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OBJECTIVES: To determine the prevalence of Chlamydia trachomatis (CT) in the population screened at sexually transmitted infection (STI) clinics on Reunion Island and to identify risk factors for CT infection. PATIENTS AND METHODS: This cross-sectional multicenter study was conducted in 2017-2018. Data were obtained from self-administered questionnaires and multiplex PCR tests. RESULTS: The overall prevalence of CT in the screened population was 8.6% (95% CI 7.7-9.5%). The prevalence of urogenital CT was highest in women under 18 (13.2%, 95% CI 9.3-18.1%) and in men who have sex with men under 18 (13.3%, 95% CI 1.6-48.2%). Risk factors associated with CT infection in multivariate analysis were: female gender, being born in Reunion Island, having had a large number of sexual partners in the past year, and being co-infected with another STI. CONCLUSIONS: The prevalence of CT in the screened population is higher in Reunion Island than in mainland France, especially in minors. Prevention campaigns targeting minors should be strengthened.
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Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Chlamydia trachomatis , Estudos Transversais , Feminino , Homossexualidade Masculina , Humanos , Masculino , Menores de Idade , Reunião/epidemiologiaRESUMO
In this study, we present an analysis of metagenome sequences obtained from a filtrate of a siphon tissue homogenate of otter clams (Lutraria rhynchaena) with swollen-siphon disease. The viral signal was mined from the metagenomic data, and a novel circular ssDNA virus was identified. Genomic features and phylogenetic analysis showed that the virus belongs to the phylum Cressdnaviricota, which consists of viruses with circular, single-stranded DNA (ssDNA) genomes. Members of this phylum have been identified in various species and in environmental samples. The newly found virus is distantly related to the currently known members of the phylum Cressdnaviricota.
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Bivalves/genética , Vírus de DNA/classificação , DNA Viral/genética , Genoma Viral , Animais , Vírus de DNA/isolamento & purificação , DNA Circular/genética , DNA de Cadeia Simples/genética , Microbiologia Ambiental , Metagenômica , Filogenia , Análise de Sequência de DNARESUMO
The amyloid precursor protein (APP) has occupied a central position in Alzheimer's disease (AD) pathophysiology, in large part due to the seminal role of amyloid-ß peptide (Aß), a proteolytic fragment derived from APP. Although the contribution of Aß to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP's involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPß), various C- and N-terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the -YENPTY- motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.
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Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Caspases/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismoRESUMO
UNLABELLED: Persistence with postmenopausal osteoporosis (PMO) medications is not well characterized beyond 12 months. Of 3,011 postmenopausal women treated in primary care, 36.8 % continued baseline PMO medication during 36 months of follow-up. Many factors were associated with nonpersistence, including newly initiating or switching therapy, and reporting moderate to severe side effects. INTRODUCTION: Persistence with postmenopausal osteoporosis (PMO) medications is not well characterized beyond 12 months. We describe 24- and 36-month persistence using patient-reported data from women with different PMO treatment histories in the US primary care setting. METHODS: Data from 3,011 participants of the Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US™, 10/2005-12/2008) and Kaplan-Meier methods were used to estimate the probability of persisting (i.e., not discontinuing or switching PMO agents) with baseline PMO medication and hazard ratios for predictors of nonpersistence 24 and 36 months after study entry. RESULTS: The probability of persisting with the baseline medication was 46.2 % (95 % confidence interval [CI] 44.2-48.1 %) during 24 months of follow-up and 36.8 % (95 % CI 34.7-38.9 %) during 36 months of follow-up. In adjusted analyses, newly initiating therapy or switching to a new agent, reporting moderate to severe side effects, having lower disease-specific quality of life scores, smoking, and residing in the South or West USA (all measured at study entry) were independent predictors of nonpersistence in both time periods. The majority of participants who discontinued therapy and had the opportunity to reinitiate (i.e., discontinued ≥4 months before the end of follow-up) restarted therapy (24 months 69 %; 36 months 75 %). CONCLUSIONS: In this primary care cohort, a minority of women continued their baseline PMO therapy during a 24- to 36-month follow-up. Supporting patients during the initiation of a new therapy or if side effects occur may improve persistence and increase the therapeutic benefit of PMO medications.
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Conservadores da Densidade Óssea/administração & dosagem , Substituição de Medicamentos/estatística & dados numéricos , Adesão à Medicação/estatística & dados numéricos , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Esquema de Medicação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/epidemiologia , Atenção Primária à Saúde , Estudos Prospectivos , Estados Unidos/epidemiologiaAssuntos
Síndrome da Imunodeficiência Adquirida/epidemiologia , Epidemias/prevenção & controle , Infecções por HIV/epidemiologia , Adulto , Usuários de Drogas/estatística & dados numéricos , Feminino , Humanos , Masculino , Vigilância da População , Prevalência , Profissionais do Sexo/estatística & dados numéricos , Minorias Sexuais e de Gênero/estatística & dados numéricos , Fatores Socioeconômicos , Vietnã/epidemiologiaRESUMO
SUMMARY: Women in POSSIBLE US™ who expressed greater treatment satisfaction at study entry were more likely to persist with osteoporosis therapy over a 1-year period. Lower satisfaction among women with moderate/severe side effects increased the risk of discontinuation/switching by 67%. Treatment satisfaction and side effect experience influence osteoporosis medication adherence. INTRODUCTION: Non-adherence is common among women using postmenopausal osteoporosis (PMO) medications. We describe the association between treatment satisfaction, measured with the Treatment Satisfaction Questionnaire for Medication (TSQM), and the risk of discontinuation/switching PMO medications using patient-reported data from a large, longitudinal cohort study. METHODS: Data from 2,405 participants in the Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US™) Study were evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HR) for the association between treatment satisfaction at study entry and self-reported discontinuation/switching of pharmacologic PMO medications over a 1-year follow-up period. Logistic regression was used to evaluate relationships between treatment satisfaction, lifestyle behaviors, and compliance with bisphosphonate dosing instructions. RESULTS: Median TSQM scores were highest (indicating greatest satisfaction) for the side effects domain [n = 1,182; median = 87.5 (Q1 = 75.0, Q3 = 100.0)] and lowest for global satisfaction [n = 2,340; median = 64.0 (Q1 = 55.7, Q3 = 77.7)]. Median scores decreased for the side effects and global satisfaction domains as patient-reported side effect severity increased. Women with higher satisfaction were less likely to discontinue/switch medications than women with lower scores (adjusted HRs for convenience 0.73, 95% CI = 0.63-0.85; effectiveness 0.82, 95% CI = 0.70-0.97; and global satisfaction 0.73, 95% CI = 0.63-0.85). Lower treatment satisfaction was particularly influential among women who reported moderate/severe side effects (HR = 0.60, 95% CI = 0.37-0.97). CONCLUSIONS: Lower treatment satisfaction was associated with a 22% (1/0.82) to 67% (1/0.60) increased risk of discontinuation/switching osteoporosis medication during 1 year of follow-up.
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Conservadores da Densidade Óssea/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Osteoporose Pós-Menopausa/tratamento farmacológico , Satisfação do Paciente , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Métodos Epidemiológicos , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Atenção Primária à Saúde/métodos , Resultado do Tratamento , Estados UnidosRESUMO
UNLABELLED: The final analysis of this 2-year, randomized, crossover study showed that postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets. After receiving both treatments, women reported greater satisfaction with injectable denosumab and preferred it over oral alendronate. INTRODUCTION: Osteoporosis patients who are non-compliant or non-persistent with therapy may have suboptimal clinical outcomes. This 2-year, randomized, open-label, crossover study compared treatment adherence between subcutaneous denosumab, 60 mg every 6 months, and oral alendronate, 70 mg once weekly. METHODS: Postmenopausal women at 25 centers in the USA and Canada with bone mineral density T-scores -4.0 to -2.0 and no prior bisphosphonate use received alendronate then denosumab, or denosumab then alendronate, over successive 12-month periods. Adherence required both compliance (denosumab injections 6 months apart or ≥ 80% of alendronate tablets) and persistence (both denosumab injections or ≥ 2 alendronate doses in the last month and completion of the treatment period). RESULTS: Of the 250 women enrolled (124 alendronate, 126 denosumab), 221 entered the second year (106 denosumab, 115 alendronate). Denosumab was associated with less non-adherence than alendronate (first year, 11.9% vs 23.4%; second year, 7.5% vs 36.5%). Risk ratios for non-adherence, non-compliance, and non-persistence favored denosumab in both years (p < 0.05). Of 198 subjects expressing treatment preference, 183 (92.4%) preferred the injections over the oral therapy. BMD improved further when subjects received denosumab after alendronate and remained stable when they received alendronate after denosumab. CONCLUSION: Based on the final results of this crossover study after women had received each treatment for up to 1 year, postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets and reported increased treatment preference and satisfaction with injectable denosumab over oral alendronate.
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Alendronato/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Preferência do Paciente , Administração Oral , Idoso , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Estudos Cross-Over , Denosumab , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Adesão à Medicação , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Ligante RANK/antagonistas & inibidores , Resultado do TratamentoRESUMO
This paper reports the design, construction, and experimental validation of a novel hand-held robot for in-office laser surgery of the vocal folds. In-office endoscopic laser surgery is an emerging trend in Laryngology: It promises to deliver the same patient outcomes of traditional surgical treatment (i.e., in the operating room), at a fraction of the cost. Unfortunately, office procedures can be challenging to perform; the optical fibers used for laser delivery can only emit light forward in a line-of-sight fashion, which severely limits anatomical access. The robot we present in this paper aims to overcome these challenges. The end effector of the robot is a steerable laser fiber, created through the combination of a thin optical fiber (Ï 0.225 mm) with a tendon-actuated Nickel-Titanium notched sheath that provides bending. This device can be seamlessly used with most commercially available endoscopes, as it is sufficiently small (Ï 1.1 mm) to pass through a working channel. To control the fiber, we propose a compact actuation unit that can be mounted on top of the endoscope handle, so that, during a procedure, the operating physician can operate both the endoscope and the steerable fiber with a single hand. We report simulation and phantom experiments demonstrating that the proposed device substantially enhances surgical access compared to current clinical fibers.
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UNLABELLED: In this study, 250 women with osteoporosis were randomized to 12 months with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly, then crossed over to the other treatment. The primary endpoint, treatment adherence at 12 months, was 76.6% for alendronate and 87.3% for denosumab. INTRODUCTION: The purpose of this study is to evaluate treatment adherence with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly. METHODS: In this multicenter, randomized, open-label, 2-year, crossover study, 250 postmenopausal women with low bone mineral density received denosumab or alendronate for 12 months, then the other treatment for 12 months. The alendronate bottle had a medication event monitoring system cap to monitor administration dates. Definitions were as follows: compliance, receiving both denosumab doses 6 (± 1) months apart or 80-100% of alendronate doses; persistence, receiving both denosumab doses and completing the month 12 visit within the visit window or ≥ 2 alendronate doses in the final month; adherence, achieving both compliance and persistence. This report includes data from the first 12 months. RESULTS: The primary study endpoint, adherence in the first 12 months, was 76.6% (95/124) for alendronate and 87.3% (110/126) for denosumab. Risk ratios for denosumab compared with alendronate at 12 months were 0.58 (p = 0.043) for non-adherence, 0.48 (p = 0.014) for non-compliance, and 0.54 (p = 0.049) for non-persistence. Subject ratings for treatment necessity, preference, and satisfaction were significantly greater for denosumab and ratings for treatment bother were significantly greater for alendronate. Adverse events were reported by 64.1% of alendronate-treated subjects and 72.0% of denosumab-treated subjects (p = 0.403). The most common adverse events were arthralgia, back pain, pain in extremity, cough, and headache (each in <10% of subjects in each group). CONCLUSIONS: Significantly greater treatment adherence was observed for subcutaneous administration of denosumab every 6 months than for oral alendronate once weekly.
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Alendronato/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Osteoporose Pós-Menopausa/tratamento farmacológico , Administração Oral , Idoso , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Colúmbia Britânica , Denosumab , Métodos Epidemiológicos , Feminino , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Osteoporose Pós-Menopausa/psicologia , Preferência do Paciente/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Resultado do TratamentoRESUMO
Amyloid ß-protein (Aß) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aß causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aß-induced synaptic injury is related to the cleavage of amyloid ß precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Aß-induced synaptic injury is markedly reduced in two models of Aß toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Aß-induced synaptic damage in the injury pathway mediated by localized caspase activation.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Caspase 3/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/toxicidade , Animais , Inibidores de Caspase/farmacologia , Espinhas Dendríticas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Mutação/genética , Neuroproteção/efeitos dos fármacosRESUMO
Thermal noise spectroscopy was used to measure the density and temperature of the main (cold) electron plasma population during 2 hours (1.5x10(5) kilometers perpendicular to the tail axis) around the point of closest approach of the International Cometary Explorer (ICE) to Comet Giacobini-Zinner. The time resolution was 18 seconds (370 kilometers) in the plasma tail and 54 seconds (1100 kilometers) elsewhere. Near the tail axis, the maximum plasma density was 670 per cubic centimeter and the temperature slightly above 1 electron volt. Away from the axis, the plasma density dropped to 100 per cubic centimeter (temperature, 2x 10(4) K) over 2000 kilometers, then decreased to 10 (1.5x 10(5)K) over 15,000 kilometers; outside that region (plasma tail), the density fluctuated between 10 and 30 per cubic centimeter and the temperature between 1x 10(5) and 4 x10(5) K. The relative density of the hot population rarely exceeded a few percent. The tail was highly asymmetrical and showed much structure. On the other antenna, shot noise was recorded from the plasma particle impacts on the spacecraft body. No evidence was found of grain impacts on the antennas or spacecraft in the plasma tail. This yields an upper limit for the dust flux or particle mass, indicating either fluxes or masses in the tail smaller than implied by the models or an anomalous grain structure. This seems to support earlier suggestions that these grains are featherlike. Outside the tail, and particularly near 10(5) kilometers from its axis, impulsive noises indicating plasma turbulence were observed.
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Ulysses spacecraft radio and plasma wave observations indicate that some variations in the intensity and occurrence rate of electric and magnetic wave events are functions of heliographic latitude, distance from the sun, and phase of the solar cycle. At high heliographic latitudes, solartype Ill radio emissions did not descend to the local plasma frequency, in contrast to the emission frequencies of some bursts observed in the ecliptic. Short-duration bursts of electrostatic and electromagnetic waves were often found in association with depressions in magnetic field amplitude, known as magnetic holes. Extensive wave activity observed in magnetic clouds may exist because of unusually large electron-ion temperature ratios. The lower number of intense in situ wave events at high latitudes was likely due to the decreased variability of the high- latitude solar wind.
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The Unified Radio and Plasma Wave (URAP) experiment has produced new observations of the Jupiter environment, owing to the unique capabilities of the instrument and the traversal of high Jovian latitudes. Broad-band continuum radio emission from Jupiter and in situ plasma waves have proved valuable in delineating the magnetospheric boundaries. Simultaneous measurements of electric and magnetic wave fields have yielded new evidence of whistler-mode radiation within the magnetosphere. Observations of aurorallike hiss provided evidence of a Jovian cusp. The source direction and polarization capabilities of URAP have demonstrated that the outer region of the lo plasma torus supported at least five separate radio sources that reoccurred during successive rotations with a measurable corotation lag. Thermal noise measurements of the lo torus densities yielded values in the densest portion that are similar to models suggested on the basis of Voyager observations of 13 years ago. The URAP measurements also suggest complex beaming and polarization characteristics of Jovian radio components. In addition, a new class of kilometer-wavelength striated Jovian bursts has been observed.
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OBJECTIVE: To assess the role of environment, medical care and individual risks factors for P. aeruginosa colonization and infection. STUDY DESIGN AND SETTING: A French multicentric prospective study involved ten ICUs for a five months period. Every adult patient newly hospitalized in ICUs with no P. aeruginosa carriage up to 48 hours after admission was included and weekly screened before discharge or death. Screening swabs were either rectal, sputum or oropharyngeal samples. Hydric environment was also sampled each week. Data on patient clinical features, environmental and device exposures, and antibiotics supports were regularly collected. Multivariate analysis was performed with a multistate model. RESULTS: The overall prevalence of P. aeruginosa carriage was 15.3% (201/1314). Risk factors associated with patient colonization were: use of inactive antibiotics against P. aeruginosa (HR = 1.60 [1.15-2.21] p<0.01), tap water contamination at the entry in the room (HR = 1.66 [1.01-2.27] p<0.05) and mechanical invasive ventilation (HR = 4.70 [2.66-8.31] p<0.0001). Active antibiotics prevented from colonization (HR = 0.67 [0.48-0.93] p = 0.02) and from infection (HR = 0.64 [0.41-1.01] p = 0.05). Interaction between hydric environment antibiotics support was not statistically associated with patient colonization. CONCLUSION: Hydric contamination and antibiotics pressure seem to remain key independent risk factors in P. aeruginosa colonization. These results advocate the need to carry on preventive and targeted interventions toward healthcare associated infections.
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Infecção Hospitalar/epidemiologia , Hospitalização , Unidades de Terapia Intensiva/estatística & dados numéricos , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa/fisiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Feminino , França/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Fatores de RiscoRESUMO
OBJECTIVES: Melioidosis may be endemic in many tropical developing countries, but diagnosis of the disease is currently unreliable in resource-limited areas. We aimed to validate a simple and cheap laboratory algorithm for the identification of Burkholderia pseudomallei from clinical specimens in parts of Vietnam where the disease has not previously been reported. METHODS: In June 2015, we conducted training courses at five general hospitals in north-central provinces in order to raise awareness of the disease and to introduce a simple and cheap laboratory identification algorithm for B. pseudomallei including the three-antibiotic disc test. RESULTS: Until the end of the year (7 months later), 94 suspected B. pseudomallei strains resistant to gentamicin and colistin but sensitive to amoxicillin/clavulanic acid were detected in clinical specimens from 70 patients. All strains were further confirmed as B. pseudomallei by using a specific TTSS1 real-time PCR assay and recA sequencing analysis. Among positive blood cultures, positive rates with B. pseudomallei ranged from 3.4% (5/147) to 10.2% (32/312) in the various clinics. A total of 82.8% (58/70) patients were bacteraemic, with a mortality of 50% (18/36) among patients with known outcome. No death occurred in nonbacteraemic patients. CONCLUSIONS: Our results demonstrate that the introduction of a simple and easy-to-perform laboratory algorithm for the identification of B. pseudomallei from clinical samples, together with clinical awareness raising, can lead to the diagnosis of a significant number of melioidosis cases in resource-limited clinical laboratories which previously did not identify the pathogen.
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Algoritmos , Técnicas de Tipagem Bacteriana/métodos , Hemocultura/métodos , Burkholderia pseudomallei/isolamento & purificação , Melioidose/diagnóstico , Amoxicilina/farmacologia , Antibacterianos/farmacologia , Ácido Clavulânico/farmacologia , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Feminino , Gentamicinas/farmacologia , Humanos , Masculino , Melioidose/microbiologia , Melioidose/mortalidade , Recombinases Rec A/genética , VietnãRESUMO
Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on patho-physiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations. Primary hepatocytes experienced 48-hour exposure to OCA at concentrations approximating therapeutic (0.5µM) and supratherapeutic (10µM) levels. Global transcriptomics by RNAseq was complimented by cellular viability (MTT), CYP activity assays, and secreted FGF19 levels in the media. Dose-dependent, transcriptional effects suggested suppression of bile acid synthesis (↓CYP7A1, ↓CYP27A1) and increased bile efflux (↑ABCB4, ↑ABCB11, ↑OSTA, ↑OSTB). Pleiotropic effects included suppression of TGFß and IL-6 signaling pathways, and signatures suggestive of HDL suppression (↑SCARB1, ↓ApoAI, ↓LCAT) and LDL elevation (↑ApoB, ↓CYP7A1). OCA exhibited direct FXR-mediated effects with increased FGF19 secretion. Transcriptomics revealed regulation of metabolic, anti-inflammatory, and anti-fibrotic pathways beneficial in NASH, and predicted cholesterol profiles consistent with clinical findings. Follow-up studies under lipotoxic/inflammatory conditions would corroborate these effects in a disease-relevant environment.
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Ácido Quenodesoxicólico/análogos & derivados , Hepatócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/toxicidade , Colesterol/metabolismo , Hepatócitos/metabolismo , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transcriptoma/efeitos dos fármacosRESUMO
Peripherally inserted central venous catheter (PICC) lines have become a frequently used method of intravenous access for long-term administration of antibiotics, chemotherapy, and parenteral nutrition. Catheter-related complications involving the arterial tree are rare. We report a case of a 25-year-old woman with a history of difficult PICC line placement that presented with an arteriovenous fistula in the left arm. Duplex ultrasound confirmed the diagnosis of a brachial artery-to-brachial vein arteriovenous fistula (AVF), and the patient underwent surgical repair. To our knowledge, this is the first reported case of an AVF resulting from PICC line placement. Correction of AVF is indicated to alleviate symptoms as well as to prevent future complications.
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Fístula Arteriovenosa/etiologia , Artéria Braquial/anormalidades , Veias Braquiocefálicas/anormalidades , Cateterismo Venoso Central/efeitos adversos , Adulto , Fístula Arteriovenosa/diagnóstico por imagem , Artéria Braquial/diagnóstico por imagem , Veias Braquiocefálicas/diagnóstico por imagem , Feminino , Humanos , UltrassonografiaRESUMO
Acute acalculous cholecystitis remains a diagnostic challenge in critically ill trauma patients. Laboratory studies are nonspecific and associated injuries or mental status changes may mask clinical signs and symptoms. We conducted a retrospective study to assess the utility of ultrasound in the diagnosis of acute acalculous cholecystitis. We hypothesized that ultrasound is inadequate as a screening tool for acute acalculous cholecystitis. The abdominal ultrasounds of all patients undergoing evaluation for acute acalculous cholecystitis in a 40-month period at our Level I trauma center were reviewed. Thickened gallbladder wall, pericholecystic fluid and emphysematous gallbladder were considered positive sonographic criteria. Sludge, cholelithiasis, and hydrops were considered suggestive. Patients who did not undergo cholecystectomy had their gallbladders evaluated either during subsequent laparotomy or at autopsy or they were discharged from the hospital without need for intervention. Sixty-two patients were included. Twenty-one patients underwent cholecystectomy for presumed acute acalculous cholecystitis. The data revealed a sensitivity of 30 per cent (6/20) and a specificity of 93 per cent (39/42) for ultrasound evaluation. Twenty patients had subsequent hepatobiliary scans [hepato-iminodiacetic acid (HIDA)] with a sensitivity of 100 per cent (12/12) and specificity of 88 per cent (7/8). Our data do not support ultrasound as a reliable routine screening tool for acute acalculous cholecystitis. Despite its convenience as a bedside procedure ultrasound has insufficient sensitivity to justify its use and a more sensitive diagnostic tool should be used.
Assuntos
Colecistite/diagnóstico por imagem , Doença Aguda , Adulto , Colecistectomia , Colecistite/epidemiologia , Colecistite/cirurgia , Colecistocinina , Comorbidade , Estado Terminal , Humanos , Iminoácidos , Pessoa de Meia-Idade , Cintilografia , Estudos Retrospectivos , Ultrassonografia , Ferimentos e Lesões/epidemiologiaRESUMO
Trihalomethanes (THMs) are important disinfection byproducts (DBPs) in drinking water. To understand the magnitude of exposure to THMs for the people in southern Taiwan, models are used to estimate the inhalation exposure associated with drinking water based on raw water quality. Two parts of models are used in this study, one for estimating THM concentration from raw water quality, and one for estimating inhalation exposure to people. Important raw water quality and operational parameters, including TOC, UV254, pH, temperature, chlorine dosage, and water residence time of a major water treatment plant in south Taiwan were collected. An empirical THM formation model was then employed to predict the THM concentration at consumers' dwellings based on the parameters collected. Differences between the predicted results and experimental data were found to be small, indicating that the model is appropriate. The predicted THM concentration distribution was served as input parameters for the exposure models. Three major scenarios associated with probable inhalation exposure of THMs, including shower, pre- and post-cooking activities, and cooking processes, were considered in the exposure models. The model results show that the mean inhalation exposure of THMs for shower, pre- and post-cooking activities, and cooking processes are 26.4, 1.56, 3.29 micrograms/day, respectively. The total inhalation exposure (summation of the three scenarios) was found to be comparable with that for direct ingestion, indicating that inhalation is an important pathway for THM exposure from drinking water.