Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis

Targeting targeted agents: open issues for clinical trial design

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Low-Radiation-Dose Modified Small Bowel CT for Evaluation of Recurrent Crohn's Disease

Crohn's disease affects any part of the GI tract, commonly the terminal ileum. To decrease radiation exposure we developed a low-radiation-dose unenhanced CT (modified small Bowel CT, MBCT) to evaluate the small bowel using hyperdense oral contrast. Technique. MBCT was investigated in patients with pathologically proven Crohn's disease presenting with new symptoms from recurrent inflammation or stricture. After ethics board approval, 98 consecutive patients were retrospectively evaluated. Kappa values from two independent reviewers were calculated for presence of obstruction, active inflammation versus chronic stricture, and ancillary findings. Forty-two patients underwent surgery or colonoscopy within 3 months. Results. Kappa was 0.84 for presence of abnormality versus a normal exam and 0.89 for differentiating active inflammation from chronic stricture. Level of agreement for presence of skip areas, abscess formation, and fistula was 0.62, 0.75, and 0.78, respectively. In the subset with “gold standard” follow-up, there was 83% agreement. Conclusions. MBCT is a low-radiation technique with good to very good interobserver agreement for determining presence of obstruction and degree of disease activity in patients with Crohn's disease. Further investigation is required to refine parameters of disease activity compared to CT enterography and small bowel follow through

Multidisciplinary Retroperitoneal and Pelvic Soft-Tissue Sarcoma Case Conferences: The Added Value that Radiologists Can Provide

Clinical Vignette: A 50-year-old woman presents to the emergency department with increasing abdominal pain. Abdominal computed tomography imaging reveals an expanded inferior vena cava–filling defect that is suspicious for a retroperitoneal sarcoma, possibly a primary leiomyosarcoma of the inferior vena cava. The surgery team discusses the case with the radiologist, and all agree that there are multiple challenges with obtaining a tissue diagnosis and determining resectability. Thus, it is decided that this patient should be discussed at a multidisciplinary case conference. In the present article, we feature a case-based scenario focusing on the role of the radiologist in this type of multidisciplinary team