Key points• In intestine, nutrients including glucose and amino acids and non-nutrients including bile acids increase secretion of anti-diabetic gut peptides such as gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY).• Facilitative glucose transporter pathways in addition to active electrogenic transporter pathways contribute to GIP, GLP-1 and PYY secretion; in particular, the facilitative glucose transporter 2 (GLUT2) is involved.• Sucralose, in the presence of glucose, can strongly and acutely upregulate GIP, GLP-1 and PYY secretion in a time scale of minutes.• Amino acid-stimulated GIP, GLP-1 and PYY secretion is acutely regulated by the calcium-sensing receptor (CasR).• The results establish new functions for GLUT2 and CasR as regulators of gut peptide secretion that sense nutrients and provide signalling pathways for the release of GIP, GLP-1 and PYY.Abstract Intestinal enteroendocrine cells (IECs) secrete gut peptides in response to both nutrients and non-nutrients. Glucose and amino acids both stimulate gut peptide secretion. Our hypothesis was that the facilitative glucose transporter, GLUT2, could act as a glucose sensor and the calcium-sensing receptor, CasR, could detect amino acids in the intestine to modify gut peptide secretion. We used isolated loops of rat small intestine to study the secretion of gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) secretion stimulated by luminal perfusion of nutrients or bile acid. Inhibition of the sodium-dependent glucose cotransporter 1 (SGLT1) with phloridzin partially inhibited GIP, GLP-1 and PYY secretion by 45%, suggesting another glucose sensor might be involved in modulating peptide secretion. The response was completely abolished in the presence of the GLUT2 inhibitors phloretin or cytochalasin B. Given that GLUT2 modified gut peptide secretion stimulated by glucose, we investigated whether it was involved in the secretion of gut peptide by other gut peptide secretagogues. Phloretin completely abolished gut peptide secretion stimulated by artificial sweetener (sucralose), dipeptide (glycylsarcosine), lipid (oleoylethanolamine), short chain fatty acid (propionate) and major rat bile acid (taurocholate) indicating a fundamental position for GLUT2 in the gut peptide secretory mechanism. We investigated how GLUT2 was able to influence gut peptide secretion mediated by a diverse range of stimulators and discovered that GLUT2 affected membrane depolarisation through the closure of K + ATP -sensitive channels. In the absence of SGLT1 activity (or presence of phloridzin), the secretion of GIP, GLP-1 and PYY was sensitive to K + ATP -sensitive channel modulators tolbutamide and diazoxide. L-Amino acids phenylalanine (Phe), tryptophan (Trp), asparagine (Asn), arginine (Arg) and glutamine (Gln) also stimulated GIP, GLP-1 and PYY secretion, which was completely abolished when extracellular Ca 2+ was absent. The gut peptide response stimulated by the amino acids...

The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species. IMPORTANCEFiloviruses represent a major public health threat in Africa and an emerging global concern. Largely driven by the U.S. biodefense funding programs and reinforced by the 2014 outbreaks, current immunotherapeutics are primarily focused on a single filovirus species called Ebola virus (EBOV) (formerly Zaire Ebola virus). However, other filoviruses including Sudan, Bundibugyo, and Marburg viruses have caused human outbreaks with mortality rates as high as 90%. Thus, cross-protective immunotherapeutics are urgently needed. Here, we describe monoclonal antibodies with cross-reactivity to several filoviruses, including the first report of a cross-neutralizing antibody that exhibits protection against Ebola virus and Sudan virus in mice. Our results further describe a novel combination of antibodies with enhanced protective efficacy. These results form a basis for further development of effective immunotherapeutics against filoviruses for human use. Understanding the cross-protective epitopes are also important for rational design of pan-ebolavirus and pan-filovirus vaccines.

Three months after diagnosis of Wegener granulomatosis, an 84-year-old woman who was treated with cyclophosphamide (CPY) and prednisone developed deranged liver function tests (LFTs). Treatment with CPY was held, which led to normalization of LFTs, but after reinitiating of CPY, LFTs started increasing. Liver biopsy showed noncaseating epithelioid granulomas within liver lobules consistent with granulomatous hepatitis. Patient died within 2 months secondary to liver failure. This elevation of transaminases was considered to be secondary to CPY-induced hepatotoxicity. Involvement of liver in patients with Wegener granulomatosis is seen but it presents with necrotizing granulomatous vasculitis. CPY-induced hepatitis is an extremely rare phenomenon with only 1 case reported in literature. Clinicians and hepatologists should be aware of this potentially serious complication when CPY therapy is initiated. Baseline LFTs and periodic assessment are recommended before and during treatment with CPY.

There are limited data regarding the ability to crush tablets or open capsules for antiretroviral agents. This lack of data is problematic when encountering patients who cannot swallow these tablets or capsules, especially for patients who are mechanically ventilated. Furthermore, many antiretroviral agents do not have an oral or intravenous solution available. The authors address this issue by reviewing all commercially available antiretroviral agents to determine whether they could crush tablets or open capsules.

Turnover, career interruptions, and plateauing are expensive for corporations trying to stay ahead. Unfortunately for businesses today, women with executive potential are leaving, interrupting, or plateauing their careers, thereby increasing the costs for corporate America. The money companies invest in recruitment, training, and development is more likely to be lost when these women leave, take time off, or stop short of full executive potential. It is important that employers learn the right lesson from all the studies now being conducted. Specifically, the return on investments in hiring, training, and keeping women executives can be increased by implementing certain practices and policies. Due to changes in demographic trends, corporations must become responsive to the needs of the women that they employ if they are to have the best and brightest of all those entering the work force.