Miracle-dz/UniFAR-FTUs huggingface dataset:
Interactions between Recreational Drugs and Antiretroviral Agents

OBJECTIVE: To summarize existing data regarding potential interactions between recreational drugs and drugs commonly used in the management of HIV-positive patients. DATA SOURCES: Information was obtained via a MEDLINE search (1966–August 2002) using the MeSH headings human immunodeficiency virus, drug interactions, cytochrome P450, medication names commonly prescribed for the management of HIV and related opportunistic infections, and names of commonly used recreational drugs. Abstracts of national and international conferences, review articles, textbooks, and references of all articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Literature on pharmacokinetic interactions was considered for inclusion. Pertinent information was selected and summarized for discussion. In the absence of specific data, prediction of potential clinically significant interactions was based on pharmacokinetic and pharmacodynamic properties. RESULTS: All protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of the cytochrome P450 system. Many classes of recreational drugs, including benzodiazepines, amphetamines, and opioids, are also metabolized by the liver and can potentially interact with antiretrovirals. Controlled interaction studies are often not available, but clinically significant interactions have been observed in a number of case reports. Overdoses secondary to interactions between the “rave” drugs methylenedioxymethamphetamine (MDMA) or γ-hydroxybutyrate (GHB) and PIs have been reported. PIs, particularly ritonavir, may also inhibit metabolism of amphetamines, ketamine, lysergic acid diethylmide (LSD), and phencyclidine (PCP). Case series and pharmacokinetic studies suggest that nevirapine and efavirenz induce methadone metabolism, which may lead to symptoms of opiate withdrawal. A similar interaction may exist between methadone and the PIs ritonavir and nelfinavir, although the data are less consistent. Opiate metabolism can be inhibited or induced by concomitant PIs, and patients should be monitored for signs of toxicity and/or loss of analgesia. PIs should not be coadministered with midazolam and triazolam, since prolonged sedation may occur. CONCLUSIONS: Interactions between agents commonly prescribed for patients with HIV and recreational drugs can occur, and may be associated with serious clinical consequences. Clinicians should encourage open dialog with their patients on this topic, to avoid compromising antiretroviral efficacy and increasing the risk of drug toxicity.
Long‐term Exposure to Lifelong Therapies

Summary: Three categories of highly active antiretroviral therapy (HAART)associated major toxic effects have been identified: nucleoside‐related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life‐threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long‐term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.
Comparison of Gene Expression Profiles Induced By Coarse, Fine, and Ultrafine Particulate Matter

Coarse, fine, and ultrafine particulate matter (PM) fractions possess different physical properties and chemical compositions and may produce different adverse health effects. Studies were undertaken to determine whether or not gene expression patterns may be used to discriminate among the three size fractions. Airway epithelial cells obtained from 6 normal individuals were exposed to Chapel Hill coarse, fine or ultrafine PM (250 μg/ml) for 6 and 24 h (n = 3 different individuals each). RNA was isolated and hybridized to Affymetrix cDNA microarrays. Significant genes were identified and mapped to canonical pathways. Expression of selected genes was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). The numbers of genes altered by coarse, fine, and ultrafine PM increased from 0, 6, and 17 at 6 h to 1281, 302, and 455 at 24 h, respectively. The NRF2-mediated oxidative stress response, cell cycle:G2/M DNA damage checkpoint regulation, and mitotic roles of polo-like kinase were the top three pathways altered by all three fractions. Fine and ultrafine PM displayed more similar gene expression patterns. One example was the increased expression of metallothionein isoforms, reflecting the higher zinc content associated with fine and ultrafine fractions. A set of 10 genes was identified that could discriminate fine and ultrafine PM from coarse PM. These results indicate that common properties shared by the three size fractions as well as size-specific factors, e.g., compositions, may determine the effects on gene expression. Genomic markers may be used to discriminate coarse from fine and ultrafine PM.
Review of oral cholecystographic agents for the management of hyperthyroidism.

OBJECTIVE Although the use of oral cholecystographic agents (OCAs) had declined due to limited availability, there is literature to suggest it is an effective medication for thyrotoxicosis in appropriate clinical situations. METHODS The authors performed a PubMed search and systematically reviewed all the English written case reports, original studies and reviews from 1953 to 2012. Additional information was supplemented from available online pharmacologic databases. RESULTS The off-label use of OCAs was reviewed for the management of neonatal and adult Graves' disease, subacute thyroiditis, amiodarone-induced thyroiditis (AIT), exogenous hyperthyroidism, toxic multinodular goiter (TMNG), thyrotropinoma, thyrotoxicosis during pregnancy, rapid pre-operative control of hyperthyroidism, and thyroid storm. Adverse effects were also reviewed. CONCLUSION OCAs generally are effective agents in treating thyrotoxicosis in the etiologies reviewed. OCAs are clinically relevant in patients who require rapid control, such as in the pre-operative state or patient who cannot tolerate a thyrotoxicosis state. OCA may also be beneficial in situations where other anti-thyroidal medication would be hazardous or ineffective, such as thionamide allergy or exogenous thyrotoxicosis. Given concern for long-term relapse, OCAs should be considered a short-term bridge to definitive therapy. OCAs are limited in TMNG and should be second line after glucocorticoids in AIT II. OCAs do not preclude the use of radioactive iodine, which can be performed one week after OCA therapy.
DNA Substrate-Induced Activation of the Agrobacterium VirB/VirD4 Type IV Secretion System

ABSTRACT The bitopic membrane protein VirB10 of the Agrobacterium VirB/VirD4 type IV secretion system (T4SS) undergoes a structural transition in response to sensing of ATP binding or hydrolysis by the channel ATPases VirD4 and VirB11. This transition, detectable as a change in protease susceptibility, is required for DNA substrate passage through the translocation channel. Here, we present evidence that DNA substrate engagement with VirD4 and VirB11 also is required for activation of VirB10. Several DNA substrates (oncogenic T-DNA and plasmids RSF1010 and pCloDF13) induced the VirB10 conformational change, each by mechanisms requiring relaxase processing at cognate oriT sequences. VirD2 relaxase deleted of its translocation signal or any of the characterized relaxases produced in the absence of cognate DNA substrates did not induce the structural transition. Translocated effector proteins, e.g., VirE2, VirE3, and VirF, also did not induce the transition. By mutational analyses, we supplied evidence that the N-terminal periplasmic loop of VirD4, in addition to its catalytic site, is essential for early-stage DNA substrate transfer and the VirB10 conformational change. Further studies of VirB11 mutants established that three T4SS-mediated processes, DNA transfer, protein transfer, and pilus production, can be uncoupled and that the latter two processes proceed independently of the VirB10 conformational change. Our findings support a general model whereby DNA ligand binding with VirD4 and VirB11 stimulates ATP binding/hydrolysis, which in turn activates VirB10 through a structural transition. This transition confers an open-channel configuration enabling passage of the DNA substrate to the cell surface.
Growth-related oncogene alpha induction of apoptosis in osteoarthritis chondrocytes.

OBJECTIVE To evaluate the apoptotic effect of the chemokine growth-related oncogene alpha (GROalpha), which we recently reported to be up-regulated in osteoarthritis (OA) chondrocytes. Chondrocyte apoptosis is considered to be a major determinant of cartilage damage in OA, a disease resulting from the aberrant production of inflammatory mediators (cytokines and chemokines) and effectors (matrix metalloproteinases and reactive oxygen and nitrogen species) by chondrocytes. METHODS We investigated the apoptotic effect of GROalpha on isolated human cells and on in vitro-cultured cartilage explants by conventional methods (morphology, detection of DNA fragmentation in situ and in solution, exposure of phosphatidylserine) and by analysis of "early" biochemical events (plasma membrane depolarization, activation of caspase 3, and phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase). RESULTS We clearly demonstrated that GROalpha was able to initiate a series of morphologic, biochemical, and molecular changes that led to chondrocyte apoptosis. Moreover, we found that additional signals delivered from the extracellular matrix (ECM) were essential in the control of chondrocyte susceptibility to GROalpha-induced apoptosis, since cell death was detected only when cells were stimulated after reestablishment of their proper interactions with the ECM, or in cartilage explant samples with reduced ECM, as indicated by decreased Safranin O staining. CONCLUSION GROalpha can induce apoptosis in articular chondrocytes, and the induction is dependent upon additional signals from the ECM. These findings are relevant to understanding the pathogenesis of OA, in view of the availability of the GROalpha chemokine in the joint space in the course of this rheumatic disease.
Modulatory role of 17β‐estradiol in the tumor microenvironment of thyroid cancer

Thyroid cancer (TC) is an endocrine related cancer and is well coupled with the female reproductive hormone, 17β‐estradiol (estrogen). Plenty of articles have discussed the role of tumor microenvironment (TME) with different types of tumors in a broad‐spectrum but the role of female reproductive hormone, that is, involvement of estrogen in TME of TC have not been reviewed elsewhere. The aim of this review is to analyze how 17β‐estradiol affects the TME of TC and also that subsequently leads to progression of cancer. This review is given a new insight on: 1) the estrogen's involvement in TME of TC; 2) how it interferes with the complex cross talk of signaling pathways established between cancer cells, host cells, and their surrounding extracellular matrix; and 3) the important factors of microenvironment comprising inflammation, hypoxia, angiogenesis, metastasis, various growth factors and fibroblasts in stromal cells. © 2015 IUBMB Life, 68(2):85–96, 2016
Application of computer simulation modeling in the health care sector: a survey

This article aims to present examples of computer simulation models that support decision-making processes in the health care sector. The objective of this review is to propose a system of classification of health care topic areas examined with the assistance of simulation methods. The categories described in literature were expanded and a detailed taxonomy for sub-groups was formulated. Usefulness of simulation modeling techniques was investigated and an attempt was made to correlate the simulation approach with a corresponding health care application group from the suggested classification.
Effects of PspA and Antibodies to PspA on Activation and Deposition of Complement on the Pneumococcal Surface

ABSTRACT Streptococcus pneumoniae infection is a frequent cause of pneumonia, otitis media, meningitis, and septicemia. Pneumococcal surface protein A (PspA) is an important virulence factor on the pathogen surface, and it is known to interfere with complement activation. In this study, flow cytometry was used to study the effects of PspA and antibodies to PspA on the deposition of complement C3 on the surface of a capsular type 3 strain, WU2, and its PspA− mutant, JY1119. Using naive mouse serum as a complement source, measurable deposition of C3 was observed within 4 min on PspA− pneumococci, and the amount of surface-bound C3 accumulated rapidly as the amount of serum was increased. In contrast, very little C3 was deposited on the PspA+ strain. In nonimmune mouse serum, the classical pathway was the dominant activation pathway triggered by PspA− pneumococci. Accordingly, EGTA blocked almost all of the complement activation. Moreover, a significant amount of C3 was still deposited on the PspA− strain when serum from factor B-deficient mice was used. This deposition was not observed on the PspA+ pneumococci, indicating that PspA may inhibit complement deposition via the classical pathway. Furthermore, under the conditions we tested, PspA also inhibited C3 deposition when the classical pathway was initiated by antibodies to capsular polysaccharide. Antibodies to PspA could overcome the anticomplementary effect of PspA, allowing for increased complement activation and C3 deposition onto PspA+ bacteria.
Comparative toxicity of pyrethroid insecticides to two estuarine crustacean species, Americamysis bahia and Palaemonetes pugio

Pyrethroid insecticides are widely used on agricultural crops, as well as for nurseries, golf courses, urban structural and landscaping sites, residential home and garden pest control, and mosquito abatement. Evaluation of sensitive marine and estuarine species is essential for the development of toxicity testing and risk‐assessment protocols. Two estuarine crustacean species, Americamysis bahia (mysids) and Palaemonetes pugio (grass shrimp), were tested with the commonly used pyrethroid compounds, lambda‐cyhalothrin, permethrin, cypermethrin, deltamethrin, and phenothrin. Sensitivities of adult and larval grass shrimp and 7‐day‐old mysids were compared using standard 96‐h LC50 bioassay protocols. Adult and larval grass shrimp were more sensitive than the mysids to all the pyrethroids tested. Larval grass shrimp were approximately 18‐fold more sensitive to lambda‐cyhalothrin than the mysids. Larval grass shrimp were similar in sensitivity to adult grass shrimp for cypermethrin, deltamethrin, and phenothrin, but larvae were approximately twice as sensitive to lambda‐cyhalothrin and permethrin as adult shrimp. Acute toxicity to estuarine crustaceans occurred at low nanogram per liter concentrations of some pyrethroids, illustrating the need for careful regulation of the use of pyrethroid compounds in the coastal zone. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1099–1106, 2014.
Identification of a novel antiapoptotic functional domain in simian virus 40 large T antigen

The ability of DNA tumor virus proteins to trigger apoptosis in mammalian cells is well established. For example, transgenic expression of a simian virus 40 (SV40) T-antigen N-terminal fragment (N-termTag) is known to induce apoptosis in choroid plexus epithelial cells. SV40 T-antigen-induced apoptosis has generally been considered to be a p53-dependent event because cell death in the brain is greatly diminished in a p53-/- background strain and is abrogated by expression of wild-type (p53-binding) SV40 T antigen. We now show that while N-termTags triggered apoptosis in rat embryo fibroblasts cultured in low serum, expression of full-length T antigens unable to bind p53 [mut(p53-)Tags] protected against apoptosis without causing transformation. One domain essential for blocking apoptosis by T antigen was mapped to amino acids 525 to 541. This domain has >60% homology with a domain of adenovirus type 5 E1B 19K required to prevent E1A-induced apoptosis. In the context of both wild-type T antigen and mut(p53-)Tags, mutation of two conserved amino acids in this region eliminated T antigen's antiapoptotic activity in REF-52 cells. These data suggest that SV40 T antigen contains a novel functional domain involved in preventing apoptosis independently of inactivation of p53.
Effect of interleukin 1beta on the HPA axis in H1-receptor knockout mice.

OBJECTIVES AND METHODS Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H(1) receptors (H(1)R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H(1)R knockout on IL-1beta-induced ACTH secretion in adult male mice. RESULTS In H(1)R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1beta whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1beta stimulation, whereas in wild-type mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1beta-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1beta-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1beta-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1beta-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice. CONCLUSION We conclude that the lack of the gene for histamine H(1)R does not seem to be crucial for the ACTH and CORT response to IL-1beta, either due to possible functional compensation in the H(1)R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.
Predictors of atypical femoral fractures during long term bisphosphonate therapy: A case series & review of literature

Background & objectives: Bisphosphonates (BPs) are the most widely prescribed medicines for the treatment of osteoporosis because of their efficacy and favourable safety profile. There have been, several reports on an increased incidence of atypical femoral fractures after long term treatment with BPs. The objective of this study was to evaluate the clinical presentation including prodromal symptoms, skeletal radiograph findings, type and duration of BPs received and treatment outcome of patients who developed atypical femoral fractures during bisphosphonate therapy. Methods: In this retrospective study, eight patients with atypical femoral fractures were analysed based on clinical features, biochemical and radiological investigations. Results: Of the eight patients, who sustained atypical femoral fractures, six were on alendronate and two were on zoledronate therapy before the fractures. In addition to BPs, two patients were on long term corticosteroid therapy for rheumatoid arthritis and Addison's disease. Three patients had bilateral atypical femoral fractures. Except one, all of them had prodromal symptoms prior to fracture. Skeletal radiograph showed cortical thickening, pointed (beaking of) cortical margin and transverse fracture in meta-diaphyseal location. Serum calcium, phosphate, alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) concentrations were within the reference range in all patients. Interpretation & conclusions: Long term bisphosphonate therapy may increase the risk of atypical femoral fractures. Presence of prodromal pain, thickened cortex with cortical beaking may be an early clue for predicting the atypical fractures. High risk patients need periodical skeletal survey and a close follow up for early detection of cases.
Metagenomic analysis of bacterial infections by means of high-throughput DNA sequencing

DNA sequencing technology has undergone a remarkable and continuous improvement in recent years. The so-called ‘high-throughput DNA sequencers’ can determine hundreds of megabases of DNA sequences per run. We have been applying these new sequencers to the analysis of infectious diseases, especially bacterial infections. We review the efficacy of these sequencers, mainly based on our own experiences. The approach described here can be viewed as a metagenomic analysis of infectious diseases. The approach is in principle a method that does not depend on the type of target pathogens, so that it is possible to analyze various microorganisms, including bacteria, viruses, fungi and parasites, with a single common protocol. Applying this novel approach to cases in which infectious diseases are suspected because of environmental evidence, but the causative agent has not been indentified, may lead to the discovery of unknown, novel pathogens. Also, the approach enables us to conduct an unbiased analysis of dynamics of the pathogen and associated microbiota in human specimens during the course of infectious diseases.