Miracle-dz/UniFAR-FTUs huggingface dataset:
Vitamin D and Clinical Outcomes in Dialysis

Most dialysis patients are vitamin D deficient, including deficiencies in both activated vitamin D (1, 25‐dihydroxyvitamin D) and the less active 25‐hydroxyvitamin D. These and other abnormalities associated with chronic kidney disease (CKD), if they remain untreated, lead to secondary hyperparathyroidism and bone changes, such as osteitis fibrosa cystica. Activated vitamin D has been proven to decrease parathyroid hormone (PTH) levels in dialysis patients and is currently used for this indication. There are multiple other potential “pleotrophic” effects associated with vitamin D therapy. These include associations with lower all‐cause and cardiovascular mortality, lower rates of infections and improved glycemic indexes. Meta‐analyses of multiple observational studies have shown activated vitamin D therapy to be associated with improved survival. Observational data also suggest fewer infections and better glucose control. There have been no randomized clinical trials powered to evaluate mortality or other clinical outcomes. Small trials of nutritional vitamin D (ergocalciferol and cholecalciferol) showed increases in 25‐hydroxyvitamin D levels without hypercalcemia or hyperphosphatemia, even when given in addition to activated vitamin D therapy. While activated vitamin D therapy is associated with improved outcomes, it also leads to higher fibroblast growth factor 23 (FGF‐23) levels, which may be detrimental in dialysis patients. Further research is needed to evaluate whether activated or nutritional vitamin D therapy are beneficial in dialysis patients for outcomes other than secondary hyperparathyroidism.
Incorporating an Exercise Detection, Grading, and Hormone Dosing Algorithm Into the Artificial Pancreas Using Accelerometry and Heart Rate

In this article, we present several important contributions necessary for enabling an artificial endocrine pancreas (AP) system to better respond to exercise events. First, we show how exercise can be automatically detected using body-worn accelerometer and heart rate sensors. During a 22 hour overnight inpatient study, 13 subjects with type 1 diabetes wearing a Zephyr accelerometer and heart rate monitor underwent 45 minutes of mild aerobic treadmill exercise while controlling their glucose levels using sensor-augmented pump therapy. We used the accelerometer and heart rate as inputs into a validated regression model. Using this model, we were able to detect the exercise event with a sensitivity of 97.2% and a specificity of 99.5%. Second, from this same study, we show how patients’ glucose declined during the exercise event and we present results from in silico modeling that demonstrate how including an exercise model in the glucoregulatory model improves the estimation of the drop in glucose during exercise. Last, we present an exercise dosing adjustment algorithm and describe parameter tuning and performance using an in silico glucoregulatory model during an exercise event.
Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome.

RATIONALE Bronchiolitis obliterans syndrome (BOS) remains the leading cause of death after lung transplantation. Treatment is difficult, although azithromycin has recently been shown to improve FEV(1). The exact mechanism of action is unclear. HYPOTHESES (1) Azithromycin reduces airway neutrophilia and interleukin (IL)-8 and (2) airway neutrophilia predicts the improvement in FEV(1). METHODS Fourteen lung transplant patients with BOS (between BOS 0-p and BOS 3) were treated with azithromycin, in addition to their current immunosuppressive treatment. Before and 3 mo after azithromycin was introduced, bronchoscopy with bronchoalveolar lavage (BAL) was performed for cell differentiation and to measure IL-8 and IL-17 mRNA ratios. RESULTS The FEV(1) increased from 2.36 (+/- 0.82 L) to 2.67 L (+/- 0.85 L; p = 0.007), whereas the percentage of BAL neutrophilia decreased from 35.1 (+/- 35.7%) to 5.7% (+/- 6.5%; p = 0.0024). There were six responders to azithromycin (with an FEV(1) increase of > 10%) and eight nonresponders. Using categorical univariate linear regression analysis, the main significant differences in characteristics between responders and nonresponders were the initial BAL neutrophilia (p < 0.0001), IL-8 mRNA ratio (p = 0.0009), and the postoperative day at which azithromycin was started (p = 0.036). There was a significant correlation between the initial percentage of BAL neutrophilia and the changes in FEV(1) after 3 mo (r = 0.79, p = 0.0019). CONCLUSION Azithromycin significantly reduces airway neutrophilia and IL-8 mRNA in patients with BOS. Responders have a significantly higher BAL neutrophilia and IL-8 compared with nonresponders and had commenced treatment earlier after transplantation. BAL neutrophilia can be used as a predictor for the FEV(1) response to azithromycin.
Intractable Epilepsy

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Concentration of soluble intercellular adhesion molecule-1 in serum samples from patients with endometriosis collected during the luteal phase of the menstrual cycle.

BACKGROUND Soluble intercellular adhesion molecule-1 (sICAM-1), released by endometriotic lesions, is involved in the regulation of cytotoxic processes. Altered levels of sICAM-1 in the circulation could parallel its deregulation in the peritoneal cavity. We therefore investigated whether sICAM-1 could represent a serum marker for endometriosis. METHODS sICAM-1 levels were measured by enzyme-linked immunosorbent assay in serum samples from 176 subjects with surgically confirmed endometriosis (134 patients with stage I-II and 42 patients with stage III-IV) and 198 controls with no surgical evidence of the disease. All serum samples were collected during the luteal phase of the menstrual cycle. Detailed information about demographics, symptoms and clinical profile were collected. RESULTS Mean levels of sICAM-1 appeared significantly reduced in patients with stage III-IV endometriosis in a crude comparison of means. However, when means were adjusted for potential confounders such as the pre-operative indication or fertility status, no significant difference between cases with stage III-IV disease and controls was observed. CONCLUSIONS Serum levels of sICAM-1 during the luteal phase of the cycle are not able to discriminate women suffering from endometriosis from controls when confounders are taken into account. These results underline the importance of careful identification of confounders, based on patients' demographic and clinical data in studies aiming at discovering diagnostic markers for endometriosis.
Leptin actions on the reproductive neuroendocrine axis in sheep.

There is a growing literature on the role of leptin in appetite and neuroendocrine regulation in domestic ruminants. Circulating leptin concentration is higher in fat than in thin sheep, is reduced by chronic underfeeding and is higher in sheep subjected to long-day rather than short-day photoperiods. Leptin is reduced acutely by fasting and increases after meals so that there are long- and short-term components to the systemic leptin signal. Nutritional stimulation of reproductive neuroendocrine output is associated with increased circulating concentrations of leptin; peripheral leptin administration restores LH secretion in fasted sheep, and leptin is permissive (although not a trigger) for puberty. Intracerebroventricular (i.c.v.) pharmacological leptin infusion stimulates LH in underfed but not in well-fed sheep, and reduces food intake in well-fed sheep. A single i.c. v. pharmacological injection or physiological infusion of leptin stimulates LH in well-fed sheep, with or without a concomitant decrease in appetite. Furthermore, these appetite and LH responses are differentially affected by photoperiod, indicating that different neuronal pathways may mediate the two responses. Hypothalamic leptin receptors co-localize with orexigenic and anorexigenic neurones, some of which contact GnRH cells, but the confluence of leptin signalling with photoperiod (melatonin) signalling remains unresolved. Photoperiod-entrained sheep provide potential models of altered central leptin sensitivity, in which downstream mechanisms regulating appetite and GnRH may be dissociated.
Diagnosis, surveillance, and epidemiologic evaluation of viral infections in pediatric cardiac transplant recipients with the use of the polymerase chain reaction.

BACKGROUND Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperative morbidity and mortality in heart transplant recipients. These infections have classically been diagnosed by history, physical examination, peripheral viral cultures, and serologic studies. These methods are often time-consuming and lack sensitivity. Positive viral cultures from the heart are rarely obtained, and viral myocarditis and acute cellular rejection are unable to be differentiated histologically. We have therefore used the polymerse chain reaction to diagnose possible viral infection in pediatric heart transplant recipients with findings consistent with acute unexplained rejection. METHODS Polymerase chain reaction was used as an aid to diagnose cytomegalovirus infection of cardiac tissue obtained by right ventricular endomyocardial biopsy and follow its long-term course. In addition, polymerase chain reaction was used to diagnose infection of the heart by other viruses in patients with clinical and histologic evidence of rejection, especially those with unexplained late rejection or chronic rejection. Polymerase chain reaction primers were designed to amplify nucleic acid sequences from cytomegalovirus, parvovirus, adenovirus, herpes simplex virus, Epstein-Barr virus, and the RNA viruses of the Enterovirus family. RESULTS Forty patients underwent serial right ventricular endomyocardial biopsy (129 samples) for rejection surveillance with positive results obtained in 41 samples (32%) from 21 patients. Viral genome amplified included cytomegalovirus in 16 samples, adenovirus in 14, enterovirus in 6, parvovirus in 3, and herpes simplex virus in 2. In 13 of the 21 patients positive for viral genome (62%), endomyocardial biopsy histologic scores were consistent with multifocal moderate to severe rejection (Internal Society for Heart and Lung Transplantation scores of 3A or greater). CONCLUSIONS Polymerase chain reactions may be used as a rapid and sensitive method to evaluate postoperative viral infections in heart transplant recipients, especially in those with late-onset rejection or chronic rejection. Polymerase chain reaction may also be useful in the serial analysis of cytomegalovirus status in transplant recipients. The use of multiple viral primers improves the diagnostic evaluation of these patients and may lead to a better understanding of the epidemiologic characteristics of posttransplantation viral infections and the cause of late or chronic rejection.
Specific Structural Motifs Determine TRAP220 Interactions with Nuclear Hormone Receptors

ABSTRACT The TRAP coactivator complex is a large, multisubunit complex of nuclear proteins which associates with nuclear hormone receptors (NRs) in the presence of cognate ligand and stimulates NR-mediated transcription. A single subunit, TRAP220, is thought to target the entire complex to a liganded receptor through a domain containing two of the signature LXXLL motifs shown previously in other types of coactivator proteins to be essential for mediating NR binding. In this work, we demonstrate that each of the two LXXLL-containing regions, termed receptor binding domains 1 and 2 (RBD-1 and RBD-2), is differentially preferred by specific NRs. The retinoid X receptor (RXR) displays a weak yet specific activation function 2 (AF2)-dependent preference for RBD-1, while the thyroid hormone receptor (TR), vitamin D3 receptor (VDR), and peroxisome proliferator-activated receptor all exhibit a strong AF2-dependent preference for RBD-2. Using site-directed mutagenesis, we show that preference for RBD-2 is due to the presence of basic-polar residues on the amino-terminal end of the core LXXLL motif. Furthermore, we show that the presence and proper spacing of both RBD-1 and RBD-2 are required for an optimal association of TRAP220 with RXR-TR or RXR-VDR heterodimers bound to DNA and for TRAP220 coactivator function. On the basis of these results, we suggest that a single molecule of TRAP220 can interact with both subunits of a DNA-bound NR heterodimer.
Genetic evidence for role of carotenoids in age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS).

PURPOSE We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS). METHODS Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC). RESULTS A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0-4.9). CONCLUSIONS Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.
Chondrocyte deformation and local tissue strain in articular cartilage: A confocal microscopy study

It is well accepted that mechanical forces can modulate the metabolic activity of chondrocytes, although the specific mechanisms of mechanical signal transduction in articular cartilage are still unknown. One proposed pathway through which chondrocytes may perceive changes in their mechanical environment is directly through cellular deformation. An important step toward understanding the role of chondrocyte deformation in signal transduction is to determine the changes in the shape and volume of chondrocytes during applied compression of the tissue. Recently, a technique was developed for quantitative morphometry of viable chondrocytes within the extracellular matrix using three‐dimensional confocal scanning laser microscopy. In the present study, this method was used to quantify changes in chondrocyte morphology and local tissue deformation in the surface, middle, and deep zones in explants of canine articular cartilage subjected to physiological levels of matrix deformation. The results indicated that at 15% surface‐to‐surface equilibrium strain in the tissue, a similar magnitude of local tissue strain occurs in the middle and deep zones. In the surface zone, local strains of 19% were observed, indicating that the compressive stiffness of the surface zone is significantly less than that of the middle and deep zones. With this degree of tissue deformation, significant decreases in cellular height of 26, 19, and 20% and in cell volume of 22, 16, and 17% were observed in the surface, middle, and deep zones, respectively. The deformation of chondrocytes in the surface zone was anisotropic, with significant lateral expansion occurring in the direction perpendicular to the local split‐line pattern. When compression was removed, there was complete recovery of cellular morphology in all cases. These observations support the hypothesis that deformation of chondrocytes or a change in their volume may occur during in vivo joint loading and may have a role in the mechanical signal transduction pathway of articular cartilage.
Flexible mating: cross‐pollination affects sex‐expression in a marine clonal plant

Many functionally hermaphroditic plants have evolved mechanisms to reduce interference between the sex functions and to optimize reproductive output. In addition to physical mechanisms such as the spatial (herkogamy) and temporal (dichogamy) separation of male and female functions, plasticity in sex expression by means of mate‐recognition (flexible mating) could be important in plants with variable access to cross‐pollen. This applies particularly to clonal plants because of their modular growth form. We experimentally tested for the effects of pollen source and vegetative neighbourhood on instantaneous sex ratio and seed production in the self‐compatible clonal marine angiosperm Zostera marina L. To this end, we exposed the (monoecious) flowering shoots to self and cross‐pollen and to neighbourhoods of their own and a mix of foreign vegetative shoots. Flowering shoots that had been exposed to cross‐pollen showed (1) a significantly lower female/male ratio at peak flowering, evidence for mate‐recognition, and (2) a significantly higher seed set by the end of the season. Both effects were independent of the genetic composition of their vegetative neighbourhood. The results suggest that Z. marina maintains a cryptic self‐incompatibility system not previously described for angiosperms with sub‐aqueous pollination. In Z. marina, and possibly other self‐compatible clonal plant species, mate‐recognition could be a means of increasing the out‐crossing probability for flowering shoots with central positions within their clone.
Profiling of cytokines in human epithelial ovarian cancer ascites.

BACKGROUND The behavior of tumor cells is influenced by the composition of the surrounding tumor environment. The importance of ascites in ovarian cancer (OC) progression is being increasingly recognized. The characterization of soluble factors in ascites is essential to understand how this environment affects OC progression. The development of cytokine arrays now allows simultaneous measurement of multiple cytokines per ascites using a single array. METHODS We applied a multiplex cytokine array technology that simultaneously measures the level of 120 cytokines in ascites from 10 OC patients. The ascites concentration of a subset (n = 5) of cytokines that was elevated based on the multiplex array was validated by commercially available ELISA. The ascites level of these 5 cytokines was further evaluated by ELISA in a cohort of 38 patients. Kaplan-Meier analysis was used to assess the association of cytokine expression with progression-free survival (PFS) in this cohort. RESULTS We observed a wide variability of expression between different cytokines and levels of specific cytokines also varied in the 10 malignant ascites tested. Fifty-three (44%) cytokines were not detected in any of the 10 ascites. The level of several factors including, among others, angiogenin, angiopoietin-2, GRO, ICAM-1, IL-6, IL-6R, IL-8, IL-10, leptin, MCP-1, MIF NAP-2, osteprotegerin (OPG), RANTES, TIMP-2 and UPAR were elevated in most malignant ascites. Higher levels of OPG, IL-10 and leptin in OC ascites were associated with shorter PFS. IL-10 was shown to promote the anti-apoptotic activity of malignant ascites whereas OPG did not. CONCLUSION Our data demonstrated that there is a complex network of cytokine expression in OC ascites. Characterization of cytokine profiles in malignant ascites may provide information from which to prioritize key functional cytokines and understand the mechanism by which they alter tumor cells behavior. A better understanding of the cytokine network is essential to determine the role of ascites in OC progression.
Expression of Pit-1 mRNA and Activin/Inhibin Subunits in Clinically Nonfunctioning Pituitary Adenomas

The pituitary-specific transcriptional factor Pit-1 is known to play a role in the development and differentiation of pituitary cells. Recent investigations have suggested a role for this transcriptional factor in pituitary adenomas, especially growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas. In this study we analyzed the expression of Pit-1 mRNA and its protein in 24 clinically nonfunctioning pituitary adenomas in comparison with normal pituitary glands using in situ hybridization (ISH) and immunohistochemistry (IHC). The interaction between inhibin/activin, a member of the transforming growth factor-β family, and Pit-1 was also studied. Immunohistochemically, Pit-1 protein was detected in 9 of 24 adenomas (37.5%), and 8 of these 9 were also positive for the α subunit of glycoprotein (αSU). The expression of Pit-1 mRNA was detected in 14 of 24 (58.3%) clinically nonfunctioning adenomas, and it was found in all cases which expressed the Pit-1 protein. By the combined ISH and IHC method, Pit-1 mRNA was frequently observed in αSU-immunopositive cells in adenomas. The inhibin/activin α subunit was detected in all 24 adenomas and the βA subunit was detected in 13 of 24 adenomas. The inhibin/activin βA subunit was detected frequently with Pit-1 mRNA. From our observations, the inhibin/activin βA subunit in nonfunctioning adenomas may have related the expression of Pit-1 mRNA in these adenomas.
The Nonsteroidal Anti-Inflammatory Drug NS398 Reactivates SPARC Expression via Promoter Demethylation to Attenuate Invasiveness of Lung Cancer Cells

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to exhibit potent anticancer effects in vitro and in vivo. One of the mechanisms by which NSAIDs suppress tumorigenesis is inhibition of angiogenesis and metastasis. In this study, we used a microarray system to study the change of expression profile of metastasis-related genes regulated by NS398, a NSAID and a cyclooxygenase-2 (COX-2) inhibitor. We found that several negative regulators of cell invasion, including secreted protein acidic and rich in cysteine (SPARC), thrombospondin 1 (TSP-1), thrombospondin 3 (TSP-3), and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) are upregulated by NS398. In addition, we demonstrated that upregulation of SPARC expression by NS398 in human lung cancer cells is mediated by promoter demethylation and associated with a decrease in DNA methyltransferase (DNMT) expression. This is the first report to show that NS398 can inhibit the expression of DNMT1 and 3b. Functional assay indicated that SPARC is a critical mediator for NS398 to inhibit cell invasion. Our results provide new insights for the understanding of the anticancer actions of NSAIDs.