Miracle-dz/UniFAR-FTUs huggingface dataset:
Multi-institutional Study of Outcomes After Pediatric Heart Transplantation: Candidate Gene Polymorphism Analysis of ABCC2.

OBJECTIVES Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA. METHODS PHTx recipients from 6 institutions in the Pediatric Heart Transplantation Study (PHTS) from the period of 1993-2009, receiving MPA therapy, were genotyped for ABCC2 rs717620. Genotyping was accomplished by direct sequencing. Demographic and outcome data were limited to the data routinely collected as part of the PHTS and included RHC and mortality. RESULTS Two hundred ninety patients were identified who received MPA at some point post transplantation, of which 200 carried the GG genotype, 81 carried the AG genotype, and 9 carried the AA genotype. Follow-up time after transplantation was 6 years. RHC occurred in 76 patients and 18 patients died. In the 281 patients followed up more than 1 year, late RHC (>1 year post transplantation) occurred in 42 patients. While both RHC and late RHC were associated with the ABCC2 rs717620 GG genotype (hazard ratios: 1.80 and 4.57, respectively, p<0.05) in all patients, this association was not significant in PHTx patients receiving only MPA as the antiproliferative agent from the time of transplant (n=142). CONCLUSIONS ABCC2 rs717620 polymorphisms varied within racial groups. As a candidate gene assessment, the ABCC2 rs717620 AG and AA genotypes may be associated with improved, rather than poorer, RHC in PHTx patients receiving MPA therapy. ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation.
Acquired immunodeficiency syndrome (AIDS) in the Americas.

As of September 18, 1987, 48,104 cases of acquired immunodeficiency syndrome (AIDS) had been reported in the Americas to the Pan American Health Organization (PAHO), with a case-fatality mate of 55%. Brazil, Canada, Haiti, and the US contributed 96% of the reported cases. Excluding North America, 4966 AIDS cases were reported in the remaining 40 countries and territories of the Americas. Unlike the situation in Africa, where the 1:1 male: female ratio indicates heterosexual transmission, the profile of AIDS in the Americas is dominated by transmission between homosexual and bisexual males. In 2 countries, however, Haiti and the dominican Republic, the ratio of male to female cases is 4:1, which is intermediate between the ratio in Africa and that in the US. PAHO estimates that the true number of AIDS cases in all countries except the US and Canada may be 2-4 times higher than official reported indicate. A Regional WHO/PAHO Special Program on AIDS has been developed to prevent transmission of human immunodeficiency virus (HIV) and reduce the morbidity and mortality associated with HIV infection. Multiple strategies and activities are projected for 1987-89, but the principal goal is to help develop and implement national AIDS prevention and control programs. The strategy calls for support of research to define the epidemiology of AIDS, surveillance conducted with appropriate laboratory support, training of health care workers, and implementation of preventive measures. The PAHO program has already mobilized US$1.3 million from WHO's nonregular funding sources for AIDS prevention and control activities in the Americas. An additional US$5 million has been obtained for AIDS research in Latin America and the Caribbean.
Premature Mitochondrial Senescence and Related Ultrastructural Changes during Lung Carcinogenesis Modulation by Curcumin and Resveratrol

The present study attempted to explore the efficacy of curcumin and resveratrol in modulating premature mitochondria senescence and ultrastructural changes during lung carcinogenesis. The mice were segregated into 5 groups, which included normal control, benzo[a]pyrene (BP) treated, BP + curcumin (C) treated, BP + resveratrol (R) treated, and BP + C + R treated groups. Animals were given a single ip injection of benzo[a]pyrene in corn oil at a dose level of 100 mg/kg body weight. Treatments of curcumin and resveratrol were given orally in drinking water at a dose level of 60 mg/kg body weight and 5.7 µg/mL drinking water, respectively, 3 times a week for a total duration of 22 weeks. Ultrastructure of BP-treated mice revealed disruptions in cellular integrity along with nuclear deformation and premature mitochondrial senescence. Interestingly, supplementation of curcumin and resveratrol individually resulted in improvement of ultrahistoarchitecture of BP-treated mice but the improvement was much greater with combined supplementation of phytochemicals. Further, benzo[a]pyrene treatment revealed alterations in lung histoarchitecture, which, however, was improved appreciably following combined supplementation with curcumin and resveratrol. The present study concludes that combined supplementation with curcumin and resveratrol effectively modulates histoarchitecture as well as ultrahistoarchitecture during benzo[a]pyrene-induced lung carcinogenesis in mice. Cancer is a public health problem worldwide [12]. Lung cancer is a major cause of mortality throughout the world and is responsible for the deaths of more than one million people annually [34]. Phytochemicals have shown great potential in preventing the occurrence of cancer and other chronic diseases that result from oxidative stress induced by free radicals [56]. Phytochemicals are nonnutritive products of plants and, being nontoxic, are presently being studied the world over for their chemopreventive actions in controlling various diseases, including cancer. In the present study, curcumin and resveratrol are the phytochemicals of interest. Curcumin, a polyphenol, has been reported to have anti-invasive properties [7]. Further, curcumin has been shown to activate apoptotic machinery in patients with lung cancer [8]. On the other hand, resveratrol (trans-3,4,5- thihydroxystibene) is a phytoalexin that is present naturally in grapes as well as in a variety of medicinal plants and has been shown to exhibit antioxidant activity with a potential to induce apoptosis [910].
The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses.

POLICY POINTS Currently, there is massive production of unnecessary, misleading, and conflicted systematic reviews and meta-analyses. Instead of promoting evidence-based medicine and health care, these instruments often serve mostly as easily produced publishable units or marketing tools. Suboptimal systematic reviews and meta-analyses can be harmful given the major prestige and influence these types of studies have acquired. The publication of systematic reviews and meta-analyses should be realigned to remove biases and vested interests and to integrate them better with the primary production of evidence. CONTEXT Currently, most systematic reviews and meta-analyses are done retrospectively with fragmented published information. This article aims to explore the growth of published systematic reviews and meta-analyses and to estimate how often they are redundant, misleading, or serving conflicted interests. METHODS Data included information from PubMed surveys and from empirical evaluations of meta-analyses. FINDINGS Publication of systematic reviews and meta-analyses has increased rapidly. In the period January 1, 1986, to December 4, 2015, PubMed tags 266,782 items as "systematic reviews" and 58,611 as "meta-analyses. " Annual publications between 1991 and 2014 increased 2,728% for systematic reviews and 2,635% for meta-analyses versus only 153% for all PubMed-indexed items. Currently, probably more systematic reviews of trials than new randomized trials are published annually. Most topics addressed by meta-analyses of randomized trials have overlapping, redundant meta-analyses; same-topic meta-analyses may exceed 20 sometimes. Some fields produce massive numbers of meta-analyses; for example, 185 meta-analyses of antidepressants for depression were published between 2007 and 2014. These meta-analyses are often produced either by industry employees or by authors with industry ties and results are aligned with sponsor interests. China has rapidly become the most prolific producer of English-language, PubMed-indexed meta-analyses. The most massive presence of Chinese meta-analyses is on genetic associations (63% of global production in 2014), where almost all results are misleading since they combine fragmented information from mostly abandoned era of candidate genes. Furthermore, many contracting companies working on evidence synthesis receive industry contracts to produce meta-analyses, many of which probably remain unpublished. Many other meta-analyses have serious flaws. Of the remaining, most have weak or insufficient evidence to inform decision making. Few systematic reviews and meta-analyses are both non-misleading and useful. CONCLUSIONS The production of systematic reviews and meta-analyses has reached epidemic proportions. Possibly, the large majority of produced systematic reviews and meta-analyses are unnecessary, misleading, and/or conflicted.
Real-life treatment patterns, compliance, persistence, and medication costs in patients with hypertension in Germany

Abstract Objective: This retrospective patient data analysis was initiated to describe current treatment patterns of patients in Germany with arterial hypertension, with a special focus on compliance, persistence, and medication costs of fixed-dose and unfixed combinations of angiotensin receptor blockers (ARBs), amlodipine (AML) and hydrochlorothiazide (HCT) in Germany. Methods: The study analyzed prescription data collected by general practitioners, using the IMS Disease Analyzer database. The database was searched for patients with the diagnosis hypertension (ICD-10 code I10) and treatment data in the period 09/2009 to 08/2010. Compliance was measured indirectly based on the medication possession ratio (MPR), and persistence was defined as the duration of time from initiation to discontinuation of therapy. Medication costs were assessed from the statutory health insurance perspective in Germany. Results: In the IMS DA 406,888 observable patients in Germany were encoded with the diagnosis I10 essential hypertension. In total, 88,716 patients received prescriptions including ARBs, monotherapy (18.6%) or unfixed combinations with other anti-hypertensives (19.3%). The compliance with fixed-dose combinations of ARB with HCT, either dual or with one other anti-hypertensive drug, was significantly better, compared to unfixed combinations (mean compliance 78.1% for fixed-dose vs 71.5% for unfixed combinations of ARB with HCT, p < 0.0001; mean compliance 79.4% vs 72.0%, p < 0.0001 if an additional anti-hypertensive medication was added). Fixed-dose combinations of ARB with HCT, ARB with AML, dual only or prescribed with another anti-hypertensive medication resulted in a substantial increase of persistence, especially for patients on fixed-dose dual combinations (225.7 vs 163.6 days for ARB with HCT; 232.9 vs 178.4 days for ARB with AML, respectively). Fixed-dose combinations (varying from €1.38 to €2.20 per patient and day) were on average cheaper than unfixed combinations. Limitations: Persistence and compliance could be under- or over-estimated because their assessment was based on prescription information. For two thirds of 69,060 patients, data on compliance and persistence was missing. Conclusion: The study shows considerable variations in ARB treatment patterns among patients, with the majority of patients treated with fixed-dose or semi-fixed combination therapy. Fixed-dose combinations of ARBs with HCT and/or AML seem to result in better compliance and persistence compared to unfixed regimes of these drug classes, leading to reduction in all-cause hospitalizations, emphasizing the benefit and potential cost-savings of using fixed-dose regimes in a real-life general practice setting in Germany.
Correlation of D dimer and factor VIII levels with histopathology in patients with breast carcinoma.

INTRODUCTION There is evidence that the components of the coagulation/fibrinolytic system play a role in cancer biology and angiogenesis. Studies reveal that at the time of diagnosis, majority of the cancer patients have laboratory evidence of systemic coagulation activation. Our purpose was to investigate the significance of D-Dimer (product of fibrin degradation) and factor VIII levels in breast cancer and to evaluate its relationship with other variables such as histological characteristics, lymph node status and immunohistochemistry markers (ER, PR and Her-2neu). MATERIALS AND METHODS A prospective study was conducted in the Department of Surgery in collaboration with Departments of Medicine, Pathology and Radiodiagnosis & Imaging, Maulana Azad Medical College & Lok Nayak Hospital, New Delhi. Fifty patients with diagnosed cancer breast who were treated in surgery department were evaluated for D Dimer and factor VIII levels. D-dimer and Factor VIII levels were measured three times i.e. at the time of commencement of treatment then after three cycles of Chemotherapy (CAF Regimen) and finally after six weeks of surgery. RESULTS Significantly higher levels of D Dimer and factor VIII were observed in tumors with significant lymphovascular and adipose tissue invasion in comparison to localized tumors. The reduction in D-dimer and Factor VIII values after Surgery was significant for both D-dimer (p value 0.000) and Factor VIII (p value 0.000). The reduction in D-dimer after 3 cycles of chemotherapy was significant for D-dimer (575.51 ± 572.47 ng/ml vs. 422.45 ± 363.58 ng/ml; p value 0.046) but not significant for Factor VIII (307.83 ± 184.47 ng/ml vs. 288.78 ± 163.02 ng/ml; p value 0.151). CONCLUSION D-dimer and factor VIII may be used as yardstick for systemic adjuvant therapy in node negative < 1 cm breast cancer. D-dimer may prove to be a safe, convenient and easily available biomarker which can be combined with conventional sentinel node biopsy in clinically node negative breast cancer to assess metastatic disease in axilla and reduce false negative results.
Guidelines improve general trend of lowered cholesterol levels in type 2 diabetes patients in spite of low adherence

Background: New guidelines were introduced in Sweden in 1999 to reduce the risk of cardiovascular disease among diabetes patients. The impact of the new guidelines on lipid levels in a diabetes patient population has not been extensively studied. Our aim was to study whether the introduction of treatment goals for dyslipidaemia was reflected in lower cholesterol levels in patients with diabetes in a general population. Methods: In a population of 59,338 individuals, 971 (1.6%) had diabetes. All subjects were 40, 50 or 60 years of age and participated in the Vasterbotten Intervention Programme in 1995-2004. Cholesterol levels and use of lipid-lowering drugs were measured, and trends in cholesterol levels were analysed before and after the guidelines were introduced in 1999. Results: In this effectiveness study, there was a marked decrease in mean plasma total cholesterol levels among patients with diabetes (5.79 (± 1.21) mmol/1 in 1995-1999 and 5.07 (± 1.00) mmol/1 in 2000-2004 (p<0.001)) as well as in the non-diabetic population (5.79 (±1.15) mmol/1 and 5.41 (±1.07) mmol/1 (p<0.001)). The trend in diabetes patients was influenced by increased use of lipid-lowering agents, even though only 25.3% (male/female 26.8%/23.2%) of the diabetes patients received lipid-lowering treatment after the introduction of the new guidelines. Conclusions: Since the introduction of the guidelines, an increasing number of diabetes patients are receiving lipid-lowering drugs, which enhance a strong general trend of lowered cholesterol levels. Yet, the vast majority of diabetes patients with hypercholesterolaemia still do not receive medical treatment in accordance with the guidelines.
Transcatheter Embolization for Treatment of Acute Lower Gastrointestinal Bleeding

Treatment of lower gastrointestinal bleeding was attempted in 13 patients by selective embolization of branches of the mesenteric arteries with Gelfoam. Bleeding was adequately controlled in 11 patients with active bleeding during the examination. One patient improved after embolization but bleeding recurred within 24 hours and in another patient the catheterization was unsuccessful. Five patients with diverticular hemorrhage were embolized in the right colic artery four times, and once in the middle colic artery. Three patients had embolization of the ileocolic artery because of hemorrhage from cecal angiodysplasia, post appendectomy, and leukemia infiltration. Three patients had the superior hemorrhoidal artery embolized because of bleeding from unspecific proctitis, infiltration of the rectum from a carcinoma of the bladder, and transendoscopic polypectomy. One patient was septic and bled from jejunal ulcers. Ischemic changes with infarction of the large bowel developed in two patients and were treated by partial semi-elective colectomy, three and four days after embolization. Four other patients developed pain and fever after embolization. Transcatheter embolization of branches of mesenteric arteries is an effective way to control acute lower gastrointestinal bleeding, but still has a significant rate of complications that must be seriously weighed against the advantages of operation.
Near-infrared autofluorescence: its relationship to short-wavelength autofluorescence and optical coherence tomography in recessive stargardt disease.

PURPOSE We compared hypoautofluorescent (hypoAF) areas detected with near-infrared (NIR-AF) and short-wavelength autofluorescence (SW-AF) in patients with recessive Stargardt disease (STGD1) to retinal structure using spectral domain optical coherence tomography (SD-OCT). METHODS The SD-OCT volume scans, and SW-AF and NIR-AF images were obtained from 15 eyes of 15 patients with STGD1 and registered to each other. Thickness maps of the total retina, receptor-plus layer (R+, from distal border of the RPE to outer plexiform/inner nuclear layer boundary), and outer segment-plus layer (OS+, from distal border of the RPE to ellipsoid zone [EZ] band) were created from SD-OCT scans. These were compared qualitatively and quantitatively to the hypoAF areas in SW-AF and NIR-AF images. RESULTS All eyes showed a hypoAF area in the central macula and loss of the EZ band in SD-OCT scans. The hypoAF area was larger in NIR than SW-AF images and it exceeded the area of EZ band loss for 12 eyes. The thickness maps showed progressive thinning towards the central macula, with the OS+ layer showing the most extensive and severe thinning. The central hypoAF areas on NIR corresponded to the OS+ thinned areas, while the hypoAF areas on SW-AF corresponded to the R+ thinned areas. CONCLUSIONS Since the larger hypoAF area on NIR-AF exceeded the region of EZ band loss, and corresponded to the OS+ thinned area, RPE cell loss occurred before photoreceptor cell loss. The NIR-AF imaging may be an effective tool for following progression and predicting loss of photoreceptors in STGD1.
Identification of Conserved Residues in the E2 Envelope Glycoprotein of the Hepatitis C Virus That Are Critical for CD81 Binding

ABSTRACT Hepatitis C virus (HCV) cell entry involves interaction between the viral envelope glycoprotein E2 and the cell surface receptor CD81. Knowledge of conserved E2 determinants important for successful binding will facilitate development of entry inhibitors designed to block this interaction. Previous studies have assigned the CD81 binding function to a number of discontinuous regions of E2. To better define specific residues involved in receptor binding, a panel of mutants of HCV envelope proteins was generated, where conserved residues within putative CD81 binding regions were sequentially mutated to alanine. Mutant proteins were tested for binding to a panel of monoclonal antibodies and CD81 and for their ability to form noncovalent heterodimers and confer infectivity in the retroviral pseudoparticle (HCVpp) assay. Detection by conformation-sensitive monoclonal antibodies indicated that the mutant proteins were correctly folded. Mutant proteins fell into three groups: those that bound CD81 and conferred HCVpp infectivity, those that abrogated both CD81 binding and HCVpp infectivity, and a final group containing mutants that were able to bind CD81 but were noninfectious in the HCVpp assay. Specific amino acids conserved across all genotypes that were critical for CD81 binding were W420, Y527, W529, G530, and D535. These data significantly increase our understanding of the CD81 receptor-E2 binding process.
Photoconversion of diaminobenzidine with different fluorescent neuronal markers into a light and electron microscopic dense reaction product

This article describes methods for photoconverting diaminobenzidine (DAB) into a stable, light and electron microscopically visible dark reaction product in neurons which contain a fluorescent dye. Photoconversion of DAB has been achieved so far with the following fluorescent dyes: rhodamine labeled latex microspheres (RLM), 4,6‐diamidino‐2‐phenylindole (DAPI), 5,7‐di‐hydroxytryptamine (5,7‐DHT), Fast Blue (FB), Nuclear Yellow (NY), Diamidino Yellow (DY), Evans Blue (EB), acridine orange (AO), ethidium bromide (EBR),1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindolcarbocyanine perchlorate, D‐282 (DiI), propidium iodide (PI), and intracellularly injected Lucifer Yellow (LY). The dye is introduced into the neurons by tinctorial staining, retrograde transport, or intracellular injection. Photoconversion is conducted by incubating the tissue with the fluorescent substance‐containing cells in a DAB solution under simultaneous strong illumination with ultraviolet (UV) light. During the formation of the reaction product, the fluorescence disappears from the cell. In all cases, photoconversion provided a stable, nonfading DAB reaction product for light microscopy. In addition, at the electron microscopic level, it appeared that the photoconversion results in a homogeneously distributed, fine granular, dark, intracellularly located reaction product. With most of the retrograde tracers tested, photoconversion led only to staining of the cell bodies and the proximal portions of primary dendrites. Following photoconversion with intracellularly LY‐filled neurons and cells labeled retrogradely with DiI, DiO, and 5,7‐DHT, the reaction product was present throughout the cells, extending from the cell bodies into dendrites and dendritic appendices, and into axons. The high selectivity and methodological simplicity of photoconversion of DAB with fluorescent dyes into a stable, light and electron microscopical dense reaction product provide a promising alternative to classical neuroanatomical techniques and a new useful application of fluorescent neuronal tracers to light and electron microscopy. © 1993 Wiley‐Liss, Inc.