Metallothioneins as dynamic markers for brain disease in lysosomal disorders

Objective: To facilitate development of novel disease-modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, we sought to identify blood transcripts associated with the progression of MLD. Methods: Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative polymerase chain reaction platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in postmortem patient brains and in mouse models representing 6 other LSDs. Metallothionein expression during disease progression and in response to specific treatment was evaluated in 1 of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules. Results: Metallothionein genes were significantly overexpressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Overexpression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation, which are biochemical hallmarks of lysosomal storage diseases. Interpretation Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs

Relação do H. pylori com o desenvolvimento do câncer gástrico: revisão sistemática / Relationship of H. pylori to the development of gastric cancer: a systematic review

O presente trabalho teve por objetivo analisar a relação entre a infecção prévia por H. pylori com o desenvolvimento do câncer gástrico por meio de uma revisão sistemática. Foi feita uma busca eletrônica de artigos científicos publicados nas bases de dados Scielo, Science Direct e Medline utilizando as seguintes combinações de palavras-chave “gastric cancer associated with H. pylori”, “development of cancer by H. pylori”, “H. pylori”, “Helicobacter pylori”, “Helicobacter infections”, “stomach cancer”  “gastric cancer”, “gastric”, “gastric adenocarcinoma”, “peptic ulcer” e “gastric neoplasm” e posteriormente foi aplicado os critérios de inclusão e exclusão sendo selecionados quinze artigos publicados entre o período de 2000 e 2021. Dos 15 artigos selecionados, 11 (73,3%) estudos confirmam que a bactéria está associada diretamente ao desenvolvimento do câncer gástrico, sendo que do restante 2 (13,3%) estudos associam a bactéria com a gastrite atrófica, metaplasia e a displasia, porém, indicam que a atuação dela ocorre de maneira indireta quando relacionada ao câncer gástrico e 2 (13,3%) estudos não estabelecem a relação da bactéria com o desenvolvimento do câncer. Conclui-se que H. pylori está relacionado ao desenvolvimento do câncer gástrico em 86,7% dos estudos, enquanto os 13,3% que não estabelecem a relação

Avaliação do perfil epidemiológico da sífilis gestacional e congênita no estado de Goiás e a participação do profissional da enfermagem

Objetivo: analisar a incidência da sífilis nas gestantes no Estado de Goiás entre os anos de 2016-2020, para que possamos mensurar o impacto da sífilis gestacional sob a perspectiva do perfil epidemiológico. Metodologia: Trata-se de um estudo observacional quantitativo descritivo retrospectivo, no qual foi analisado o perfil epidemiológico dos casos de sífilis confirmados em gestantes a partir dos dados conferidos pelo Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis (DCCI) a partir do Sistema de Informação de Agravos de Notificação (SINAN). A população estudada evidencia os casos confirmados e notificados no Estado de Goiás entre 2016 e 2020. Resultados: O presente estudo evidencia dados epidemiológicos sobre a sífilis gestacional e congênita no Estado de Goiás, com um total de 643.872 casos no Brasil e 7.456 apenas no Estado de Goiás. A faixa etária mais acometida, 52,9% foi entre 20 e 29 anos, sendo o diagnóstico feito durante o pré-natal (61,22%) ou apenas no momento do parto. A antibioticoterapia a base de penicilina foi o método mais utilizado para o esquema de tratamento para gestantes com sífilis. Conclusão: Observou-se no presente estudo que os casos de sífilis no Estado de Goiás estão associados a fatores como: condições socioeconômicas e qualidade na assistência de saúde; gestantes com baixa escolaridade estão mais suscetíveis a desenvolver sífilis gestacional devido à falta de informações sobre a prevenção das IST’s, o que gera uma baixa adesão ao pré-natal, não tratamento das parcerias, reinfecção e infecção transplacentária, sendo estes, graves problemas de saúde pública. A assistência ao pré-natal, sendo um momento importantíssimo para detecção e tratamento precoce desses casos, apresenta lacunas através das vulnerabilidades da própria mulher e até mesmo dos programas no sistema de saúde

Use, tolerability, benefits and side effects of orthotic devices in Charcot-Marie-Tooth disease

Background: Shoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty. Methods: We administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services. Results: We analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs' tolerability. Quality of professional and follow-up services were perceived issues. Conclusions: The majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged

A Recent Class of Chemosensory Neurons Developed in Mouse and Rat

In most animal species, the vomeronasal organ ensures the individual recognition of conspecifics, a prerequisite for a successful reproduction. The vomeronasal organ expresses several receptors for pheromone detection. Mouse vomeronasal type-2 receptors (V2Rs) are restricted to the basal neurons of this organ and organized in four families. Family-A, B and D (family ABD) V2Rs are expressed monogenically (one receptor per neuron) and coexpress with either Vmn2r1 or Vmn2r2, two members of family-C V2Rs. Thus, basal neurons are characterized by specific combinations of two V2Rs. To investigate this issue, we raised antibodies against all family-C V2Rs and analyzed their expression pattern. We found that six out of seven family-C V2Rs (Vmn2r2-7) largely coexpressed and that none of the anti-Vmn2r2-7 antibodies significantly stained Vmn2r1 positive neurons. Thus, basal neurons are divided into two complementary subsets. The first subset (Vmn2r1-positive) preferentially coexpresses a distinct group of family-ABD V2Rs, whereas the second subset (Vmn2r2-7-positive) coexpresses the remaining group of V2Rs. Phylogenetic reconstruction and the analysis of genetic loci in various species reveal that receptors expressed by this second neuronal subset are recent branches of the V2R tree exclusively present in mouse and rat. Conversely, V2Rs expressed in Vmn2r1 positive neurons, are phylogenetically ancient and found in most vertebrates including rodents. Noticeably, the more recent neuronal subset expresses a type of Major Histocompatibility Complex genes only found in murine species. These results indicate that the expansion of the V2R repertoire in a murine ancestor occurred with the establishment of a new population of vomeronasal neurons in which coexists the polygenic expression of a recent group of family-C V2Rs (Vmn2r2-7) and the monogenic expression of a recent group of family-ABD V2Rs. This evolutionary innovation could provide a molecular rationale for the exquisite ability in individual recognition and mate choice of murine species

Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells

Recent evidence indicates that hematopoietic stem and progenitor cells (HSPCs) can serve as vehicles for therapeutic molecular delivery to the brain by contributing to the turnover of resident myeloid cell populations. However, such engraftment needs to be fast and efficient to exert its therapeutic potential for diseases affecting the central nervous system. Moreover, the nature of the cells reconstituted after transplantation and whether they could comprise bona fide microglia remain to be assessed. We demonstrate that transplantation of HSPCs in the cerebral lateral ventricles provides rapid engraftment of morphologically, antigenically, and transcriptionally dependable microglia-like cells. We show that the cells comprised within the hematopoietic stem cell compartment and enriched early progenitor fractions generate this microglia-like population when injected in the brain ventricles in the absence of engraftment in the bone marrow. This delivery route has therapeutic relevance because it increases the delivery of therapeutic molecules to the brain, as shown in a humanized animal model of a prototypical lysosomal storage disease affecting the central nervous system

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Hematopoietic stem and progenitor cells (HSPCs) can establish a long-lasting microglia-like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses due to palmitoyl-protein thioesterase-1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild-type HSPCs exerts partial but long-lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over-expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs transplant, with first demonstration of such a dose-effect benefit for a purely neurodegenerative condition like CLN1 disease; (iii) transplantation of hPPT1 over-expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1-symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals. Overall, these findings provide first evidence of efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application