impact of Voltage-Gated Calcium Channels and NMDA Receptors on Mitochondria-Mediated Neuronal Injury

Glutamate excitotoxicity, a major component of many neurodegenerative disorders, is characterized by excessive calcium influx selectively through NMDARs. However, there is a substantial uncertainty concerning why other known routes of significant calcium entry, in particular, VGCCs, are not similarly toxic. Here, we report that in the majority of neurons in rat hippocampal and cortical cultures, maximal L-type VGCC activation induces much lower calcium loading than toxic NMDAR activation. Consequently, few depolarization-activated neurons exhibit calcium deregulation and cell death. Activation of alternative routes of calcium entry induced neuronal death in proportion to the degree of calcium loading. In a small subset of neurons, depolarization evoked stronger calcium elevations, approaching those induced by toxic NMDA. These neurons were characterized by elevated expression of VGCCs and enhanced voltage-gated calcium currents, mitochondrial dysfunction and cell death. Preventing VGCC-dependent mitochondrial calcium loading resulted in stronger cytoplasmic calcium elevations, whereas inhibiting mitochondrial calcium clearance accelerated mitochondrial depolarization. Both observations further implicate mitochondrial dysfunction in VGCC-mediated cell death. Results indicate that neuronal vulnerability tracks the extent of calcium loading but does not appear to depend explicitly on the route of calcium entry.
Discriminative Auditory Fear Learning Requires Both Tuned and Nontuned Auditory Pathways to the Amygdala

The auditory system has two parallel streams in the brain that have been implicated in auditory fear learning. The lemniscal stream has selective neurons that are tonotopically organized and is thought to be important for sound discrimination. The nonlemniscal stream has less selective neurons, which are not tonotopically organized, and is thought to be important for multimodal processing and for several forms of learning. Therefore, it has been hypothesized that the lemniscal, but not the nonlemniscal, pathway supports discriminative fear to auditory cues. To test this hypothesis we assessed the effect of electrolytic lesions to the ventral, or medial, division of the medial geniculate nucleus (MGv or MGm, which correspond, respectively, to the lemniscal and the nonlemniscal auditory pathway to amygdala) on the acquisition, expression and extinction of fear responses in discriminative auditory fear conditioning, where one tone is followed by shock (conditioned stimulus, CS+), and another is not (CS−). Here we show that with single-trial conditioning control, MGv- and MGm-lesioned male rats acquire nondiscriminative fear of both the CS+ and the CS−. However, after multiple-trial conditioning, control rats discriminate between the CS+ and CS−, whereas MGv- and MGm-lesioned do not. Furthermore, post-training lesions of MGm, but not MGv, lead to impaired expression of discriminative fear. Finally, MGm-lesioned rats display high levels of freezing to both the CS+ and CS− even after an extinction session to the CS+. In summary, our findings suggest that the lemniscal pathway is important for discriminative learning, whereas the nonlemniscal is important for negatively regulating fear responses.
Accelerometers for measuring physical activity behavior in Indian children.

OBJECTIVE To examine the validity of accelerometers for characterizing habitual physical activity patterns in Indian children. DESIGN Cohort study. SETTING Holdsworth Memorial Hospital, Mysore. SUBJECTS Children (N=103, mean age 6.6 years) selected from an ongoing birth cohort study. METHODS Physical activity was measured over 7 days using accelerometers (MTI Actigraph) and concurrent parent-maintained activity diaries. Actigraph counts per minute representing sedentary (<10), light (< 400), moderate (<3000) and vigorous activity were determined using a structured activity session in a separate group of 10 children. In 46 children chosen for validating accelerometers, time spent in different activity levels according to diaries was determined. Energy Expenditure (EE) was calculated from diaries using a factorial method. RESULTS Ninety-eight children wore the monitor for > or = 4 days. Total counts and time spent in different activity levels were similar in boys and girls (P>0.2). Among 46 children chosen for comparisons, time spent in sedentary (r =0.48, P=0.001), light (r=0.70, P<0.001) and moderate activities (r=0.29, P=0.054) according to diaries correlated with those derived from counts, and total Actigraph counts correlated with EE (r=0.42, P=0.004). Bland-Altman analysis showed systematic bias, and wide limits of agreement between these methods for time spent in different activity levels. CONCLUSIONS Accelerometers are a well tolerated and objective way of measuring activity behavior in free-living children. Though accelerometer counts correlate with time spent in activity of varying intensity and energy expenditure derived from parent-maintained diaries, wide limits of agreement show that the limitations of accelerometers need to be recognized in interpreting the data that they generate.
Cyclooxygenase‐2 expression is critical for chronic UV‐induced murine skin carcinogenesis

While it has been established that both the constitutive and inducible forms of cyclooxygenase (COX‐1 and COX‐2, respectively) play important roles in chemical initiation‐promotion protocols with phorbol ester tumor promoters, the contribution of these two enzymes to ultraviolet (UV) light‐induced skin tumors has not been fully assessed. To better understand the contribution of COX‐1 and COX‐2 to UV carcinogenesis, we transferred the null allele for each isoform onto the SKH‐1 hairless strain of mouse. Due to low viability on this background with complete knockout of COX‐2, heterozygous mice were used in UV carcinogenesis experiments. While the lack of one allele of COX‐1 had no effect on tumor outcome, the lack of one allele of COX‐2 resulted in a 50–65% reduction in tumor multiplicity and a marked decrease in tumor size. Additionally, transgenic SKH‐1 mice that overexpress COX‐2 under the control of a keratin 14 promoter developed 70% more tumors than wild‐type SKH‐1 mice. The lack of one allele of either COX‐1 or COX‐2 reduced prostaglandin (PG) E2 levels in response to a single UV treatment. The proliferative response to UV was significantly reduced in COX‐2, but not COX‐1, heterozygous mice. UV‐induced apoptosis, however, was greater in COX‐2 heterozygous mice. Collectively, these results clearly establish the requirement for COX‐2 in the development of skin tumors. © 2007 Wiley‐Liss, Inc.
Discontinuous sets of knee extensions induce higher cardiovascular responses in comparison to continuous ones.

BACKGROUND The strength training can promote significant cardiovascular responses during its performance and it is interesting to devise strategies to reduce them, without compromising the strength production. OBJECTIVE To compare the acute cardiovascular responses of systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR) and double product (DP) during the unilateral knee extension (four series of 8 maximum repetitions) performed continuously or discontinuously. Both protocols involved a 2-minute interval between the series and the discontinuous protocol had an extra interval of 2 seconds between the 4th and the 5th repetitions. METHODS Eight healthy men trained in muscular strength (aged 26+/- 6 years) participated in the data collection and were randomly divided in two non-consecutive days. The cardiovascular responses were measured by photoplethysmography (Finapres, Ohmeda, Louisville, CO, USA) at rest, at the end of each series and 2 minutes after the performance of each protocol. RESULTS The discontinuous series showed significantly higher values when compared to the protocol of the continuous series for: SAP (mmHg) at the 2nd (173.1+/- 5.4 vs 152.0+/- 4.0; p=0.001), 3rd (188.9+/- 8.6 vs 162.4+/- 6.0; p=0.000) and 4th series (193.1+/- 8.1 vs 161.6+/- 5.9; p=0.000); DAP (mmHg) at the 3rd (103.8+/- 4.1 vs 86.1+/- 3.3; p=0.000) and 4th series (104.1+/- 2.7 vs 83.4+/- 3.3; p=0.000); DP (mmHg.bpm) at the 2nd (17,907.5+/- 1,350.7 vs 14,541.9+/- 1,848.0; p=0.03), 3rd (19,687.3+/- 1,444.3 vs 15,612.1+/- 1,180.3; p=0.008) and 4th series (21,271.0+/- 1,794.2 vs 15,992.0+/- 1,093.4; p=0.001). CONCLUSION The discontinuous protocol promoted higher increase in pressure responses when compared to the continuous one. However, due to the characteristics of the study design, further studies are necessary to support these findings.
Seasonal changes in amount and patterns of physical activity in women.

BACKGROUND Environmental factors including seasonal changes are important to guide physical activity (PA) programs to achieve or sustain weight loss. The goal was to determine seasonal variability in the amount and patterns of free-living PA in women. METHODS PA was measured in 57 healthy women from metropolitan Nashville, TN, and surrounding counties (age: 20 to 54 years, body mass index: 17 to 48 kg/m2) using an accelerometer for 7 consecutive days during 3 seasons within 1 year. PA counts and energy expenditure (EE) were measured in a whole-room indirect calorimeter and used to model accelerometer output and to calculate daily EE and intensity of PA expressed as metabolic equivalents (METs). RESULTS PA was lower in winter than in summer (131+/-45 vs. 144+/-54x10(3) counts/d; P=. 025) and in spring/fall (143+/-48x10(3) counts/d; P=. 027). On weekends, PA was lower in winter than in summer by 22,652 counts/d (P=.008). In winter, women spent more time in sedentary activities than in summer (difference 35 min/d; P=.007) and less time in light activities (difference -29 min/d, P=.018) and moderate or vigorous activities (difference -6 min/d, P=.051). CONCLUSIONS Women living in the southeastern United States had lower PA levels in winter compared with summer and spring/fall, and the magnitude of this effect was greater on weekends than weekdays.
Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors.

Studies of the anti-tumor activity of TNF-alpha in vivo have been hampered by the need to administer systemically toxic doses of the cytokine to obtain a curative response. To facilitate studies of the effect of high local concentrations of TNF-alpha on tumor growth and host immunity, a newly induced murine sarcoma was transduced with the gene for human TNF-alpha and the biologic characteristics of these cells were examined. We identified high and low TNF-producing tumor clones which exhibited stable TNF secretion over time. Significant amounts of membrane associated TNF were found in a high-TNF producing clone as well. No difference in the in vitro growth rates between TNF-producing and nonproducing cell lines was observed. In contrast, in vivo studies demonstrate that although unmodified parental tumor cells grew progressively when implanted s.c. in animals, tumor cells transduced with the TNF gene were found to regress in a significant number of animals after an initial phase of growth. This effect correlated with the amount of TNF produced and could be blocked with a specific anti-TNF antibody. Regressions of TNF-producing cells occurred in the absence of any demonstrable toxicity in the animals bearing these tumors. TNF-producing tumor cells could function in a paracrine fashion by inhibiting the growth of unmodified, parental tumor cells implanted at the same site. The ability of tumor cells to regress was abrogated by in vivo depletion of CD4+ or CD8+ T cell subsets and animals that had experienced regression of TNF-producing tumors rejected subsequent challenges of parental tumor. Our studies thus show that tumor cells elaborating high local concentrations of TNF regress in the absence of toxicity in the host and that this process requires the existence of intact host immunity. Studies of the lymphocytes infiltrating the gene modified tumors and attempts to use TNF gene modified tumor infiltrating lymphocytes to deliver high local concentrations of TNF to the tumor site without inducing systemic toxicity are underway.
Upregulation of interleukin 21 and promotion of interleukin 17 production in chronic or recurrent Vogt-Koyanagi-Harada disease.

OBJECTIVES To analyze the expression and potential role of interleukin (IL) 21 in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. METHODS Blood samples were obtained from patients with VKH disease and from healthy control subjects. Serum IL-21 level and IL-21 messenger RNA (mRNA) expression by peripheral blood mononuclear cells (PBMCs) were determined by enzyme-linked immunosorbent assay and by reverse transcriptase-polymerase chain reaction, respectively. Interleukin 17 and interferon γ levels in the supernatants of PBMCs and CD4(+) T cells cultured with anti-CD3 and anti-CD28 antibodies in the presence or absence of recombinant IL-21 were detected by enzyme-linked immunosorbent assay. RESULTS The results showed a significantly increased serum IL-21 level, as well as higher IL-21 mRNA expression by PBMCs, in patients having chronic or recurrent active VKH disease compared with patients having inactive VKH disease and with controls. In vitro experiments showed that recombinant IL-21 significantly increased IL-17 production by PBMCs and by CD4(+) T cells from patients and from controls. However, recombinant IL-21 did not affect interferon γ expression by PBMCs or by CD4(+) T cells. CONCLUSION Interleukin 21 may be involved in the pathogenesis of chronic or recurrent VKH disease, possibly by promoting IL-17 secretion. CLINICAL RELEVANCE Findings from the present study suggest that IL-21 may be a potential target in the development of therapy for VKH disease.
Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney

The regulation of sodium transport in the kidney is important for maintenance of extracellular fluid volume and arterial blood-pressure regulation. The major sodium transporters and channels in individual renal tubule segments have been identified via physiological techniques, and complementary DNAs for all of the key sodium transporters and channels expressed along the renal tubule have been cloned. Complementary DNA probes and antibodies are now being used to investigate the molecular basis of renal tubule sodium-transport regulation. This review summarizes some of the major observations made in the past year that are relevant to the regulation of the major sodium transporters in the proximal tubule (the type 3 sodium-hydrogen exchanger, NHE3), the thick ascending limb of Henle (the bumetanide-sensitive sodium-potassium-chloride cotransporter, NKCC2), and the distal convoluted tubule (the thiazide-sensitive sodium-chloride cotransporter, NCC).
Inequality among 32 London Boroughs: An S factor analysis

A dataset of 30 diverse socioeconomic variables was collected covering 32 London boroughs. Factor analysis of the data revealed a general socioeconomic factor. This factor was strongly related to GCSE (General Certificate of Secondary Education) scores (r's .683 to .786) and had weak to medium sized negative relationships to demographic variables related to immigrants (r's -.295 to -.558). Jensen's method indicated that these relationships were related to the underlying general factor, especially for GCSE (coefficients |.48| to |.69|). In multiple regression, about 60% of the variance in S outcomes could be accounted for using GCSE and one variable related to immigrants.
Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review

Posaconazole is an extended‐spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD).
SANDO syndrome in a cohort of 107 patients with CPEO and mitochondrial DNA deletions

Objective The sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) syndrome is a subgroup of mitochondrial chronic progressive external ophthalmoplegia (CPEO)-plus disorders associated with multiple mitochondrial DNA (mtDNA) deletions. There is no systematic survey on SANDO in patients with CPEO with either single or multiple large-scale mtDNA deletions. Methods In this retrospective analysis, we characterised the frequency, the genetic and clinical phenotype of 107 index patients with mitochondrial CPEO (n=66 patients with single and n=41 patients with multiple mtDNA deletions) and assessed these for clinical evidence of a SANDO phenotype. Patients with multiple mtDNA deletions were additionally screened for mutations in the nuclear-encoded POLG, SLC25A4, PEO1 and RRM2B genes. The clinical, histological and genetic data of 11 patients with SANDO were further analysed. Results None of the 66 patients with single, large-scale mtDNA deletions fulfilled the clinical criteria of SANDO syndrome. In contrast, 9 of 41 patients (22%) with multiple mtDNA deletions and two additional family members fulfilled the clinical criteria for SANDO. Within this subgroup, multiple mtDNA deletions were associated with the following nuclear mutations: POLG (n=6), PEO1 (n=2), unidentified (n=2). The combination of sensory ataxic neuropathy with ophthalmoparesis (SANO) was observed in 70% of patients with multiple mtDNA deletions but only in 4% with single deletions. The combination of CPEO and sensory ataxic neuropathy (SANO, incomplete SANDO) was found in 43% of patients with multiple mtDNA deletions but not in patients with single deletions. Conclusion The SANDO syndrome seems to indicate a cluster of symptoms within the wide range of multisystemic symptoms associated with mitochondrial CPEO. SANO seems to be the most frequent phenotype associated with multiple mtDNA deletions in our cohort but not or is rarely associated with single, large-scale mtDNA deletions.
Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients

Summary Cardiovascular events are more frequent in high-risk coronary artery disease (CAD) patients on dual antiplatelet therapy with a residual platelet reactivity (RPR) than in those showing inhibition of ADP-inducible platelet activation. It is known that post-interventional RPR is a clinically important entity confirming it as a risk factor for thrombo-is-chaemic events. Multiple electrode platelet aggregometry (MEA) on whole blood has been recently proposed as a rapid tool to evaluate RPR in high-risk CAD patients on clopidogrel therapy. It was the aim of this study to detect RPR in 801 high-risk CAD patients on dual antiplatelet therapy comparing MEA with the VerifyNow P2Y12 assay on whole blood and classical light transmission aggregation (LTA) on plateletrich plasma. ADP (10 μM) was employed as agonist for MEA and LTA. The prevalence of RPR was 20.6% by MEA, 16.1% by LTA and 30.8% by VerifyNow. MEA showed a significant correlation (rho=0.62, p<0.0001) with VerifyNow and a moderate agreement (k=0.52, p<0.001) with 81.5% of concordant values. A significant correlation was found between MEA and LTA (rho=0.71, p<0.001) with a good agreement (k=0.63, p<0.001) and 88.8% of concordant values. MEA in relation to LTA showed a sensitivity of 80% and a specificity of 91%. MEA might represent a reliable method and valid alternative in comparison with other available platelet function assays. It might help to guide antiplatelet therapy and thus improve clinical outcome of high-risk CAD patients.