Treatment of hereditary hypotrichosis simplex of the scalp with topical gentamicin.

BACKGROUND: Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid-like material, which interferes with normal hair follicle cycle. OBJECTIVES: As gentamicin has been shown to mediate ribosomal read-through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN . METHODS: We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read-through across a causative CDSN mutation. RESULTS: Using a reporter assay, we initially showed that gentamicin induces read-through activity across an HSS-causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score. CONCLUSIONS: Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin. The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis. Disorders caused by nonsense mutations are amenable to ribosomal read-through using gentamicin. What does this study add? Gentamicin enhanced read-through activity and promoted full-length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN. Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS.

A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN.

BACKGROUND: Dowling-Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ-secretase subunit protein presenilin enhancer. OBJECTIVES: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS. METHODS: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. RESULTS: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. CONCLUSIONS: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.

Segmental basal cell naevus syndrome caused by an activating mutation in smoothened.

Aberrant sonic hedgehog signalling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in basal cell naevus syndrome (BCNS). Mutations in smoothened (SMO) encoding a receptor for sonic hedgehog have been reported in sporadic BCCs but not in BCNS. We report a case with multiple BCCs, pits and comedones in a segmental distribution over the upper part of the body, along with other findings compatible with BCNS. Histopathologically, there were different types of BCC. A heterozygous mutation (c.1234C>T, p.L412F) in SMO was detected in three BCCs but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with the type 1 mosaic form of BCNS. The p.L412F mutation was found experimentally to result in increased SMO transactivating activity, and the patient responded to vismodegib therapy. Activating mutations in SMO may cause BCNS. The identification of a gain-of-function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC, with implications for the treatment of these tumours, whether sporadic or inherited.

Hantavirus pulmonary syndrome in a highly endemic area of Brazil.

Hantavirus pulmonary syndrome (HPS) is the most frequently reported fatal rodent-borne disease in Brazil, with the majority of cases occurring in Santa Catarina. We analysed the clinical, laboratory and epidemiological data of the 251 confirmed cases of HPS in Santa Catarina in 1999-2011. The number of cases ranged from 10 to 47 per year, with the highest incidences in 2004-2006. Gastrointestinal tract manifestations were found in >60% of the cases, potentially confounding diagnosis and leading to inappropriate therapy. Dyspnoea, acute respiratory failure, renal failure, increased serum creatinine and urea levels, increased haematocrits and the presence of pulmonary interstitial infiltrate were significantly more common in HPS patients who died. In addition, we demonstrated that the six cases from the midwest region of the state were associated with Juquitiba virus genotype. The case-fatality rate in this region, 19·2%, was lower than that recorded for other mesoregions. In the multivariate analysis increase of serum creatinine and urea was associated with death by HPS. Our findings help elucidate the epidemiology of HPS in Brazil, where mast seeding of bamboo can trigger rodent population eruptions and subsequent human HPS outbreaks. We also emphasize the need for molecular confirmation of the hantavirus genotype of human cases for a better understanding of the mortality-related factors associated with HPS cases in Brazil.

Problemas associados ao uso de plantas medicinais comercializadas no Mercadão de Madureira, município do Rio de Janeiro, Brasil / Problems associated with the use of medicinal plants commercialized in "Mercadão de Madureira", Rio de Janeiro City, Brazil

O uso de plantas medicinais pela população brasileira é prática tradicional, sendo muitas vezes o único recurso utilizado na atenção básica de saúde. O uso terapêutico dessas plantas envolve várias etapas da cadeia produtiva, sendo a procedência, coleta, secagem, armazenamento, comércio, modo de preparo pelo usuário e uso. O objetivo desse trabalho documental, de caráter exploratório, foi levantar a produção científica existente sobre os problemas associados a cada uma dessas etapas e discutir as questões relacionadas à carência de estudos para comprovar a eficácia farmacológica e a ausência de riscos toxicológicos, bem como a prática de autodiagnóstico. As vinte plantas mais comercializadas em grande mercado do município do Rio de Janeiro em agosto de 2007 serviram de base para o levantamento documental do presente estudo. Dessas, seis apresentaram propriedades tóxicas comprovadas dependendo do preparo e uso, a arnica (Solidago chilensis Meyen), aroeira (Shinus terebinthifolius Raddi.), arruda (Ruta graveolens L.), babosa (Aloe vera L.), confrei (Symphytum officinale L.) e poejo (Mentha pulegium Lam. & DC.). A Agência Nacional de Vigilância Sanitária aponta contra indicações para boldo-do-Chile (Peumus boldus Molina), chapéu-de-couro (Echinodorus macrophyllus Micheli), erva-cidreira (Lippia alba N.E.Br.), erva-de-bicho (Polygonum spp.), espinheira-santa (Maytenus spp.), picão (Bidens pilosa L.), poejo (Mentha pulegium Lam.) e tanchagem (Plantago major L.). O abajerú, arnica, boldo-do-Chile, confrei, erva-de-bicho e espinheira-santa tiveram relato de problemas de identificação na coleta e comercialização frente a outras morfologicamente semelhantes. Plantas cultivadas e silvestres apresentam variabilidade de princípios ativos influenciados por fatores ambientais e genéticos, como chapéu-de-couro (Echinodorus macrophyllus Micheli), erva-cidreira (Lippia alba N.E.Br.) e erva-de-bicho (Polygonum spp.). A contaminação e o comprometimento da preservação dos princípios ativos pela secagem e armazenamento inadequados foram relatados para o guaco (Mikania glomerata Sprengel), camomila (Chamomilla recutita L.), erva-cidreira, chapéu-de-couro e boldo-do-Chile (Peumus boldus Molina). Pode-se constatar que todas as etapas da cadeia produtiva das plantas medicinais apresentam desafios para que se possa garantir identificação da espécie, disponibilidade, qualidade, segurança e eficácia de uso.

The use of medicinal plants by the Brazilian population is a traditional practice and is often the main resource used in primary healthcare. The therapeutic use of these plants involves several steps in the supply chain: origin, harvest, drying, storage, form of preparation by the user and use. The aim of this documental study of exploratory nature was to survey the scientific literature about the problems associated with each of those steps and discuss the issues related to the lack of studies to prove the pharmacological efficacy and the absence of toxicological risks, as well as the autodiagnosis practice. The 20 plants most commercialized in a large market of Rio de Janeiro City in August 2007 were the basis for the documental survey of the present study. Of these, six had proven toxic properties depending on their preparation and use: arnica (Solidago chilensis Meyen), aroeira (Shinus terebinthifolius Raddi.), rue (Ruta graveolens L.), "babosa" (Aloe vera L.), comfrey (Symphytum officinale L.) and pennyroyal (Mentha pulegium Lam. & DC.). The National Agency for Sanitary Surveillance shows contraindications for: "boldo-do-Chile" (Peumus boldus Molina), "chapéu-de-couro" (Echinodorus macrophyllus Micheli), lemon balm (Lippia alba N.E.Br.), "erva-de-bicho" (Polygonum spp.), "espinheira-santa" (Maytenus spp.), "picão" (Bidens pilosa L.), pennyroyal (Mentha pulegium Lam.) and plantain (Plantago major L.). "Abajerú", arnica, "boldo-do-Chile", comfrey, "erva-de-bicho" and "espinheira-santa" were reported to show identification problems in the harvest and in the commercialization compared to morphologically similar plants. Cultivated and wild plants showed variability in active principles influenced by environmental and genetic factors: "chapéu-de-couro" (Echinodorus macrophyllus Micheli), lemon balm (Lippia alba N.E.Br.) and "erva-de-bicho" (Polygonum spp.). Contamination and compromising of the preservation of active principles due to inadequate drying and storage was reported for guaco (Mikania glomerata Sprengel), camomile (Chamomilla recutita L.), lemon balm, "chapéu-de-couro" and "boldo-do-Chile" (Peumus boldus Molina). All stages of the supply chain of medicinal plants constitute challenges to ensure the proper species identification, availability, quality, safety, and efficacy of their use.

Epidemiological profile of snakebites in Rio de Janeiro, Brazil, 2001-2006

All snakebites registered in Rio de Janeiro state, Brazil, between 2001 and 2006 were analyzed. Of these, the snake species involved was identified in 2,431 cases, most of which were caused by Bothrops (2,347). Most victims were male (78.4%) and the age group most frequently attacked was between 20 and 39 years (38.4%). As for severity, 1,118 (45.9%) were classified as minor, 748 (30.7%) as moderate, and 209 (8.6%) as severe. Progression towards complete cure occurred in 1,567 patients; 39 had sequelae; three died; and clinical outcomes were not monitored in 822 cases. The time between bite and first medical attention was less than three hours in 74.6% of cases. Most occurred in municipalities with vast areas of preserved Atlantic Forest: Angra dos Reis (208), Rio de Janeiro (197), Parati (186), Teresópolis (134), and Petrópolis (110). Accident frequency was highest between November and April, in which the daily average is practically twice that observed in other months. Although results show that Rio de Janeiro state has a good level of medical care, it could be improved by creating multidisciplinary teams that include doctors, biologists, and nurses. The Vital Network for Brazil helps to promote a stimulating environment for this type of training, with both traditional courses and distance learning. Training hours must be increased to improve the skills of professionals responsible for victim care.(AU)

Mutagenesis of Gln294 of the reverse transcriptase of human immunodeficiency virus type-2 and its effects on the ribonuclease H activity.

Despite the high homology between human immunodeficiency virus type-1 (HIV-1) and human immunodeficiency virus type-2 (HIV-2) reverse transcriptases (RTs), the ribonuclease H (RNase H) level of HIV-2 RT is lower than that of HIV-1 RT, while the DNA polymerase of both RTs is similar. We conducted mutagenesis of HIV-2 RT Gln294 (shown to control the RNase H activity level when modified to a Pro in the smaller p54 subunit and not in the larger p68 subunit) to various residues, and assayed the activities of all mutants. All exhibited an RNase H that is higher than the wild-type (WT) HIV-2 RT level, although the DNA polymerase of all mutants equals WT HIV-2 RT level. These results represent a unique case, where every mutation induces an increase rather than a decrease in an enzyme's activity.

[Drug impact on human poisoning in Brazil]. / Impacto dos medicamentos nas intoxicações humanas no Brasil.

This article analyzes the role of pharmaceuticals in human poisoning in Brazil from 1993 to 1996, based on data from the National Network of Poison Control Centers. Results are presented according to cause, age group, sex, and evolution. The paper discusses measures aimed at preventing this serious public health problem, which primarily impacts children under five years of age in accidents caused by inappropriate use of medicines. The authors also analyze the association between female gender and deaths caused by intentional intake of drugs.

Bipolar hemiarthroplasty for fracture of the femoral neck.

Controversy in the treatment of displaced femoral neck fractures in the elderly focuses on the use of fixation versus the use of a prosthesis. Beginning in 1980, at The New York Hospital-Cornell Medical Center, it became routine to treat elderly patients for displaced fractures with bipolar hemiarthroplasty. This retrospective study evaluates the morbidity, mortality, and clinical and social functioning of 246 consecutive patients treated with bipolar hemiarthroplasty for Garden III and Garden IV nonpathological fractures. Follow-up ranged from 1 to 6 years. Of the 246 patients with 247 femoral neck fractures, 201 were female and 45 were male; the average age was 78 years. Fourteen patients (5.7%) died during the postoperative hospitalization. Thirty-one patients (13.3%) died within the first year following surgery. Mortality was related to the number of preexisting medical conditions: patients with four or more preexisting conditions had a significantly higher mortality than others (p less than 0.001: chi 2). The overall wound infection rate was 3.2%. There were only two failures (0.9%), both for deep infection, requiring Girdlestone debridement. One patient was revised for infection with successful reimplantation. There were two postoperative dislocations (0.9%), both reduced closed. Only one bipolar (0.4%) required conversion to a total hip replacement for a fractured acetabulum, none for arthritic wear. No radiographic evidence of significant acetabular erosion or protrusion nor femoral component loosening was noted. Clinical results were evaluated using the Hospital for Special Surgery Hip Rating Scale.(ABSTRACT TRUNCATED AT 250 WORDS)

Bipolar hemiarthroplasty for fracture of the femoral neck. Clinical review with special emphasis on prosthetic motion.

The results of a consecutive series of 120 bipolar replacements of the femoral head that had been done for the treatment of a fracture of the femoral neck were reviewed. Ninety patients were followed for a minimum of two years. At the latest follow-up, eighty-two (91 per cent) of the patients were free of major pain, and eighty-three (92 per cent) were considered to have satisfactory motion and muscle power. Postoperative function often was limited by underlying medical problems. Seventy-five patients (83 per cent) either returned to the level of function that they had had before the fracture or used only a cane, which they had not needed previously. There was no important deterioration of the results with time. For twenty-six of the prostheses, roentgenograms were made with the patient bearing weight in order to determine the relative motion at the two sites of articulation of the bipolar prosthesis. The roentgenograms demonstrated the presence and maintenance of motion at both bearing surfaces.

Adenocarcinoid of the appendix presenting as bilateral Krukenberg's tumor of the ovaries. Immunohistochemical and ultrastructural studies and literature review.

A patient with an adenocarcinoid of the appendix presented with bilateral Krukenberg's tumors of the ovaries. Immunohistochemical and ultrastructural studies revealed a selective ability of the mucinous (goblet cell) component of the appendiceal neoplasm to metastasize. A review of the literature has revealed nine previously published cases of appendiceal adenocarcinoid metastatic to the ovaries. All showed involvement of both ovaries, but none provided unequivocal evidence of a metastatic proliferating carcinoid element. As the appendiceal lesion is often grossly inconspicuous, it may be overlooked in cases presenting initially with ovarian tumors. Routine appendectomy is therefore recommended in such patients where no grossly obvious primary tumor is evident.

Assessment of morbidity and mortality in primary cytoreductive surgery for advanced ovarian carcinoma.

Even with wider application of cytoreductive surgery for advanced ovarian cancer, there is still a lack of adequate documentation concerning morbidity and mortality associated with this surgery. The purpose of this paper is to provide such information. This report is based on a retrospective analysis of 60 patients with Stage III and IV disease who had maximal cytoreductive surgery at the Long Island Jewish-Hillside Medical Center between January 1975 and February 1982. This analysis was focused on variables related to morbidity and mortality associated with the procedure. The results indicated that operating time, blood loss, intraoperative and postoperative complications, postoperative morbidity, and the length of hospital stay were acceptable. Only one operative mortality was encountered. The presence of a gynecologic oncologist in the operating room was crucial in carrying out optimal cytoreductive surgery. It is concluded that morbidity and mortality in primary maximal cytoreductive surgery for advanced ovarian carcinoma are acceptable and the surgery should be performed if feasible.