Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca(2+)) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca(2+)/metabolic coupling process [CMCP]) by Ca(2+) mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes. METHODS: Glucose- and Ca(2+)-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia. RESULTS: Glucose stimulation of cytosolic Ca(2+) and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca(2+) channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia. CONCLUSIONS/INTERPRETATION: These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca(2+) influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.

The function and fate of neutrophils at the inflamed site: prospects for therapeutic intervention.

Neutrophils play a key role in the immediate non-specific immune response, and defects in their function increase host susceptibility to a range of infective agents. However, excess activation and/or delayed clearance of these cells from an inflamed site can lead to significant tissue damage. Neutrophil priming by agents such as endotoxin, granulocyte macrophage colony stimulating factor (GM-CSF), platelet activating factor (PAF) and tumour necrosis factor-alpha (TNF alpha) may play a pivotal role in modulating the adhesive and secretory properties of these cells. Priming also appears to affect the survival of neutrophils by delaying constitutive apoptosis. The unique signal transduction events that control neutrophil priming and apoptosis, and particularly the importance of the phospholipase C and phosphoinositide 3-kinase pathways, suggest opportunities for selective pharmacological intervention.

Aminopeptidases as potential targets for the control of the Australian sheep blowfly, Lucilia cuprina.

A series of experiments were carried out to investigate the role of proteinase enzymes in the growth of larvae of the sheep blowfly, Lucilia cuprina. First, instar larvae were incubated on an artificial growth media in the presence of various concentrations of inhibitors of all the major proteinase classes. Inhibitors of serine proteinases and aminopeptidases were found to cause significant growth inhibition and in some cases death of the larvae within 24 h, suggesting that these enzymes were the major classes involved in protein digestion in the gut of the insect. A second group of experiments analysed the effects of two inhibitors from the same or different proteinase classes in the growth media. Synergistic inhibition of larval growth was observed with the incorporation of inhibitors of serine proteinases and aminopeptidases. The results suggest that these classes of proteinases are both central to protein digestion in this insect, probably in the gut, and that the inhibition of both types of activity leads to an almost complete blockade of digestion. Testing in vivo gave similar results with infections on sheep skin inhibited by either serine proteinase or aminopeptidase enzyme inhibitors and the combination of both stopped the infection process. The role of aminopeptidases in larval metabolism and as potential targets for blowfly control agents is examined.

Inhalant abuse and juvenile delinquency: a control study in Albuquerque, New Mexico.

This paper examines the relationship between inhalant abuse and delinquency among juveniles in Albuquerque, New Mexico. The arrest records of 100 juvenile delinquents identified as chronic inhalant abusers are compared with two control groups (N = 100 each) of other delinquents from Albuquerque. One control group was stratified on age, sex, and ethnicity, and the other was a simple random sample. The demographic characteristics of inhalant abusers indicated an overrepresentation of young, male Hispanics from large, poor, disrupted families where siblings were involved in both the abuse of inhalants and a variety of other delinquent activities. The inhalant abusers were much more likely to be arrested for virtually every type and category of delinquent activity. Specifically, inhalant abusers are considerably more criminal regarding total offenses committed, status offenses, crimes against property, crimes against persons, and criminal and violent offenses. Therefore, this study has indicated a strong relationship between inhalant abuse and juvenile delinquency.

Neuroelectric blocking factors in human and animal sera evaluated using the isolated frog spinal cord.

The effects of sera from guinea-pigs with experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS) patients were evaluated and compared with the activity of control sera using the isolated frog spinal cord. Ventral root responses (VRR) were recorded during supramaximal ipsilateral dorsal root stimulation in the presence and absence of 25% serum. In control experiments with normal human and guinea-pig sera we observed a consistent, reversible increase in VRR averaging 20% and 17% respectively, and in no case was any significant decrease produced. In contrast, sera from EAE guinea-pigs 12 to 19 days after injection produced an equally rapid, reversible decrease in VRR. The decrease averaged 36% and was highly significant (P less than 0.0001) relative to controls. Similarly, sera from MS patients on the average decreased the VRR by 26%, and this again was significant compared with controls (P less than 10(-6).

Experimental studies of the effects of extrinsic factors on conduction in normal and demyelinated nerve. 1. Temperature.

Previous studies in experimentally demyelinated mammalian nerves have demonstrated that a reversible conduction block occurs with small increases of temperature within the animal's normal body temperature range. This phenomenon is believed to be the mechanism for clinical temperature effects in multiple sclerosis. This study examines some quantitative thermal relationships in demyelinated nerves of guinea pigs with experimental allergic neuritis. The observed results in normal and experimental animals are in good agreement with previous theoretical calculations based on the effects of temperature on the voltage and time-dependent behavior of the ionic permeabilities of the nodes of Ranvier. Guinea pigs with increasing motor dysfunction generally exhibited corresponding increases in the overall latency of the conducted action potential, as well as decreases in amplitude. In addition, the lower the initial velocity increment per degree of temperature elevation, the lower was the temperature at which conduction block began to occur. Except for a few cases in which the recorded action potential was bimodal, with response at both normal and prolonged latency, the results tended to indicate a remarkedly uniform involvement of the sciatic nerve within the region of temperature control.