Imaging Butyrylcholinesterase in Multiple Sclerosis.

PURPOSE: Molecular imaging agents targeting butyrylcholinesterase (BChE) have shown promise in other neurodegenerative disorders and may have utility in detecting changes to normal appearing white matter in multiple sclerosis (MS). BChE activity is present in white matter and localizes to activated microglia associated with MS lesions. The purpose of this study was to further characterize changes in the cholinergic system in MS pathology, and to explore the utility of BChE radioligands as potential diagnostic and treatment monitoring agents in MS. PROCEDURE: Cortical and white matter lesions were identified using myelin staining, and lesions were classified based on microglial activation patterns. Adjacent brain sections were used for cholinesterase histochemistry and in vitro autoradiography using phenyl 4-[123I]-iodophenylcarbamate (123I-PIP), a previously described small-molecule cholinesterase-binding radioligand. RESULTS: BChE activity is positively correlated with microglial activation in white matter MS lesions. There is no alteration in cholinesterase activity in cortical MS lesions. 123I-PIP autoradiography revealed uptake of radioactivity in normal white matter, absence of radioactivity within demyelinated MS lesions, and variable uptake of radioactivity in adjacent normal-appearing white matter. CONCLUSIONS: BChE imaging agents have the potential to detect MS lesions and subtle pathology in normal-appearing white matter in postmortem MS brain tissue. The possibility of BChE imaging agents serving to supplement current diagnostic and treatment monitoring strategies should be evaluated.

Hyperlipidaemia induced by a high-cholesterol diet leads to the deterioration of guanosine-3',5'-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats.

BACKGROUND AND PURPOSE: Hyperlipidaemia interferes with cardioprotective mechanisms, but the cause of this phenomenon is largely unknown, although hyperlipidaemia impairs the cardioprotective NO-cGMP system. However, it is not known if natriuretic peptide-cGMP-protein kinase G (PKG) signalling is affected by hyperlipidaemia. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidaemic rats. EXPERIMENTAL APPROACH: Male Wistar rats were rendered hyperlipidaemic by feeding with 2% cholesterol-enriched chow for 12 weeks. Hearts isolated from normal and hyperlipidaemic rats were perfused (Langendorff mode) and subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion. 8-Br-cGMP (CG, 10 nM), B-type natriuretic peptide-32 (BNP, 10 nM), S-nitroso-N-acetyl-penicillamine (SNAP, 1 microM) were perfused from 10 min prior to coronary occlusion until the 15th min of reperfusion. Infarct size (% of ischaemic risk zone) was determined by triphenyltetrazolium staining. KEY RESULTS: Treatment with CG, SNAP or BNP decreased infarct size significantly in normal hearts from its control value of 41.6 +/- 2.9% to 15.5 +/- 2.4%, 23.3 +/- 3.0% and 25.3 +/- 4.6%, respectively (P < 0.05). Protection by BNP was abolished by co-perfusion of PKG inhibitors KT5823 (600 nM) or Rp-8pCPT-PET-cGMPs (1 microM), confirming its PKG dependence. In hearts from hyperlipidaemic rats, CG, SNAP or BNP failed to decrease infarct size. Hyperlipidaemia did not alter basal myocardial PKG content, but decreased its activity as assessed by phosphorylation of cardiac troponin I. CONCLUSIONS AND IMPLICATIONS: This is the first demonstration that defects in the cardioprotective cGMP-PKG system could be a critical biochemical anomaly in hyperlipidaemia.

Reperfusion and calculated RISKs: pharmacological postconditioning of human myocardium.

The last five years have witnessed a remarkable resurgence of interest in myocardial reperfusion injury. Reperfusion is absolutely essential to salvage ischaemic myocardium but experimental and clinical studies show that reperfusion-associated injury may mask the full benefits of prompt reperfusion in acute myocardial infarction. In the current issue of the British Journal of Pharmacology, Mudalagiri et al demonstrate a protective effect against simulated reperfusion injury using exogenously applied erythropoietin in human isolated myocardium. Crucially, the benefits of erythropoietin were observed when it was administered specifically during re-oxygenation. The demonstration that the protective effects of the cytokine were dependent on PI3-kinase/Akt and ERK1/2 activation provides compelling evidence that reperfusion injury salvage kinases (RISKs) are key survival mechanisms in human myocardium, as they are in experimental animal species. Although erythropoietin may be only one of several potential pharmacological approaches in human patients, this study establishes the important proof-of-principle that activation of RISKs is protective in human myocardium and could be a promising therapeutic target in acute myocardial infarction.

Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling.

It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia-reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3'-hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen-activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3',5'-monophosphate/cGMP-dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia-reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning-related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct-limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co-A reductase inhibitors (statins), Rho-kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca(2+) homeostasis through the modification of sarcoplasmic reticulum Ca(2+) uptake mechanisms, and PKG-induced opening of ATP-sensitive K(+) channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia-reperfusion and may be a tractable therapeutic target.

Origin and significance of a founding settlement in Polynesia.

Selected prehistoric potsherds from the deepest cultural level of the oldest known archaeological site in the Kingdom of Tonga, within the Eastern Lapita province of western Polynesia, display decorative motifs characteristic of the Western Lapita province of modern-day Island Melanesia, to the west. Most of the stylistically anomalous sherds contain temper sands exotic to Tonga but, in one case, petrographically indistinguishable from temper in a Lapita sherd recovered from the Santa Cruz Islands of Melanesia, and are inferred to record maritime transport of Lapita ceramics into Tonga from Melanesia far to the west. The non-Tongan sherds found on Tongatapu provide direct physical evidence for interisland transfer of earthenware ceramics between Western and Eastern Lapita provinces, and the Nukuleka site, where they occur, is interpreted as one of the founding settlements of Polynesia.

Refinement of the Medicare diagnosis-related groups to incorporate a measure of severity.

This article presents a system under consideration by the Health Care Financing Administration (HCFA) for incorporating a measure of severity of illness into the Medicare diagnosis-related groups (DRGs). DRG assignment is one of the main factors in determining the payment made for hospital inpatient services furnished to Medicare beneficiaries. Specifically, the formula used to calculate payment for a single Medicare hospital inpatient case takes an average payment rate for a typical case and multiplies it by the relative weight of the DRG to which it is assigned. Thus, it is easy to see that the DRG relative weights have a large impact on the payment a hospital receives. In this article, we describe the Medicare DRG prospective payment system (PPS), evaluate the various classification elements available for assessing severity of illness, describe the analyses used in formulating this proposal, and present the proposed DRG severity system.

A long-term prevention study with oxprenolol in coronary heart disease.

We carried out a randomized double-blind controlled secondary-prevention trial of oxprenolol over seven years. Forty milligrams of oxprenolol or placebo was given twice daily to 1103 men 35 to 65 years old who had an acute myocardial infarction between 1 and 90 months previously. Overall, there was no difference in mortality or cardiac events between the placebo and oxprenolol groups. The major influence on prognosis was the time at which treatment was started after infarction. In 417 patients in whom treatment was started within four months of infarction oxprenolol increased the six-year cumulative survival rate from 77 to 95 per cent (P less than 0.001). In 274 patients with treatment starting between 5 and 12 months of infarction the survival rate was similar in the two groups, but in 412 patients entered between 1 and 7 1/2 years after their first infarction oxprenolol reduced the six-year survival rate from 92 to 79 per cent (P = 0.002). The increased mortality in this latter group mainly occurred late after withdrawal from active treatment. The value of low-dose oxprenolol in secondary prevention appears to be confined to patients treated relatively soon after myocardial infarction.