Sleep deprivation decreases the reproductive capacity by affecting the arrival of morulas in the uterus.

A previous animal study by our group found that sleep deprivation during preimplantation was associated with decreased pregnancy maintenance. Given its impact on human society, we aimed in the current study to assess whether sleep deprivation affects blastocyst gene expression and/or the implantation process. For this, pregnant mice (gestational day 0 [GD 0]) were assigned into paradoxical sleep deprivation (SD, 72 hr; multiple platform method) and, a control (CT) group. Animals were euthanized on GD 3.5 and blood, uterus (embryos) and fallopian tube were collected. Then, 89% of CT presented blastocysts in the uterus versus 25% from SD group. Compared to CT, SD presented lighter relative uterus weight, increased plasma concentrations of corticosterone and testosterone, decreased concentrations of progesterone and luteinizing hormone, but no statistical differences in plasma concentrations of 17ß-estradiol and follicle stimulating hormone. There were no differences in uterus and blastocyst gene expression related to embryo implantation and development, and no alteration in blastocysts global DNA methylation. Considering this, the decreased pregnancy maintenance after sleep deprivation seems not to be associated with implantation losses or developmental problems related to the blastocysts. It is likely that complications in morula development and/or its movement through the fallopian tubes affect the pregnancy rate, since only 25% of SD females presented a blastocyst on the GD 3.5. In fact, three out of four females without blastocysts in the uterus presented morula in the fallopian tubes due to a phase delay. Additionally, we suggest that the observed hormonal changes may play a role in this outcome.

A putative role for homocysteine in the pathophysiology of acute bacterial meningitis in children.

BACKGROUND: Acute bacterial meningitis frequently causes cortical and hippocampal neuron loss leading to permanent neurological sequelae. Neuron death in acute bacterial meningitis involves the excessive activation of NMDA receptors and p53-mediated apoptosis, and the latter is triggered by the depletion of NAD + and ATP cellular stores by the DNA repair enzyme poly(ADP-ribose) polymerase. This enzyme is activated during acute bacterial meningitis in response to DNA damage induced, on its turn, by reactive oxygen and nitrogen species. An excess of homocysteine can also induce this cascade of events in hippocampal neurons. The present work aimed at investigating the possible involvement of homocysteine in the pathophysiology of meningitis by comparing its concentrations in cerebrospinal fluid (CSF) samples from children with viral or acute bacterial meningitis, and control individuals. METHODS: Homocysteine and cysteine concentrations were assessed by high-performance liquid chromatography in CSF samples from nine patients with acute bacterial meningitis, 13 patients with viral meningitis and 18 controls (median age: 4 years-old; range: <1 to 13) collected by lumbar puncture at admission at the Children's Hospital Joao Paulo II - FHEMIG, from January 2010 to November 2011. RESULTS: We found that homocysteine accumulates up to neurotoxic levels within the central nervous system of patients with acute bacterial meningitis, but not in those with viral meningitis or control individuals. No correlation was found between homocysteine and cysteine concentrations and the cerebrospinal fluid standard cytochemical parameters. CONCLUSIONS: Our results suggest that HCY is produced intrathecally in response to acute bacterial meningitis and accumulates within the central nervous system reaching potentially neurotoxic levels. This is the first work to propose a role for HCY in the pathophysiology of brain damage associated with acute bacterial meningitis.

Treatment of adult MPSI mouse brains with IDUA-expressing mesenchymal stem cells decreases GAG deposition and improves exploratory behavior.

BACKGROUND: Mucopolysaccharidosis type I (MPSI) is caused by a deficiency in alpha-L iduronidase (IDUA), which leads to lysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate. While the currently available therapies have good systemic effects, they only minimally affect the neurodegenerative process. Based on the neuroprotective and tissue regenerative properties of mesenchymal stem cells (MSCs), we hypothesized that the administration of MSCs transduced with a murine leukemia virus (MLV) vector expressing IDUA to IDUA KO mouse brains could reduce GAG deposition in the brain and, as a result, improve neurofunctionality, as measured by exploratory activity. METHODS: MSCs infected with an MLV vector encoding IDUA were injected into the left ventricle of the brain of 12- or 25-month-old IDUA KO mice. The behavior of the treated mice in the elevated plus maze and open field tests was observed for 1 to 2 months. Following these observations, the brains were removed for biochemical and histological analyses. RESULTS: After 1 or 2 months of observation, the presence of the transgene in the brain tissue of almost all of the treated mice was confirmed using PCR, and a significant reduction in GAG deposition was observed. This reduction was directly reflected in an improvement in exploratory activity in the open field and the elevated plus maze tests. Despite these behavioral improvements and the reduction in GAG deposition, IDUA activity was undetectable in these samples. Overall, these results indicate that while the initial level of IDUA was not sustainable for a month, it was enough to reduce and maintain low GAG deposition and improve the exploratory activity for months. CONCLUSIONS: These data show that gene therapy, via the direct injection of IDUA-expressing MSCs into the brain, is an effective way to treat neurodegeneration in MPSI mice.

Optimal cutoff points for body mass index, waist circumference and HOMA-IR to identify a cluster of cardiometabolic abnormalities in normal glucose-tolerant Brazilian children and adolescents / Valores de corte ótimos do índice de massa corporal, circunferência abdominal e HOMA-IR para a identificação de um conjunto de anormalidades cardiometabólicas em crianças e adolescentes brasileiros com tolerância normal à glicose

OBJECTIVE: The aim of this study was to establish the best cutoff values for waist circumference (WC), body mass index (BMI) and HOMA-IR (HR) to identify a cluster (> 3) of cardiovascular risk factors (CVRF) in normal glucose-tolerant (NGT) Brazilian children and adolescents. SUBJECTS AND METHODS: Cross-sectional study of 319 individuals (aged 10 to 19y) from a southern Brazilian city. Gender-specific receiver-operating characteristics (ROC) curves were constructed to assess cutoffs values of BMI (kg/m², WC (cm), and HR. RESULTS: The areas under the ROC curves to detect a cluster of CVRF were 0.92, 0.93 and 0.68 (females), and 0.93, 0.93 and 0.89 (males), for WC, BMI and HR, respectively. The cutoff values were 83.0 and 80.5 cm (WC), 22.7 and 20.4 kg/m2 (BMI), and 1.65 and 1.95 (HR), for females and males, respectively, to detect the cluster of CVRF. CONCLUSION: These values of BMI, WC-) and (HR) detected a high proportion of NGTt Brazilian children and adolescents with a cluster of CVRF.

OBJETIVO: O objetivo deste estudo foi estabelecer os melhores valores de corte para circunferência abdominal (CA), índice de massa corpórea (IMC) e HOMA-IR (HR) para identificação da concomitância de um conjunto de fatores de risco cardiovascular (> 3) em crianças e adolescentes brasileiros com tolerância normal à glicose (TNG). SUJEITOS E MÉTODOS: Estudo transversal realizado em uma cidade do sudeste do Brasil com 319 indivíduos de 10 a 19 anos de idade. Curva ROC para cada gênero foi utilizada para estabelecimento dos valores de IMC (kg/m²), CA (cm) e HRR. RESULTADOS: As áreas sob as curvas ROC para detectar o conjunto de fatores cardiovascular foram 0,92, 0,93 e 0,68 (meninas) e 0,93, 0,93 e 0,89 (meninos) para CA, IMC e HR, respectivamente. Os valores de corte foram 83,0 e 80,5 cm (CA), 22,7 e 20,4 kg/m² (IMC) e 1,65 e 1,95 (HR), para meninas e meninos, respectivamente, para detecção do grupo de fatores de risco cardiovascular. CONCLUSÃO: Esses valores de IMC,CA e HR detectaram uma porcentagem significativa de crianças e adolescentes brasileiros com TNG e elevado risco cardiovascular.

Optimal cutoff points for body mass index, waist circumference and HOMA-IR to identify a cluster of cardiometabolic abnormalities in normal glucose-tolerant Brazilian children and adolescents.

OBJECTIVE: The aim of this study was to establish the best cutoff values for waist circumference (WC), body mass index (BMI) and HOMA-IR (HR) to identify a cluster (≥ 3) of cardiovascular risk factors (CVRF) in normal glucose-tolerant (NGT) Brazilian children and adolescents. SUBJECTS AND METHODS: Cross-sectional study of 319 individuals (aged 10 to 19y) from a southern Brazilian city. Gender-specific receiver-operating characteristics (ROC) curves were constructed to assess cutoffs values of BMI (kg/m(2), WC (cm), and HR. RESULTS: The areas under the ROC curves to detect a cluster of CVRF were 0.92, 0.93 and 0.68 (females), and 0.93, 0.93 and 0.89 (males), for WC, BMI and HR, respectively. The cutoff values were 83.0 and 80.5 cm (WC), 22.7 and 20.4 kg/m(2) (BMI), and 1.65 and 1.95 (HR), for females and males, respectively, to detect the cluster of CVRF. CONCLUSION: These values of BMI, WC-) and (HR) detected a high proportion of NGTt Brazilian children and adolescents with a cluster of CVRF.

Biochemical, biometrical and behavioral changes in male offspring of sleep-deprived mice.

Epidemiological and experimental studies suggest a high prevalence of cognitive impairment and social behavior deficits in adolescents and adults that have experienced prenatal exposure to adverse conditions. This study investigated whether sleep deprivation during the pre-implantation stage of development alters the physiological, behavioral and oxidative metabolic processes in adult male mouse offspring. One group of dams was continuously sleep-deprived using the platform technique from gestational days 0 to 3 (PSD 72). Three additional groups were sleep-deprived by gentle handling for 6h on gestational days 1 (GH 1), 2 (GH 2) or 3 (GH 3). After sleep deprivation, homocysteine, cysteine, corticosterone, estrogen and progesterone concentrations were measured from the experimental mothers and time-matched controls. The sizes and weights of the male pups were measured at various stages throughout the experiment. At PND 90, behavioral (Activity Box and Elevated Plus Maze) and biochemical parameters were assessed. The dams' plasma progesterone concentrations decreased in the PSD 72 group, and the levels of plasma estradiol increased in GH 2. Corticosterone levels were found to increase after all sleep-deprivation procedures. Homocysteine concentrations increased in the GH 2 but decreased in the PSD 72 group. The offspring of GH 1 mothers exhibited decreased superoxide dismutase activity. Exposure to sleep deprivation had a long-lasting impact on tissue weight; in particular, there was a decrease in hemilateral epididymal fat weight in mature animals from the PSD 72 group. Although some of the alterations observed in the mothers (elevated estrogen and corticosterone levels and decreased progesterone) might have played a role in the permanent alterations in the adult offspring, they were not the main cause. The homocysteine changes detected in the sleep-deprived dams may contribute to redox changes, controlling gene expression and shaping epigenetic development.