RESUMO
Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
Assuntos
Ciclo-Oxigenase 1 , Complexo IV da Cadeia de Transporte de Elétrons , Inflamação , Fígado , Fosforilação Oxidativa , Espécies Reativas de Oxigênio , Animais , Feminino , Humanos , Masculino , Camundongos , Proteína DEAD-box 58 , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Inflamação/metabolismo , Inflamação/genética , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Mutação , Biossíntese de Proteínas , Espécies Reativas de Oxigênio/metabolismo , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismoRESUMO
Correction for 'Time-, space- and energy-resolved in situ characterization of catalysts by X-ray absorption spectroscopy' by Stefan Peters et al., Chem. Commun., 2023, 59, 12120-12123, https://doi.org/10.1039/D3CC03277A.
RESUMO
A setup for dispersive X-ray absorption spectroscopy (XAS) with spatial, temporal and energy resolution is presented. Through investigation of a Mo/HZSM-5 catalyst during the dehydroaromatization of methane we observed a reduction gradient along the packed bed. Our new method represents an unprecedented addition to the analytical toolbox for in situ characterizations.
RESUMO
Mitochondrial defects are associated with aging processes and age-related diseases, including cardiovascular diseases, neurodegenerative diseases and cancer. In addition, some recent studies suggest mild mitochondrial dysfunctions appear to be associated with longer lifespans. In this context, liver tissue is considered to be largely resilient to aging and mitochondrial dysfunction. Yet, in recent years studies report dysregulation of mitochondrial function and nutrient sensing pathways in ageing livers. Therefore, we analyzed the effects of the aging process on mitochondrial gene expression in liver using wildtype C57BL/6N mice. In our analyses, we observed alteration in mitochondrial energy metabolism with age. To assess if defects in mitochondrial gene expression are linked to this decline, we applied a Nanopore sequencing based approach for mitochondrial transcriptomics. Our analyses show that a decrease of the Cox1 transcript correlates with reduced respiratory complex IV activity in older mice livers.
Assuntos
Envelhecimento , Fígado , Camundongos , Animais , Camundongos Endogâmicos C57BL , Envelhecimento/genética , Expressão Gênica , Perfilação da Expressão GênicaRESUMO
Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.
RESUMO
This contribution provides a comprehensive mechanistic picture of the gold nanoparticle synthesis by citrate reduction of HAuCl4, known as Turkevich method, by addressing five key questions. The synthesis leads to monodisperse final particles as a result of a seed-mediated growth mechanism. In the initial phase of the synthesis, seed particles are formed onto which the residual gold is distributed during the course of reaction. It is shown that this mechanism is a fortunate coincidence created by a favorable interplay of several chemical and physicochemical processes which initiate but also terminate the formation of seed particles and prevent the formation of further particles at later stages of reaction. Since no further particles are formed after seed particle formation, the number of seeds defines the final total particle number and therefore the final size. The gained understanding allows illustrating the influence of reaction conditions on the growth process and thus the final size distribution.
RESUMO
In organ transplantation, placebo-controlled clinical trials are not possible for ethical reasons, and hence non-inferiority trials are used to evaluate new drugs. Patients with a transplanted kidney typically receive three to four immunosuppressant drugs to prevent organ rejection. In the described case of a non-inferiority trial for one of these immunosuppressants, the dose is changed, and another is replaced by an investigational drug. This test regimen is compared with the active control regimen. Justification for the non-inferiority margin is challenging as the putative placebo has never been studied in a clinical trial. We propose the use of a random-effect meta-regression, where each immunosuppressant component of the regimen enters as a covariate. This allows us to make inference on the difference between the putative placebo and the active control. From this, various methods can then be used to derive the non-inferiority margin. A hybrid of the 95/95 and synthesis approach is suggested. Data from 51 trials with a total of 17,002 patients were used in the meta-regression. Our approach was motivated by a recent large confirmatory trial in kidney transplantation. The results and the methodological documents of this evaluation were submitted to the Food and Drug Administration. The Food and Drug Administration accepted our proposed non-inferiority margin and our rationale.
Assuntos
Transplante de Rim/estatística & dados numéricos , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa/estatística & dados numéricos , Teorema de Bayes , Intervalos de Confiança , Grupos Controle , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Drogas em Investigação/farmacologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Funções Verossimilhança , Metanálise como Assunto , Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration/estatística & dados numéricosRESUMO
OBJECTIVES: Noncontact mapping has been demonstrated to facilitate RF ablation of ventricular arrhythmias, but the reproducibility in the localization of endocardial exit sites during focal ventricular tachycardia ("VT") originating from defined myocardial layers has not been systematically studied. Furthermore, it remains unclear whether noncontact mapping can distinguish between endo- and epicardial foci. METHODS: In six dogs, constant pacing was applied through octopolar needle electrodes in the left ventricle to mimic VT of subendocardial, midmyocardial (mid1; mid2) or subepicardial origin. Using noncontact mapping, the site of origin was determined for each of 50 consecutive beats of all "VTs" and the variation between respective exit sites was measured. Exit sites were reconstructed for 50 consecutive beats of each "VT" and the time span between site of origin and exit site was measured as a parameter of intramural conduction. RESULTS: While subendocardial and midmyocardial (mid1, mid2) foci were pinpointed with a variation of Assuntos
Mapeamento Potencial de Superfície Corporal/métodos
, Endocárdio/fisiopatologia
, Sistema de Condução Cardíaco/fisiopatologia
, Pericárdio/fisiopatologia
, Taquicardia Ventricular/diagnóstico
, Taquicardia Ventricular/fisiopatologia
, Animais
, Cães
, Feminino
, Masculino
, Reprodutibilidade dos Testes
, Sensibilidade e Especificidade
RESUMO
BACKGROUND: Chloroquine (CQ) resistance has reached high levels in Africa in recent years. Little is known about variations of resistance between urban and rural areas. OBJECTIVES: To compare the rates of in vivo resistance to CQ and the prevalences of the main molecular marker for CQ resistance among young children from urban and rural areas in Burkina Faso. METHODS: The current analysis used the frame of a randomized controlled trial (ISRCTN27290841) on the combination CQ-methylene blue (MB) (n=177) compared to CQ alone (n=45) in young children with uncomplicated malaria. We examined clinical and parasitological failure rates as well as the prevalence of the Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) T76 mutation. RESULTS: Clinical and parasitological failure rates of CQ-MB differed significantly between urban (70%) and rural areas (29%, p<0.0001). Likewise, CQ failure rates were higher in the urban setting. Matching this pattern, pfcrt T76 was more frequently seen among parasite strains from urban areas (81%) when compared to rural ones (64%, p=0.01). In the presence of parasites exhibiting pfcrt T76, the odds of overall clinical failure were increased to 2.6-fold ([1.33, 5.16], p(LR)=0.005). CQ was detected at baseline in 21% and 2% of children from the urban and the rural study area, respectively (p(Chi)=0.002). CONCLUSION: Even within circumscribed geographical areas, CQ efficacy can vary dramatically. The differences in the prevalence of pfcrt T76 and in CQ failure rates are probably explained by a higher drug pressure in the urban area compared to the rural study area. This finding has important implications for national malaria policies.
Assuntos
Cloroquina/farmacologia , Resistência a Medicamentos/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Burkina Faso , Pré-Escolar , Cloroquina/uso terapêutico , Humanos , Lactente , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Plasmodium falciparum/isolamento & purificação , Mutação Puntual , Proteínas de Protozoários/genética , População Rural , Resultado do Tratamento , População UrbanaRESUMO
BACKGROUND AND PURPOSE: Decompressive surgery (hemicraniectomy) for life-threatening massive cerebral infarction represents a controversial issue in neurocritical care medicine. We report here the 30-day mortality and 6- and 12-month functional outcomes from the DESTINY trial. METHODS: DESTINY (ISRCTN01258591) is a prospective, multicenter, randomized, controlled, clinical trial based on a sequential design that used mortality after 30 days as the first end point. When this end point was reached, patient enrollment was interrupted as per protocol until recalculation of the projected sample size was performed on the basis of the 6-month outcome (primary end point=modified Rankin Scale score, dichotomized to 0 to 3 versus 4 to 6). All analyses were based on intention to treat. RESULTS: A statistically significant reduction in mortality was reached after 32 patients had been included: 15 of 17 (88%) patients randomized to hemicraniectomy versus 7 of 15 (47%) patients randomized to conservative therapy survived after 30 days (P=0.02). After 6 and 12 months, 47% of patients in the surgical arm versus 27% of patients in the conservative treatment arm had a modified Rankin Scale score of 0 to 3 (P=0.23). CONCLUSIONS: DESTINY showed that hemicraniectomy reduces mortality in large hemispheric stroke. With 32 patients included, the primary end point failed to demonstrate statistical superiority of hemicraniectomy, and the projected sample size was calculated to 188 patients. Despite this failure to meet the primary end point, the steering committee decided to terminate the trial in light of the results of the joint analysis of the 3 European hemicraniectomy trials.
Assuntos
Craniotomia , Descompressão Cirúrgica/estatística & dados numéricos , Infarto da Artéria Cerebral Média/cirurgia , Acidente Vascular Cerebral/cirurgia , Adulto , Feminino , Humanos , Infarto da Artéria Cerebral Média/mortalidade , Infarto da Artéria Cerebral Média/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Pericard 6 (P6) is one of the most frequently used acupuncture points, especially in preventing nausea and vomiting. At this point, the median nerve is located very superficially. OBJECTIVES: To investigate the distance between the needle tip and the median nerve during acupuncture at P6, we conducted a prospective observational ultrasound (US) imaging study. We tested the hypothesis that de qi (a sensation that is typical of acupuncture needling) is evoked when the needle comes into contact with the epineural tissue and thereby prevents nerve penetration. SETTINGS/LOCATION: The outpatient pain clinic of the Medical University of Vienna, Austria. SUBJECTS: Fifty (50) patients receiving acupuncture treatment including P6 bilaterally. INTERVENTIONS: Patients were examined at both forearms using US (a 10-MHz linear transducer) after insertion of the needle at P6. OUTCOME MEASURES: The distance between the needle tip and the median nerve, the number of nerve contacts and nerve penetrations, as well as the number of successfully elicited de qi sensations were recorded. RESULTS: Complete data could be obtained from 97 cases. The mean distance from the needle tip to the nerve was 1.8 mm (standard deviation 2.2; range 0-11.3). Nerve contacts were recorded in 52 cases, in 14 of which the nerve was penetrated by the needle. De qi was elicited in 85 cases. We found no association between the number of nerve contacts and de qi. The 1-week follow-up showed no complications or neurologic problems. CONCLUSIONS: This is the first investigation demonstrating the relationship between acupuncture needle placement and adjacent neural structures using US technology. The rate of median nerve penetrations by the acupuncture needle at P6 was surprisingly high, but these seemed to carry no risk of neurologic sequelae. De qi at P6 does not depend on median nerve contact, nor does it prevent median nerve penetration.
Assuntos
Terapia por Acupuntura/instrumentação , Antebraço/diagnóstico por imagem , Antebraço/inervação , Nervo Mediano/diagnóstico por imagem , Agulhas , Pontos de Acupuntura , Terapia por Acupuntura/métodos , Adulto , Áustria , Feminino , Humanos , Masculino , Qi , Valores de Referência , Projetos de Pesquisa , UltrassonografiaRESUMO
The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.
Assuntos
Cloroquina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Azul de Metileno/administração & dosagem , Azul de Metileno/uso terapêutico , Burkina Faso/epidemiologia , Pré-Escolar , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Lactente , Malária Falciparum/epidemiologia , Masculino , Azul de Metileno/efeitos adversos , Distribuição Aleatória , Falha de TratamentoRESUMO
BACKGROUND: In the nationwide German Acupuncture Trials (GERAC), verum acupuncture, mirroring the Traditional Chinese Medicine (TCM) acupuncture style, was tested against sham acupuncture and guideline standard therapy for the entities classified in the West as chronic low back pain (LBP) and gonarthrosis (GON). OBJECTIVE: The objective was to develop broadly consensual acupuncture and control protocols for the treatment of LBP and GON in the GERAC trials. METHODOLOGY: Extensive literature study and consultation with acupuncture experts were consulted. Personal interviews, both free and structured, e-mail discussions, and phone conferences were used as well. RESULTS: Broadly consensual acupuncture protocols for LBP and GON for verum and invasive sham acupuncture were developed. They included semistandardized point combinations with clearly described point selection rules based on TCM acupuncture diagnosis. A procedure was developed to help ensure homogenous treatment quality in a large multicenter trial. CONCLUSIONS: With 1162 randomized patients for LBP and 1039 patients for GON, the GERAC study design allowed acupuncture to be tested in a naturalistic environment. The rigorous study design and large number of physician investigators guaranteed a high external validity for the results. The results will help determine the significance of Chinese acupuncture in the context of Western medicine for the treatment of LBP and GON.
Assuntos
Terapia por Acupuntura/normas , Procedimentos Clínicos/organização & administração , Dor Lombar/terapia , Osteoartrite do Joelho/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Pontos de Acupuntura , Medicina Baseada em Evidências/normas , Feminino , Alemanha , Humanos , Masculino , Estudos Multicêntricos como Assunto/normas , Guias de Prática Clínica como Assunto/normas , Projetos de Pesquisa , Resultado do TratamentoRESUMO
Recall is an active reconstruction process likely to distort past experiences. This distortion, known as recall bias, seems to manifest itself differently in sick and healthy people. A recall bias has been documented in several disorders, but never investigated in borderline personality disorder (BPD). To determine recall bias in BPD, we assessed momentary and retrospective ratings of specific emotions in 50 patients with BPD and 50 healthy controls (HCs), using the methodology of 24-hour ambulatory monitoring. Our data reveal a group-specific valence-dependent recall bias of retrospective self-report, indicated by a different overall recall pattern in HCs and BPD. BPD patients show an overall negative recall pattern, whereas HCs show a positive recall pattern. A traditional questionnaire approach does not distinguish between symptoms of the disorder and recall bias, although the pathological mechanisms underlying them as well as the appropriate treatment strategies may be different.
Assuntos
Transtorno da Personalidade Borderline/diagnóstico , Emoções , Rememoração Mental , Inquéritos e Questionários , Afeto , Viés , Transtorno da Personalidade Borderline/psicologia , Diagnóstico Diferencial , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Nível de Saúde , Humanos , Monitorização Ambulatorial , PsicometriaRESUMO
BACKGROUND: Despite the popularity of acupuncture, evidence of its efficacy for reducing pain remains equivocal. OBJECTIVE: To assess the efficacy and safety of traditional Chinese acupuncture (TCA) compared with sham acupuncture (needling at defined nonacupuncture points) and conservative therapy in patients with chronic pain due to osteoarthritis of the knee. DESIGN: Randomized, controlled trial. SETTING: 315 primary care practices staffed by 320 practitioners with at least 2 years' experience in acupuncture. PATIENTS: 1007 patients who had had chronic pain for at least 6 months due to osteoarthritis of the knee (American College of Rheumatology [ACR] criteria and Kellgren-Lawrence score of 2 or 3). INTERVENTIONS: Up to 6 physiotherapy sessions and as-needed anti-inflammatory drugs plus 10 sessions of TCA, 10 sessions of sham acupuncture, or 10 physician visits within 6 weeks. Patients could request up to 5 additional sessions or visits if the initial treatment was viewed as being partially successful. MEASUREMENTS: Success rate, as defined by at least 36% improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 26 weeks. Additional end points were WOMAC score and global patient assessment. RESULTS: Success rates were 53.1% for TCA, 51.0% for sham acupuncture, and 29.1% for conservative therapy. Acupuncture groups had higher success rates than conservative therapy groups (relative risk for TCA compared with conservative therapy, 1.75 [95% CI, 1.43 to 2.13]; relative risk for sham acupuncture compared with conservative therapy, 1.73 [CI, 1.42 to 2.11]). There was no difference between TCA and sham acupuncture (relative risk, 1.01 [CI, 0.87 to 1.17]). LIMITATIONS: There was no blinding between acupuncture and traditional therapy and no monitoring of acupuncture compliance with study protocol. In general, practitioner-patient contacts were less intense in the conservative therapy group than in the TCA and sham acupuncture groups. CONCLUSIONS: Compared with physiotherapy and as-needed anti-inflammatory drugs, addition of either TCA or sham acupuncture led to greater improvement in WOMAC score at 26 weeks. No statistically significant difference was observed between TCA and sham acupuncture, suggesting that the observed differences could be due to placebo effects, differences in intensity of provider contact, or a physiologic effect of needling regardless of whether it is done according to TCA principles.
Assuntos
Terapia por Acupuntura , Anti-Inflamatórios/uso terapêutico , Osteoartrite do Joelho/complicações , Manejo da Dor , Modalidades de Fisioterapia , Terapia por Acupuntura/efeitos adversos , Adulto , Anti-Inflamatórios/efeitos adversos , Doença Crônica , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Cooperação do Paciente , Modalidades de Fisioterapia/efeitos adversos , Estudos Prospectivos , Método Simples-CegoRESUMO
Glucose-6-phosphate dehydrogenase (G6PD) deficient individuals are at increased risk of developing haemolysis following treatment with various antimalarial drugs. Reliable field tests for G6PD deficiency are thus needed in chemotherapy studies and their validity has to be assessed. In two phase II clinical trials on methylene blue (MB) antimalarial therapy in rural Burkina Faso, paediatric and adult participants were tested for G6PD deficiency. The results of a haemoglobin-adjusted nicotinamide adenine dinucleotide phosphate (NADPH) fluorescence test on paper (NFP test) were compared with polymerase chain reaction (PCR)-based G6PD genotyping also using blood samples on filter papers. This is the first study comparing sensitivity and specificity of the two methods. There was good agreement between the NFP test results and the PCR findings. The estimate of the sensitivity of the NFP test was 98.2% (95.8-99.6%) and the specificity was 97.1% (94.2-99.2%). In conclusion, the NFP assay is a reliable and inexpensive method for large-scale G6PD deficiency screening in rural West Africa.
Assuntos
Países em Desenvolvimento , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Adolescente , Adulto , Idoso , Burkina Faso , Ensaios Enzimáticos Clínicos/métodos , Eritrócitos/enzimologia , Glucosefosfato Desidrogenase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Saúde da População Rural , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. OBJECTIVES: The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. METHODS: In this hospital-based randomized controlled trial, 226 children (6-59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. RESULTS: No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. CONCLUSION: MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.
Assuntos
Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Azul de Metileno/efeitos adversos , Azul de Metileno/uso terapêutico , Burkina Faso , Pré-Escolar , Quimioterapia Combinada , Doença de Depósito de Glicogênio Tipo I , Humanos , LactenteRESUMO
INTRODUCTION: The herbal medicinal product kava-kava, used for treating anxiety disorders, was assessed positively by the Cochrane Review. However, it was withdrawn from the market in Switzerland and Germany due to cases of liver failure and 'unproven' efficacy. METHODS: A protocol for the meta-analysis based on patient source data was written, a literature search was done, and six placebo-controlled, randomized trials with the kava extract WS1490 were identified. The endpoints were the change in HAMA during treatment (continuous and binary). RESULTS: WS1490 has an effective success rate of OR=3.3 (95% confidence interval of 2.09-5.22) in patients with non-psychotic anxiety disorders. The continuous outcome supports this result: mean improvement with WS1490 by 5.94 (95% confidence interval -0.86 to 12.8) points on the HAMA scale better than placebo. Kava seems to be more effective in females and in younger patients. DISCUSSION: This meta-analysis has no publication bias, no remarkable heterogeneity and is based on trials with high methodological standards. It is concluded that WS1490, and possibly other kava extracts, are effective. Therefore they remain alternatives to benzodiazepines, selective serotonin re-uptake inhibitors (SSRIs) and other antidepressants in the treatment of non-psychotic anxiety disorders.
Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Kava , Fitoterapia , Extratos Vegetais/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz (EFV) and nevirapine (NVP) taken in combination with nucleoside reverse transcriptase inhibitors (NRTIs) have both shown to be just as highly effective as protease inhibitors (PIs) in reducing viral load in patients infected with HIV. Our study compares the performance of these two NNRTIs with each other. This was a non-randomized, prospective, two-arm, multi-centre trial. We evaluated all patients with an EFV- or NVP-containing antiretroviral regimen. The primary endpoint was the difference in success rates defined as a viral load of =50 copies/mL at week 48. chi(2)-tests were used for naïve and pretreated patients using intention-to-treat (ITT) and on-treatment analysis. As secondary endpoints, a viral load of =500 copies/mL and CD4 count at week 48 for naïve patients were evaluated. A Cox regression was used to adjust for prespecified covariates. We included 662 patients (NVP 337, EFV 325). The difference in success rates in the ITT analysis was 4.5% ( -11.5%, 19.0%), P=0.578. Pretreated patients with a triple therapy show a difference of 10.1 (-0.3, 20.6), P=0.056. Non-significant results appeared for all secondary analyses. In this trial, no difference between EFV and NVP in combination with NRTI backbone therapy can be shown, regarding viral load. Further randomized studies are necessary to evaluate possible differences.
Assuntos
Infecções por HIV/tratamento farmacológico , Nevirapina/uso terapêutico , Oxazinas/uso terapêutico , Alcinos , Benzoxazinas , Ciclopropanos , Quimioterapia Combinada , Feminino , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Masculino , Nevirapina/administração & dosagem , Oxazinas/administração & dosagem , Estudos Prospectivos , Carga ViralRESUMO
New drug combinations against falciparum malaria which are both effective and affordable for Sub-Saharan African populations are urgently needed. The combination of the well-known drugs chloroquine (CQ) and methylene blue (MB) is such a promising new regimen. However, there is some concern that MB could cause development of haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition which is prevalent in malaria-endemic regions. Against this background, 74 G6PD-deficient but otherwise healthy adult men were given a 3-day oral regimen of a total of 1500 mg CQ and 780 mg MB in the District Hospital of Nouna in north-western Burkina Faso. Haemolysis did not occur, haemoglobin levels remained stable or even rose in the study participants, and the drug regimen was well tolerated. Therefore, standard dosages of MB appear to be safe in G6PD-deficient African populations with predominantly class III G6PD deficiency.