The mammalian target of rapamycin (mTOR) is a critical sensor of nutritional sufficiency. Although much is known about the regulation of mTOR in response to growth factors, much less is known about the regulation of mTOR in response to nutrients. Amino acids have no impact on the signals that regulate Rheb, a GTPase required for the activation of mTOR complex 1 (mTORC1). Phospholipase D (PLD) generates a metabolite, phosphatidic acid, that facilitates association between mTOR and the mTORC1 co-factor Raptor. We report here that elevated PLD activity in human cancer cells is dependent on both amino acids and glucose and that amino acid-and glucose-induced increases in mTORC1 activity are dependent on PLD. Amino acid-and glucose-induced PLD and mTORC1 activity were also dependent on the GTPases RalA and ARF6 and the type III phosphatidylinositol-3-kinase hVps34. Thus, a key stimulatory event for mTORC1 activation in response to nutrients is the generation of phosphatidic acid by PLD.The mammalian target of rapamycin (mTOR) 2 is a critical regulator of cell growth and cell cycle progression. mTOR is activated in response to both growth factors and nutrients (1). mTOR exists as two complexes, mTORC1 and mTORC2. Although both mTORC1 and mTORC2 are responsive to growth factors, mTORC1 is believed to be the primary sensor of nutrient and energy sufficiency (2-4). mTORC1 is activated in response to insulin and other peptide hormones that activate type I phosphatidylinositol (PI) 3-kinases (PI3Ks) that generate PI 3,4,5-trisphosphate. The activation of mTORC1 via PI3K involves the Akt-mediated suppression of the tuberous sclerosis complex (TSC), which consists of TSC1 and TSC2. TSC1/2 functions as a GTPase-activating protein for Rheb (Ras homologue enriched in brain), a GTPase that directly interacts with and contributes to the activation of mTORC1 (2). Although Rheb is required for the amino acid stimulation of mTORC1, starving cells of amino acids has no effect on GTP loading (4 -7). In addition, amino acid starvation was still able to suppress mTORC1 in cells lacking the Rheb GTPase-activating complex protein TSC2 (4 -7). Therefore, although there is a requirement for GTP-bound Rheb for induction of mTORC1 by amino acids, amino acids do not impact on Rheb activity, indicating that regulation of Rheb does not stimulate mTORC1 in response to amino acids.It was recently reported that Rag GTPases are critical for targeting mTORC1 to lysosomal compartments in response to amino acids (8 -10), and a model was proposed whereby the targeting of mTOR to lysosomal membranes containing GTPbound Rheb was sufficient to activate mTORC1 (10, 11). However, several other factors implicated in the regulation of mTORC1 in response to amino acids were not accounted for in this model. The Ras family GTPase RalA was reported to be required for amino acid induction of mTORC1 (12). Significantly, RalA is constitutively associated with phospholipase D1 (PLD1) (13,14). PLD1 generates the lipid second messenger phosphatidic acid (PA), which is r...

Introduction It is estimated that approximately one-tenth of the US population suffers from substance use disorders (SUD), a problem that is compounded when one considers the impact that drug addiction could have on treatment outcomes for many other chronic diseases. Thus, addiction medicine has become an important component of many successful urban primary care practices and residencies across the country. Our program sought to improve the confidence of our residents in managing SUD by instituting a team-based learning (TBL) activity that focused on the diagnosis and medication-assisted treatment of these illnesses. Methods The class of 80 internal medicine residents were divided into groups of approximately 16 residents, and during the TBL sessions further divided into teams of three to four. Each TBL session consisted of an individual readiness assurance test, a group discussion of the correct answers, and a PowerPoint-based team application activity. Surveys were conducted for each group to assess the residents' attitudes after completing the activity. Results Of residents, 69 of 80 completed the survey. The response to the TBL exercise was overwhelmingly positive, with most residents in agreement that the activity increased their knowledge and confidence in diagnosing and treating patients with SUD. Discussion Overall, this TBL activity was well received by the residents and subjectively increased their competence in managing patients with SUD. In addition, our modification to the traditional TBL format suggested that the theories and spirit behind TBL can be successfully adapted to meet the challenges and intricacies of internal medicine residency education.

Phenytoin is a commonly used anti-seizure agent, which stabilizes neuronal membranes by blocking voltage-gated sodium channels to inhibit the propagation of action potentials during convulsions. However, phenytoin has also been shown to have antiarrhythmic effects as it can prolong the effective refractory period of ventricular pacemaker cells. Adverse cardiac effects such as junctional bradycardia are usually seen with intravenous use. Cardiovascular dysfunction is not well recognized in oral phenytoin toxicity. Here we present a case of junctional bradycardia due to oral phenytoin toxicity, which resolved spontaneously with the discontinuation of phenytoin. This case report will serve to increase awareness of the adverse cardiovascular effects of oral phenytoin toxicity to improve the recognition and treatment of these adverse effects.

Secondary hyperkalemic paralysis is a life-threatening manifestation of hyperkalemia seen with a potassium level of 7 or above 7 milliequivalents per liter (Meq/L) in an acute or chronic state. Standard hyperkalemic treatment should be initiated upon diagnosis with emergency dialysis in refractory cases. Here we present the case of a patient with end-stage renal disease (ESRD) compliant with dialysis three times a week. The patient presented with generalized ascending flaccid paralysis and was found to have serum potassium of 9.6 Meq/L. Spontaneous resolution of the paralysis was observed shortly after the completion of one hemodialysis session. The goal of this case report is to raise awareness of a life-threatening complication of electrolyte imbalances in ESRD even in patients that are compliant with dialysis.