Exploring Ubiquinone Biosynthesis Inhibition as a Strategy for Improving Atovaquone Efficacy in Malaria.

Atovaquone (AV) acts on the malaria parasite by competing with ubiquinol (UQH2) for its union to the mitochondrial bc1 complex, preventing the ubiquinone-8 and ubiquinone-9 (UQ-8 and UQ-9) redox recycling, which is a necessary step in pyrimidine biosynthesis. This study focused on UQ biosynthesis in Plasmodium falciparum and adopted proof-of-concept research to better elucidate the mechanism of action of AV and improve its efficacy. Initially, UQ biosynthesis was evaluated using several radioactive precursors and chromatographic techniques. This methodology was suitable for studying the biosynthesis of both UQ homologs and its redox state. Additionally, the composition of UQ was investigated in parasites cultivated at different oxygen saturations or in the presence of AV. AV affected the redox states of both UQ-8 and UQ-9 homologs by increasing the levels of the respective reduced forms. Conversely, low-oxygen environments specifically inhibited UQ-9 biosynthesis and increased the antimalarial efficacy of AV. These findings encouraged us to investigate the biological importance and the potential of UQ biosynthesis as a drug target based on its inhibition by 4-nitrobenzoate (4-NB), a 4-hydroxybenzoate (4-HB) analog. 4-NB effectively inhibits UQ biosynthesis and enhances the effects of AV on parasitic growth and respiration rate. Although 4-NB itself exhibits poor antimalarial activity, its 50% inhibitory concentration (IC50) value increased significantly in the presence of a soluble UQ analog, p-aminobenzoic acid (pABA), or 4-HB. These results indicate the potential of AV combined with 4-NB as a novel therapy for malaria and other diseases caused by AV-sensitive pathogens.

Epidemiology and fungal species distribution of superficial mycoses in Northeast Brazil.

OBJECTIVE: Dermatomycoses are superficial fungal infections which affect the skin, hair and nails of humans and animals. Male and female patients of all ages are affected by this condition. The main etiological agents of dermatomycoses are the dermatophytes fungi of the genera Trichophyton, Microsporum and Epidermophyton, while the main yeasts belong to the genera Candida, Malassezia and Trichosporon. The variation in the distribution of dermatomycoses worldwide justify the conduction of epidemiological studies in order to contribute for the better understanding of patterns of mycological cutaneous infections. This study was conducted from April 2013 to December 2014. MATERIAL AND METHODS: A total of 205 patients were evaluated, while 235 clinical specimens were obtained. From our positive cases of mycological examination, 73 (64.6%) patients were female, while 40 (35.4%) were male. Scales from the skin and nails were collected and observed at optical microscopy after potassium hydroxide clarification. Cultures were performed on Sabouraud Dextrose Agar added chloramphenicol. Identification was performed by classic methodology. RESULTS: We found that the glabrous skin was the largest source of dermatomycoses (30.11%), followed by toenails (27.4%) and fingernails (17.7%). Regarding onychomycosis, the most affected population was over 50 years old. Trichophyton rubrum was the dermatophyte fungal species more commonly found. Most of the patients with pityriasis versicolor were adults and female. Another important fact observed is that Candida parapsilosis was the most prevalent species. Finally, a high incidence of T. tonsurans in cases of superficial mycoses was observed. CONCLUSION: Our results clearly demonstrate peculiarities in terms of etiological agents of dermatophytoses distribution in a specific region of Brazil.

Falls in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To determine the prevalence of falls in human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and possible factors associated to their occurrence. SETTING: Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz (FIOCRUZ) - Brazil. METHODS: Thirty-six HAM/TSP patients able to walk at least 20 m were assessed by a questionnaire. Data regarding gender, age, duration of disease (DD), HTLV-I proviral load (HPL), frequency of physical activity (FCA), use of walking aids, functional ambulation level, the number of falls and associated injuries in the last year were reviewed. Multiple correspondence analysis was used to group characteristics of this sample according to the fall occurrence. RESULTS: The prevalence of falls was 63.9% and we observed injuries in 47.8% of the cases. Four groups were identified in the descriptive analysis. One group was formed by faller individuals, men <60 years, independent ambulation, FCA≥3 times per week and HPL <6.6 copies per 100 cells (group B). The other one comprised non-faller patients, women ≥60 years, restricted ambulation, DD ≥7 years, use of orthosis, FCA 0-1 time per week and HPL ≥6.6 copies per 100 cells (group D). The others two groups comprised individuals that did not use orthosis (group A) and those that FCA was two times per week and DD <7 years (group C). CONCLUSION: Falls occur in roughly two-thirds of ambulatory HAM/TSP patients and are associated with significant morbidity. Further studies with a larger number of patients are necessarily to identify risk factors in order to elaborate specific programs to prevent falls in this population.

Perfil do conhecimento de cuidadores de pacientes pediátricos sobre medicamentos prescritos / Profile of the knowledge of pediatric patient caregivers about prescribed medicines

O raro contato entre os profissionais de saúde e o cuidador do paciente pediátrico, associado ao pouco tempo disponibilizado pelo profissional farmacêutico durante a dispensação, não são suficientes para a geração de informações significativas, podendo acarretar falhas no fluxo de informação e não adesão involuntária do paciente ao tratamento. O objetivo do trabalho foi coletar dados sobre o perfil do conhecimento dos cuidadores de pacientes pediátricos a respeito de medicamentos dispensados na Farmácia Ambulatorial do Hospital Infantil Albert Sabin (HIAS), com enfoque para os medicamentos do Componente Especializado da Assistência Farmacêutica nas especialidades de Neurologia e Pneumologia. Trata-se de um estudo prospectivo. A coleta de dados ocorreu entre novembro de 2007 e maio de 2008, utilizando-se um questionário semiestruturado. De acordo com os dados coletados, 87,7% (n=50) eram do gênero feminino; o grau de escolaridade, predominante, foi o ensino médio completo; a renda média familiar ficou compreendida entre um e dois salários mínimos, equivalente a 63,1% dos casos. As questões sobre informações sobre os medicamentos dispensados configuraram-se dessa forma: 12% desconhecem o nome do medicamento prescrito; 14% desconhecem a indicação do medicamento; 7% desconhecem como administrá-lo; 29,8% desconhecem o tempo de tratamento; 82,5% desconhecem o que é reação adversa a medicamento. Foram consideradas como respostas insatisfatórias aquelas que não foram condizentes com as informações contidas nas bulas e/ou receituários médicos dos medicamentos. A análise dos dados permitiu verificar que há, em relação à falta de informação dos entrevistados, dados significantes que podem comprometer a terapia, prejudicando a saúde do paciente.

The rare contacts between health professionals and adult caregivers of pediatric patients in a hospital outpatient pharmacy, together with the short time available during the dispensing, are insufficient to generate a meaningful flow of information, and can lead to an unintentional lack of patient compliance to the treatment. The objective of the study was to collect data on the profile of knowledge of pediatric patient caregivers, regarding medicines dispensed in the outpatient pharmacy at the Hospital Infantil Albert Sabin (a childrens hospital), focusing on those who obtain medicines from the Specialized Pharmaceutical Care component of the Public Health Service, in the specialties of Neurology and Pulmonology. This prospective study was based on data collected from November 2007 to May 2008, using a semi-structured questionnaire. According to the results, 87.7% of the caregivers (n = 50) were female; they were predominantly educated to high school level; the median family income was between one and two times the ?minimum wage? (inflation-adjusted official subsistence wage), 63.1% of incomes falling within this range(?). Questions of fact about the medication dispensed elicited the following profile of respondents? knowledge: 12% did not know the name of the drug, 14% the reason for taking the drug, 7% how to administer the medicine, 29.8% the treatment time and 82.5% did not know about adverse reactions to the medication. Answers considered unsatisfactory were those that were inconsistent with the information contained in the package inserts and / or medical prescriptions of the drugs. Data analysis showed that there was a significant lack of information among the respondents that could impair the adherence to drug therapy and affect patient health.

The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes.

The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.

Clinical and laboratory features greatly overlap in patients with macroprolactinemia or monomeric hyperprolactinemia.

AIM: The aim of this study was to evaluate the clinical and laboratory features of 64 patients with macroprolactinemia and to compare them to those of individuals with monomeric hyperprolactinemia. METHODS: The study included 64 patients (54 women and 10 men) with macroprolactinemia and 96 patients (70 women and 26 men) with monomeric hyperprolactinemia (32 with prolactinomas). RESULTS: Symptoms related to prolactin (PRL) excess were found in about 44% of individuals from the macroprolactinemia group and in 88.5% of patients with monomeric hyperprolactinemia (P<0.0001). However, the frequency of menstrual disturbances (oligomenorrhea or amenorrhea), galactorrhea and erectile dysfunction did not differ in both groups. In contrast, the association of galactorrhea and menstrual disturbances was significantly more prevalent in women with monomeric hyperprolactinemia. Although mean PRL levels were higher in patients with monomeric hyperprolactinemia (565.9+/-2726.4 vs 113.3+/-94.5 ng/mL, P<0.001), there was a great overlap between both groups. Among macroprolactinemic patients, pituitary magnetic resonance imaging revealed an image suggestive of a microadenoma in 7 (10.9%) and a macroadenoma in 1 (1.6%). Normalization of PRL levels during therapy with dopamine agonists was significantly more frequent in patients with monomeric hyperprolactinemia than in subjects with macroprolactinemia (78.6% vs 32%, P=0.0006). CONCLUSION: Our data show that symptoms related to PRL excess are frequently found in subjects with macroprolactinemia. Moreover, no clinical or laboratory features could reliably differentiate macroprolactinemic patients from those with monomeric hyperprolactinemia. Therefore, the screening for macroprolactin should not be restricted to asymptomatic patients.

Comparative cytogenetic studies of Bufo ictericus, B. paracnemis (Amphibia, Anura) and an intermediate form in sympatry

Specimens of Bufo ictericus, Bufo paracnemis and a third type, considered an intermediate subgroup between these species, were cytogenetically studied by conventional Giemsa staining, C-banding and staining of the nucleolus organizer region (NOR). The nuclear DNA content and seroproteins were also analyzed to characterize these species, and verify the possibility of hybridization between them. Karyotypes and cytogenetic markers were essentially equal on the basis of the methods used. The DNA nuclear content found was 6.25 ± 0.30 pg/DNA in Bufo ictericus; 7.57 ± 0.40 pg/DNA in Bufo paracnemis and 7.04 ± 0.29 pg/DNA in the intermediate subgroup. Eletrophoresis of total blood serum in Bufo ictericus, Bufo paracnemis and the intermediate specimens revealed a remarkable difference in the patterns of the protein bands whose molecular weight corresponded to that of albumin. While the parental species presented two different bands, the intermediate form presented 4. However, only three of these bands were seen in each specimen. The results obtained pointed to a high probability for natural hybridization between Bufo ictericus and Bufo paracnemis in the site and specimens studied

Central 5-HT3 receptor stimulation by m-CPBG increases blood glucose in rats.

The aim of the present study was to investigate the role of central 5-HT3 receptors on the control of blood glucose in stressed and non-stressed rats in both fasted and fed states. Adult Wistar male rats had each their third ventricle cannulated 7 days before the experiments. Injections of m-CPBG, a selective 5-HT3 receptor agonist, induced a significant increase in blood glucose in non-stressed rats in both fasted and in fed states. The same procedure was unable to modify stress-induced hyperglycemia. The hyperglycemic effect of m-CPBG central administration was blocked by pretreatment with ondansetron, a specific 5-HT3 receptor antagonist, indicating that the effects here obtained with m-CPBG were a result of its interaction with 5-HT3 receptors. Third ventricle injections of ondansetron alone were not able to modify blood glucose in non-stressed animals and did not change the hyperglycemic responses observed after immobilization stress. We conclude that pharmacological activation of the central 5-HT3 receptor induces a hyperglycemic effect in non-stressed animals.

[Creutzfeldt-Jakob disease: case report with spinal cord involvement]. / Doença de Creutzfeldt-Jakob: a propósito de um caso com comprometimento medular.

Creutzfeldt-Jakob disease (CJD) is the most common subacute transmissible spongiform encephalopathy. Approximately 85% of the cases are sporadic. The remaining 15% consist of genetic and iatrogenic forms. We report a sporadic form of CJD with spinal cord involvement and a clinical manifestation characterized by dementia and cerebellar syndrome, myofasciculation with absent reflexes and seizures. The two last manifestations are rare. The clinical hypothesis was probable CJD which was confirmed with autopsy and immunohistochemistry. We conclude that CJD should always be suspected when rapidly progressive dementia occurs and the absence of pyramidal or extrapyramidal signs suggest a spinal cord and/or peripheral nerve involvement.

[Segmental dystonia as manifestation of cavernous angioma: case report]. / Distonia segmentar como manifestação de angioma cavernoso: relato de caso.

Dystonia is a neurologic syndrome whose etiology is not well recognized. We report a sixteen year old patient with difficulty in playing piano, with disability of the left hand, forearm and arm. Short after, she underwent "absence" crises and headache. Neuroradiological exams showed a deep temporal lobe cavernous angioma. It is a rare association between both diseases and there are no reports about segmental dystonia associated to pseudoabsence epilepsy and sporadic migraine secondary to cavernous angioma. Twenty five per cent of dystonias have a secondary cause and we suggest a neuroradiologic investigation.

[Preterm neonates treated in intensive care units: development of interaction behavior in the first year of life] / Recém-nascidos pré-termo internados em unidade de terapia intensiva: desenvolvimento da conduta interativa no primeiro ano de vida.

OBJECTIVE: The aim of this research was to characterize the interaction during the first year of preterm infants whose weight was lower than 2000g and who had been in neonatal intensive care units for at least 10 days. METHOD: Fifty-three infants were observed during a year, twenty-one being boys and thirty-two girls. These infants were assessed regarding seventeen kinds of behavior which we considered important in person to person relationship, i.e., behavior which led to interaction or maintained it. In our analysis we considered the age at which the child was seen, sex, weight at birth, new born classification, time of hospitalization and neurological diagnosis.RESULTS: An analysis of the results showed that there was an evolution in the way preterm infants interacted although the progress was smaller than the one of their pair terms. The occurrence of communicative behavior was not affected by sex, weight at birth or newborn classification (adequate or small for gestational age). The postnatal time of hospitalization affected the occurrence of the behavior smiles to the reflected image in mirror. The infants diagnosed as being neurologically impaired showed a statistically significant smaller occurrence of behaviors: respond to smiles and speech by smiling, play peek-a-boo, protest at mothers departure, point to desired objects and carry out given orders. CONCLUSIONS: The infants diagnosed as having neurological disabilities showed a delay in more complex forms of interaction. The infants with more than 35 days of hospitalization showed alteration in the self-body construction, related to personality build up.

Temporomandibular joint and mandibular growth alterations in patients with juvenile rheumatoid arthritis.

OBJECTIVE: To determine the frequency and type of lesions of the temporomandibular joints (TMJ) as well as orthodontic alterations present in patients with juvenile rheumatoid arthritis (JRA). METHODS: Twenty-six patients had their TMJ evaluated clinically and by high resolution computer tomography. The patients were also submitted to orthodontic evaluation. Children with isolated malocclusion were used as a control group. RESULTS: Computer tomography detected TMJ alterations in 13 (50%) patients with JRA. Bilateral mild lesions were the most frequent. TMJ alterations were especially observed in young patients with JRA with the systemic and polyarticular type of onset. Worse functional class and corticosteroid therapy were also related to TMJ involvement. We observed orthodontic alterations in 18 patients with JRA (69%): midline deviation, convex facial profile. Class II molar relation, crowded lower anterior teeth, anterior open bite, and reduction in the maximum opening of the mouth. Severe TMJ lesions were correlated to cephalometric alterations, suggesting decreased mandibular growth.