REPERFUSION FOLLOWING MYOCARDIAL ISCHAEMIA ENHANCES INOSITOL PHOSPHATE RELEASE IN THE ISOLATED PERFUSED RAT HEART

1. Global myocariial ischaemia (MI) for periods greater tan 5 min caused an inhibition of phosphatidylinositol specific phospholipase C (PtdIns-PLC) activity. 2. Two min reperfusion following a 20 min MI period, a time point associated with reperfusion-induced arrhythmias, resulted in an activation of PtdIns-PLC activity, dependent on endogenous noradrenaline and mediated via al-adrenoceptors. 3. This 2 min reperfusion response, in contrast to healthy myocardium, resulted in: (i) enhanced PtdIns-PLC activity; (ii) increased sensitivity to endogenous noradrenaline; (iii) rapid increases in inositol(1,4,5)trisphosphate (Ins(1,4,5)P3); and (iv) PLC hydrolysis primarily of PtdIns(4,5)P₂, such that the majority of InsP isomers derive from Ins(1,4,5)P₃. 4. Together, these data suggest a functional role for Ins(1,4,5)P3 under postischaemic reperfusion conditions, and provide a possible link between al-adrenoceptor stimulation of the PtdIns turnover pathway and reperfusion injury.     

Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents.

The efficient and non-toxic nuclear delivery of steric-block oligonucleotides (ON) is a prerequisite for therapeutic strategies involving splice correction or exon skipping. Cationic cell penetrating peptides (CPPs) have given rise to much interest for the intracellular delivery of biomolecules, but their efficiency in promoting cytoplasmic or nuclear delivery of oligonucleotides has been hampered by endocytic sequestration and subsequent degradation of most internalized material in endocytic compartments. In the present study, we compared the splice correction activity of three different CPPs conjugated to PMO(705), a steric-block ON targeted against the mutated splicing site of human beta-globin pre-mRNA in the HeLa pLuc705 splice correction model. In contrast to Tat48-60 (Tat) and oligoarginine (R(9)F(2)) PMO(705) conjugates, the 6-aminohexanoic-spaced oligoarginine (R-Ahx-R)(4)-PMO(705) conjugate was able to promote an efficient splice correction in the absence of endosomolytic agents. Our mechanistic investigations about its uptake mechanisms lead to the conclusion that these three vectors are internalized using the same endocytic route involving proteoglycans, but that the (R-Ahx-R)(4)-PMO(705) conjugate has the unique ability to escape from lysosomial fate and to access to the nuclear compartment. This vector, which has displays an extremely low cytotoxicity, the ability to function without chloroquine adjunction and in the presence of serum proteins. It thus offers a promising lead for the development of vectors able to enhance the delivery of therapeutic steric-block ON in clinically relevant models.     

ERP evidence of impaired central nervous system function in virally suppressed HIV patients on antiretroviral therapy.

OBJECTIVE: To examine the effects of human immunodeficiency virus (HIV) on central nervous system (CNS) function in patients receiving antiretroviral therapy (ART) who have suppressed viral loads. METHODS: Event-related brain potentials (ERPs) were recorded from 15 virally suppressed HIV patients and 15 age-, sex-, and education-matched controls while they performed a 3-stimulus auditory oddball task. The amplitude and latency of the P3a, P3b, and early auditory components were examined in HIV patients and controls. RESULTS: Virally suppressed HIV patients on ART were more depressed than controls, as determined by the Beck Depression Inventory (BDI). After controlling for the effects of depression, HIV patients had smaller P2, P3a, and P3b amplitudes and longer P3a and P3b latency than control subjects. BDI scores correlated positively with N1 latency in HIV patients and negatively with P3b amplitude in all subjects. CONCLUSIONS: These electrophysiological results suggest that, even in the absence of detectable levels of HIV in the peripheral blood, viral replication persists in the CNS and continues to cause disease in HIV patients on ART.     

Changes in muscle morphology in dialysis patients after 6 months of aerobic exercise training.

BACKGROUND: In the present study we investigated the effect of a 6-month aerobic exercise programme on the morphology of the gastrocnemius muscle of end-stage renal disease (ESRD) patients. METHODS: Twenty-four ESRD patients volunteered to participate in the training programme and underwent muscle biopsy before training. Eighteen patients completed the training programme of whom nine agreed to a post-training biopsy (one woman and eight men, mean age 56 +/- 15 years). Data are presented for the nine subjects who were biopsied before (PRE) and after training (POST) and separately for the 15 subjects for whom we only have a biopsy before training (cross-sectional group). RESULTS: There were no significant differences (P > 0.05) in fibre type distribution or myosin heavy chain (MyHC) expression between the cross-sectional and PRE/POST groups. The mean cross-section fibre area after training (POST) increased by 46% compared with the PRE training status (P < 0.01). The proportion of atrophic fibres decreased significantly after training in type I, IIa and IIx fibre populations (from 51 to 15%, 58 to 21% and 62 to 32%, respectively). Significant differences were also found in capillary contact per fibre (CC/F), with the muscle having 24% (P < 0.05) more CC/F compared with the PRE training status. No significant differences in cytochrome c oxidase concentration were found between the groups. CONCLUSIONS: In conclusion, exercise appeared to be beneficial in renal rehabilitation by correcting the fibre atrophy, increasing the cross-section fibre area and improving the capillarization in the skeletal muscle of renal failure patients.     

Ampullary carcinoma: Demonstration by current MR techniques

The objective of this study was to demonstrate the appearance of ampullary carcinoma using current MR techniques, including fat suppression, gadolinium enhancement, and MR cholangiography. Nine patients with ampullary carcinoma were examined by MRI at 1.5 T. MR examinations included T1-weighted spoiled gradient echo, T1-weighted fat-suppressed, and immediate postgadolinium spoiled gradient echo images for all patients and MR cholangiography for three patients. The imaging features of ampullary carcinomas, including tumor size and morphology, signal intensity, and enhancement characteristics, were determined. Ampullary carcinomas shown on MR images ranged in size from 1.5 to 5.5 cm. Tumors were low in signal intensity on precontrast T1-weighted spoiled gradient echo and T1-weighted fat-suppressed images relative to normal pancreatic tissue and enhanced less than normal pancreas on immediate postgadolinium spoiled gradient echo images. Tumor conspicuity was greatest on immediate postgadolinium spoiled gradient echo images. MR cholangiography demonstrated high grade obstruction of the common bile duct and mild dilatation of the pancreatic duct at the level of the ampulla with abrupt termination of the ducts in two untreated patients and moderate dilatation of the common bile duct in one patient who had a biliary stent. Ampullary carcinomas can be demonstrated on MR images as small masses arising at the ampulla. Tumors are well defined on immediate postgadolinium spoiled gradient echo images.     

Trusting patients, trusting nurses

Abstract  The general expectation that patients should be willing to trust nurses is rarely explored or challenged despite claims of diminishing public trust in social and professional institutions. Everyday meanings of trust take account of circumstance and suggest that our understanding of what it means to trust is contextually bound. However, in the context of health care, to trust implies a particular understanding which becomes apparent when abuses of this trust are reported and acknowledged as scandals. The predominant assumption in the literature that trust is something that occurs between equally competent adults cannot explain trust in nursing precisely because of the unequal power relationships between patients on the one hand and healthcare professionals on the other. Moreover, the tendency to conflate terms such as trust, reliance, confidence and so on suggests that confusion permeates discussions of trust in nursing. In this paper, I argue in support of Annette Baier's requirement of good will (or lack of ill will) as the essential feature of trust, and outline how this account (i) enables us to make the necessary distinctions between trust on the one hand and 'trust pretenders' on the other; and (ii) lays the foundations for understanding trust in relationships, such as those between patients and nurses, where power differentials exist.