No abstract

The G protein ␤ subunit G␤5 deviates significantly from the other four members of G␤-subunit family in amino acid sequence and subcellular localization. To detect the protein targets of G␤5 in vivo, we have isolated a native G␤5 protein complex from the retinal cytosolic fraction and identified the protein tightly associated with G␤5 as the regulator of G protein signaling (RGS) protein, RGS7. Here we show that complexes of G␤5 with RGS proteins can be formed in vitro from the recombinant proteins. The reconstituted G␤5-RGS dimers are similar to the native retinal complex in their behavior on gel-filtration and cationexchange chromatographies and can be immunoprecipitated with either anti-G␤5 or anti-RGS7 antibodies. The specific G␤5-RGS7 interaction is determined by a distinct domain in RGS that has a striking homology to G␥ subunits. Deletion of this domain prevents the RGS7-G␤5 binding, although the interaction with G␣ is retained. Substitution of the G␥-like domain of RGS7 with a portion of G␥1 changes its binding specificity from G␤5 to G␤1. The interaction of G␤5 with RGS7 blocked the binding of RGS7 to the G␣ subunit G␣o, indicating that G␤5 is a specific RGS inhibitor.Signal transduction through heterotrimeric (G␣␤␥) G proteins is governed by the cycle of GTP binding and hydrolysis by the G␣ subunit (G␣). An activated receptor catalyzes the exchange of GDP bound to G␣ initially for GTP, leading to the dissociation of G␣ from the tightly associated G␤␥-subunit complex. In this active state, the G protein modulates the activity of second messenger-generating effector enzymes and ion channels until GTP hydrolysis returns the cascade to its resting state. It has been known for a number of years that the rate of intrinsic GTPase activity of G␣ in vitro is much slower than the rate of termination of some physiological responses. Therefore, it has been proposed that additional factors accelerate GTPase activity in vivo. One class of G protein GTPaseactivating proteins (GAPs) are G protein effectors such as cGMP phosphodiesterase (1) and phospholipase C (2). Most of the G protein effector molecules, however, do not posses GAP activity. In the past 2 years, a new class of GAPs for G proteins, termed regulators of G protein signaling (RGS), has emerged (for reviews, see refs. 3-5). Thus far, about 20 RGS proteins have been discovered in mammals. RGS vary dramatically in size (from 23 to 160 kDa) and sequence, but they all have a common ''RGS domain'' (Ϸ120 aa), which is responsible for the binding to the G␣ subunits and is sufficient for the GAP activity of RGS (6, 7). The function of the other domains in the RGS proteins remains largely unexplored. However, it had been shown that RGS12 contains a PDZ domain (8), and protein p115 RhoGEF, which has a GAP activity for G␣ subunits G␣12 and G␣13, is also a guanine nucleotide-exchange factor for a small G protein, Rho (9). These findings indicate that, in addition to their interaction with G␣ subunits, RGS proteins might interact with other molecules.While inve...

Fournier gangrene (FG) is a rare and life-threatening urosurgical emergency characterized most often by a polymicrobial infection of the perineal, genital, or perianal region. FG has an increased incidence in male patients, patients with alcoholism, and patients with immunocompromise including human immunodeficiency virus (HIV) and uncontrolled diabetes. FG often begins as a simple abscess or cellulitis with progression to necrotizing soft tissue infection (NSTI). Delays in diagnosis and treatment confer high mortality. Early recognition and high clinical suspicion are important in making a timely diagnosis, as early manifestations are often subtle. The most significant modifiable risk factor associated with NSTI mortality is delay to surgical intervention. Coordination of both inpatient medical and surgical teams to implement appropriate therapy is vital to successful outcomes. The emergency medicine clinician must be vigilant for this condition and be aware of risk factors, prognostic indicators, and proper treatment protocols to recognize FG early and initiate appropriate management. The objective of this review is to provide updated and relevant information regarding recognition, diagnosis, and management of FG for the emergency medicine provider.

Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and deep venous thrombosis (DVT), is a major cause of morbidity and mortality of particular relevance for intensivists and hospitalists. Acute VTE is usually managed with parenteral unfractionated heparin or low-molecular-weight heparin, followed by an oral vitamin K antagonist. Data are lacking for optimal treatment of less common occurrences, such as upper extremity DVT, and for approaches such as thrombolysis for PE associated with early signs of hemodynamic compromise or inferior vena cava filters when anticoagulation is contraindicated. Direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are now added to the armamentarium of agents available for acute management of VTE and/or reducing the risk of recurrence. This review outlines an algorithmic approach to acute VTE treatment: from aggressive therapies when anticoagulation may be inadequate, to alternative choices when anticoagulation is contraindicated, to anticoagulant options in the majority of patients in whom anticoagulation is appropriate. Evidence-based guidelines and the most recent DOAC clinical trial data are discussed in the context of the standard of care. Situations and treatment approaches for which data are unavailable or insufficient are identified. VTE therapy in care transitions is discussed, as are choices for secondary prevention.

Splenic artery pseudoaneurysm (SAP) is an uncommon etiology of acute abdominal pain, requiring a high degree of clinical suspicion to diagnose in a timely manner. There are currently no reports of spontaneous SAP ruptures in the emergency medicine literature. We report a case of a man who presented with acute abdominal pain secondary to an SAP. A computed tomography angiography scan of the abdomen revealed a ruptured SAP with hemoperitoneum. He successfully underwent emergency laparotomy and surgical ligation of his SAP with splenectomy. SAP rupture remains an under-recognized etiology of abdominal pain, even though it is the most frequent type of visceral pseudoaneurysm. Our case herein reinforces the importance of a broad list of differential diagnoses in the patient with acute abdominal pain, as well as the importance of the emergency physician in identifying an emergent condition and then directing the initial stabilization, resuscitation, and management.