Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model.

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

Structural basis of the leukocyte integrin Mac-1 I-domain interactions with the platelet glycoprotein Ib.

Cell-surface receptor interactions between leukocyte integrin macrophage-1 antigen (Mac-1, also known as CR3, αMß2, CD11b/CD18) and platelet glycoprotein Ibα (GPIbα) are critical to vascular inflammation. To define the key residues at the binding interface, we used nuclear magnetic resonance (NMR) to assign the spectra of the mouse Mac-1 I-domain and mapped the residues contacting the mouse GPIbα N-terminal domain (GPIbαN) to the locality of the integrin metal ion-dependant adhesion site (MIDAS) surface. We next determined the crystal structures of the mouse GPIbαN and Mac-1 I-domain to 2 Å and 2.5 Å resolution, respectively. The mouse Mac-1 I-domain crystal structure reveals an active conformation that is stabilized by a crystal contact from the α7-helix with a glutamate side chain completing the octahedral coordination sphere of the MIDAS Mg2+ ion. The amino acid sequence of the α7-helix and disposition of the glutamic acid matches the C-terminal capping region α-helix of GPIbα effectively acting as a ligand mimetic. Using these crystal structures in combination with NMR measurements and docking analysis, we developed a model whereby an acidic residue from the GPIbα leucine-rich repeat (LRR) capping α-helix coordinates directly to the Mac-1 MIDAS Mg2+ ion. The Mac-1:GPIbαN complex involves additional interactions consolidated by an elongated pocket flanking the GPIbαN LRR capping α-helix. The GPIbαN α-helix has an HxxxE motif, which is equivalent by homology to RxxxD from the human GPIbαN. Subsequent mutagenesis of residues at this interface, coupled with surface plasmon resonance studies, confirmed the importance of GPIbαN residues H218, E222, and the Mac-1 MIDAS residue T209 to formation of the complex.

Air in the gastric wall of a patient with AIDS.

Emphysematous gastritis is a rare infection of the gastric wall with 55%-60% mortality. A 44-year-old man with AIDS, hepatitis C, and intravenous drug use presented with a 1-day history of acute-onset abdominal pain, nausea, and nonbloody, nonbilious emesis. On examination, he was afebrile without other vital sign abnormalities. He had epigastric abdominal tenderness without rebound or guarding. The peripheral-blood leukocyte count was elevated to 12.8 with 93.8% neutrophils. The patient's clinical presentation markedly improved with IV fluids and broad-spectrum antibiotic therapy. His presentation and radiologic findings, including gastric intramural air and air in the portal vein, are consistent with emphysematous gastritis. Conservative management is first-line for milder cases of emphysematous gastritis. Exploratory laparotomy and total gastrectomy are indicated only in severe cases such as transmural ischemia and peritonitis. Immune-compromised status is a predisposing factor and associated with subtler findings than the classic dramatic clinical presentation.

The late presenting STEMI: How ECG scores can be used to estimate event time.

INTRODUCTION: Patients presenting with ST elevation myocardial infarction (STEMI) derive significant benefit from timely percutaneous coronary intervention (PCI). Electrocardiogram (ECG) scoring systems can complement history to estimate the infarction age and inform clinical decision-making. CASE: A 76year old man presented with eight days of dyspnea on exertion and chest pain. Triage ECG showed ST elevation and Q waves in the anterior leads. The patient was taken for coronary angiography and found to have a 100% occlusion of the left anterior descending artery. DISCUSSION: Determining timing of acute coronary syndromes is challenging. ECG indices aid clinical history by quantifying infarction acuity.

A Pathway to Freedom: An Evaluation of Screening Tools for the Identification of Trafficking Victims.

OBJECTIVES: Because training residents and faculty to identify human trafficking victims is a major public health priority, the authors review existing assessment tools. METHODS: PubMed and Google were searched using combinations of search terms including human, trafficking, sex, labor, screening, identification, and tool. RESULTS: Nine screening tools that met the inclusion criteria were found. They varied greatly in length, format, target demographic, supporting resources, and other parameters. Only two tools were designed specifically for healthcare providers. Only one tool was formally assessed to be valid and reliable in a pilot project in trafficking victim service organizations, although it has not been validated in the healthcare setting. CONCLUSIONS: This toolbox should facilitate the education of resident physicians and faculty in screening for trafficking victims, assist educators in assessing screening skills, and promote future research on the identification of trafficking victims.