Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway.

The astrocytic cystine/glutamate antiporter system x c - (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson's disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT-/-) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT-/- mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT-/- mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT-/- mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT-/- mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system x c - in mechanisms of dopaminergic cell loss and its interaction with aging.

Knowledge of intrapartum care among obstetric care providers in rural Kenya.

BACKGROUND: Kenya did not meet its maternal mortality ratio (MMR) target under the Millennium Development Goals. The aim of this study was to examine the gaps in knowledge of intrapartum care among obstetric care providers (OCPs) in rural Nandi County, Kenya. METHODS: This cross-sectional study in 2015 surveyed 326 nurses, midwives, clinical officers and physicians about their knowledge, attitudes and practices related to normal labor and childbirth, immediate newborn care and management of obstetric complications. RESULTS: Self-reported intrapartum knowledge among OCPs was insufficient according to accepted international standards. The mean total knowledge score for all OCPs based on a validated 30-question inventory was 62% (range 23-90%). Only 14 providers (4%) scored as 'competent' (a score ≥80%). Scores were higher for OCPs who had received pre- and postemployment emergency obstetric care training and those with higher levels of confidence in their skills. Survey respondents identified a lack of knowledge as one of the greatest barriers to high-quality patient care. CONCLUSIONS: Increasing training opportunities for OCPs may improve the quality of obstetric care provided to women in Kenya and other high-MMR locations in sub-Saharan Africa and enable progress toward achieving the ambitious Sustainable Development Goals target for maternal survival.

Inpatient healthcare provider bypassing by women and their children in urban Bo, Sierra Leone.

INTRODUCTION: Bypassing refers to a person's decision to seek care at a healthcare facility that is not the nearest one of its type to the person's home. METHODS: This study examined inpatient care facility bypassing in urban Bo, Sierra Leone using data from 1,980 women with children 15 years of age and younger who were interviewed in 2010-2011. The locations of residential structures and hospitals were identified using a geographic information system (GIS), and the road distances from participating households to the nearest and preferred inpatient care facilities were measured. RESULTS: Nine inpatient care facilities serve Bo residents, but more than 70% of the participating women reported that the city's main public hospital (Bo Government Hospital), located in the city center, was their preferred inpatient care provider. Participants resided within a median distance of 0.9 km (Interquartile range (IQR): 0.6, 1.8) from their closest inpatient facility, but they would travel a median distance of 2.4 km (IQR: 1.0, 3.3) to reach their preferred providers. About 87% of the women would bypass their nearest inpatient care facility to access care at a preferred provider. Bypassing rates were similar for various demographic and socioeconomic groups, but higher for women living farther from the city center. CONCLUSION: Although Bo has a diverse healthcare marketplace, access to affordable advanced care options is limited. Most women in Bo would choose to bypass facilities nearer to their homes to seek the low-cost and comprehensive care offered by Bo Government Hospital.

Health-care availability, preference, and distance for women in urban Bo, Sierra Leone.

OBJECTIVES: To examine the diversity of the health-care providers in urban Bo, Sierra Leone, identify the types of health-care facilities preferred by women for fevers, and analyze the road network distances from homes to preferred health-care providers. METHODS: A population-based random sampling method was used to recruit 2419 women from Bo. A geographic information system was used to measure the road distance from each woman's home to her preferred provider. RESULTS: Preferred health-care providers for acute febrile illnesses (commonly referred to as "malaria" in the study communities) were hospitals (62.3 %), clinics (12.6 %), and pharmacies (12.4 %). Participants lived a median distance of 0.6 km from the nearest provider, but on average each woman lived 2.2 km one-way from her preferred provider. Women living farther from the city center had preferred providers significantly farther from home than women living downtown. CONCLUSIONS: The diverse health-care marketplace in Bo allows women to select clinical facilities from across the city. Most women prefer a malaria care provider farther from home than they could comfortably walk when ill.

Parenting practices and tobacco use in middle school students in low- and middle-income countries.

BACKGROUND: Parenting practices have been shown to have a strong influence on adolescent tobacco use in high-income countries. This study examined whether parenting practices also were associated with tobacco use by middle school students (approximately ages 13-15) in low- and middle-income countries. METHODS: A secondary analysis was performed on data from 106,041 middle school students in 27 countries who participated in the Global School-Based Health Survey conducted between 2003 and 2007. RESULTS: In nearly all countries, boys and older students were significantly more likely to use tobacco than girls and younger students. In most countries, students who reported a high level of parental understanding or a high level of parental awareness of their children's activities were significantly less likely to use tobacco than other students. The children of parents who used tobacco were significantly more likely to use tobacco than children of non-users. After adjustment for age, sex, and parental tobacco use, the associations between parental understanding and awareness were statistically significant in 16 and 24 countries, respectively, of the 26 countries with parental tobacco use data. CONCLUSION: This multivariate analysis shows that positive parenting practices are significantly associated with decreased tobacco use among adolescents in low- and middle-income countries, which matches previous findings from high-income countries. Educating parents on the importance of their parenting practices may be an effective component of school-based programs aimed at reducing adolescent tobacco use.

Pyomyositis in Amazonian Ecuador.

Pyomyositis occurs when intramuscular abscesses appear in one or more body sites. Analysis of data from 165 patients with tropical pyomyositis diagnosed at a hospital in rural Amazonian Ecuador from 1980 to 1989 and 1995 to 2005 found that pyomyositis is more likely to affect males than females and more likely to affect children than adults. Abscesses were most commonly located on a lower extremity. Significant changes in patients' profiles between 1980 and 1989 and 1995 and 2005 were not found.

Bullying among middle-school students in low and middle income countries.

This analysis of data from the Global School-based Student Health Survey examined the prevalence of bully victimization in middle-school students in 19 low- and middle-income countries and also explored the relationship between bullying, mental health and health behaviors. In most countries, boys were more likely than girls to report being bullied and the prevalence of bullying was lower with increasing age. Students who reported being bullied in the past month were more likely than non-bullied students to report feelings of sadness and hopelessness, loneliness, insomnia and suicidal ideation. Bullied students also reported higher rates of tobacco use, alcohol use, drug use and sexual intercourse.

Etiology of acute undifferentiated febrile illness in the Amazon basin of Ecuador.

We conducted a longitudinal observational study of 533 patients presenting to two hospitals in the Ecuadorean Amazon basin with acute undifferentiated febrile illness (AUFI) from 2001 through 2004. Viral isolation, reverse transcription-polymerase chain reaction (RT-PCR), IgM seroconversion, and malaria smears identified pathogens responsible for fever in 122 (40.1%) of 304 patients who provided both acute and convalescent blood samples. Leptospirosis was found in 40 (13.2%), malaria in 38 (12.5%), rickettsioses in 18 (5.9%), dengue fever in 16 (5.3%), Q fever in 15 (4.9%), brucellosis in 4 (1.3%), Ilhéus infection in 3 (1.0%), and Venezuelan equine encephalitis (VEE), Oropouche, and St. Louis encephalitis virus infections in less than 1% of these patients. Viral isolation and RT-PCR on another 229 participants who provided only acute samples identified 3 cases of dengue fever, 2 of VEE, and 1 of Ilhéus. None of these pathogens, except for malaria, had previously been detected in the study area.

Bullying and symptoms of depression in chilean middle school students.

BACKGROUND: The goal of this study was to assess the association between bullying and symptoms of depression among middle school students in Chile. METHODS: Secondary data analysis of Chile's 2004 Global School-Based Health Survey. RESULTS: A total of 8131 middle school students participated in the study. Forty-seven percent of students reported having been bullied in the past month and 30% reported having been sad and hopeless for 2 or more weeks in the past year. Students in the seventh and eighth grades were more likely to report having been bullied in the past month than students in ninth grade. Ninth grade students reported higher levels of loneliness, difficulty sleeping, and suicidal thoughts than students in the seventh and eighth grades. Boys were more likely than girls to report being bullied in the past month, but girls were more likely than boys to report symptoms of depression, such as prolonged feelings of sadness and hopelessness, loneliness, difficulty sleeping, and suicidal thoughts. Students who reported being bullied in the past month were more likely than nonbullied students to report symptoms of depression. A higher number of days of being bullied in the past month was associated with a statistically significant increase in reported rates of sadness and hopelessness (p < .001). CONCLUSIONS: Bullying is common among middle school children in Chile, and bullying and symptoms of depression are strongly linked. This finding is consistent with studies of bullying and depression in adolescents from other parts of the world.

Selection of S18326 as a new potent and selective boronic acid direct thrombin inhibitor.

Using enzymatic microassays, the potency of a series of new boroarginine tripeptides was determined versus thrombin and a panel of serine-proteases implicated in the coagulation and fibrinolysis pathways. The inhibition of the serine-protease complement factor I was also studied. Factor I regulates the alternate pathway of the complement and its inhibition appears to be responsible for the toxic effects of the orally available thrombin inhibitor Ac-D-Phe-Pro-boroArg (DuP-714). The structure of the new boronic acid derivatives tested was modified from that of DuP-714 by replacing the proline in the P2 position by N-cycloalkyl-glycine residues of increasing size (S18989: cyclopropyl; S18563: cyclobutyl; S18326: cyclopentyl; S18229: cyclohexyl). All compounds were found to be slow-tight binding inhibitors of thrombin versus purified human fibrinogen. Replacement of proline by N-cycloalkyl-glycines did not decrease the anti-thrombin potency of the substances up to the cyclopentyl size and this result was confirmed by classical coagulation assays with human plasma in vitro. In contrast, the inhibitory activities of the four new boronic acids were found to be lower than those of DuP-714 versus plasmin, urokinase (u-PA), plasmatic kallikrein, activated protein C (aPC) and complement factor I. The cyclopentyl derivative S18326 is a slightly more active inhibitor of thrombin than DuP-714 (initial IC50 values 3.99 +/- 0.18 nM versus 4.73 +/- 0.27 nM, respectively). Moreover S18326 was identified as the most selective compound of the series with relative potencies being 2 to 29 fold higher than that of DuP-714 versus the panel of serine-proteases tested; the rank order of potency versus the other serine-proteases for S18326 was t-PA>kallikrein>aPC>factor I>plasmin>fXa>u-PA. These results indicate that the size of the thrombin hydrophobic pocket S2 is sufficient to accept larger residues than proline in the P2 position of Ac-D-Phe-X-boroArg derivatives while this is not the case for other important serine-proteases of the fibrinolysis, coagulation and complement pathways. The N-cyclopentyl glycine containing derivative S 18326, which is the most potent and the most selective anti-thrombin compound of the series, currently undergoes major preclinical testing.

New tripeptidic thrombin inhibitors. Influence of P2 and P3 residues on activity and selectivity.

Structural variations of P2 and P3 residues in tripeptidic boroarginine thrombin inhibitors led to compounds with similar potency than reference compound DuP 714, but with enhanced selectivity for thrombin compared to plasmin.