Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.     

Preliminary Study of the Fungal Ecology at the Haematology and Medical-Oncology Ward in Bamako,Mali

Data on fungal epidemiology in sub-Saharan African countries are scarce. This exploratory study aimed to characterize the fungal flora at the Onco-Haematology ward of the National Teaching Hospital of Point G in Bamako, Mali. A cross-sectional survey was conducted in the dry and in the rainy seasons. Nasal swab and sputum samples were collected from the hospitalized patients while airborne fungal spores were collected using electrostatic dust-fall collectors. Fungi were identified by their morphological characteristics and MALDI-TOF mass spectrometry. Candida albicans was the most frequent yeast species colonizing patients; Aspergillus species were isolated in 86 % of the patients and were the main airborne environmental contaminants. Overall, airborne fungal contamination rates increased from 33.8 % in the dry to 66.2 % in the rainy season (p < 0.001). The most frequent Aspergillus species were Aspergillus niger (36.6 %) and Aspergillus flavus (32.92 %). In contrast, Aspergillus fumigatus (5.43 %) was relatively rare. This high level of fungal exposure raises concern regarding the management of at-risk patients in this Onco-Haematology ward and stresses the need for strengthening the mycological diagnostic capacities to accompany the implementation of adapted fungal infection prevention and management policies.     

Population Genetics of Two Key Mosquito Vectors of Rift Valley Fever Virus Reveals New Insights into the Changing Disease Outbreak Patterns in Kenya

Rift Valley fever (RVF) outbreaks in Kenya have increased in frequency and range to include northeastern Kenya where viruses are increasingly being isolated from known (Aedes mcintoshi) and newly-associated (Ae. ochraceus) vectors. The factors contributing to these changing outbreak patterns are unclear and the population genetic structure of key vectors and/or specific virus-vector associations, in particular, are under-studied. By conducting mitochondrial and nuclear DNA analyses on >220 Kenyan specimens of Ae. mcintoshi and Ae. ochraceus, we uncovered high levels of vector complexity which may partly explain the disease outbreak pattern. Results indicate that Ae. mcintoshi consists of a species complex with one of the member species being unique to the newly-established RVF outbreak-prone northeastern region of Kenya, whereas Ae. ochraceus is a homogeneous population that appears to be undergoing expansion. Characterization of specimens from a RVF-prone site in Senegal, where Ae. ochraceus is a primary vector, revealed direct genetic links between the two Ae. ochraceus populations from both countries. Our data strongly suggest that unlike Ae. mcintoshi, Ae. ochraceus appears to be a relatively recent, single ''introduction'' into Kenya. These results, together with increasing isolations from this vector, indicate that Ae. ochraceus will likely be of greater epidemiological importance in future RVF outbreaks in Kenya. Furthermore, the overall vector complexity calls into question the feasibility of mosquito population control approaches reliant on genetic modification.     

Combined Ablation and Resection (CARe) as an Effective Parenchymal Sparing Treatment for Extensive Colorectal Liver Metastases

Background

Combined intra-operative ablation and resection (CARe) is proposed to treat extensive colorectal liver metastases (CLM). This multicenter study was conducted to evaluate overall survival (OS), local recurrence-free survival (LRFS), hepatic recurrence-free survival (HRFS) and progression-free survival (PFS), to identify factors associated with survival, and to report complications.

Materials and Methods

Four centers combined retropectively their clinical experiences regarding CLM treated by CARe. CLM characteristics, pre- and post-operative chemotherapy regimens, surgical procedures, complications and survivals were analyzed.

Results

Of the 288 patients who received CARe, 210 (73%) had synchronous and 255 (88%) had bilateral CLM. Twenty-two patients (8%) had extrahepatic disease. Median follow-up was 3.17 years (95%CI 2.83–4.08). Median OS was 3.33 years (95%CI 3.08–4.17) and 5-year OS was 37% (95%CI 29–45). One- and 5-year LRFS from ablated lesions were 87.9% (95%CI 83.3–91.2) and 78.0% (95%CI 71–83), respectively. Median HRFS and PFS were 14 months (95%CI 11–18) and 9 months (95%CI 8–11), respectively. One hundred patients experienced complications: 29 grade I, 68 grade II–III–IV, and three deaths. In the multivariate models adjusted for center, the occurrence of complications was confirmed as a major independent factor associated with 3-year OS (HR 1.80; P = 0.008). Five-year OS was 25.6% (95%CI 14.9–37.6) for patients with complications and 45% (95%CI 33.3–53.4) for patients without.

Conclusions

Recent strategies facing advanced CLM include non-anatomic resections, portal-induced hypertrophy of the future remnant liver and aggressive medical preoperative treatments. CARe has the qualities of an approach that allows effective tumor clearance while maintaining good tolerance for the patient.     

A comparison of thick smears, QBC malaria, PCR and PATH falciparum malaria test trip in Plasmodium falciparum diagnosis.

Blood samples from 182 patients presenting at the out-patient clinic in Richard-Toll. Senegal were analysed by Thick smear microscopy, the QBC, PCR and the new dipstick PATH Malaria assay which detects the histidine rich protein II antigen of Plasmodium falciparum. Thick smear microscopy was used as the reference method. Sensitivity, specificity, predictive positive and negative values were 100%, 83.6%, 93.4% and 100% QBC respectively; 100%, 72.7%, 89.4% and 100% for PCR; 96%, 92.7%, 96.8% and 91% for the PATH assay. PATH assay failed to detect one positive sample with Plasmodium malariae. Assays were also compared with regard to the expense of equipment and reagents and speed and ease of use. The rapid PATH assay can be performed with minimal training and may be specially useful in areas where P. falciparum is the predominant malaria species, in epidemic malaria regions, and where skilled microscopy is not readily available.