Effects of E coli endotoxin on pancreatic hormones and blood flow

Studies were performed on anesthetized dogs to determine the relationship between endotoxin-induced alterations in pancreatic blood flow (PBF) and hormones that originate partially or completely from the pancreas. PBF was estimated in six dogs by radioactive microspheres (praeendoxin, 25 and 240 minutes postendotoxin). Insulin, glucagon, pancreatic polypeptide (PP), and somatostatin-like immunoreactivity (SLI) were assayed in arterial and portal venous blood. Cardiac output and mean arterial blood pressure (MABP) decreased 25 minutes after endotoxin administration (50% and 40%, respectively) and returned toward normal levels by four hours. However, there was 74% decrease in PBF at 25 minutes and a further drop four hours after endotoxin. Hormonal responses were characterized by a short-lived increase in arterial insulin, corresponding to a transient increase in blood glucose. Insulin release increased shortly after endotoxin. Arterial glucagon and PP increased two to five hours after endotoxin. There was a suggestion that the increase in PP was of nonpancreatic origin. Little change in plasma SLI was noted following endotoxin. Thus, it appears that endotoxin altered the release of different pancreatic hormones with a variable time courses.     

The effects of diets deficient in calcium or phosphorus in the presence and absence of supplements of vitamin D on the secondary cementum and alveolar bone of young rats

Weanling rats were maintained for 14 weeks on diets low in calcium (0.026 per cent) or low in phosphorus (0.06 per cent) with or without the addition of vitamin D. The formation of secondary cementum was most severely disturbed by a double deficiency of calcium and vitamin D. The disturbance caused by diets deficient in phosphorus and vitamin D whilst serious was not so severe. In contrast a simple deficiency of phosphorus caused a greater disruption of cementum formation than did a simple lack of calcium.

The observation that phosphorus deficiency per se caused a greater metabolic disturbance in the forming secondary cementum than a simple deficiency of calcium is in accord with previous findings for bone and incisor dentine. In relation to a deficiency of phosphorus, cementum reacts in a manner similar to bone, in relation to calcium deficiency its behaviour is more akin to that of the incisor dentine.     

Minor injuries telemedicine

A minor injuries telemedicine network in Grampian connects 14 accident and emergency departments in community hospitals to a teaching hospital department. In a six-month study, 407 new telemedicine consultations met the inclusion criteria. Rates of transfer for treatment to the base hospital were used as an outcome measure. Fourteen out of a total of 19 members of medical staff gave telemedical advice. They were mainly middle-grade accident and emergency doctors. Transfer rates were 16-48% (median 29%) across staff. The rates did not seem to be affected by the base doctor's seniority, but were a reflection of that doctor's experience of and confidence in using videoconferencing equipment for clinical purposes. Transfer rates decreased as experience increased. Training for doctors undertaking the provision of specialist advice should include the clinical practicalities of making remote diagnoses.     

Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency,genetic mechanisms,and clinical significance

Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules over-expressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.     

Induction of hepatic cytochrome P450 enzymes: methods,mechanisms, recommendations,and in vitro–in vivo correlations

Induction of drug-clearance pathways (Phase 1 and 2 enzymes and transporters) can have important clinical consequences. Inducers can (1) increase the clearance of other drugs, resulting in a decreased therapeutic effect, (2) increase the activation of pro-drugs, causing an alteration in their efficacy and pharmacokinetics, and (3) increase the bioactivation of drugs that contribute to hepatotoxicity via reactive intermediates. Nuclear receptors are key mediators of drug-induced changes in the expression of drug-clearance pathways. However, species differences in nuclear receptor activation make the prediction of cytochrome P450 (CYP) induction in humans from data derived from animal models problematic. Thus, in vitro human-relevant model systems are increasingly used to evaluate enzyme induction. In this review, the authors’ current understanding of the mechanisms of enzyme induction and the in vitro methods for assessing the induction potential of new drugs will be discussed. Relevant issues and considerations surrounding proper study design and the interpretation of in vitro results will be discussed in light of the current US Food and Drug Administration (FDA) recommendations.     

Effect of variable annular reduction on functional tricuspid regurgitation and right ventricular dynamics in an ovine model of tachycardia-induced cardiomyopathy

ObjectiveTo investigate the effect of variable tricuspid annular reduction (TAR) on functional tricuspid regurgitation (FTR) and right ventricular (RV) dynamics in ovine tachycardia-induced cardiomyopathy.MethodsNine adult sheep underwent implantation of a pacemaker with an epicardial lead and were paced at 200 to 240 bpm until the development of biventricular dysfunction and functional TR was noted. During reoperation on cardiopulmonary bypass, 6 sonomicrometry crystals were placed around the tricuspid annulus (TA) and 14 were placed on the RV epicardium. Annuloplasty suture was placed around the TA and externalized to an epicardial tourniquet. After weaning from cardiopulmonary bypass, echocardiographic, hemodynamic, and sonomicrometry data were acquired at baseline and during 5 progressive TARs achieved with suture cinching. TA area and RV free wall strains and function were calculated from crystal coordinates.ResultsAfter pacing, changes in left ventricular (LV) ejection fraction and RV fractional area decreased significantly. Mean TA diameter increased from 25.1 ± 2.9 mm to 31.5 ± 3.3 mm (P = .005), and median TR (range, 0-3+) increased from 0 (0) to 3 (2) (P = .004). Progressive suture cinching reduced the TA area by 18 ± 6%, 38 ± 11%, 56 ± 10%, 67 ± 9%, and 76 ± 8%. Only aggressive annular reductions (67% and 76%) decreased TR significantly, but these were associated with deterioration of RV function and strain. A moderate annular reduction of 56% led to a substantial reduction of TR with little deleterious effect on regional RV function.ConclusionsA moderate TAR of approximately 50% may be most advantageous for correction of functional TR and simultaneous maintenance of regional RV performance. Additional subvalvular interventions may be needed to achieve complete valvular competence.