Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats

The aim of this work was to study in rats the nasal route for the brain delivery of the vasoactive intestinal peptide (VIP) neuropeptide. After evaluating VIP stability in solutions obtained from nasal washes, the effect of formulation parameters (pH 4-9, 0-1% (w/v) lauroylcarnitine (LC), hypo- or isoosmolality) on the brain uptake of intranasally administered VIP (10(-8)M)/125I-VIP (300,000 cpm/ml) was studied, using an in situ perfusion technique. Brain radioactivity distribution was assessed by quantitative autoradiographic analysis. Results were compared to intravenously administered VIP. With a hypotonic formulation at pH 4 containing 0.1% LC and 1% bovine serum albumin, VIP stability was satisfactory and loss by adsorption was minimal. Using this formulation, around 0.11% of initial radioactivity was found in the brain after 30 min perfusion and was located in the olfactory bulbs, the midbrain and the cerebellum. HPLC analysis of brain and blood extracts demonstrated the presence of intact VIP in brain and its complete degradation in the blood compartment. By intravenous administration, no intact VIP was found either in brain or in blood. In conclusion, intact VIP could be delivered successfully to the brain using the intranasal route for administration

Language representation and presurgical language mapping in pediatric epilepsy: A narrative review

AbstractAs one of the most common neurological diseases in children, epilepsy affects 0.9–2% of children. Complex interactions among the etiologies of the epilepsy, interictal discharges, seizures and antiepileptic drugs lead to cognitive impairments in children with epilepsy. Since epilepsy is considered as a network disorder that seizures have widespread impact on many parts of the brain, childhood epilepsy can even affect the normal development of language. About 25% of children with epilepsy do not respond to medications, therefore brain surgery is considered as a treatment option for some of them. Presurgical neuropsychological evaluations including language mapping is recommended to preserve cognitive and language abilities of patients after surgery.  Functional magnetic resonance imaging as a non-invasive technique for presurgical language mapping   has been widely recommended in many epileptic centers. The present study reviewed language representation and presurgical language mapping in children with epilepsy. In addition, mapping language in children with epilepsy helps to localize epileptogenic zone, to predict cognitive outcome of epilepsy surgery, and possible cognitive rehabilitation. This review gathered information about language representation and language mapping in pediatric   epilepsy settings. Key Words: pediatric epilepsy, language development, presurgical evaluation, language lateralit

Default mode network segregation and social deficits in autism spectrum disorder: Evidence from non-medicated children DMN in children with ASD

AbstractFunctional pathology of the default mode network is posited to be central to social-cognitive impairment in autism spectrum disorders (ASD). Altered functional connectivity of the default mode network's midline core may be a potential endophenotype for social deficits in ASD. Generalizability from prior studies is limited by inclusion of medicated participants and by methods favoring restricted examination of network function. This study measured resting-state functional connectivity in 22 8–13 year-old non-medicated children with ASD and 22 typically developing controls using seed-based and network segregation functional connectivity methods. Relative to controls the ASD group showed both under- and over-functional connectivity within default mode and non-default mode regions, respectively. ASD symptoms correlated negatively with the connection strength of the default mode midline core—medial prefrontal cortex–posterior cingulate cortex. Network segregation analysis with the participation coefficient showed a higher area under the curve for the ASD group. Our findings demonstrate that the default mode network in ASD shows a pattern of poor segregation with both functional connectivity metrics. This study confirms the potential for the functional connection of the midline core as an endophenotype for social deficits. Poor segregation of the default mode network is consistent with an excitation/inhibition imbalance model of ASD

Same habitat types but different use: evidence of context-dependent habitat selection in roe deer across populations

International audienceWith the surge of GPS-technology, many studies uncovered space use of mobile animals and shed light on the underlying behavioral mechanisms of habitat selection. Habitat selection and variation in either occurrence or strength of functional responses (i.e. how selection changes with availability) have given new insight into such mechanisms within populations in different ecosystems. However, linking variation in habitat selection to site-specific conditions in different populations facing contrasting environmental conditions but the same habitat type has not yet been investigated. We aimed to fill this knowledge gap by comparing within-home range habitat selection across 61 female roe deer (Capreolus capreolus) during the most critical life history stage in three study areas showing the same habitat types but with different environmental conditions. Female roe deer markedly differed in habitat selection within their home range, both within and among populations. Females facing poor environmental conditions clearly displayed a functional response, whereas females facing rich environmental conditions did not show any functional response. These results demonstrate how the use of a given habitat relative to its availability strongly varies in response to environmental conditions. Our findings highlight that the same habitat composition can lead to very different habitat selection processes across contrasted environments

Questioning the rise of gelatinous zooplankton in the World's oceans

During the past several decades, high numbers of gelatinous zooplankton species have been reported in many estuarine and coastal ecosystems. Coupled with media-driven public perception, a paradigm has evolved in which the global ocean ecosystems are thought to be heading toward being dominated by “nuisance” jellyfish. We question this current paradigm by presenting a broad overview of gelatinous zooplankton in a historicalcontext to develop the hypothesis that population changes reflect the human-mediated alteration of global ocean ecosystems. To this end, we synthesize information related to the evolutionary context of contemporary gelatinous zooplankton blooms, the human frame of reference forchanges in gelatinous zooplankton populations, and whether sufficient data are available to have established the paradigm. We conclude that the current paradigm in which it is believed that there has been a global increase in gelatinous zooplankton is unsubstantiated, and we develop a strategy for addressing the critical questions about long-term, human-related changes in the sea as they relate to gelatinous zooplankton blooms

DNA replication stress restricts ribosomal DNA copy number

Ribosomal RNAs (rRNAs) in budding yeast are encoded by ~100–200 repeats of a 9.1kb sequence arranged in tandem on chromosome XII, the ribosomal DNA (rDNA) locus. Copy number of rDNA repeat units in eukaryotic cells is maintained far in excess of the requirement for ribosome biogenesis. Despite the importance of the repeats for both ribosomal and non-ribosomal functions, it is currently not known how “normal” copy number is determined or maintained. To identify essential genes involved in the maintenance of rDNA copy number, we developed a droplet digital PCR based assay to measure rDNA copy number in yeast and used it to screen a yeast conditional temperature-sensitive mutant collection of essential genes. Our screen revealed that low rDNA copy number is associated with compromised DNA replication. Further, subculturing yeast under two separate conditions of DNA replication stress selected for a contraction of the rDNA array independent of the replication fork blocking protein, Fob1. Interestingly, cells with a contracted array grew better than their counterparts with normal copy number under conditions of DNA replication stress. Our data indicate that DNA replication stresses select for a smaller rDNA array. We speculate that this liberates scarce replication factors for use by the rest of the genome, which in turn helps cells complete DNA replication and continue to propagate. Interestingly, tumors from mini chromosome maintenance 2 (MCM2)-deficient mice also show a loss of rDNA repeats. Our data suggest that a reduction in rDNA copy number may indicate a history of DNA replication stress, and that rDNA array size could serve as a diagnostic marker for replication stress. Taken together, these data begin to suggest the selective pressures that combine to yield a “normal” rDNA copy number

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): a randomised, open-label phase 2/3 trial

BACKGROUND: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma. METHODS: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m(2) by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m(2) by body surface area once every 4 weeks; intravenous topotecan 4 mg/m(2) by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting. FINDINGS: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9–15·0) compared with 7·2 months (5·6–9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36–0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths. INTERPRETATION: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma. FUNDING: NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis