Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita is defined by the presence of contractures across two or more major joints and results from reduced or absent fetal movement. Here, we present three consanguineous families affected by lethal arthrogryposis multiplex congenita. By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126. GPR126 encodes G-protein-coupled receptor 126, which has been shown to be essential for myelination of axons in the peripheral nervous system in fish and mice. A previous study reported that Gpr126(-/-) mice have a lethal arthrogryposis phenotype. We have shown that the peripheral nerves in affected individuals from one family lack myelin basic protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral axons during fetal development. Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling, and our biochemical assays indicated that the missense substitution (p.Val769Glu [c.2306T>A]) impairs autoproteolytic cleavage of GPR126. Our data indicate that GPR126 is critical for myelination of peripheral nerves in humans. This study adds to the literature implicating defective axoglial function as a key cause of severe arthrogryposis multiplex congenita and suggests that GPR126 mutations should be investigated in individuals affected by this disorder.

Excess weight and abdominal obesity in postmenopausal Brazilian women: a population-based study.

BACKGROUND: The menopause is associated with a tendency to gain weight. Several alterations in fat deposits occur, leading to changes in the distribution of body fat. There are strong indications that, in middle age, obesity is associated with increased mortality. This study set out to determine the factors associated with the prevalence of overweight and abdominal obesity in postmenopausal women in a population-based study in Brazil. METHODS: The sample included 456 women, aged 45-69 years, residing in the urban area of Maringa, Parana. Systematic sampling, with a probability proportional to the size of the census sector, was performed. Behavioral, economic, and sociodemographic data were collected, and body mass index (BMI) and waist circumference (WC) were determined. RESULTS: According to BMI criteria (≥25.0 kg/m2), 72.6% of the women were overweight, and according to WC (≥88 cm), 63.6% had abdominal obesity. Based on logistic regression analysis, the factors that were most closely associated with overweight were: having three or more children (odds ratio (OR): 1.78; 95% confidence interval (CI): 1.06-3.00); and not taking hormone replacement therapy (OR: 1.69; 95% CI: 1.06-2.63). The prevalence of abdominal obesity was positively associated with greater parity (OR: 1.34, 95% CI: 1.05-1.72) and age older than 65 years (OR: 1.50; 95% CI: 1.03-2.19). CONCLUSIONS: This study found that the prevalences of overweight and abdominal obesity were higher for postmenopausal women who had three or more children. Age over 65 years was also a risk factor for abdominal obesity and no use of hormonal replacement therapy was a risk factor for overweight.

Suicide mortality among youth in southern Brazil: a spatiotemporal evaluation of socioeconomic vulnerability.

OBJECTIVE: To conduct a geospatial analysis of suicide deaths among young people in the state of Paraná, southern Brazil, and evaluate their association with socioeconomic and spatial determinants. METHODS: Data were obtained from the Mortality Information System and the Brazilian Institute of Geography and Statistics. Data on suicide mortality rates (SMR) were extracted for three age groups (15-19, 20-24, and 25-29 years) from two 5-year periods (1998-2002 and 2008-2012). Geospatial data were analyzed through exploratory spatial data analysis. We applied Bayesian networks algorithms to explore the network structure of the socioeconomic predictors of SMR. RESULTS: We observed spatial dependency in SMR in both periods, revealing geospatial clusters of high SMR. Our results show that socioeconomic deprivation at the municipality level was an important determinant of suicide in the youth population in Paraná, and significantly influenced the formation of high-risk SMR clusters. CONCLUSION: While youth suicide is multifactorial, there are predictable geospatial and sociodemographic factors associated with high SMR among municipalities in Paraná. Suicide among youth aged 15-29 occurs in geographic clusters which are associated with socioeconomic deprivation. Rural settings with poor infrastructure and development also correlate with increased SMR clusters.

Thrombin generation test with the calibrated automated thrombogram and anticoagulant activity of Mentha crispa.

: Evaluate the in-vitro effect of Mentha crispa extract on blood coagulation, compare the conventional coagulometric tests with thrombin generation test (TGT), and study the qualitative micromolecular composition of M. crispa. Extract of M. crispa was incubated with plasma and used in the coagulometric tests: prothrombin and activated partial thromboplastin times, fibrinogen, and TGT. A phytochemical prospection was performed to evaluate the chemical composition of this extract. The extract was efficient in prolonging prothrombin time and activated partial thromboplastin time, and reducing fibrinogen levels and TGT parameters, indicating that the extract of M. crispa inhibited the intrinsic and extrinsic pathways of blood coagulation. The results obtained in TGT are in agreement with the results of conventional coagulometric tests and the in-vitro anticoagulant activity of M. crispa suggests that its use by patients using oral anticoagulants deserves caution.

Primary structure, behavioral and electroencephalographic effects of an epileptogenic peptide from the sea anemone Bunodosoma cangicum.

The primary structure of cangitoxin (CGX), a 4958 Da peptide from the sea anemone Bunodosoma cangicum, was determined: GVACRCDSDGPTVRGNSLSGTLWLTGGCPSGWHNCRGSGPFIGYCCKK. CGX contains all the 11 residues that are conserved and the 5 that are conservatively substituted within or between the type 1 and type 2 sequences of sea anemone peptides with specific action on voltage-sensitive sodium channels. Furthermore, it also has 6 identities (Asp9, Arg14, Asn16, Leu18, Trp33 and Lys48) and 1 homology (Arg36) in the 8 residues of the pharmacophore of the sea anemone ApB which are essential for interaction with mammalian sodium channels. The intrahippocampal injection of CGX induces several sequential behavioral alterations--episodes of akinesia alternating with facial automatisms and head tremor, salivation, rearing, jumping, barrel-rolling, wet dog shakes and forelimb clonic movements--and the electroencephalography analysis shows that they were followed by important seizure periods that gradually evolved to status epilepticus that lasted 8-12 h, similar to that observed in the acute phase of the pilocarpine model of epilepsy. These results suggest that CGX may be an important tool to develop a new experimental model of status epilepticus which may contribute to understanding the etiology of epilepsy and to test the effects of new antiepileptic drugs.

Suicide mortality among youth in southern Brazil: a spatiotemporal evaluation of socioeconomic vulnerability

Objective: To conduct a geospatial analysis of suicide deaths among young people in the state of Paraná, southern Brazil, and evaluate their association with socioeconomic and spatial determinants. Methods: Data were obtained from the Mortality Information System and the Brazilian Institute of Geography and Statistics. Data on suicide mortality rates (SMR) were extracted for three age groups (15-19, 20-24, and 25-29 years) from two 5-year periods (1998-2002 and 2008-2012). Geospatial data were analyzed through exploratory spatial data analysis. We applied Bayesian networks algorithms to explore the network structure of the socioeconomic predictors of SMR. Results: We observed spatial dependency in SMR in both periods, revealing geospatial clusters of high SMR. Our results show that socioeconomic deprivation at the municipality level was an important determinant of suicide in the youth population in Paraná, and significantly influenced the formation of high-risk SMR clusters. Conclusion: While youth suicide is multifactorial, there are predictable geospatial and sociodemographic factors associated with high SMR among municipalities in Paraná. Suicide among youth aged 15-29 occurs in geographic clusters which are associated with socioeconomic deprivation. Rural settings with poor infrastructure and development also correlate with increased SMR clusters.

[The factors associated with physical inactivity in a city in southern Brazil]. / Fatores associados à inatividade física no lazer em município do Sul do Brasil.

OBJECTIVE: This study was aimed at determining the prevalence of and factors associated with gender-related physical inactivity in an urban area of a city in southern Brazil. METHODS: Data was obtained from a survey monitoring risk factors regarding chronic non-communicable diseases (NCD) in adults living in Maringá, Paraná, and the random sampling of 453 people living in the chosen urban area. RESULTS: The sample involved 351 women and 102 men; women's physical inactivity rate was 87.5 % and 86.3 % for men. Multivariate regression stated that women aged 50 to 59 years of age were physically active (p=0.01) and those having received 0-8 years of education had become inactive during their leisure time (p=0.02). Compared to males, women who reported being ex-smokers were classified as being active (p=0.03) and those who recognized their state of health as fair were classified as having become inactive during their spare time (p=0.04). CONCLUSION: Inactivity was thus observed amongst both males and females in the target population, even though risk varied and there were distinct protection levels; this would therefore soon become a modifiable risk factor. NCD prevention and control measures must thus be taken through surveillance strategies and monitoring the population's health status.

Risk factors for cervical HPV infection and genotypes distribution in HIV-infected South Brazilian women.

BACKGROUND: Human Papillomavirus (HPV) infection is particularly burdensome for women infected with human immunodeficiency virus (HIV), which increases their risk of developing cervical lesions and cancer (CC). We conducted a molecular study of the distribution of cervical HPV genotypes and the risk factors for this infection in HIV-infected Brazilian women. FINDINGS: Cervical and endocervical samples for Papanicolaou screening and HPV detection were collected from 178 HIV-infected women using highly active antiretroviral therapy (HAART) of Maringá city/Brazil. Risk factors were assessed using a standardized questionnaire, and the data regarding to HIV infection from medical records. HPV was detected by polymerase chain reaction (PCR), and genotyping using PCR-restriction fragment length polymorphism analysis. HIV infection was well controlled, but women with a current CD4+ T lymphocyte count between 200-350 cells/mm3 (37.6%) had a two-fold greater risk of HPV infection than those with > 350 cells/mm3 (26.4%). HPV was associated with parity ≥3, hormonal contraceptive use and current smoker. HPV infection occurred with high frequency (46.6%) but a low frequency of cervical abnormalities was detected (7.30%), mainly low-grade squamous intraephitelial cervical lesions (LSIL) (84.6%). A high frequency of multiple HPV infections was detected (23.0%), and the most frequent HPV genotype was HPV-72 (6.7%), followed by -16, -31 and -51 (6.14% each). CONCLUSIONS: We showed that HAART use does not protect HIV-infected women from HPV, but appear to exert some protection against cervical lesions development. This study provides other important information about risk factors and cervical HPV in HIV-infected women, which can contribute to planning protocols.

A new structurally atypical bradykinin-potentiating peptide isolated from Crotalus durissus cascavella venom (South American rattlesnake).

Venom glands of some snakes synthesize bradykinin-potentiating peptides (BPP's) which increase bradykinin-induced hypotensive effect and decrease angiotensin I vasopressor effect by angiotensin-converting enzyme (ACE) inhibition. The present study shows a new BPP (BPP-Cdc) isolated from Crotalus durissus cascavella venom: Pro-Asn-Leu-Pro-Asn-Tyr-Leu-Gly-Ile-Pro-Pro. Although BPP-Cdc presents the classical sequence IPP in the C-terminus, it has a completely atypical N-terminal sequence, which shows very low homology with all other BPPs isolated to date. The pharmacological effects of BPP-Cdc were compared to BBP9a from Bothrops jararaca and captopril. BPP-Cdc (1 µM) significantly increased BK-induced contractions (BK; 1 µM) on the guinea pig ileum by 267.8% and decreased angiotensin I-induced contractions (AngI; 10 nM) by 62.4% and these effects were not significantly different from those of BPP9a (1 µM) or captopril (200 nM). Experiments with 4-week hypertensive 2K-1C rats show that the vasopressor effect of AngI (10 ng) was decreased by 50 µg BPP-Cdc (69.7%), and this result was similar to that obtained with 50 µg BPP9a (69.8%). However, the action duration of BPP-Cdc (60 min) was 2 times greater than that of BPP-9a (30 min). On the other hand, the hypotensive effect of BK (250 ng) was significantly increased by 176.6% after BPP-Cdc (50 µg) administration, value 2.5 times greater than that obtained with BPP9a administered at the same doses (71.4%). In addition, the duration of the action of BPP-Cdc (120 min) was also at least 4 times greater than that of BPP-9a (30 min). Taken together, these results suggest that BPP-Cdc presents more selective action on arterial blood system than BPP9a. Besides the inhibition of ACE, it may present other mechanisms of action yet to be elucidated.

Simultaneous detection of seven sexually transmitted agents in human immunodeficiency virus-infected Brazilian women by multiplex polymerase chain reaction.

We determined the prevalence of seven clinically important pathogens that cause sexually transmitted infections (STIs) (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, herpes simplex virus 1 [HSV-1], HSV-2, and Treponema pallidum), by using a multiplex polymerase chain reaction (M-PCR) in samples from Brazilian woman infected with human immunodeficiency virus 1 (HIV-1) and uninfected Brazilian women (controls). The M-PCR assay identified all STIs tested for and surprisingly, occurred association between the control and STIs. This association was probably caused by excellent HIV infection control and regular monitoring in these women established by public health strategies in Brazil to combat HIV/acquired immunodeficiency syndrome. Studies using this M-PCR in different populations may help to better elucidate the roles of STIs in several conditions.

Fatores associados à inatividade física no lazer em município do Sul do Brasil / The factors associated with physical inactivity in a city in southern Brazil / Factores asociados con la inactividad física en una ciudad en el Sur de Brasil

Objetivo O objetivo deste estudo foi verificar a prevalência e fatores associados à inatividade física no lazer, segundo sexo, em residentes da área urbana de um município do Sul do Brasil. Métodos Os dados foram obtidos da pesquisa de monitoramento de fatores de risco para doenças crônicas não transmissíveis em adultos da cidade de Maringá, Paraná, através de inquérito populacional e amostra de 453 indivíduos. Resultados Foram avaliados 351 mulheres e 102 homens. A taxa de inatividade física no lazer foi de 87,5 % e 86,3 % para as mulheres e homens, respectivamente. Após regressão multivariada, notou-se que as mulheres com idade entre 50 e 59 anos estão fisicamente ativas (p=0,01), e aquelas com 0 a 8 anos de estudo, apresentaram-se inativas no lazer (p=0,02). E relação aos homens, os que declararam ser ex-fumantes, classificaram-se como ativos (p=0,03) e os que reconheceram o estado de saúde como regular, apresentaram-se inativos no lazer (p=0,04). Conclusão Foi possível perceber que embora com variáveis de risco e proteção distintas, a inatividade na população adulta encontra-se presente em ambos os sexos, e logo, por ser um fator de risco modificável, deve integrar-se no rol das medidas de prevenção e controle de doenças, através de estratégias de vigilância e monitoramento do estado de saúde da população.

Objective This study was aimed at determining the prevalence of and factors associated with gender-related physical inactivity in an urban area of a city in southern Brazil. Methods Data was obtained from a survey monitoring risk factors regarding chronic non-communicable diseases (NCD) in adults living in Maringá, Paraná, and the random sampling of 453 people living in the chosen urban area. Results The sample involved 351 women and 102 men; women's physical inactivity rate was 87.5 % and 86.3 % for men. Multivariate regression stated that women aged 50 to 59 years of age were physically active (p=0.01) and those having received 0-8 years of education had become inactive during their leisure time (p=0.02). Compared to males, women who reported being ex-smokers were classified as being active (p=0.03) and those who recognized their state of health as fair were classified as having become inactive during their spare time (p=0.04). Conclusion Inactivity was thus observed amongst both males and females in the target population, even though risk varied and there were distinct protection levels; this would therefore soon become a modifiable risk factor. NCD prevention and control measures must thus be taken through surveillance strategies and monitoring the population's health status.

Objetivo El objetivo de este estudio fue determinar la prevalencia y los factores asociados con inactividad física, por sexo, en los residentes de un área urbana en una ciudad del sur de Brasil. Métodos Los datos se obtuvieron de una encuesta de seguimiento de los factores de riesgo de enfermedades crónicas entre los adultos de la ciudad de Maringá, Paraná, de la cual se tomó una muestra de 453 personas. Resultados Se estudiaron 351 mujeres y 102 hombres. La tasa de inactividad física fue del 87,5 % y del 86,3 % para las mujeres y los hombres, respectivamente. Después de un análisis de regresión multivariada, se observó que las mujeres de edades comprendidas entre 50 y 59 años son físicamente activas (p=0,01), y las que tienen 0-8 años de estudio se han convertido en inactivas durante el tiempo libre (p=0,02). En comparación, los hombres que reportaron ser ex fumadores fueron clasificados como activos (p=0,03) y los que reconocen el estado de salud como regular, se habían convertido en inactivos durante el tiempo libre (p=0,04). Conclusión Se pudo observar que, si bien con diferentes riesgos y distinta protección, la inactividad en adultos está presente en ambos sexos, y que se convierte en un factor de riesgo modificable. Las medidas de prevención y de control de las enfermedades se deben integrar a través de estrategias de vigilancia y seguimiento del estado de salud de la población.