Timmcook6219

Exome sequencing has enabled molecular diagnoses for rare disease patients but often with initial diagnostic rates of ~25-30%. Here we develop a robust computational pipeline to rank variants for reassessment of unsolved rare disease patients. A comprehensive web-based patient report is generated in which all deleterious variants can be filtered by gene, variant characteristics, OMIM disease and Phenolyzer scores, and all are annotated with an ACMG classification and links to ClinVar. The pipeline ranked 21/34 previously diagnosed variants as top, with 26 in total ranked ≤7th, 3 ranked ≥13th; 5 failed the pipeline filters. Pathogenic/likely pathogenic variants by ACMG criteria were identified for 22/145 unsolved cases, and a previously undefined candidate disease variant for 27/145. This open access pipeline supports the partnership between clinical and research laboratories to improve the diagnosis of unsolved exomes. It provides a flexible framework for iterative developments to further improve diagnosis.

Spinal cord injury (SCI) with atlantoaxial dislocation (AAD) is often fatal. We present the case of a resuscitated patient with AAD and traumatic subarachnoid hemorrhage (SAH) at the craniovertebral junction (CVJ).

We present the case of an 84-year-old man who suffered an observed cardiopulmonary arrest. Cardiopulmonary resuscitation was initiated and spontaneous circulation returned. In the emergency room, the patient's Glasgow Coma Scale was 3 (E1V1M1). No spontaneous respiration was noted. Neuroimaging revealed SAH at the CVJ. Contrast-enhanced computed tomography (CT) revealed a vessel running through the left C2/3 intervertebral foramen into the spinal canal. The ventral space of spinal cord revealed contrast enhancement. Angiography revealed extravasation from the spinal branch of the left vertebral artery, without venous filling. It did not appear to be a vascular malformation with an arteriovenous shunt, but rather a traumatic laceration of the artery. Plain CT and CT angiography suggested AAD. Magnetic resonance imaging revealed injury to the medulla oblongata and upper cervical spinal cord, with AAD and retrodental subligamentous hemorrhage. We embolized the branch of the left vertebral artery and performed a C1 laminectomy. The patient moved his extremities postoperatively.

This was a case of injury to the medulla oblongata and upper cervical spinal cord due to AAD with SAH. This is the first report of resuscitated case of traumatic AAD with SAH in the CVJ. Traumatic AAD should be included in the differential diagnosis in case of SAH in CVJ, which may be misdiagnosed as intrinsic SAH.

This was a case of injury to the medulla oblongata and upper cervical spinal cord due to AAD with SAH. This is the first report of resuscitated case of traumatic AAD with SAH in the CVJ. Traumatic AAD should be included in the differential diagnosis in case of SAH in CVJ, which may be misdiagnosed as intrinsic SAH.Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis. Here we report the identification of the hexosamine D-mannosamine (ManN) as an EC mitogen and survival factor for bovine and human microvascular EC, with an additivity with VEGF. ManN inhibits glycosylation in ECs and induces significant changes in N-glycan and O-glycan profiles. We further demonstrate that ManN and two N-glycosylation inhibitors stimulate EC proliferation via both JNK activation and the unfolded protein response caused by ER stress. ManN results in enhanced angiogenesis in a mouse skin injury model. ManN also promotes angiogenesis in a mouse hindlimb ischemia model, with accelerated limb blood flow recovery compared to controls. MIK665 manufacturer In addition, intraocular injection of ManN induces retinal neovascularization. Therefore, activation of stress pathways following inhibition of protein glycosylation can promote EC proliferation and angiogenesis and may represent a therapeutic strategy for treatment of ischemic disorders.Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine's effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.Recurrent pregnancy loss is a distressing pregnancy disorder experienced by ~2.5% of women trying to conceive. Recurrent pregnancy loss is defined as the failure of two or more clinically recognized pregnancies before 20-24 weeks of gestation and includes embryonic and fetal losses. The diagnosis of an early pregnancy loss is relatively straightforward, although progress in predicting and preventing recurrent pregnancy loss has been hampered by a lack of standardized definitions, the uncertainties surrounding the pathogenesis and the highly variable clinical presentation. The prognosis for couples with recurrent pregnancy loss is generally good, although the likelihood of a successful pregnancy depends on maternal age and the number of previous losses. Recurrent pregnancy loss can be caused by chromosomal errors, anatomical uterine defects, autoimmune disorders and endometrial dysfunction. Available treatments target the putative risk factors of pregnancy loss, although the effectiveness of many medical interventions is controversial.