Analysis of Synaptic Proteins in the Cerebrospinal Fluid as a New Tool in the Study of Inborn Errors of Neurotransmission

Abstract In a few rare diseases, specialised studies in cerebrospinal fluid (CSF) are required to identify the underlying metabolic disorder. We aimed to explore the possibility of detecting key synaptic proteins in the CSF, in particular dopaminergic and gabaergic, as new procedures that could be useful for both pathophysiological and diagnostic purposes in investigation of inherited disorders of neurotransmission. Dopamine receptor type 2 (D2R), dopamine transporter (DAT) and vesicular monoamine transporter type 2 (VMAT2) were analysed in CSF samplesfrom 30 healthy controls (11 days to 17 years) by western blot analysis. Because VMAT2 was the only protein with intracellular localisation, and in order to compare results, GABA vesicular transporter, which is another intracellular protein, was also studied. Spearman’s correlation and Student’s t tests were applied to compare optical density signals between different proteins. All these synaptic proteins could be easily detected and quantified in the CSF. DAT, D2R and GABA VT expression decrease with age, particularly in the first months of life, reflecting the expected intense synaptic activity and neuronal circuitry formation. A statistically significant relationship was found between D2R and DAT expression, reinforcing the previous evidence of DAT regulation by D2R. To our knowledge, there are no previous studies on human CSF reporting a reliable analysis of these proteins. These kinds of studies could help elucidate new causes of disturbed dopaminergic and gabaergic transmission as well as understanding different responses to L-dopa in inherited disorders affecting dopamine metabolism. Moreover, this approach to synaptic activity in vivo can be extended to different groups of proteins and diseases.

Atypical Case of Mediterranean Spotted Fever

The authors present a case of atypical severe (malignant) Mediterranean spotted fever, with a brief review on the subject. Although not previously described in Brazil, the possibility of imported cases, especially from Portuguese tourists, is real. This case report highlights the severe form of the disease and the possibility of atypical presentation with confounding differential diagnosis. A brief review of classical presentation is also done. The authors believe it is a valid paper and a good contribution to your Journal of Infectious Diseases. The content of the manuscript represents the views of the coauthors, and neither the corresponding author nor the coauthors have submitted duplicate or overlapping manuscripts elsewhere.

Amniocentesis in HIV Pregnant Women: 16 Years of Experience

The iatrogenic risk of HIV vertical transmission, calculated in initial epidemiologic studies, seemed to counterindicate invasive prenatal diagnosis (PND) procedures. The implementation of highly active antiretroviral therapy (HAART) represented a turning point in PND management, owing to a rapid and effective reduction of maternal viral load (VL). In the present study, we identified cases of vertical transmission in HIV-infected pregnant women who did amniocentesis in the second trimester of pregnancy (n = 27), from 1996 to 2011. We divided our sample into Group A--women under HAART when submitted to amniocentesis (n = 20) and Group B--women without antiretroviral therapy before amniocentesis (n = 7). We had 1 case of vertical transmission in Group B. Preconceptional or early first trimester HIV serology is essential to avoid performing an amniocentesis without antiretroviral therapy or viral suppression. When there is an indication for amniocentesis in an HIV-infected pregnant woman, it should be done if the patient is on HAART and, if possible, when VL is undetectable. Nowadays, with combined first trimester screening test to select pregnancies with high risk of aneuploidies, advanced maternal age is a less frequent indication to perform PND invasive procedures, representing an outstanding gain in prenatal diagnosis of this population.

Prognostic Value of VEGF in Patients Submitted to Percutaneous Coronary Intervention

We examined the longitudinal changes of VEGF levels after percutaneous coronary intervention for predicting major adverse cardiac events (MACE) in coronary artery disease (CAD) patients. VEGF was measured in 94 CAD patients' serum before revascularization, 1-month and 1-year after. Independently of clinical presentation, patients had lower VEGF concentration than a cohort of healthy subjects (median, IQ: 15.9, 9.0-264 pg/mL versus 419, 212-758 pg/mL; P < 0.001) at baseline. VEGF increased to 1-month (median, IQ: 276, 167-498 pg/mL; P < 0.001) and remained steady to 1-year (median, IQ: 320, 173-497 pg/mL; P < 0.001) approaching control levels. Drug eluting stent apposition and previous medication intake produced a less steep VEGF evolution after intervention (P < 0.05). Baseline VEGF concentration <40.8 pg/mL conveyed increased risk for MACE in a 5-year follow-up. Results reflect a positive role of VEGF in recovery and support its importance in CAD prognosis.

Analysis of Highly Conserved Regions of the 3'UTR of MECP2 Gene in Patients with Clinical Diagnosis of Rett Syndrome and Other Disorders Associated with Mental Retardation

In this work we explored the role of the 3'UTR of the MECP2 gene in patients with clinical diagnosis of RTT and mental retardation; focusing on regions of the 3'UTR with almost 100% conservation at the nucleotide level among mouse and human. By mutation scanning (DOVAM-S technique) the MECP2 3'UTR of a total of 66 affected females were studied. Five3'UTR variants in the MECP2 were found (c.1461+9G>A, c.1461+98insA, c.2595G>A, c.9961C>G and c.9964delC) in our group of patients. None of the variants found is located in putative protein-binding sites nor predicted to have a pathogenic role. Our data suggest that mutations in this region do not account for a large proportion of the RTT cases without a genetic explanation.

Caracterização da Utilização de Sugamadex no Centro Hospitalar de Lisboa Central - Hospital de S. José

Introdução O sugamadex é uma gama ciclodextrina modificada que forma um complexo com os bloqueadores neuromusculares rocurónio e vecurónio, revertendo o bloqueio neuromuscular (BNM) induzido por estes fármacos1,2,3,4. O sugamadex apresentou valor terapêutico acrescentado em relação aos anticolinesterásicos, nomeadamente à neostigmina, para a reversão do BNM causado pelo rocurónio e vecurónio1,3. No Hospital de São José (HSJ) este medicamento foi introduzido em Outubro de 2010 para a reversão do BNM profundo e nas situações de risco de vida imediato associadas a via aérea difícil com impossibilidade de ventilar e de entubar. A dispensa do sugamadex é efectuada por reposição de stock mediante envio de justificação clínica aos Serviços Farmacêuticos (SF). Objetivo Caracterizar a utilização de sugamadex no HSJ: evolução do consumo, serviços clínicos utilizadores e adequação da utilização clínica face às indicações aprovadas pela Comissão de Farmácia e Terapêutica (CFT). Métodos Pesquisa e análise bibliográfica. Recolha, através da do sistema de gestão integrada do circuito do medicamento, dos dados de consumo desde Outubro de 2010 até Junho de 2015, por semestre e por serviço clínico. Recolha das indicações terapêuticas em que o sugamadex foi administrado, no período acima referido, através da consulta das justificações clínicas. Análise retrospectiva dos dados recolhidos. Resultados Apresentação gráfica dos consumos de sugamadex nos serviços utilizadores no período em estudo. Apresentação gráfica das indicações terapêuticas em que foi administrado, por serviço e no período em estudo. Conclusões O consumo de sugamadex tem um evidente crescimento desde o seu início de utilização. A justificação dominante para a utilização do sugamadex é a curarização residual. Verifica-se um alargamento do âmbito de utilização, face às indicações aprovadas pela CFT. Decorridos cinco anos de utilização, justifica-se uma reavaliação das indicações de utilização no HSJ pela CFT. Bibliografia 1. Chambers D, Paulden M, Paton F, Heirs M, Duffy S, Craig D, et al. Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment. Health Technol Assess 2010;14(39). 2. De Boer HD, Van Egmond J, Driessen JJ, Booij LH. Update on the management of neuromuscular block: Focus on sugammadex. Neuropsychiatr Dis Treat 2007;3:539-44. 3. Relatório avaliação prévia de medicamento para uso humano em meio hospitalar – DCI – Sugamadex (06-05-2010) – Infarmed - acedido a 27/08/2015 www.infarmed.pt. 4. Resumo das Características do Medicamento Bridion® 100 mg/ml solução injectável - acedido a 27/08/2015 www.ema.europa.eu/.

Lights and Shadows about the Effectiveness of IVF in HIV Infected Women: A Systematic Review

Background. HIV infected women have higher rates of infertility. Objective. The purpose of this literature review is to evaluate the effectiveness of fresh IVF/ICSI cycles in HIV infected women. Materials and Methods. A search of the PubMed database was performed to identify studies assessing fresh nondonor oocyte IVF/ICSI cycle outcomes of serodiscordant couples with an HIV infected female partner. Results and Discussion. Ten studies met the inclusion criteria. Whenever a comparison with a control group was available, with the exception of one case, ovarian stimulation cancelation rate was higher and pregnancy rate (PR) was lower in HIV infected women. However, statistically significant differences in both rates were only seen in one and two studies, respectively. A number of noncontrolled sources of bias for IVF outcome were identified. This fact, added to the small size of samples studied and heterogeneity in study design and methodology, still hampers the performance of a meta-analysis on the issue. Conclusion. Prospective matched case-control studies are necessary for the understanding of the specific effects of HIV infection on ovarian response and ART outcome.

Undetectable Levels of CSF Amyloid-β Peptide in a Patient with 17β-Hydroxysteroid Dehydrogenase Deficiency

17β-hydroxysteroid dehydrogenase 10 (HSD10) deficiency is a rare X-linked inborn error of isoleucine catabolism. Although this protein has been genetically implicated in Alzheimer's disease pathogenesis, studies of amyloid-β peptide (Aβ) in patients with HSD10 deficiency have not been previously reported. We found, in a severely affected child with HSD10 deficiency, undetectable levels of Aβ in the cerebrospinal fluid, together with low expression of brain-derived neurotrophic factor, α-synuclein, and serotonin metabolites. Confirmation of these findings in other patients would help elucidating mechanisms of synaptic dysfunction in this disease, and highlight the role of Aβ in both early and late periods of life.

Rhinoscleroma in a 5-year-old Portuguese Child

Rhinoscleroma is a chronic granulomatous infectious disease that is rare in Western Europe. We report the case of a 5-year-old Portuguese boy diagnosed with rhinoscleroma in the context of recurrent epistaxis. He had a 6-month course of antibiotic (amoxicillin plus clavulanate) therapy with full recovery.

Anti-N-methyl-D-Aspartate Receptor Encephalitis with Positive Serum Antithyroid Antibodies, IgM Antibodies Against Mycoplasma Pneumoniae and Human Herpesvirus 7 PCR in the CSF

We report the case of a boy with an encephalopathy associated with extrapyramidal and psychiatric symptoms and anti-N-methyl-D-aspartate receptor antibodies. He had positive serum antithyroid antibodies, IgM antibodies against Mycoplasma pneumoniae and human herpesvirus 7 polymerase chain reaction in the cerebrospinal fluid. He was successfully treated with rituximab, after steroids, intravenous immunoglobulin and plasma exchange. The pathophysiology of this disorder may be post-infectious and autoimmune.

Severe Israeli Spotted Fever with Multiorgan Failure in a Child

An increased risk of severe and fatal Israeli spotted fever (ISF) has been observed in adults, mostly associated with ISF strain. Here, we report a case of severe ISF with multiorgan failure in a Portuguese child.

EULAR Recommendations for Women's Health and the Management of Family Planning, Assisted Reproduction, Pregnancy and Menopause in Patients with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

IL10 Low-Frequency Variants in Behçet's Disease Patients

To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility.