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Objectives: The worldwide shortage of intravenous (IV) Omnipaque iodinated contrast (Iohexol, GE Healthcare; Milwaukee, WI, USA) forced institutions to adopt various policies regarding contrast allocation. We sought to evaluate the impact of our hospital's response to the shortage, which was to decrease the dose of IV contrast from 100 mL to 75 mL for patients weighing between 45.4 and 136 kg (100-300 lbs) undergoing abdominal computed tomography (CT) examinations. The main objective was to assess for any differences in liver attenuation and enhancement between contrast dosages. Secondary outcomes included assessing differences in aortic and portal vein attenuation, the variance in attenuation measurements, and whether radiology reports included the correct IV contrast dose. Material and Methods: Consecutive CT abdomen or CT abdomen and pelvis examinations without and with contrast were analyzed for the 3 months before the contrast shortage and for 3 months during the contrast shortage. Attenuation in Hounsfield units (HUs) was measured in the liver on pre-contrast and portal venous phase images. Vessel attenuation was measured in the aorta (arterial phase) and main portal vein (portal venous phase). Standard deviation of liver attenuation measurements was recorded as an indicator of signal-to-noise. Liver enhancement was calculated as the difference between liver portal venous phase attenuation and pre-contrast attenuations. Results: Thirty-nine fixed dose (100 mL) and 36 reduced dose (75 mL) consecutive CT studies were included in the study. There were no significant differences between the two groups with respect to baseline characteristics such as age, weight, body mass index, and gender. There was no significant difference in pre-contrast liver attenuation between groups, but there was statistically significant greater liver attenuation (99.6 vs. 91.2 HU, P = 0.04) and liver enhancement (51.5 vs. 39.1 HU, P < 0.0001) during the portal venous phase for the fixed-dose group compared to the reduced dose group. There was significantly greater main portal vein opacification during the portal venous phase for the fixed dose group (146.6 vs. 122.2 HU, P < 0.0001). No significant difference was found in aortic opacification during the arterial phase (245 vs. 254 HU, P = 0.52). There was no difference in the standard deviation of liver attenuation measurements on the portal venous phase between the groups. The dose was reported correctly in all the patients receiving the fixed dose and in 92% of patients receiving the reduced dose, which was not statistically significant (P = 0.11). Conclusion: Reducing the IV contrast dose from 100 mL to 75 mL Omnipaque 350 in patients weighing 45.4-136 kg (100-300 lbs) undergoing an abdominal CT examination resulted in significantly decreased portal vein opacification and liver enhancement. In particular, liver enhancement and calculated iodine concentrations fell below suggested thresholds for adequate conspicuity of liver lesions. The change in contrast administration protocol also led to more errors in contrast dose reporting in the radiologist's report. These findings are broadly applicable to many practice settings and can help inform strategies in response to any potential future-iodinated contrast shortage.
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BACKGROUND: Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases. METHODS: We ascertained five individuals with monoallelic pathogenic variants in MORC2, previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy; and a rare form of spinal muscular atrophy. RESULTS: One of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2-related disorder, four of whom had clinical features strongly suggestive of CS. CONCLUSIONS: Our findings indicate that some forms of MORC2-related disorder have phenotypic similarities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2-related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diagnostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders.
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Síndrome de Cockayne , Microcefalia , Humanos , Síndrome de Cockayne/genética , Enzimas Reparadoras del ADN/genética , Fenotipo , Microcefalia/genética , Mutación/genética , Factores de Transcripción/genéticaRESUMEN
Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long-read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.
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Distrofia Muscular de Duchenne , Secuenciación de Nanoporos , Nanoporos , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Secuenciación del ExomaRESUMEN
Recently, H(2)S (an environmental toxin) was proposed to induce cytotoxicity not only by inhibiting cytochrome oxidase but also by generating reactive oxygen species [Truong, D., Eghbal, M., Hindmarsh, W., Roth, Sh., O'Brien, P., 2006. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab. Rev. 38, 733-744]. In the following, evidence is presented supporting the use of hydroxocobalamin (vitamin B(12a)) as an antidote against H(2)S poisoning. More than 60% of the mice administered 35 mg/kg (0.63 mmol/kg) of NaSH (LD(90)) survived (at 24 h) when hydroxocobalamin (0.25 mmol/kg) was given after NaSH administration whereas less than 15% of the mice survived without hydroxocobalamin. Hydroxocobalamin (50-100 microM) or cobalt (50-100 microM) also prevented hepatocyte cytotoxicity induced by NaSH (500 microM). Furthermore, adding hydroxocobalamin 60 min later than NaSH still showed some protective activity. Catalytic amounts of hydroxocobalamin or cobalt added to a solution containing NaSH caused the disappearance of NaSH and induced oxygen uptake, indicative of NaSH oxidation and Co reduction, respectively.
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Antídotos/farmacología , Cobalto/farmacología , Contaminantes Ambientales/toxicidad , Hepatocitos/efectos de los fármacos , Sulfuro de Hidrógeno/toxicidad , Hidroxocobalamina/farmacología , Sulfuros/toxicidad , Complejo Vitamínico B/farmacología , Animales , Antídotos/uso terapéutico , Catalasa/metabolismo , Supervivencia Celular/efectos de los fármacos , Sistema Libre de Células/efectos de los fármacos , Sistema Libre de Células/metabolismo , Cobalto/uso terapéutico , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/metabolismo , Sulfuro de Hidrógeno/metabolismo , Hidroxocobalamina/uso terapéutico , Técnicas In Vitro , Dosificación Letal Mediana , Masculino , Ratones , Oxidación-Reducción , Oxígeno/metabolismo , Intoxicación/etiología , Intoxicación/prevención & control , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Sulfuros/metabolismo , Factores de Tiempo , Complejo Vitamínico B/uso terapéuticoRESUMEN
BACKGROUND: We compared the quality of structured abstracts of original research articles from the British Medical Journal (BMJ), Canadian Medical Association Journal (CMAJ), and the Journal of the American Medical Association (JAMA) from 1991 to 1992 and 2001 to 2002 between journals. METHODS: A random, stratified sample of 54 abstracts from 2001 to 2002 in BMJ, CMAJ, and JAMA was compiled and coded. Two blinded raters reviewed 27 abstracts each against 33 objective criteria, separated into eight categories (purpose, research design, setting, subjects, intervention, measurement of variables, results, and conclusion). The quality score was the proportion of criteria present (range = 0-1). RESULTS: The overall mean quality score (0.74) for 2001-2002 was significantly higher than the 1988-1989 unstructured abstracts (mean = 0.57; p<0.001) but not different from the 1991-1992 structured abstracts (mean = 0.74; p>0.05). In 2001-2002, abstracts of CMAJ and JAMA (both means = 0.76) improved significantly over 1991-1992 (p<0.05) and scored significantly higher than BMJ (mean = 0.71; d.f. = 16, p<0.05). Some individual criteria scores (intervention, statistical information) improved but information was found consistently under-represented in areas that imply shortcomings of the studies. INTERPRETATION: We found a consistency in abstract quality regardless of the precise format used by different journals. This indicates that the framework for research articles already in place should be maintained and further modification of the framework may not necessarily improve the abstract quality.
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Indización y Redacción de Resúmenes/normas , Edición/normas , Canadá , Estudios de Seguimiento , Control de Calidad , Reino Unido , Estados UnidosRESUMEN
Mitochondria play a critical role in generating most of the cell's energy as ATP. They are also involved in other metabolic processes such as urea generation, haem synthesis and fatty acid beta-oxidation. Disruption of mitochondrial function by drugs can result in cell death by necrosis or can signal cell death by apoptosis (e.g., following cytochrome c release). Drugs that injure mitochondria usually do so by inhibiting respiratory complexes of the electron chain; inhibiting or uncoupling oxidative phosphorylation; inducing mitochondrial oxidative stress; or inhibiting DNA replication, transcription or translation. It is important to test for mitochondrial toxicity early in drug development as impairment of mitochondrial function can induce various pathological conditions that are life threatening or can increase the progression of existing mitochondrial diseases.
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Mitocondrias/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/toxicidad , Transporte de Electrón/efectos de los fármacos , Humanos , Hipoglucemiantes/toxicidad , Mitocondrias/metabolismo , Proteínas Mitocondriales/biosíntesis , Fosforilación Oxidativa/efectos de los fármacos , Estrés Oxidativo , Desacopladores/toxicidadRESUMEN
OBJECTIVE: Characteristics of Canadian RA patients started on anti-tumor necrosis factor (TNF) treatment were compared with 12 other countries. METHODS: Data from the Optimization of HUMIRA trial (OH) were compared with Canadian real world studies [Ontario Biologics Research Initiative (OBRI) and the Real-Life Evaluation of Rheumatoid Arthritis in Canadians Receiving HUMIRA (REACH)], and to data from American, Australian, British, Czech, Danish, Dutch, Finnish, German, Italian, Norwegian, Spanish, and Swedish RA databases. Patient characteristics and temporal trends at initiation of anti-TNF therapy were compared between countries. RESULTS: Baseline Disease Activity Scores (DAS28) varied from 5.3 to 6.6. Lower disease severity was noted in databases from countries with less restrictive anti-TNF coverage: Dutch [based on previous disease-modifying antirheumatic drugs (DMARD) use, DAS28, swollen joint count (SJC), tender joint count (TJC), Health Assessment Questionnaire Disability Index (HAQ-DI), Danish (previous DMARD use, DAS28), Norwegian (DAS28, SJC, TJC, visual analog scale (VAS) of global health), and Swedish (DAS28, SJC, TJC, HAQ-DI)]. RA databases showed lower disease scores than did OH (P < 0.05). The US databases also showed lower disease severity (CORRONA: previous DMARD use, SJC, TJC; National Data Bank for Rheumatic Diseases: HAQ, P < 0.001). The UK and Czech Republic had restrictive coverage and higher mean baseline DAS28 than OH (P < 0.001). Baseline DAS28 in the registries with published data lowered over time (British, Norwegian, Danish, and Swedish) but less for the British (P < 0.001). CONCLUSIONS: These results confirm that regional variation exists between the 13 countries analyzed in the initiation of treatment with anti-TNF agents among RA patients and suggest that in some cases this variation may be increasing. In some countries the mean baseline disease severity declined over time and regional reimbursement policies and differences in physician preferences may be influencing initiation of anti-TNF therapy in RA.
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anticuerpos Monoclonales/economía , Antirreumáticos/economía , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/fisiopatología , Bases de Datos Factuales , Evaluación de la Discapacidad , Femenino , Accesibilidad a los Servicios de Salud , Estado de Salud , Humanos , Reembolso de Seguro de Salud , Masculino , Persona de Mediana Edad , Selección de Paciente , Pautas de la Práctica en Medicina , Sistema de Registros , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
OBJECTIVE: We compared variations among Canadian provinces in rheumatoid arthritis (RA) initiating anti-tumor necrosis factor (TNF) therapy. METHODS: Data were obtained from the Optimization of Humira trial (OH) and from the Ontario Biologics Research Initiative (OBRI). Baseline characteristics were compared between regions: Ontario (ON), Quebec (QC), and other provinces (OTH). We compared Ontario OH to OBRI patients who were initiating anti-TNF therapy. RESULTS: In 300 OH patients, mean age was 54.8 years (13.3). There were 151 (50.3%) ON patients, 57 from QC (19%), and 92 from OTH (30.7%). Regional differences were seen in the number of disease-modifying antirheumatic drugs (DMARD) ever taken (ON: 3.8 ± 1.4, QC: 3.1 ± 1.1, OTH: 3.3 ± 1.4; p < 0.001); swollen joint count (SJC; ON: 10.9 ± 5.9, QC: 9.0 ± 4.4, OTH: 11.3 ± 5.6; p = 0.033); tender joint count (TJC; ON: 12.2 ± 7.5, QC: 10.3 ± 5.7, OTH: 14.4 ± 7.6; p = 0.003); 28-joint Disease Activity Score (DAS28; ON: 5.8 ± 1.2, QC: 5.6 ± 1.0, OTH: 6.0 ± 1.1; p = 0.076); and Health Assessment Questionnaire (ON: 1.4 ± 0.7, QC: 1.7 ± 0.7, OTH: 1.5 ± 0.7; p = 0.060). DMARD-ever use differed: methotrexate (ON: 94.7%, QC: 93%, OTH: 84.8%; p = 0.025); leflunomide (ON: 74.8%, QC: 21.1%, OTH: 51.1%; p < 0.001); sulfasalazine (ON: 51%, QC: 38.6%, OTH: 25%; p < 0.001); myochrysine (ON: 9.3%, QC: 0%, OTH: 15.2%; p = 0.008); and hydroxychloroquine (ON: 67.5%, QC: 86%, OTH: 66.3%; p = 0.018). In comparison to ON OH patients, 95 OBRI patients initiating first anti-TNF had lower SJC (p = 0.017), TJC (p = 0.008), and DAS28 (p = 0.05). CONCLUSION: In Quebec, where access to anti-TNF is less restrictive, patients had lower SJC and TJC. ON used more DMARD, especially leflunomide, as mandated by the provincial government. Both provincial funding criteria and prescribing habits may contribute to differences. Canadian rheumatologists may vary in treatment decisions, but patients generally have similar DAS28 when initiating anti-TNF therapy.
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Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Anciano , Anticuerpos Monoclonales/economía , Antirreumáticos/economía , Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Canadá , Femenino , Humanos , Reembolso de Seguro de Salud , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema de Registros , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
RATIONALE: The toxicity of H2S has been attributed to its ability to inhibit cytochrome c oxidase in a similar manner to HCN. However, the successful use of methemoglobin for the treatment of HCN poisoning was not successful for H2S poisonings even though the ferric heme group of methemoglobin scavenges H2S. Thus, we speculated that other mechanisms contribute to H2S induced cytotoxicity. Experimental procedure. Hepatocyte isolation and viability and enzyme activities were measured as described by Moldeus et al. (1978), and Steen et al. (2001). RESULTS: Incubation of isolated hepatocytes with NaHS solutions (a H2S source) resulted in glutathione (GSH) depletion. Moreover, GSH depletion was also observed in TRIS-HCl buffer (pH 6.0) treated with NaHS. Several ferric chelators (desferoxamime and DETAPAC) and antioxidant enzymes (superoxide dismutase [SOD] and catalase) prevented cell-free and hepatocyte GSH depletion. GSH-depleted hepatocytes were very susceptible to NaHS cytotoxicity, indicating that GSH detoxified NaHS or H2S in cells. Cytotoxicity was also partly prevented by desferoxamine and DETAPC, but it was increased by ferric EDTA or EDTA. Cell-free oxygen consumption experiments in TRIS-HCl buffer showed that NaHS autoxidation formed hydrogen peroxide and was prevented by DETAPC but increased by EDTA. We hypothesize that H2S can reduce intracellular bound ferric iron to form unbound ferrous iron, which activates iron. Additionally, H2S can increase the hepatocyte formation of reactive oxygen species (ROS) (known to occur with electron transport chain). H2S cytotoxicity therefore also involves a reactive sulfur species, which depletes GSH and activates oxygen to form ROS.