Miracle-dz/UniFAR-FTUs huggingface dataset:
Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer's disease: a volumetric MRI study

Asymmetry of brain structures is common to many species and is even present in utero. Some developmental, pathological, and dementing diseases are associated with alterations in normal anatomical asymmetries. Anatomical asymmetries, however, have been only superficially studied in Alzheimer's disease. Recent evidence indicates that the allele ε4 of the apolipoprotein E (ApoE), a well known risk factor for Alzheimer's disease, might play a part in determining some brain morphological changes both in normal carriers and in patients with Alzheimer's disease. This study evaluated the effect of the ApoE genotype on hippocampal asymmetry in patients with Alzheimer's disease carrying 0, 1, and 2 copies of the allele. Volumetric right-left differences of the hippocampi were computed in 28 right handed patients with Alzheimer's disease (14 -/-, 9 ε4/-, and 5 ε4/4) and 30 controls without detectable cognitive deficit. In controls, the right hippocampus was larger than the left, whereas in patients with Alzheimer's disease this asymmetry was progressively reduced with increasing gene dose of the ε4 allele, and the asymmetry was reversed in the ε4/4 Alzheimer's disease group. The mean right-left volume differences were: 1.2, 0.7, 0.2, and -1.0 in controls, -/-, ε4/-, and ε4/4 patients, respectively (sex adjusted p for trend=0.017). The data indicate a dose dependent effect of the ApoE ε4 allele on hippocampal volume asymmetry in Alzheimer's disease.
Work remains meaningful despite time out of the workplace and chronic pain

Abstract Purpose: Although work has been found to be meaningful and a source of motivation to return to work in certain disabled populations, it was unclear if this was also true for people experiencing a long period of unemployment and job loss due to a musculoskeletal injury. Therefore, the aim of this phenomenological study was to explore the meaning of work for those with chronic work disability due to a musculoskeletal injury. Method: The data from 27 interviews, conducted with 9 participants, was analyzed using the Empirical Phenomenological Psychological method. Results: Work remained central to the lives of the participants and aligned with previous valued work outcomes and goals regardless of the amount of time away from work. These findings point to the importance of recognizing the ongoing centrality of work for those with chronic work disability and the importance of tapping into work values and beliefs to provide workers with the motivation needed to get past physical and systemic barriers to return to work. Conclusions: This study shows that a shift in focus back to meaning not only has benefits for people with chronic work disability, but for occupational therapists in their ability to make a unique and effective contribution to the field of work disability. Implications for rehabilitation The chronic work disabled population remains one of the most challenging to return to work. Reflection on the meaning of work provides motivation needed for clients to overcome barriers to work including chronic pain. Exploring meaning is not difficult or time consuming in vocational rehabilitation.
Intravital Förster resonance energy transfer imaging reveals elevated [Ca2+]i and enhanced sympathetic tone in femoral arteries of angiotensin II‐infused hypertensive biosensor mice

• It is desirable to study altered artery function in hypertension in living animals, where factors influencing artery function are intact. • We infused ‘biosensor’ mice chronically with angiotensin II to produce hypertension, and used intravital Förster resonance energy transfer microscopy to measure, simultaneously, [Ca2+]i and artery diameter in vivo. • Femoral arteries in hypertensive mice had increased basal (resting) [Ca2+]i and were more constricted than femoral arteries in saline‐infused mice. These differences were abolished by blocking (1) all peripheral sympathetic nerve activity (SNA), or (2) vascular α1‐adrenoceptors, but not by blocking vascular angiotensin II or arginine vasopressin receptors. • Neither contractility nor structural changes were found in femoral arteries of angiotensin II‐infused mice. • The results support previous suggestions that angiotensin II infusion raises blood pressure by acting on the CNS to increase SNA, which increases smooth muscle [Ca2+]i. Infused angiotensin II does not act directly on arterial angiotensin II receptors.
Non‐inferiority test and confidence interval for the difference in correlated proportions in diagnostic procedures based on multiple raters

The efficacy of diagnostic procedures is generally evaluated on the basis of the results from multiple raters. However, there are few adequate methods of performing non‐inferiority tests with confidence intervals to compare the accuracies (sensitivities or specificities) when multiple raters are considered. We propose new statistical methods for comparing the accuracies of two diagnostic procedures in a non‐inferiority trial, on the basis of the results from multiple independent raters who are also independent of the study centers. We consider a study design in which each patient is subjected to two diagnostic procedures and all images are read by all raters. By assuming a multinomial distribution for matched‐pair categorical data arising from the study design, we derive a score‐based full menu, that is, a non‐inferiority test, confidence interval and sample size formula, for inference of the difference in correlated proportions between the two diagnostic procedures. We conduct Monte Carlo simulation studies to examine the validity of the proposed methods, which showed that the proposed test has a size closer to the nominal significance level than a Wald‐type test and that the proposed confidence interval has better empirical coverage probability than a Wald‐type confidence interval. We illustrate the proposed methods with data from a study of diagnostic procedures for the diagnosis of oesophageal carcinoma infiltrating the tracheobronchial tree. Copyright © 2011 John Wiley & Sons, Ltd.
From transcriptome to proteome: Differentially expressed proteins identified in synovial tissue of patients suffering from rheumatoid arthritis and osteoarthritis by an initial screen with a panel of 791 antibodies

Global scale molecular profiling of diseased tissues is an important first step to unravel candidate target molecules that are involved in the pathogenesis of a disease. We have performed a comparative molecular characterization at the transcriptome (microarray with 12 526 gene specificities) and proteome level (multi‐Western blot PowerBlot™ with 791 antibodies) of synovial tissue from rheumatoid arthritis (RA) compared to osteoarthritis (OA) patients. From the panel of 791 antibodies, 260 (33%) detected their corresponding protein. Out of 58 unambiguous changes at the protein level only 16 coincided at the transcript level (28%). Stat1, p47phox and manganese superoxide dismutase were shown to be reproducibly overexpressed in RA versus OA synovial tissue by Western blots with a panel of 8 RA versus 8 OA samples. Cathepsin D was among the most prominent proteins scored to be underexpressed in RA by the PowerBlot™ whereas no differences of the respective transcript were observed. The lower abundance of cathepsin D protein in RA compared to OA tissue was also reproduced in other patient samples. Immunohistochemistry assigned the Stat1 protein in RA synovial tissue mainly to macrophages and T lymphocytes and the p47phox protein in particular to macrophages. In conclusion, our approach provided us with new candidate molecules for further analysis of rheumatic diseases and stressed the importance of studies at the protein level.
Recent transmission of drug-resistant Mycobacterium tuberculosis in a prison population in southern Brazil

ABSTRACT We conducted a cross-sectional, retrospective study, characterized by classical and molecular epidemiology, involving M. tuberculosis isolates from a regional prison in southern Brazil. Between January of 2011 and August of 2014, 379 prisoners underwent sputum smear microscopy and culture; 53 (13.9%) were diagnosed with active tuberculosis. Of those, 8 (22.9%) presented with isoniazid-resistant tuberculosis. Strain genotyping was carried out by 15-locus mycobacterial interspersed repetitive unit-variable-number tandem-repeat analysis; 68.6% of the patients were distributed into five clusters, and 87.5% of the resistant cases were in the same cluster. The frequency of drug-resistant tuberculosis cases and the rate of recent transmission were high. Our data suggest the need to implement an effective tuberculosis control program within the prison system.
The Arthroscopic All-Inside Tibial-Inlay Reconstruction of the Posterior Cruciate Ligament: Medium-Term Functional Results and Complication Rate

Abstract The present study evaluates the medium-term functional and radiological outcome as well as complications following an arthroscopic tibial inlay reconstruction of the posterior cruciate ligament (PCL). A total of 39 patients (mean age: 32.6 ± 12.4 years) with acute and chronic PCL instabilities received a single-bundle all-inside arthroscopic tibial inlay reconstruction with quadriceps tendon autograft and were available for clinical follow-up on average after 3.8 ± 1.8 years. Assessment was conducted utilizing visual analogue scale (VAS), International Knee Documentation Committee (IKDC), Tegner, Lysholm, and knee injury and osteoarthritis outcome (KOOS) scores. VAS, Tegner, Lysholm, and subjective IKDC-scores averaged to 2.75 ± 1.95, 4 (1–9), 77.19 ± 17.54, and 75.18 ± 19.29 points, respectively. Mean KOOS results were 80.66 ± 1.98 for pain, 74.72 ± 17.72 for symptoms, 88.44 ± 13.95 for activities of daily life, 65.35 ± 27.96 for sports and recreation, and 60.01 ± 25.36 for quality of life. Overall IKDC-score rating was A2, B28, C5, and D4. The overall complication rate of 5.4% was caused by one superficial infection, one patellar fracture, and one lesion to the popliteal artery. Arthroscopic tibial inlay reconstruction is a valuable procedure regarding medium-term subjective and objective outcome measures. Return to sports, subjective satisfaction, and objective stability are predictable. The complication rate is acceptable but particular precaution is recommended to protect the popliteal artery and adjacent structures at risk.
SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice

How the nuclei in mammalian skeletal muscle fibers properly position themselves relative to the cell body is an interesting and important cell biology question. In the syncytial skeletal muscle cells, more than 100 nuclei are evenly distributed at the periphery of each cell, with 3–8 nuclei anchored beneath the neuromuscular junction (NMJ). Our previous studies revealed that the KASH domain–containing Syne-1/Nesprin-1 protein plays an essential role in anchoring both synaptic and nonsynaptic myonuclei in mice. SUN domain–containing proteins (SUN proteins) have been shown to interact with KASH domain–containing proteins (KASH proteins) at the nuclear envelope (NE), but their roles in nuclear positioning in mice are unknown. Here we show that the synaptic nuclear anchorage is partially perturbed in Sun1, but not in Sun2, knockout mice. Disruption of 3 or all 4 Sun1/2 wild-type alleles revealed a gene dosage effect on synaptic nuclear anchorage. The organization of nonsynaptic nuclei is disrupted in Sun1/2 double-knockout (DKO) mice as well. We further show that the localization of Syne-1 to the NE of muscle cells is disrupted in Sun1/2 DKO mice. These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning.
β-Dystroglycan as a Target for MMP-9, in Response to Enhanced Neuronal Activity*

Matrix metalloproteinase-9 has recently emerged as an important molecule in control of extracellular proteolysis in the synaptic plasticity. However, no synaptic targets for its enzymatic activity had been identified before. In this report, we show that β-dystroglycan comprises such a neuronal activity-driven target for matrix metalloproteinase-9. This notion is based on the following observations. (i) Recombinant, autoactivating matrix metalloproteinase-9 produces limited proteolytic cleavage of β-dystroglycan. (ii) In neuronal cultures, β-dystroglycan proteolysis occurs in response to stimulation with either glutamate or bicuculline and is blocked by tissue inhibitor of metalloproteinases-1, a metalloproteinase inhibitor. (iii) β-Dystroglycan degradation is also observed in the hippocampus in vivo in response to seizures but not in the matrix metalloproteinase-9 knock-out mice. (iv) β-Dystroglycan cleavage correlates in time with increased matrix metalloproteinase-9 activity. (v) Finally, β-dystroglycan and matrix metalloproteinase-9 colocalize in postsynaptic elements in the hippocampus. In conclusion, our data identify the β-dystroglycan as a first matrix metalloproteinase-9 substrate digested in response to enhanced synaptic activity. This demonstration may help to understand the possible role of both proteins in neuronal functions, especially in synaptic plasticity, learning, and memory.
Magnetosome chains are recruited to cellular division sites and split by asymmetric septation

Magnetotactic bacteria navigate along magnetic field lines using well‐ordered chains of membrane‐enclosed magnetic crystals, referred to as magnetosomes, which have emerged as model to investigate organelle biogenesis in prokaryotic systems. To become divided and segregated faithfully during cytokinesis, the magnetosome chain has to be properly positioned, cleaved and separated against intrachain magnetostatic forces. Here we demonstrate that magnetotactic bacteria use dedicated mechanisms to control the position and division of the magnetosome chain, thus maintaining magnetic orientation throughout divisional cycle. Using electron and time‐lapse microscopy of synchronized cells of Magnetospirillum gryphiswaldense, we confirm that magnetosome chains undergo a dynamic pole‐to‐midcell translocation during cytokinesis. Nascent chains were recruited to division sites also in division‐inhibited cells, but not in a mamK mutant, indicating an active mechanism depending upon the actin‐like cytoskeletal magnetosome filament. Cryo‐electron tomography revealed that both the magnetosome chain and the magnetosome filament are spilt into halves by asymmetric septation and unidirectional indentation, which we interpret in terms of a specific adaptation required to overcome the magnetostatic interactions between separating daughter chains. Our study demonstrates that magnetosome division and segregation is co‐ordinated with cytokinesis and resembles partitioning mechanisms of other organelles and macromolecular complexes in bacteria.
Influenza Virus Susceptibility and Resistance to Oseltamivir

Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to highly conserved, essential amino acids in the catalytic site of the enzyme, and that the activity of neuraminidase is critical for virus release from infected cells and subsequent virus spread, the drug was expected to have a low propensity to select for viable resistant mutants. Indeed, viruses with neuraminidase (and haemagglutinin) substitutions conferring reduced susceptibility to oseltamivir have been generated with difficulty in vitro, and these mutants generally have reduced infectivity and transmissibility compared with wild-type virus in animal models. Studies of seasonal influenza isolates collected before the introduction of oseltamivir show an absence of naturally occurring resistance. Few resistant mutants have arisen during clinical trials of oseltamivir in seasonal influenza, with cumulative data from all Roche-sponsored studies indicating an incidence of resistance of 0.32% in adults (0.4%, including low-level mutants detected by genotyping alone in mixed virus populations) and 4.1% (5.4%) in children. Higher incidences of resistance were observed in two small Japanese studies, in which children received a different dosing schedule from their Western counterparts. In summary, the overall incidence of influenza virus resistance associated with the seasonal use of oseltamivir is currently low and resistant viruses might be of little clinical significance, except perhaps in immunocompromised individuals. However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential.
Protocatechuic acid inhibits cancer cell metastasis involving the down‐regulation of Ras/Akt/NF‐κB pathway and MMP‐2 production by targeting RhoB activation

BACKGROUND AND PURPOSE Protocatechuic acid (PCA) is plentiful in edible fruits and vegetables and is thus one anti‐oxidative component of normal human diets. However, the molecular mechanisms involved in the chemopreventive activity of PCA are poorly understood. Here, we investigated the mechanism(s) underlying the anti‐metastatic potential of PCA.
Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution.

OBJECTIVE To determine the incidence and prognosis of peripartum cardiomyopathy (PPCM) in rural Haiti. PATIENTS AND METHODS Prospectively identified patients with PPCM treated at the Hospital Albert Schweitzer (HAS), Deschapelles, Haiti, were included in this study. Patients who presented to HAS from February 1, 2000, to January 31, 2005, were identified through a search of the HAS PPCM Registry. Clinical and serial echocardiographic data were collected on these patients. RESULTS The 5-year experience confirms the high incidence of PPCM in this area, approximately 1 case per 300 live births, which is severalfold the estimated incidence in the United States (estimated 1 case per 3000 to 4000 live births). In this population, the ratio of PPCM deaths for the 5-year period was 47.1 per 100,000 births compared with the US ratio of 0.62 per 100,000 births. The mortality rate was 15.3% (15 deaths of 98 patients), and the mean follow-up was 2.2 years (range, 1 month to 5 years). Five years after the initiation of the HAS PPCM Registry search, 26 (28%) of 92 patients with PPCM observed for at least 6 months had regained normal left ventricular function. The difference in left ventricular echocardiographic features at diagnosis between deceased patients and survivors was not statistically significant: mean end-diastolic dimension (6.2 vs 5.8 cm; P=.08), ejection fraction (22% vs 25%; P=.12), and fractional shortening (16% vs 15%; P=.46). Left ventricular echocardiographic features at diagnosis were unable to predict individually who would eventually recover, although a statistically significant difference occurred at diagnosis between the recovered group and nonrecovered group for mean ejection fraction (28% vs 23%; P<.001) and fractional shortening (17% vs 14%; P=.004). CONCLUSION Peripartum cardiomyopathy occurs significantly more commonly in rural Haiti on a per capita basis than in the United States. Patients with PPCM have a higher mortality rate and a poorer return of normal ventricular function.
Cyanide production by Pseudomonas fluorescens helps suppress black root rot of tobacco under gnotobiotic conditions

Pseudomonas fluorescens CHA0 suppresses black root rot of tobacco, a disease caused by the fungus Thielaviopsis basicola. Strain CHA0 excretes several metabolites with antifungal properties. The importance of one such metabolite, hydrogen cyanide, was tested in a gnotobiotic system containing an artificial, iron‐rich soil. A cyanidenegative (hcn) mutant, CHA5, constructed by a gene replacement technique, protected the tobacco plant less effectively than did the wild‐type CHA0. Complementation of strain CHA5 by the cloned wild‐type hcn+ genes restored the strain's ability to suppress disease. An artificial transposon carrying the hcn+ genes of strain CHA0 (Tnhcn) was constructed and inserted into the genome of another P.fluorescens strain, P3, which naturally does not produce cyanide and gives poor plant protection. The P3::Tnhcn derivative synthesized cyanide and exhibited an improved ability to suppress disease. All bacterial strains colonized the roots similarly and did not influence significantly the survival of T.basicola in soil. We conclude that bacterial cyanide is an important but not the only factor involved in suppression of black root rot.
Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans

Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits. SIGNIFICANCE STATEMENT People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline.