Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. METHODS: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 µg/L), 24 h urinary copper excretion (100-900 µg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 µg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting). FINDINGS: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 µg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 µg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 µg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 µg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 µg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 µg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy. INTERPRETATION: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease. FUNDING: Orphalan.

Small fiber dysfunction in patients with Wilson's disease / Disfunção de fibras finas em pacientes com doença de Wilson

Objective: Patients with Wilson’s disease (WD) may develop a wide variety of neuropsychiatric symptoms, but there are few reports of autonomic dysfunction. Here, we described evidence of small fiber and/or autonomic dysfunction in 4 patients with WD and levodopa-responsive parkinsonism. Method: We reviewed the charts of 4 patients with WD who underwent evaluation for the presence of neuromuscular dysfunction and water-induced skin wrinkling test (SWT). Results: Two men and 2 women (33±3.5 years) with WD were evaluated. They all had parkinsonism at some point during their disease course. Parkinsonism on patient 4 almost completely subsided with treatment of WD. Two patients had significant sensory and 2 significant autonomic complaints, including syncopal spells. NCS/EMG was normal in all but SWT was abnormal in half of them (mean 4-digit wrinkling of 0.25 and 1). Discussion: A subset of patients with WD exhibit evidence of abnormal skin wrinkling test (small fiber neuropathy). .

Objetivo: Pacientes com doença de Wilson (DW) podem desenvolver uma ampla variedade de sintomas neuropsiquiátricos, mas existem poucos relatos de disfunção autonômica. Aqui, nós descrevemos evidência de disfunção de fibras finas/autonômica em 4 pacientes com DW e parkinsonismo responsivo à levodopa. Método: Nós revisamos os prontuários de 4 pacientes com DW que foram submetidos a avaliação neuromuscular e ao teste de quantificação do enrugamento cutâneo (TEC). Resultados: Dois homens e 2 mulheres (33±3,5 anos) com DW foram avaliados. Todos apresentaram parkinsonismo durante o curso de sua doença. Parkinsonismo no paciente 4 quase completamente desapareceu com tratamento da DW. Dois pacientes apresentaram queixas sensitivas e 2 apresentaram queixas autonômicas significativas incluindo episódios de síncope. Eletroneuromiografia foi normal em todos e TEC foi anormal em metade deles (score do TEC nos 4 dedos de 0,25 e 1). Discussão: Um subgrupo de pacientes com DW apresenta evidência de TEC anormal (neuropatia de fibras finas). .

Small fiber dysfunction in patients with Wilson's disease.

OBJECTIVE: Patients with Wilson's disease (WD) may develop a wide variety of neuropsychiatric symptoms, but there are few reports of autonomic dysfunction. Here, we described evidence of small fiber and/or autonomic dysfunction in 4 patients with WD and levodopa-responsive parkinsonism. METHOD: We reviewed the charts of 4 patients with WD who underwent evaluation for the presence of neuromuscular dysfunction and water-induced skin wrinkling test (SWT). RESULTS: Two men and 2 women (33±3.5 years) with WD were evaluated. They all had parkinsonism at some point during their disease course. Parkinsonism on patient 4 almost completely subsided with treatment of WD. Two patients had significant sensory and 2 significant autonomic complaints, including syncopal spells. NCS/EMG was normal in all but SWT was abnormal in half of them (mean 4-digit wrinkling of 0.25 and 1). DISCUSSION: A subset of patients with WD exhibit evidence of abnormal skin wrinkling test (small fiber neuropathy).

Development and validation of the Intrinsic Religiousness Inventory (IRI).

OBJECTIVE: The role of religious involvement in mental health has been increasingly investigated in psychiatric research; however, there is a shortage of scales on religiousness in Portuguese. The present study aimed to develop and validate a brief instrument to assess intrinsic religiosity (Intrinsic Religiousness Inventory - IRI) in two Brazilian samples. METHOD: The initial version was based on literature review and experts' suggestions. University students (sample 1; n = 323) and psychiatric patients (sample 2; n = 102) completed the Duke Religiosity Index (DUREL), the IRI, an instrument of spirituality measurement (WHOQOL-SRPB), as well as measurements of anxiety and depressive symptoms. RESULTS: The IRI showed adequate internal consistence reliability in sample 1 (Cronbach's α = 0.96; 95% CI; 0.95-0.97) and sample 2 (α = 0.96; 95% CI; 0.95-0.97). The IRI main component analyses indicated a single factor, which explained 73.7% and 74.9% of variance in samples 1 and 2, respectively. Strong correlations between IRI and intrinsic subscale of the DUREL were observed (Spearman's r ranging from 0.87 to 0.73 in samples 1 and 2, respectively, p < 0.001). The IRI showed good test-retest reliability (intraclass correlation coefficients > 0.70). CONCLUSION: These data indicate that the IRI is a valid instrument and may contribute to study intrinsic religiosity in Brazilian samples.

Development and validation of the Intrinsic Religiousness Inventory (IRI) / Desenvolvimento e validação do Inventário de Religiosidade Intrínseca (IRI)

OBJECTIVE: The role of religious involvement in mental health has been increasingly investigated in psychiatric research; however, there is a shortage of scales on religiousness in Portuguese. The present study aimed to develop and validate a brief instrument to assess intrinsic religiosity (Intrinsic Religiousness Inventory - IRI) in two Brazilian samples. METHOD: The initial version was based on literature review and experts' suggestions. University students (sample 1; n = 323) and psychiatric patients (sample 2; n = 102) completed the Duke Religiosity Index (DUREL), the IRI, an instrument of spirituality measurement (WHOQOL-SRPB), as well as measurements of anxiety and depressive symptoms. RESULTS: The IRI showed adequate internal consistence reliability in sample 1 (Cronbach's α = 0.96; 95 percent CI; 0.95-0.97) and sample 2 (α = 0.96; 95 percent CI; 0.95-0.97). The IRI main component analyses indicated a single factor, which explained 73.7 percent and 74.9 percent of variance in samples 1 and 2, respectively. Strong correlations between IRI and intrinsic subscale of the DUREL were observed (Spearman's r ranging from 0.87 to 0.73 in samples 1 and 2, respectively, p < 0.001). The IRI showed good test-retest reliability (intraclass correlation coefficients > 0.70). CONCLUSION: These data indicate that the IRI is a valid instrument and may contribute to study intrinsic religiosity in Brazilian samples.

OBJETIVO: O papel da religiosidade em saúde mental vem sendo objeto de intensa investigação. Estudos devem ser executados em diferentes locais e culturas. O presente estudo objetiva desenvolver e validar um instrumento breve para mensurar religiosidade intrínseca (Inventário de Religiosidade Intrínseca - IRI) em duas amostras brasileiras. MÉTODO: A versão inicial foi baseada na revisão de literatura e em sugestões de especialistas. Estudantes universitários (amostra 1; n = 323) e pacientes psiquiátricos (amostra 2; n = 102) preencheram o Índice de Religiosidade de Duke (DUREL), o IRI, uma medida de espiritualidade (WHOQOL-SRPB), bem como medidas de sintomas ansiosos e depressivos. RESULTADOS: O IRI apresentou consistência interna adequada nas amostras 1 (α de Cronbach = 0,96; IC 95 por cento; 0,95-0,97) e 2 (α = 0,96; IC 95 por cento; 0,95-0,97). Análises de componentes principais indicaram um único fator que explicou 73,7 por cento e 74,9 por cento da variância nas amostras 1 e 2, respectivamente. Foram observadas fortes correlações entre o IRI e a subescala de religiosidade intrínseca da DUREL (r de Spearman de 0,87 a 0,73 nas amostras 1 e 2, respectivamente, p < 0,001). O IRI apresentou boa validade teste-reteste (coeficientes de correlação intraclasse > 0,70). CONCLUSÃO: Os dados indicam que o IRI é um instrumento válido e pode contribuir para estudar religiosidade intrínseca em amostras brasileiras.

Repeated cisplatin treatments inhibit gastrointestinal motility and induces baroreflex changes and mechanical hyperalgesia in rats.

Cisplatin is a chemotherapy agent known for its neurotoxicity. We evaluated the effect of cisplatin on the gastric emptying (GE), gastrointestinal (GI) transit of liquid, baroreflex function, thermal, and mechanical withdrawal latencies in rats. Cisplatin increased the GE of liquid with doses ≥ 2 mg.kg(-1) by 59.7-77.4%. This GE delay was not present two weeks after the treatment with five doses of cisplatin at 1 mg.kg(-1). Cisplatin also enhanced baroreflex gain possibly by increasing sympathetic activity. Our results demonstrated that cisplatin (2-10 mg.kg(-1)) causes autonomic neuropathy with GI and baroreflex changes and mechanical but not thermal hyperalgesia in rats.

On the spectrum of leprosy neuropathies: multifocal inflammatory neuropathy heralding leprosy relapse.

We report a 52 year-old woman with a past history of lepromatous leprosy (14 years prior to our first evaluation) who presented with progressive weakness and severe arm/leg pain. CSF analysis revealed elevated protein level with normal cell count. Skin and sural nerve biopsy showed no bacilli. Immunomodulatory treatment led to major improvement on clinical, CSF and electrodiagnostic grounds, but after one year of treatment, skin test revealed leprosy relapse. To our knowledge, this is the first report of a multifocal inflammatory neuropathy heralding leprosy relapse. Extended neurological work-up may be important in unexplained neuropathy progression after leprosy treatment.

Complicaçöes clínicas de injúrias medulares / Medical complications of spinal injuries

Lesöes medulares säo eventos catastróficos inesperados que acomentem anualmente milhares de indivíduos de todas as faixas etárias, determinando complicaçöes clínicas que persistiräo pelo restane de suas vidas. Com a melhoria da qualidade do atendimento , espera-se que em serviços especializados 94 por cento dos pacientes sobrevivam ao primeiro internamento hospitalar. O aumento da sobrevida, além da grande incidência de múltiplas complicaçöes (muitas delas restritas a tal grupo de pacientes, tais como hiperreflexia autonômica), aponta para a necessidade de uma maior divulgaçäo das peculiaridades fisiopatológicas a fim de possibilitar uma melhoria no manejo de tais pacientes. O objetivo do presente trabalho é revisar as complicaçöes clínicas imediatas e tardias das lesöes medulares