Miracle-dz/UniFAR-FTUs huggingface dataset:
Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease

Objective: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD). Methods: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed. Results: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD. Conclusions: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.
Healthcare burden of depression in adults with arthritis

ABSTRACT Introduction: Arthritis and depression are two of the top disabling conditions. When arthritis and depression exist in the same individual, they can interact with each other negatively and pose a significant healthcare burden on the patients, their families, payers, healthcare systems, and society as a whole. Areas covered: The primary objective of this review is to summarize, identify knowledge gaps and discuss the challenges in estimating the healthcare burden of depression among individuals with arthritis. Electronic literature searches were performed on PubMed, Embase, EBSCOhost, Scopus, the Cochrane Library, and Google Scholar to identify relevant studies. Expert Commentary: Our review revealed that the prevalence of depression varied depending on the definition of depression, type of arthritis, tools and threshold points used to identify depression, and the country of residence. Depression exacerbated arthritis-related complications as well as pain and was associated with poor health-related quality of life, disability, mortality, and high financial burden. There were significant knowledge gaps in estimates of incident depression rates, depression attributable disability, and healthcare utilization, direct and indirect healthcare costs among individuals with arthritis.
Diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis

Background: The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients may be difficult to establish because ABPA shares many characteristics with coexisting atopy or other lung infections in these patients. This study aimed to evaluate the sensitivity and specificity of various paraclinical parameters in the diagnosis of ABPA in patients with CF.
Anti-Hsp65 antibodies recognize M proteins of group A streptococci

Group A streptococcal M protein and the mycobacterial heat shock protein, hsp65, are strong bacterial immunogens that have been linked to arthritis and autoimmunity. Recent evidence has shown that streptococcal arthritis and adjuvant arthritis may be related to epitopes shared between group A streptococci and hsp65. We investigated the possibility that immunological similarities were shared between streptococcal M protein and hsp65. Antibodies against the 65-kDa heat shock protein of Mycobacterium tuberculosis were tested for reactivity with group A streptococci and purified recombinant M proteins (rM5 and rM6). Rabbit polyclonal anti-hsp65 serum was highly reactive with M type 5 Streptococcus pyogenes and rM5 and rM6 proteins in an enzyme-linked immunosorbent assay (ELISA). A mouse anti-hsp65 monoclonal antibody (MAb), IIC8, reacted with streptococcal M types 5, 6, 19, 24, and 49 in an ELISA but showed no reactivity with an isogenic streptococcal mutant which did not express M protein. Anti-hsp65 MAb IIC8 recognized rM5 and rM6 proteins in the ELISA, and MAbs IIC8 and IIH9 reacted strongly with rM6 protein in Western immunoblots. The binding of M protein by anti-hsp65 MAbs was shown to be inhibited by both hsp65 and M protein. These data show that anti-hsp65 antibodies recognize streptococcal M proteins.
The Influence of Internal Time, Time Awake, and Sleep Duration on Cognitive Performance in Shiftworkers

To date, studies investigating the consequences of shiftwork have predominantly focused on external (local) time. Here, we report the daily variation in cognitive performance in rotating shiftworkers under real-life conditions using the psychomotor vigilance test (PVT) and show that this function depends both on external and internal (biological) time. In addition to this high sensitivity of PVT performance to time-of-day, it has also been extensively applied in sleep deprivation protocols. We, therefore, also investigated the impact of shift-specific sleep duration and time awake on performance. In two separate field studies, 44 young workers (17 females, 27 males; age range 20–36 yrs) performed a PVT test every 2 h during each shift. We assessed chronotype by the MCTQShift (Munich ChronoType Questionnaire for shiftworkers). Daily sleep logs over the 4-wk study period allowed for the extraction of shift-specific sleep duration and time awake in a given shift, as well as average sleep duration (“sleep need”). Median reaction times (RTs) significantly varied across shifts, depending on both Local Time and Internal Time. Variability of reaction times around the 24 h mean (≈ ±5%) was best explained by a regression model comprising both factors, Local Time and Internal Time (p < .001). Short (15th percentile; RT15%) and long (85th percentile; RT85%) reaction times were differentially affected by Internal Time and Local Time. During night shifts, only median RT and RT85% were impaired by the duration of time workers had been awake (p < .01, consistent with the highest sleep pressure), but not RT15%. Proportion of sleep before a test day (relative to sleep need) significantly affected median RT and RT85% during morning shifts (p < .01). RT15% was worst in the beginning of the morning shift, but improved to levels above average with increasing time awake (p < .05), whereas RT85% became worse (p < .05). Hierarchical mixed models confirmed the importance of chronotype and sleep duration on cognitive performance in shiftworkers, whereas the effect of time awake requires further research. Our finding that both Local Time and Internal Time, in conjunction with shift-specific sleep behavior, strongly influence performance extends predictions derived from laboratory studies. (Author correspondence: roenneberg@lmu.de)
Hormone stimulation of androgen receptor mediates dynamic changes in DNA methylation patterns at regulatory elements

DNA methylation is an epigenetic modification that contributes to stable gene silencing by interfering with the ability of transcriptional regulators to bind to DNA. Recent findings have revealed that hormone stimulation of certain nuclear receptors induces rapid, dynamic changes in DNA methylation patterns alongside transcriptional responses at a subset of target loci, over time. However, the ability of androgen receptor (AR) to dynamically regulate gene transcription is relatively under-studied and its role in the regulation of DNA methylation patterns remains to be elucidated. Here we demonstrate in normal prostate cells that hormone stimulated AR activity results in dynamic changes in the transcription rate and DNA methylation patterns at the AR target genes, TIPARP and SGK1. Time-resolved chromatin immunoprecipitation experiments on the SGK1 locus reveals dynamic recruitment of AR and RNA Polymerase II, as well as the recruitment of proteins involved in the DNA demethylation process, TET1 and TDG. Furthermore, the presence of DNA methylation at dynamic regions inhibits protein binding and transcriptional activity of SGK1. These findings establish AR activity as a contributing factor to the dynamic regulation of DNA methylation patterns at target genes in prostate biology and infer further complexity involved in nuclear receptor mediation of transcriptional regulation.
Effect of Cognate Human CD4+ T Cell and Endothelial Cell Interactions Upon Chemokine Production

Background. In vitro studies have shown that cognate recognition of antigen presented by endothelial cells (EC) causes T cell activation, proliferation, and cytokine release and alters the transmigration of T cells. Here we have investigated chemokine induction caused by cognate interactions between human CD4+ T cells and MHC class II-expressing EC. Methods. HLA-DR–restricted CD4+ T cells were cocultured with HLA-DR–expressing allogeneic Eahy.926, aortic, or heart microvascular EC. Chemokine mRNA expression was measured by RTPCR, and chemokine protein secreted was measured by a cytokine array system and ELISA. Molecules involved in chemokine secretion were identified using blocking monoclonal antibodies, and cellular sources of chemokines determined by intracellular chemokine staining. Coculture supernatants were also used in chemotaxis assays. Results. Nine different chemokine mRNA and proteins were expressed because of noncognate interactions between T cells and EC. Cognate interactions induced de novo expression of four chemokines and upregulation of seven chemokines. Levels of CCL3, CCL8, and CXCL10 secreted into supernatants were in the nanomolar range and were chemotactic for T cells and monocytes. Blocking antibodies to HLA-DR and LFA-3 abrogated production of CCL3, CCL8, and CXCL10. Blocking antibodies to interferon-&ggr; and tumor necrosis factor-&agr; inhibited CCL8 and CXCL10 but not CCL3 production. CCL3 and CXCL10 were produced by both T cells and EC. Conclusions. Cognate interactions between alloreactive CD4+ T cells and MHC class II-expressing EC results in a specific pattern of chemokine production. These chemokines could play important roles in recruitment of leukocytes into vascularised allografts.
Krüppel-like Factor 15 (KLF15) Is a Key Regulator of Podocyte Differentiation*

Background: Podocyte dedifferentiation is the hallmark of many glomerular kidney diseases. Results: Krüppel-like factor 15 (KLF15) increases podocyte differentiation; KLF15 null mice exhibit more injury in models of kidney disease. Conclusion: KLF15 is a novel transcriptional regulator of podocyte differentiation; a loss of KLF15 increases the susceptibility to kidney injury. Significance: Identification of KLF15 in mediating podocyte differentiation provides new insight into kidney disease. Podocyte injury resulting from a loss of differentiation is the hallmark of many glomerular diseases. We previously showed that retinoic acid (RA) induces podocyte differentiation via stimulation of the cAMP pathway. However, many podocyte maturity markers lack binding sites for RA-response element or cAMP-response element (CREB) in their promoter regions. We hypothesized that transcription factors induced by RA and downstream of CREB mediate podocyte differentiation. We performed microarray gene expression studies in human podocytes treated with and without RA to identify differentially regulated genes. In comparison with known CREB target genes, we identified Krüppel-like factor 15 (KLF15), a kidney-enriched nuclear transcription factor, that has been previously shown to mediate cell differentiation. We confirmed that RA increased KLF15 expression in both murine and human podocytes. Overexpression of KLF15 stimulated expression of differentiation markers in both wild-type and HIV-1-infected podocytes. Also, KLF15 binding to the promoter regions of nephrin and podocin was increased in RA-treated podocytes. Although KLF15−/− mice at base line had minimal phenotype, lipopolysaccharide- or adriamycin-treated KLF15−/− mice had a significant increase in proteinuria and podocyte foot process effacement with a reduction in the expression of podocyte differentiation markers as compared with the wild-type treated mice. Finally, KLF15 expression was reduced in glomeruli isolated from HIV transgenic mice as well as in kidney biopsies from patients with HIV-associated nephropathy and idiopathic focal segmental glomerulosclerosis. These results indicate a critical role of KLF15 in mediating podocyte differentiation and in protecting podocytes against injury.
The Bedford Alzheimer Nursing Severity Scale for the Severely Demented: Validation Study

We evaluated the floor effect and convergent, discriminant, and known-group validity of the Bedford Alzheimer Nursing Severity scale (BANS-s), a rating scale comprising cognitive and functional items recently developed for grading severe dementia. Ninety-nine demented patients (81 females and 18 males aged 55–100 years) in two nursing homes were assessed with the BANS-s, established cognitive and functional scales [Mini Mental State Examination, the extended version of the Clinical Dementia Rating (CDR), Katz's basic activities of daily living, Tinetti balance and gait, and Crichton scales], a behavioral scale (UCLA Neuropsychiatric Inventory), and indicators of malnutrition (Prognostic Nutritional Index). A relevant proportion (40%) of patients scored close to the floor of all scales except BANS-s and CDR, which showed a more uniform distribution of scores throughout the possible range. Convergent validity of BANS-s with the other cognitive and functional scales was good, with Pearson's r ranging from 0.62 to 0.79. Discriminant validity analysis of BANS-s versus the UCLA Neuropsychiatric Inventory showed that the two scales measure different domains (Pearson's r = 0.36). To test known-group validity, all patients were divided into two groups of different dementia severity as defined by the Prognostic Nutritional Index. BANS-s and CDR were the scales with the best ability to discriminate malnourished from nonmalnourished patients. As a further validity test, the 37 patients reaching the floor on other cognitive and functional scales were divided into two subgroups of different dementia severity as defined by the Tinetti scale. BANS-s but not CDR was able to differentiate the two groups.
Allergy among veterinary medicine students in The Netherlands

Background Veterinary medicine students who practice with animals are potentially exposed to many occupational agents, yet sensitisation and allergic symptoms among this group have not been studied extensively. Objective The objective of this study was to estimate the prevalence of sensitisation and allergic symptoms in veterinary medicine students in association with study specialisation over time. Methods A questionnaire-based cross-sectional study was conducted. Blood was collected and tested for total and specific serum IgE for 16 different common and study-specific allergens using enzyme immunoassay. Results New development of self-reported allergic symptoms to various allergens occurred in 8.7%, of which 44% was deducted against animals. Handling farm animals was strongly associated with self-reported allergies to various allergens (OR=6.9, 95% CI 1.9 to 25) and animal allergens (OR=12, 95% CI 1.4 to 103). Sensitisation to at least one allergen occurred in 33.1%. Sensitisation prevalence tended to be elevated in later years of the equine study program. In contrast to self-reported allergies, the prevalence of sensitisation to any allergen decreased with prolonged study duration for those specialising in farm animal health (years 3–5: OR=0.5, 95% CI 0.3 to 1.1; year 6: OR=0.2, 95% CI 0.1 to 0.5). This was independent of whether people were raised on a farm, which is in itself a protective factor for allergy and sensitisation. Conclusion This study provides evidence of an elevated prevalence of allergic symptoms with increasing years of veterinary study, suggesting that contact with animals, more specifically contact to farm animals, is a risk factor for the development of symptoms.
Reduction of Vertebral Blood Flow by Segmental Vessel Occlusion: An Intraoperative Study Using Laser Doppler Flowmetry

Study Design. During anterior spinal surgery, vertebral perfusion was assessed by laser Doppler flowmetry. Blood flow changes were assessed after unilateral ligation and contralateral compression of the segmental vessels. Objective. To assess the influence of unilateral and bilateral segmental vessel occlusion on vertebral blood flow. Summary of Background Data. During anterior spinal surgery, segmental vessels are frequently being ligated. The reduced blood supply to the vertebrae may impair intervertebral fusion, and the decreased spinal cord perfusion may lead to ischemic myelopathy. To our knowledge, this is the first in vivo study to investigate vertebral blood flow. Methods. There were 10 patients who underwent anterior release for adult idiopathic scoliosis (n = 6), Scheuermann disease (n = 3), and posttraumatic kyphosis (n = 1). A high-power laser Doppler flowmeter was used to assess vertebral blood flow. Measurements were performed in 19 thoracic and 4 lumbar vertebrae (n = 23) after unilateral segmental vessel ligation and additional temporary digital compression of the contralateral vessels. Results. Initial mean blood flow was 49.1 ± 27.6 arbitrary units, and all signals were pulsatile. The blood flow decreased by a mean of 8% after unilateral ligation of the segmental vessels. With additional compression of the contralateral vessels, the signal heights decreased significantly by 54% (mean 18.3 ± 7.8 arbitrary units, P = 0.00003), and a loss of the pulsatile pattern was observed in 75% of the vertebrae. On release of digital compression, the signal height as well as the pulsatility promptly returned. Conclusions. Unilateral ligation of segmental vessels led only to a slight decrease of the vertebral blood flow. Future studies may show whether sparing the segmental vessels during anterior fusion enhances bone graft incorporation, thus decreasing the rate of pseudarthrosis. According to clinical data, the risk of neurologic injury through unilateral ligation is negligible. Bilateral segmental vessel occlusion markedly reduced vertebral bloodflow. Therefore, when treating patients with a higher neurologic risk or in revision cases, the surgeon should always consider sparing the segmental vessels.
Impact of voluntary vs enforced compliance of third-generation cephalosporin use in a teaching hospital.

STUDY OBJECTIVE The purpose of this study was to assess and compare the impact of voluntary compliance and enforced compliance with institutional guidelines for initiating third-generation cephalosporin therapy. DESIGN An audit of third-generation cephalosporin use during a 6-month period shortly after ceftriaxone and ceftazidime were added to the hospital formulary already containing cefotaxime was performed. During this period, compliance to institutional guidelines for initiating therapy was voluntary. A follow-up audit during a similar 6-month period was performed to assess compliance with institutional guidelines shortly after an enforcement policy was placed in effect. The results of these two audits were compared to assess usage patterns of these cephalosporins, compliance rates with institutional guidelines for initiating therapy, use of susceptibility testing to guide therapy, effect of use of these drugs on susceptibility patterns within the hospital, and third-generation cephalosporin costs during periods when institutional policy was unenforced and enforced. RESULTS Only 24.2% of 66 courses of third-generation cephalosporins were initiated in compliance with institutional guidelines during the initial audit period. Susceptibility testing revealed an organism susceptible to a first-generation cephalosporin in 13 courses but in only six instances was a switch to the more narrow-spectrum antibiotic performed. At the time routine susceptibility testing to ceftazidime and ceftriaxone was instituted, 92% of Enterobacter cloacae were sensitive to ceftriaxone and 89% of Pseudomonas aeruginosa were sensitive to ceftazidime. Fifteen months later, when voluntary compliance to institutional policy was terminated, 70% of E cloacae were sensitive to ceftriaxone and 73% of P aeruginosa were sensitive to ceftazidime. During the last 6 months of this period, pharmacy expenditures totaled $50,000. The second audit revealed 85.4% of 48 courses of treatment complied with guidelines for initiating therapy. Since enforcement was instituted, sensitivity of E cloacae to ceftriaxone has risen to 88% and sensitivity of P aeruginosa to ceftazidime has increased to 80%. Pharmacy expenditures decreased to $23,000.
Club cell protein 16 and disease progression in chronic obstructive pulmonary disease.

RATIONALE Club (Clara) cell protein 16 (CC-16) is a protein that is synthesized predominantly in the lungs and is detectable in serum. Its expression decreases with lung injury and smoking, and is thus a marker of bronchial cell dysfunction. OBJECTIVES To evaluate the possibility of using serum CC-16 as a biomarker for disease progression in chronic obstructive pulmonary disease (COPD). METHODS We measured serum CC-16 levels from 4,724 subjects with mild-to-moderate airflow limitation in the Lung Health Study. Using a linear regression model, we determined the relationship of serum CC-16 concentrations to decline in lung function over 9 years. In addition, to determine whether CC-16 plays a major role in the pathogenesis of mild COPD, we exposed CC-16-deficient (-/-) mice to 6 months of cigarette smoke. MEASUREMENTS AND MAIN RESULTS Reduced serum concentrations of CC-16 were associated with accelerated decline in FEV1 over 9 years (P < 0.0001), and this association persisted after adjustments for age, sex, race, smoking status, airway reactivity, body mass index, and baseline FEV1 (P = 0.0002). However, CC-16(-/-) mice did not demonstrate an enhanced risk of emphysema or small airway remodeling in response to cigarette smoke. CONCLUSIONS Serum CC-16 is associated with disease progression, and may assist in the identification of "rapid progressors. " However, the absence of CC-16 does not appear to modify the risk of cigarette-related COPD in mice.
Antibiotic-induced diarrhea: specificity of abdominal CT for the diagnosis of Clostridium difficile disease.

PURPOSE To evaluate the specificity of abdominal computed tomography (CT) in the diagnosis of Clostridium difficile disease. MATERIALS AND METHODS The authors retrospectively reviewed CT scans of 64 patients with C difficile disease and 30 control subjects with diarrhea and negative findings for C difficile disease at stool tests. RESULTS Colon wall thickening (range, 4-22 mm; mean, 11.7 mm; median, 11 mm) was seen in 39 patients (61%) with C difficile disease. Other findings included focal colon wall thickening (n = 28) and pancolonic thickening (n = 11). Two patients had only right-sided and transverse colon involvement. CT-specific diagnostic features of C difficile disease, such as nodular haustral thickening or the accordion pattern, were present in 17% of patients. No colonic abnormality was detected in 25 patients (39%). Seven of the 30 (23%) control subjects had colon wall thickening. Six of those seven subjects were subsequently determined to have ischemic colitis. The sensitivity of CT in the detection of colon abnormalities in patients with C difficile disease was 85%, and the specificity was 48%. CONCLUSION Specific CT features of C difficile disease are uncommon. A considerable number of patients (39%) with C difficile disease have normal abdominal CT scans.