GHB-Induced Cognitive Deficits During Adolescence and the Role of NMDA Receptor

We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex.     

E-cadherin expression in postnatal Schwann cells is regulated by the cAMP-dependent protein kinase a pathway

Expression of E-cadherin in the peripheral nervous system is a highly regulated process that appears postnatally in concert with the development of myelinating Schwann cell lineage. As a major component of autotypic junctions, E-cadherin plays an important role in maintaining the structural integrity of noncompact myelin regions. In vivo, the appearance of E-cadherin in postnatal Schwann cell is accompanied by the disappearance of N-cadherin, suggesting reciprocal regulation of the two cadherins during Schwann cell development. The molecular signal that regulates the cadherin switch in Schwann cell is unclear. Using a neuron-Schwann cell co-culture system, here we show that E-cadherin expression is induced by components on the axonal membrane. We also show that the axonal effect is mediated through cAMP-dependent protein kinase A (cAMP-PKA) activation in the Schwann cell: (1) inhibition of cAMP-PKA blocks axon-induced E-cadherin expression and (2) cAMP elevation in the Schwann cell is sufficient to induce E-cadherin expression. In addition, cAMP-dependent E-cadherin expression is promoted by contact between adjacent Schwann cell membranes, suggesting its role in autotypic junction formation during myelination. Furthermore, cAMP-induced E-cadherin expression is accompanied by suppression of N-cadherin expression. Therefore, we propose that axon-dependent activation of cAMP-PKA serves as a signal that promotes cadherin switch during postnatal development of Schwann cells.     

Relief from sleep apnea after radiation and chemotherapy

Superior vena cava syndrome (SVCS) can result from extrinsic compression by a primary tumor, mediastinal lymph nodes metastases, benign lesions, or intraluminal thrombosis. The association between obstructive sleep apnea and SVCS has not been extensively evaluated. To our knowledge, only 5 cases of obstructive sleep apnea in SVCS have been reported in the literature. We presented a 53-year-old man who was admitted with dyspnea, edema of the face, and excessive daytime sleepiness. Chest radiography and computed tomography revealed lung cancer. A biopsy of the tumor revealed squamous cell carcinoma. Obstructive sleep apnea was diagnosed by polysomnography (apnea hypopnea index: 13 per hour). After radiation and chemotherapy, edema of the face, snoring, and daytime sleepiness were alleviated, and the patient's apnea hypopnea index decreased to 0.6 per hour. In conclusion, there is a relationship between obstructive sleep apnea and SVCS.     

Structural imaging of the brain reveals decreased total brain and total gray matter volumes in obese but not in lean women with polycystic ovary syndrome compared to body mass index-matched counterparts

Purpose: To detect differences in global brain volumes and identify relations between brain volume and appetite-related hormones in women with polycystic ovary syndrome (PCOS) compared to body mass index-matched controls.

Methods: Forty subjects participated in this study. Cranial magnetic resonance imaging and measurements of fasting ghrelin, leptin and glucagon-like peptide 1 (GLP-1), as well as GLP-1 levels during mixed-meal tolerance test (MTT), were performed.

Results: Total brain volume and total gray matter volume (GMV) were decreased in obese PCOS compared to obese controls (p?p?p?Conclusion: This study, investigating structural brain alterations in PCOS, suggests volumetric reductions in global brain areas in obese women with PCOS. Functional studies with larger sample size are needed to determine physiopathological roles of these changes and potential effects of long-term medical management on brain structure of PCOS.     

Permanent neonatal diabetes with arthrogryposis multiplex congenita and neurogenic bladder – a new syndrome?

Abstract: Neonatal diabetes mellitus is a rare (1/400 000 newborns) but potentially devastating condition, which may be transient or permanent; typical symptoms occur within the first 4 wk of life. The transient form is a developmental insulin production disorder that resolves postnatally. Fifty to 60% of cases can be seen as transient form. Cases that require lifelong insulin therapy can be described as permanent condition. This fraction of cases is less common than the transient form. There are no clinical features that can predict whether a neonate with diabetes mellitus but no other dysmorphology will eventually have permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus. Some metabolic or genetic defects such as complete deficiency of glucokinase or heterozygous activating mutations of KCNJ11, encoding Kir6.2, were found in patients with PNDM. A preterm female infant with a gestational age of 36 wk was admitted to the neonatal intensive care unit in the first hours of life due to prematurity and intra‐uterine growth retardation. She was diagnosed as having arthrogryposis multiplex congenita on the first day. Hyperglycemia was detected on the third day of life, and she required insulin treatment. The patient is now 6 yr old with PNDM, arthrogryposis multiplex, neurogenic bladder, immune deficiency, constipation, and ichthyosis. Is this a new form of neonatal diabetes mellitus?     

Missense mutation in the ATPase,aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion

Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans.     

Measurement of the distance and angle between the aorta and superior mesenteric artery: normal values in different BMI categories

Aim The purpose of the study was to reveal the values of the distance and angle between the superior mesenteric artery (SMA) and aorta according to body mass index in normal population. Material and methods The study was performed on 524 routine abdominal CT examinations. On axial and reformatted sagittal–oblique sagittal images, the distance and the angle between superior mesenteric artery (SMA) and aorta were measured at the location where the duodenum crosses. Body mass index (BMI, Kg/m2) was calculated. The cases were divided into four groups according to the BMI categories (Group 1: BMI<18.5, Group 2: BMI 18.5–24.9, Group 3: BMI 25–29.9, Group 4: BMI>30) in both genders. For each gender group, mean values of distance and angle measurements were calculated with standard deviations and 95% confidence intervals. For each gender group, Pearson correlation coefficients were calculated between the distance and BMI, as well as between the angle and BMI. Spearman correlation coefficients were calculated between the distance and BMI category, as well as between the angle and BMI category. Results For both genders, there was a moderate and significant positive correlation between the distance and BMI. The correlation between the angle and BMI was low, but significant and positive (P < 0.001). The correlations between the BMI category and aortomesenteric distance or angle were moderate and significantly positive, as well (P < 0.001). Conclusion The aortomesenteric angle and distance significantly correlate with BMI in normal population. The mean values, we report, may be used as normal values to help reach the diagnosis of superior mesenteric artery syndrome.     

Palmitic acid substitution on cationic polymers for effective delivery of plasmid DNA to bone marrow stromal cells

Nonviral gene carriers are actively explored in gene therapy due to safety concerns of the viral carriers. To design effective gene carriers for modification of bone marrow stromal cells (BMSC), an important cell phenotype for clinical application of gene therapy, cationic polymers polyethyleneimine (PEI), and poly-L-Lysine (PLL) were substituted with palmitic acid (PA) via amide linkages. Depending on the reaction conditions, PEI and PLL was substituted with 2.2-5.2 and 13.4-16.2 PA per polymer chain. The PA substituted polymers displayed slightly lower binding efficiency towards a plasmid containing Enhanced Green Fluorescent Protein (pEGFP) in an agarose gel binding assay. The cell binding of PLL-PA, but not PEI-PA, was particularly enhanced, resulting in higher percentage of the cells displaying a significant polymer uptake. pEGFP delivery into the BMSC was also significantly increased with the PLL-PA (vs. PLL), but not PEI-PA (vs. PEI). The transfection efficiency of PLL-PA was significantly higher ( approximately fivefold) than the unmodified polymer. We conclude that PA substitution on PLL provides an effective carrier for transfection of primary cells derived from the bone marrow.