Purinergic receptors on insulin-secreting cells

Summary— The insulin secreting B cell is fitted with the two types of purinergic receptors: P₂ (for ATP and/or ADP) and P₁ (for adenosine). The activation of P₂ purinoceptors by ATP or ADP evokes a biphasic stimulation of insulin secretion from isolated perfused rat pancreas; this stimulation is dose-dependent between 10^?6 and 10^?4 M. Non hydrolysable structural analogues are also effective, and the relative potency of various agonists (2-methylthio ATP ? ATP = ADP = α, β-methylene ATP ? AMP) gave evidence for a P_2y purinoceptor subtype. Proposed mechanisms include both an increased Ca²⁺ uptake and an increased intracellular Ca²⁺ mobilization via the hydrolysis of polyphosphoinositides. ATP (or ADP) potentiates physiological insulin-secreting agents (glucose and acetylcholine) and P₂ purinoceptors could play a physiological role in the stimulation of insulin secretion. The activation of P₁ purinoceptors (adenosine receptors) decreases insulin secretion. Using structural analogues of adenosine, the receptor was characterized as an A₁ subtype; it is coupled to a pertussis toxin sensitive G protein and it inhibits adenylate cyclase. It is of physiological relevance that the B cell has the two types of purinoceptors with opposite effects. Recently, a metabolically stable structural analogue of ADP, adenosine-5′-0-(2-thiodiphosphate) or ADPßS, has been described as a potent secretory agent, effective at nanomolar concentrations on isolated perfused rat pancreas. In vivo, this substance is able to increase insulin secretion and to improve glucose tolerance after IV administration in rats and oral administration in dogs. Furthermore in streptozotocin-induced diabetes, ADPßS retains its insulin secreting effects. These results suggest that P_2y purinoceptors could be a new target for antidiabetic drugs.     

INTRACEREBRAL HAEMORRHAGE IN A YOUNG ADULT: CONSIDER AMPHETAMINE ABUSE

SUMMARY We present the case of a young female who suffered a massive intracerebral bleed following the ingestion of a small quantity of amphetamine (speed). Physicians should be aware that amphetamine abuse can lead to cerebrovascular events in young adults.     

Adrenaline,Noradrenaline and Dopamine Level Estimation in Depression : Does it Help?

Background

Abnormalities of catecholaminergic function have been hypothesised in causation of depressive illness. Electroconvulsive therapy (ECT) is postulated to have noradrenergic mechanism of action. We studied the clinical utility of estimating catecholamines level changes after ECT.

Methods

Plasma adrenaline, noradrenaline and dopamine in healthy controls and depressed patients were estimated by high performance liquid chromatography with electrochemical detection method before and after ECT.

Result

Mean ± standard deviation of plasma adrenaline, noradrenaline and dopamine in controls was 36.7 ± 13.2, 209.3 ± 76, 21.8 ± 9.5 ng/L respectively, while in depressed patients before and after ECT it was found to be 32.5 ± 12.0, 419.3 ± 167.7, 22.1 ± 16.0ng/ L and 37.2 ± 19.6, 386.1 ± 168.4, 22.3 ± 15.5ng/L respectively. Correlation of adrenaline, noradrenaline and dopamine concentration with scores of Beck Depression Inventory, Suicidal Ideation Scale and Melancholia Inventory was positive but statistically not significant and poor. Based on the cut off values of noradrenaline, only 62% cases could be categorized as abnormal, which after ECT reduced to 50%, whereas post ECT psychiatric ratings was normal in about 78% cases.

Conclusion

There is no clinical significance of estimating adrenaline, noradrenaline and dopamine in depressed patients.Key Words: Electroconvulsive therapy, Adrenaline, Noradrenaline, Dopamine, Psychiatric scales     

A crucial role for TNF-α in mediating neutrophil influx induced by endogenously generated or exogenous chemokines,KC/CXCL1 and LIX/CXCL5

Background and purpose:

Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP-2/CXCL2 and LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice.

Experimental approach:

Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)-α. Cytokine and chemokine levels were determined in peritoneal exudates and in supernatants of macrophages and mast cells by elisa. CXCR2 and intercellular adhesion molecule 1 (ICAM-1) expression was determined using immunohistochemistry and confocal microscopy.

Key results:

Antigen challenge induced dose- and time-dependent neutrophil recruitment and production of KC/CXCL1, LIX/CXCL5 and TNF-α, but not MIP-2/CXCL2, in peritoneal exudates. Neutrophil recruitment was inhibited by treatment with reparixin (CXCR1/2 antagonist), anti-KC/CXCL1, anti-LIX/CXCL5 or anti-TNF-α antibodies and in tumour necrosis factor receptor 1-deficient mice. Intraperitoneal injection of KC/CXCL1 and LIX/CXCL5 induced dose- and time-dependent neutrophil recruitment and TNF-α production, which were inhibited by reparixin or anti-TNF-α treatment. Macrophages and mast cells expressed CXCR2 receptors. Increased macrophage numbers enhanced, while cromolyn sodium (mast cell stabilizer) diminished, LIX/CXCL5-induced neutrophil recruitment. Macrophages and mast cells from immunized mice produced TNF-α upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM-1 on mesenteric vascular endothelium, which was inhibited by anti-TNF-α or anti-LIX/CXCL5.

Conclusion and implications:

Following antigen challenge, CXCR2 ligands are produced and act on macrophages and mast cells triggering the production of TNF-α, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM-1.     

Screening patients for subclinical atherosclerosis with non-contrast cardiac CT

Accurate risk assessment may be helpful in decreasing cardiovascular events through more appropriate targeting of preventive measures. Traditional risk assessment may be refined with the selective use of coronary artery calcium score (CACS) or other methods of subclinical atherosclerosis measurement. This article reviews information pertaining to the clinical use of CACS for assessing coronary atherosclerosis as a useful predictor of coronary artery disease (CAD) in certain population of patients. Coronary calcification is a marker of atherosclerosis that can be quantified with the use of cardiac CT and it is proportional to the extent and severity of atherosclerotic disease. The published studies demonstrate a high sensitivity of CACS for the presence of coronary artery disease but a much lower specificity for obstructive CAD depending on the magnitude of the CACS. Several large clinical trials have found clear, incremental predictive value of CACS over the Framingham risk score when used in asymptomatic patients. However, early detection of CAD by Electron Beam Tomography (EBT) screening has not convincingly demonstrated a reduction in mortality and morbidity. Nevertheless, relevant prognostic information obtained may be useful to initiate or intensify appropriate treatment strategies to slow the progression of existing atherosclerotic vascular disease. Current data suggest intermediate-risk patients may benefit most from further risk stratification with cardiac CT, as CAC testing is effective at identifying increased risk and in one study motivating effective behavioral changes. Randomized clinical trials will help determine if selective use of cardiac CT in the intermediate-risk patient would lead to more appropriate use of pharmacologic therapy and improved clinical outcomes.