Miracle-dz/UniFAR-FTUs huggingface dataset:
Dietary nitrate‐induced increases in human muscle power: high versus low responders

Maximal neuromuscular power is an important determinant of athletic performance and also quality of life, independence, and perhaps even mortality in patient populations. We have shown that dietary nitrate (NO3−), a source of nitric oxide (NO), improves muscle power in some, but not all, subjects. The present investigation was designed to identify factors contributing to this interindividual variability. Healthy men (n = 13) and women (n = 7) 22–79 year of age and weighing 52.1–114.9 kg were studied using a randomized, double‐blind, placebo‐controlled, crossover design. Subjects were tested 2 h after ingesting beetroot juice (BRJ) either containing or devoid of 12.3 ± 0.8 mmol of NO3−. Plasma NO3− and nitrite (NO2−) were measured as indicators of NO bioavailability and maximal knee extensor speed (Vmax), power (Pmax), and fatigability were determined via isokinetic dynamometry. On average, dietary NO3− increased (P < 0.05) Pmax by 4.4 ± 8.1%. Individual changes, however, ranged from −9.6 to +26.8%. This interindividual variability was not significantly correlated with age, body mass (inverse of NO3− dose per kg), body mass index (surrogate for body composition) or placebo trial Vmax or fatigue index (in vivo indicators of muscle fiber type distribution). In contrast, the relative increase in Pmax was significantly correlated (r = 0.60; P < 0.01) with the relative increase in plasma NO2− concentration. In multivariable analysis female sex also tended (P = 0.08) to be associated with a greater increase in Pmax. We conclude that the magnitude of the dietary NO3−‐induced increase in muscle power is dependent upon the magnitude of the resulting increase in plasma NO2− and possibly female sex.
Differences in mortality after fracture of hip: the East Anglian audit

Abstract Objective: To investigate differences between hospitals in clinical management of patients admitted with fractured hip and to relate these to mortality at 90 days. Design: A prospective audit of process and outcome of care based on interviews with patients, abstraction from records with standard proforma, and follow up at three months. Data were analysed with {chi}2 test and forward stepwise regression modelling of mortality. Setting: All eight hospitals in East Anglia with trauma orthopaedic departments. Patients: 580 consecutive patients admitted for fracture of neck of femur. Main outcome measure: Mortality at 90 days. Results: Patients admitted to each hospital were similar with respect to age, sex, pre-existing illnesses, and activities of daily living before fracture. In all, 560 (97%) were treated surgically, by a range of grades of surgeon. Two hundred and sixty one patients (45%; range between hospitals 10-91%) received pharmaceutical thromboembolic prophylaxis, 502 (93%; 81-99%) perioperative antibiotic prophylaxis. The incidence of fatal pulmonary emboli differed between patients who received and those who did not receive prophylaxis against deep vein thrombosis (P=0.001). Mortality at 90 days was 18%, differing significantly between hospitals (5-24%). One hospital had significantly better survival than the others (odds ratio 0.14; 95% confidence interval 0.04-0.48; P-0.0016). Conclusions: No single factor or aspect of practice accounted for this protective effect. Lower mortality may be associated with the cumulative effects of several aspects of the organisation of treatment and the management of fracture of the hip, including thromboembolic pharmaceutical prophylaxis, antibiotic prophylaxis, and early mobilisation. Key messages Key messages Being older, having a poorer level of activities of daily living, being male, and having a history of cardiovascular disease were important determinants of death One of the hospitals had a much higher survival rate. This seemed to be due to an aggregate effect of the total package of care Routine thromboembolic prophylaxis is indicated for patients with fractured hip Written policies that include prophylaxis should be developed and implemented for this vulnerable group of patients if mortality is to be improved
Does an encouraging letter encourage attendance at psychiatric out-patient clinics? The Leeds PROMPTS randomized study

Background The aim was to reduce non-attendance for first-time consultations at psychiatric out-patient clinics. Method The study was a pragmatic randomized controlled trial; the setting was seven inner-city UK out-patient clinics in Leeds. The participants were 764 subjects of working age with an appointment to attend a psychiatric out-patient clinic for the first time. The intervention was an ‘orientation statement’ letter delivered 24–48 h before the first appointment compared with standard care. The primary outcome measure was attendance at the first appointment; secondary outcomes included hospitalization, transfer of care, continuing attendance, discharge, presentation at accident and emergency and death by 1 year. Results Follow-up was for 763 out of 764 subjects (>99%) for primary and for 755 out of 764 subjects (98.8%) of secondary outcome data. The orientation statement significantly reduced the numbers of people failing to attend [79 out of 388 v. 101 out of 376 subjects, relative risk 0.76, 95% confidence interval (CI) 0.59–0.98, number needed to treat 16, 95% CI 10–187]. Conclusions Prompting people to go to psychiatric out-patient clinics for the first time encourages them to attend. Pragmatic trials within a busy working environment are possible and informative.
Behavioral and Synaptic Plasticity Are Impaired upon Lack of the Synaptic Protein SAP47

The synapse-associated protein of 47 kDa (SAP47) is a member of a phylogenetically conserved gene family of hitherto unknown function. In Drosophila, SAP47 is encoded by a single gene (Sap47) and is expressed throughout all synaptic regions of the wild-type larval brain; specifically, electron microscopy reveals anti-SAP47 immunogold labeling within 30 nm of presynaptic vesicles. To analyze SAP47 function, we used the viable and fertile deletion mutant Sap47156, which suffers from a 1.7 kb deletion in the regulatory region and the first exon. SAP47 cannot be detected by either immunoblotting or immunohistochemistry in Sap47156 mutants. These mutants exhibit normal sensory detection of odorants and tastants as well as normal motor performance and basic neurotransmission at the neuromuscular junction. However, short-term plasticity at this synapse is distorted. Interestingly, Sap47156 mutant larvae also show a 50% reduction in odorant–tastant associative learning ability; a similar associative impairment is observed in a second deletion allele (Sap47201) and upon reduction of SAP47 levels using RNA interference. In turn, transgenically restoring SAP47 in Sap47156 mutant larvae rescues the defect in associative function. This report thus is the first to suggest a function for SAP47. It specifically argues that SAP47 is required for proper behavioral and synaptic plasticity in flies—and prompts the question whether its homologs are required for proper behavioral and synaptic plasticity in other species as well.
A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer

Our aim was to evaluate the clinical effectiveness of chemotherapy treatments currently licensed in Europe and recommended by the National Institute for Health and Care Excellence (NICE) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). A systematic search of MEDLINE, EMBASE and the Cochrane Library for randomised controlled trials (RCTs) published from 2001 to 2010 was carried out. Relative treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using standard meta-analysis and mixed treatment comparison methodology. A total of 23 RCTs were included: 18 trials compared platinum-based chemotherapy, two compared pemetrexed and three compared gefitinib. There are no statistically significant differences in OS between any of the four third-generation chemotherapy regimens. There is statistically significant evidence that pemetrexed+platinum increases OS compared with gemcitabine+platinum. There are no statistically significant differences in OS between gefitinib and docetaxel+platinum or between gefitinib and paclitaxel+platinum. There is a statistically significant improvement in PFS with gefitinib compared with docetaxel+platinum and gefitinib compared with paclitaxel+platinum. Due to reduced generic pricing, third-generation chemotherapy regimens (except vinorelbine) are still competitive options for most patients. This research provides a comprehensive evidence base, which clinicians and decision-makers can use when deciding on the optimal first-line chemotherapy treatment regimen for patients diagnosed with locally advanced or metastatic NSCLC.
Prognostic value of bone marrow histology in chronic lymphocytic leukemia. A study of 335 untreated cases from a single institution.

BACKGROUND AND METHODS A significant correlation between bone marrow (BM) histology, survival and disease progression (DP) probability has been observed by several authors in chronic lymphocytic leukemia (CLL). The prognostic value of BM histologic patterns on survival and disease progression probability was investigated in 335 B-CLL patients. RESULTS Actuarial survival probability estimated by univariate analysis proved to be significantly influenced by stage (p < 0.0001), BM histology (p = 0.01), and by the following parameters: anemia (p = 0.0005), splenomegaly (p < 0.001), CLL-related symptoms (p < 0.01), thrombocytopenia (p < 0.01), number of involved nodal areas (p = 0.01) and peripheral lymphocyte count over 30 x 10(9)/L (p < 0.05). In this series we did not detect a discriminating prognostic effect for BM histology within the individual stages. Cox multivariate regression analysis failed to demonstrate a significant value for BM histology, while stage and anemia emerged as the best prognostic variables. Actuarial DP free probability in 294 untreated patients with A and B stages was significantly related to stage (p < 0.00001) and to BM pattern (p = 0.01). CONCLUSIONS Despite the clear correlation between the D pattern of BM involvement and advanced and early progressive disease, we were unable to demonstrate an independent prognostic value for BM histology. These findings suggest that stage emerged as the best predictive factor of survival probability in our B-CLL patients.
Perfusion Computed Tomography Evaluation of Cerebral Hemodynamic Impairment in Patients With Unilateral Chronic Steno-Occlusive Disease: A Comparison With the Acetazolamide Challenge 99mTc-Hexamethylpropyleneamine Oxime Single-Photon Emission Computed Tomography

Purpose: The purpose of this study was to determine which pefusion computed tomography (PCT) parameter is the most valid predictor of cerebral vascular reserve (CVR) as determined by 99mTc-hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT). Methods: Single-photon emission computed tomography with acetazolamide challenge and PCT were used in 23 patients with unilateral steno-occlusive vascular disease. After coregistration of the PCT and SPECT images, we assessed the relationship between the PCT parameters and SPECT findings and the predictive values of the PCT parameters for decreased CVR. Results: All PCT parameters of cerebral blood flow, cerebral blood volume, and mean transit time (MTT) were significantly correlated with SPECT regional cerebral blood flow ratios (P < 0.01). The MTT values more strongly correlated with acetazolamide effect than with cerebral blood volume or cerebral blood flow (P < 0.001). The MTT difference (values in the pathological hemisphere minus the values in the contralateral hemisphere) was a threshold of 1.5 seconds, with a sensitivity of 88% and a specificity of 70% for predicting decreased CVR. Conclusion: Mean transit time is the most predictive parameter for assessing decreased CVR in patients with unilateral steno-occlusive vascular disease.
A novel process for optimizing musculoskeletal allograft tissue to improve safety, ultrastructural properties, and cell infiltration.

BACKGROUND This study evaluated the properties of scaffold derived from freeze-dried human Achilles tendon allograft for use in anterior cruciate ligament (ACL) reconstruction. Our hypothesis was that such an allograft could be processed using a method to remove cellular and infectious material, producing a cytocompatible, architecturally modified scaffold possessing tensile properties suitable for ACL reconstruction. METHODS Fifty-two allografts were provided by a tissue bank. Twenty-one were used as controls to assess cellularity, DNA content, microarchitecture, porosity, cytocompatibility, and tensile properties in vitro (n = 13) and in vivo (n = 8). Thirty-one were processed to produce scaffolds that were similarly assessed for these properties in vitro (n = 23) and in vivo (n = 8). The elimination of added enveloped and nonenveloped viruses was also determined in vitro after each processing step. RESULTS A subjective decrease in cellularity and a significant decrease in DNA content were observed in the scaffolds compared with the allografts from which they had been derived. The porosity was increased significantly, and the scaffolds were cytocompatible in vitro. Processing resulted in significantly increased elongation of the scaffolds (138% of the elongation of the unprocessed allograft) during tensile testing. No other significant differences in tensile properties were observed in vitro or in vivo. The number of infiltrating host cells and the depth to which those cells infiltrated were significantly greater in the scaffolds. No enveloped viruses and only two of 10(8) nonenveloped viruses were detected in the scaffolds after processing, corresponding to a sterility assurance level of 0.2 × 10(-7). CONCLUSIONS Allografts were processed using a method that removed cellular and infectious material to produce a decellularized, cytocompatible, architecturally modified scaffold with tensile properties that differed minimally from those of human allograft tissue both in vitro and in vivo. The scaffold production process also resulted in an increase in porosity that led to increased cell infiltration in vivo.
Chromatin Opening and Stable Perturbation of Core Histone:DNA Contacts by FoxO1*

FoxO1, a member of the forkhead rabdomyosarcoma (FoxO) subfamily of transcription factors, binds DNA via a highly conserved winged-helix “forkhead box” motif used by other regulatory proteins to mediate their effects through chromatin binding and remodeling. To examine how FoxO1 regulates target genes in chromatin, we studied the binding of purified recombinant FoxO1 protein to nucleosome particles and chromatin arrays containing the insulin-like growth factor-binding protein 1 promoter. We found that FoxO1 is able to bind to its cognate sites within the insulin-like growth factor-binding protein 1 promoter on a nucleosome. This binding stably perturbs core histone:DNA contacts extending up- and downstream from sites of FoxO1 binding without disrupting the underlying core particle. FoxO1 is able to harness these capabilities to bind to and de-condense linker histone-compacted chromatin arrays. Chromatin opening by FoxO1 requires both the N and C termini of the protein, which are also required for high affinity core histone binding and, in the case of the N terminus, nucleosome perturbation. We suggest that the chromatin binding and remodeling functions revealed here for FoxO1 endow all FoxO factors with the ability to initiate and dynamically modulate active chromatin states, enabling their diverse roles as gene regulatory factors in metabolism, cell survival, apoptosis, cell cycle progression, DNA repair, and protection against oxidative stress.
Detoxification of Croton tiglium L. seeds by Ayurvedic process of Śodhana

Objective: Croton tiglium seeds, known as Jamālgoṭa in Hindi, Marathi, and Urdu is well-known for its toxicity (severe purgative action). In Ayurvedic texts, the plant is known as Kumbhinî0 and is used for the treatment of constipation after Śodhana (detoxification process) of the seeds with Godugdha (cow milk). Material and Methods: In the present study, C. tiglium seeds were purified with cow milk as reported in Ayurvedic classics. Phorbol esters equivalent to phorbol-12-myristate-13-acetate (PMA) and crotonic acid contents were quantified by high-performance liquid chromatography method in the seeds of C. tiglium before and after the purification process. Results: The content of the phorbol ester equivalent to PMA in unpurified and purified sample was found to be 5.2 mg/100 g and 1.8 mg/100 g of dried seeds of C. tiglium, respectively. The quantity of crotonic acid in unpurified seeds of C. tiglium was found to be 0.102 mg/100 g of dried seeds while it was absent in the purified seed extract of C. tiglium. Conclusion: The toxicity of C. tiglium seeds may be due to the presence of phorbol esters and crotonic acid along with other constituents. These constituents are oil soluble and may be removed by cow milk during the process of Śodhana . Reduction in the level of these constituents after the purification decreases the toxicity of C. tiglium seeds. Reduction in the oily content from the seeds of C. tiglium during the purification process is also supported by the results obtained from the physiochemical parameters.
Cognitive declines one year after unilateral deep brain stimulation surgery in parkinson's disease: A controlled study using reliable change

Conflicting research suggests that deep brain stimulation surgery, an effective treatment for medication-refractory Parkinson's disease (PD), may lead to selective cognitive declines. We compared cognitive performance of 22 PD patients who underwent unilateral DBS to the GPi or STN to that of 19 PD controls at baseline and 12 months. We hypothesized that compared to PD controls, DBS patients would decline on tasks involving dorsolateral prefrontal cortex circuitry (letter fluency, semantic fluency, and Digit Span Backward) but not on other tasks (Vocabulary, Boston Naming Test), and that a greater proportion of DBS patients would fall below Reliable Change Indexes (RCIs). Compared to controls, DBS patients declined only on the fluency tasks. Analyses classified 50% of DBS patients as decliners, compared to 11% of controls. Decliners experienced less motor improvement than non-decliners. The present study adds to the literature through its hypothesis-driven method of task selection, inclusion of a disease control group, longer-term follow-up and use of Reliable Change. Our findings provide evidence that unilateral DBS surgery is associated with verbal fluency declines and indicate that while these changes may not be systematically related to age, cognitive or depression status at baseline, semantic fluency declines may be more common after left-sided surgery. Finally, use of Reliable Change highlights the impact of individual variability and indicates that fluency declines likely reflect significant changes in a subset of patients who demonstrate a poorer surgical outcome overall.
Insurance type and minority status associated with large disparities in prelisting dialysis among candidates for kidney transplantation.

BACKGROUND AND OBJECTIVES Disparities in time to placement on the waiting list on the basis of socioeconomic factors decrease access to deceased-donor renal transplantation for some groups of patients with end-stage renal disease. This study was undertaken to determine candidate factors that influence duration of dialysis before placement on the waiting list among candidates for deceased-donor renal transplantation in the United States from January 2001 to December 2004 and the impact of Medicare eligibility rules on access. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Access to the waiting list was measured as the percentage of all wait-listed candidates in the Scientific Registry of Transplant Recipients database who were listed before dialysis and by the duration of dialysis before placement on the waiting list. Multivariate logistic and linear regressions were used to determine variables that were predictive of preemptive listing and the duration of dialysis before listing. RESULTS The odds for preemptive placement on the waiting list improved during the course of the study period, whereas the median duration of prelisting dialysis did not. The candidate factors that were associated with low rates of preemptive listing and prolonged exposure to prelisting dialysis included Medicare insurance, minority race/ethnicity, and low educational attainment. In patients who were listed after the age of 64 yr, the adverse effect of Medicare insurance on access largely disappeared. CONCLUSIONS The disparity in dialysis exposure could potentially be diminished by concerted efforts on the part of the nephrology and transplant communities to promote early referral and preemptive placement on the waiting list, by calculating waiting time from the date of initiation of dialysis for patients who are on dialysis at the time of referral, and by relaxing Medicare eligibility requirements.
A wound-induced [Ca2+]i increase and its transcriptional activation of immediate early genes is important in the regulation of motility.

Upon mechanical wounding of a confluent quiescent monolayer, cells move into the denuded zone. However, it is not well known what signaling cascade connects release from contact inhibition to cell movement at the wound edge. Mechanical wounding induced an increase in the concentration of intracellular free Ca2+ ([Ca2+]i) in endothelial cells at the wound edge. The [Ca2+]i signal was required for the transcriptional activation of two immediate early genes (IEGs), c-fos and c-jun, since blocking Ca2+ influx with Gd3+ or EGTA reduced IEG transcription, while augmenting Ca2+ influx increased IEG transcription. The transcriptional activation of the IEGs depended on protein kinase C and calmodulin-dependent protein kinase since treatment with the inhibitors Calphostin C and KN-62 significantly reduced IEG expression. Briefly blocking Ca2+ influx also produced a long-term reduction of cell motility, while augmenting Ca2+ influx increased cell motility. To evaluate whether expression of IEGs might control cell movement, we microinjected sense or antisense cDNA to c-fos into cells after wounding. Antisense c-fos cDNA inhibited motility, while sense cDNA increased motility rates. These results suggested that the [Ca2+]i rise, induced by wounding, regulated the initiation of subsequent motility through the transcriptional activation of IEGs during wounding.
Identification of the Enzyme Required for Activation of the Small Ubiquitin-like Protein SUMO-1*

The ubiquitin-like protein SUMO-1 is conjugated to a variety of proteins including Ran GTPase-activating protein 1 (RanGAP1), IκBα, and PML. SUMO-1-modified proteins display altered subcellular targeting and/or stability. We have purified the SUMO-1-activating enzyme from human cells and shown that it contains two subunits of 38 and 72 kDa. Isolation of cDNAs for each subunit indicates that they are homologous to ubiquitin-activating enzymes and to the Saccharomyces cerevisiae enzymes responsible for conjugation of Smt3p and Rub-1p. In vitro, recombinant SAE1/SAE2 (SUMO-1-activating enzyme) was capable of catalyzing the ATP-dependent formation of a thioester linkage between SUMO-1 and SAE2. The addition of the SUMO-1-conjugating enzyme Ubch9 resulted in efficient transfer of the thioester-linked SUMO-1 from SAE2 to Ubch9. In the presence of SAE1/SAE2, Ubch9, and ATP, SUMO-1 was efficiently conjugated to the protein substrate IκBα. As SAE1/SAE2, Ubch9, SUMO-1, and IκBα are all homogeneous, recombinant proteins, it appears that SUMO-1 conjugation of IκBα in vitrodoes not require the equivalent of an E3 ubiquitin protein ligase activity.