Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

Mitochondrial diseases: an overview of genetics, pathogenesis, clinical features and an approach to diagnosis and treatment

Defects in structures or functions of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis and other metabolic pathways have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogenecity of mitochondrial diseases. This article focuses on the recent advances in the field of mitochondrial disorders with respect to the consequences for an advanced clinical and genetic diagnostics. In addition, an overview on recently identified genetic defects and their pathogenic molecular mechanisms are given.     

Genetic mapping of genes regulating the thymus size in back-cross rats between the laboratory BUF/Mna strain and the MITE strain derived from the wild rat, Rattus norvegicus

The thymoma prone BUF/Mna (B) rat is a useful model for Studying the genes responsible for thymus enlargement during the stage of young growth. Among the strains of rats, B rats have the largest thymuses at al stages of life. A locus, Ten-1 , which contributes to thymus enlargement in back-cross (BC) rats between the B and WKY/NCrj (W) strains, was mapped on chromosome 1. To determine the precise location of the bus, (B×(B×MITE)F1) BC rats were generated by crossing the B strain with the Inbred MITE (M) strain, which was established from captured, Japanese wild rats, and were examined by linkage study using polymerase chain reaction with 67 microsatellite markers. Linkages with thymus enlargements were found In genotypes of seven markers, BSIS, LSN, MYL2, IGF2, PBPC2, D1Mgh11 , and D1Mit6 , by X^2-test and Student's t -test, which confirmed the presence of the genetic locus associated with thymus enlargement, Ten-1 , in this region. Paradoxically, a suppressive locus, Tsu-1 , to thymus enlargement was also found on chromosome 3, showing linkages of phenotype of the small thymus with genotypes of SCN2A, CAT D3Mit16 , and D3Mit13 . By analyses of mapmaker/exp and mapmaker/qtl, Ten-1 was mapped at 4.6 cM proximal from IGF2 locus on chromosome 1 and Tsu-1 at 4.0 cM proximal from CAT locus on chromosome 3, respectively.     

Learning disabilities and school problems in a regional cohort of extremely low birth weight (less than 1000 G) children: a comparison with term controls

We compared the prevalence of learning disabilities at age 8 years in a subgroup of 68 of 129 (53%) regional cohort of extremely low birth weight (ELBW) children who were considered "normal" neurologically and intellectually (IQ greater than or equal to 85) with that of 114 term group matched controls (C). Both groups were tested with a battery of psychoeducational measures, and parents and teachers completed questionnaires on the school performance of the children. ELBW children were comparable with C on measures of intelligence (ELBW 101 +/- 8, C 104 +/- 11), language, and academic achievement but fared significantly less well in motor performance (p less than .0001). The prevalence of learning disabilities (by predefined criteria) in ELBW children (26%) was not increased compared with C (19%). However, teachers rated significantly more ELBW children as performing below grade level than were C (31% vs 16%, p less than .05), and by parent report, a higher proportion of ELBW children had received special assistance in school compared with C (37% vs 16%, p less than .001). We conclude that although the prevalence of learning disabilities in normal ELBW children was not different from that in controls, ELBW children did less well and utilized more special resources.     

Elevated maternal serum-free β-human chorionic gonadotropin (β-hCG) and reduced risk of spontaneous preterm delivery*

Objective: To evaluate the relationship between first and second trimester maternal serum-free β-hCG and the risk of spontaneous preterm delivery (PTD).

Study design: This was a case-control study of women evaluated and delivered at our institution from 2011 to 2015. Spontaneous PTD was defined as delivery before 37 weeks due to spontaneous preterm labor or premature rupture of membranes. Patient with multifetal gestation and those with medically indicated term or PTD were excluded.

Results: Of 877 women meeting the inclusion criteria, 173 delivered preterm and 704 delivered at term, and 8.1% had high free β-hCG in one or both trimesters. High maternal first and/or second trimester free β-hCG (≥95th percentile) was associated with lower rates of PTD. Thirty-two women with high free β-hCG in both first and second trimesters delivered at term. Gestational age at delivery and birth weights were lower in women who did not have high free β-hCG in any trimester. Low free β-hCG (≤5th percentile) in either trimester was not associated with an increased or decreased likelihood of PTD. Logistic regression demonstrated an independent association of high free β-hCG (≥95th percentile) with a reduced likelihood of PTD. Stratified analysis revealed a stronger impact of this association in women with no prior history of PTD.

Conclusions: High free β-hCG, in the absence of risk factors for medically indicated PTD, is associated with a reduced likelihood of spontaneous PTD and may represent a marker indicating lower risk.     

Criteria for Emergency Brain MRI During Stroke-Alert

ObjectivesIntravenous (IV) tissue plasminogen activator (tPA) should be given to patients with acute ischemic stroke (AIS) and avoided in stroke mimics (SM). Select use of emergency brain magnetic resonance imaging (eMRI-brain) in stroke-alerts aids diagnosis, but accepted utilization criteria for eMRI-brain do not currently exist. We developed criteria for eMRI-brain and report the yield of eMRI-brain in stroke-alert patients.Materials and MethodsWe developed three history-based criteria for performing eMRI-brain during stroke-alerts: (1) history of previous similar deficits, (2) change in consciousness at onset of symptoms, (3) symptom presentation consistent with migraine aura. We then performed a retrospective chart review of patients who presented as a stroke-alert over a 5-year period and determined how these criteria affected administration of IV tPA to AIS and SM patients.ResultsAmong 3,512 stroke-alerts, 230 (8.1%) patients met our criteria for eMRI-brain exams: 217 (92.6%) had SM and 17 (7.4%) had AIS. Our IV tPA decision-making analysis showed that based on eMRI-brain IV tPA was less frequently administered to SM patients (PCC-0.841, p=0.036) with less failures to administer IV tPA to patients with AIS (PCC -0.907, p-value=0.013, Pearson correlation coefficient). No patients became ineligible for IV tPA due to MRI-related time delays.ConclusionsOur history based criteria for performing eMRI-brain during stroke-alerts show a high yield of stroke mimics. Selective eMRI-brain improves decision-making accuracy regarding IV tPA administration.