Recruitment of Plasma Membrane GABA-A Receptors by Submembranous Gephyrin/Collybistin Clusters.

It has been shown that subunit composition is the main determinant of the synaptic or extrasynaptic localization of GABAA receptors (GABAARs). Synaptic and extrasynaptic GABAARs are involved in phasic and tonic inhibition, respectively. It has been proposed that synaptic GABAARs bind to the postsynaptic gephyrin/collybistin (Geph/CB) lattice, but not the typically extrasynaptic GABAARs. Nevertheless, there are no studies of the direct binding of various types of GABAARs with the submembranous Geph/CB lattice in the absence of other synaptic proteins, some of which are known to interact with GABAARs. We have reconstituted GABAARs of various subunit compositions, together with the Geph/CB scaffold, in HEK293 cells, and have investigated the recruitment of surface GABAARs by submembranous Geph/CB clusters. Results show that the typically synaptic α1ß3γ2 GABAARs were trapped by submembranous Geph/CB clusters. The α5ß3γ2 GABAARs, which are both synaptic and extrasynaptic, were also trapped by Geph/CB clusters. Extrasynaptic α4ß3δ GABAARs consistently showed little or no trapping by the Geph/CB clusters. However, the extrasynaptic α6ß3δ, α1ß3, α6ß3 (and less α4ß3) GABAARs were highly trapped by the Geph/CB clusters. AMPA and NMDA glutamate receptors were not trapped. The results suggest: (I) in the absence of other synaptic molecules, the Geph/CB lattice has the capacity to trap not only synaptic but also several typically extrasynaptic GABAARs; (II) the Geph/CB lattice is important but does not play a decisive role in the synaptic localization of GABAARs; and (III) in neurons there must be mechanisms preventing the trapping of several typically extrasynaptic GABAARs by the postsynaptic Geph/CB lattice.

Collybistin SH3-protein isoforms are expressed in the rat brain promoting gephyrin and GABA-A receptor clustering at GABAergic synapses.

Collybistin (CB) is a guanine nucleotide exchange factor (GEF) selectively localized at GABAergic and glycinergic postsynapses. Analysis of mRNA shows that several isoforms of collybistin are expressed in the brain. Some of the isoforms have a SH3 domain (CBSH3+) and some have no SH3 domain (CBSH3-). The CBSH3+ mRNAs are predominantly expressed over CBSH3-. However, in an immunoblot study of mouse brain homogenates, only CBSH3+ protein isoforms were detected, proposing that CBSH3- protein might not be expressed in the brain. The expression or lack of expression of CBSH3- protein is an important issue because CBSH3- has a strong effect in promoting the postsynaptic clustering of gephyrin and GABA-A receptors (GABAA Rs). Moreover CBSH3- is constitutively active; therefore lower expression of CBSH3- protein might play a relatively stronger functional role than the more abundant but self-inhibited CBSH3+ isoforms, which need to be activated. We are now showing that: (a) CBSH3- protein is expressed in the brain; (b) parvalbumin positive (PV+) interneurons show higher expression of CBSH3- protein than other neurons; (c) CBSH3- is associated with GABAergic synapses in various regions of the brain and (d) knocking down CBSH3- in hippocampal neurons decreases the synaptic clustering of gephyrin and GABAA Rs. The results show that CBSH3- protein is expressed in the brain and that it plays a significant role in the size regulation of the GABAergic postsynapse.

Thrombosis of the inferior vena cava secondary to incidental portal vein aneurysm.

Aneurysm of the portal vein is a rare type of visceral aneurysm that is largely asymptomatic although some patients may develop symptoms or secondary complications. In this report, we present the first case in the literature of inferior vena cava (IVC) thrombosis arising as a consequence of portal vein aneurysm. A 95-year-old male with past medical history significant for hypertension, hypercholesterolemia, type II diabetes mellitus, benign prostatic hyperplasia, and gastroesophageal reflux presented to the emergency department with several days of altered mental status, disorganized behavior, visual hallucinations, and weight loss. Contrast-enhanced computed tomography of the patient's abdomen and pelvis was performed to assess for infection or malignancy. The study revealed a large saccular aneurysm of the proximal portal vein arising near the portal confluence. Compression of the adjacent IVC was also seen which contained a hypoattenuating filling defect, probably representing thrombus. Incidental large hepatic cysts were seen, and a 6 mm pancreatic cyst was also identified which likely represented an intra-ductal papillary mucinous neoplasm . He was determined not to be a surgical candidate due to age, comorbidities, and absence secondary symptoms. The patient was discharged on quetiapine and enoxaparin for management of agitation and IVC thrombosis, respectively. This case demonstrates the increasing rates of detection of portal vein aneurysm and the range of complications that may arise as a result.

An Evidence-based Physical Therapy Prescription for Adults With X-linked Hypophosphatemia.

Context: X-linked hypophosphatemia (XLH) is a rare and progressive metabolic phosphate-wasting disorder characterized by lifelong musculoskeletal comorbidities. Despite considerable physical disability, there are currently no disease-specific physical therapy (PT) recommendations for XLH designed to improve engagement and confidence in performing activities of daily living (ADL). Objective: The objective of this patient-centered study was to develop an evidence-based PT program to address gaps in the management of adult XLH without imposing unintended harm. Methods: Creation of the program was informed by a prior controlled clinical study to evaluate the physical and functional effect of XLH on adulthood, and guided by the physical presentation of participants, subjective data and patient goals acquired at intake, and by performance on multiple active range of motion (ROM) movements from the standing position. A weekly standardized interview process was used to assess progression of physical and functional abilities, gains and concerns, and to obtain timely feedback to inform future exercise modifications. Outcomes were evaluated using validated functional tools and subjective data obtained throughout the study. Results: A remote 12-week PT program was created based on collected data. Open and closed kinetic-chain exercises were developed and implemented. Functional improvements were documented, and weekly surveys indicated improved abilities and confidence to engage in ADL. Minimal improvements were observed in active upper and lower extremity ROM, reflective of substantial bony restrictions characteristic of XLH. Conclusion: This study represents the first disease-specific PT recommendations for XLH to mitigate the unique physical challenges of the adult disorder that can be modified to adapt to the current progression status of the adult disorder.

Perforated sigmoid colon in the setting of chicken bone ingestion and diverticulitis: A case report.

INTRODUCTION: Diverticular perforation due to foreign body ingestion is an uncommon but important cause of gastrointestinal tract injury. The aim of this study is to discuss relevant findings seen in diverticulitis caused by foreign bodies and its treatment. CASE PRESENTATION: In this report, we present a case of a 30-year-old woman who presented to the emergency department with two days of severe abdominal pain and diarrhea. Computed tomography of the patient's abdomen and pelvis revealed micro-perforations of the sigmoid colon with pneumoperitoneum and an intraluminal foreign body. She subsequently underwent an exploratory laparotomy with sigmoid resection and end-to-end anastomosis due to acute diverticulitis complicated by feculent peritonitis. Gross examination of the excised specimen revealed two large perforations and an intraluminal chicken bone. After a six-day hospitalization, the patient was discharged with an excellent prognosis. DISCUSSION AND CONCLUSION: Prompt radiological evaluation and classification of the degree of diverticulitis using the Hinchey classification system in this patient helped guide definitive treatment. Usage of this classification scheme in foreign body diverticulitis is valuable in determining whether a surgical or non-surgical approach is necessary.

Bilateral supraclavicular abscesses following trigger point injections.

A 54-year-old-woman presented to the emergency department with worsening bilateral shoulder pain six days after trigger point injections in the bilateral supraclavicular areas for chronic pain. A computed tomography scan of the neck revealed bilateral irregular rim enhancing fluid collections. Image-guided percutaneous drainage resulted in marked improvement and near complete resolution by 17 days post-drainage. This case demonstrates the need for early detection of soft-tissue infection and abscess formation related to interventional pain procedures to avoid potentially life-threatening complications, such as Staphylococcus aureus bacteremia.