Glial mechanisms underlying substance use disorders.

Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive-like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll-like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia-neural communication, and the profound effects that glial-derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region-specific functions, and glia in different brain regions have distinct contributions to drug-associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug-induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.

Weight assessment in cardiac patients: implications for prescription of low molecular weight heparin.

BACKGROUND: Many drugs such as low molecular weight heparin (LMWH) are administered at "patient weight adjusted" doses. Obtaining an accurate measurement of a patient's weight may not always be possible. The aim of this study was to assess patterns and accuracy of weight estimation and implications for drug dosing. METHODS: The study comprised three parts: (1) inpatient weight documentation was reviewed over a 4 week period (January 2008); (2) a questionnaire was distributed to healthcare staff; (3) healthcare staff were asked to estimate the weight of patients. These estimates took place in three locations: the coronary care unit, cardiac catheterisation laboratory, and the cardiac outpatient department. RESULTS: (1) In 385 patient notes, only 192 (49.9%) had a record of the patient's weight. The dose of LMWH was correct only 51% of the time. (2) Doctors were more likely to estimate a patient's weight than nurses (85 vs 51%, p = 0.003). (3) 50 healthcare staff made 533 weight estimations on 182 patients. There was a tendency to overestimate the weight of lighter patients and underestimate the weight of heavier patients (p<0.001). Patients were more accurate than healthcare staff at estimating their weight (80% vs 39%, p<0.001) and female patients were more likely to be accurate than men (62% vs 44%, p = 0.035). CONCLUSIONS: In our institution weight estimation occurs and may result in inaccurate prescription of LMWH. Estimating a patient's weight should be discouraged but if necessary the patient reported weight is likely to be most accurate. Unless there is significant investment in improved technology to allow obese or acutely unwell patients to be weighed, the dangerous practice of weight estimation is likely to continue.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.

Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

Genetic determinants of sensitivity to diazepam in inbred mice.

Mice from 15 standard inbred strains were tested for sensitivity to several effects of acute diazepam (DZ). Strains differed in sensitivity to DZ-induced: low-dose stimulation and high-dose depression of locomotor activity, hypothermia, and ataxia assessed on a rotarod. Correlations among strain means indicated that sensitivity to a particular effect of DZ generalized well across doses. Sensitivities to some of the different behavioral responses also were significantly correlated. For example, strains sensitive to DZ-induced increases in activity were significantly less sensitive to the drug's hypothermic effects. These results suggest that there are multiple genetic determinants of behavioral sensitivity to DZ effects. That is, genetically influenced sensitivity to DZ is not monolithic but is somewhat specific to the particular response variable studied, a result that also characterizes genetic control of responses to other drugs.

Neural sensitivity to pentylenetetrazol convulsions in inbred and selectively bred mice.

In these experiments, sensitivity to the convulsant drug pentylenetetrazol (PTZ) was measured in 10 inbred mouse strains, and in 4 mouse lines selectively bred for severe (WSP1, WSP2) or minimal (WSR1, WSR2) ethanol withdrawal convulsions. Using a timed infusion procedure, sensitivity to convulsions was assessed by measures of latency to convulsion, effective dose (ED) infused at time of convulsion, and brain concentration (BC) of PTZ at time of convulsion. In addition, ED and latency to convulsion were measured in WSP and WSR mice at 5 different concentrations of PTZ. Higher concentrations, which increased rate of drug infusion, reduced latency but had little effect on ED. WSP1 mice were slightly more sensitive to PTZ than WSR1 mice, but WSP2 mice were equally or less sensitive than WSR2 mice. Among the inbred strains, latency, ED and brain PTZ concentration were found to be highly correlated, suggesting that pharmacokinetic factors do not significantly influence access of PTZ to sites of action in the central nervous system. The C57BL/6J strain was least sensitive by all measures, while DBA/2J mice were highly sensitive. The BALB/cJ strain was the most sensitive strain as assessed by ED and latency, but BC indicated relatively average sensitivity. Apparently, pharmacokinetic factors in this strain result in a relatively rapid accumulation of drug in brain, making it appear to be more sensitive. Thus, although ED provides a reliable estimate of neural sensitivity in general, genetic factors exist which, in some strains, modify access of PTZ and possibly other drugs to brain, potentially affecting determination of sensitivity in the absence of a measure of brain drug concentration.

Assessment of left ventricular regional wall motion with blood pool tomography: comparison of 11CO PET with 99Tcm SPECT.

Left ventricular contraction is routinely assessed by radionuclide ventriculography. Although a planar image is conventionally used, tomography has been to improve the detection of wall motion abnormalities. A blood pool image is often used in positron emission tomography on which to superimpose metabolic tracers. Can this image also be used to assess left ventricular contraction? Nine healthy controls, mean (S.D.) age 55 (5) years, and 12 patients, mean (S.D.) age 61 (8) years, with normal, proven or suspected left ventricular damage underwent blood pool tomography with 11CO positron emission tomography (PET) and 99Tcm single photon emission computed tomography (SPECT). A normal value of ejection fraction and range of phase were defined. The normal left ventricular ejection fraction was > or = 37% for PET and > or = 40% for SPECT. The ejection fractions obtained by the two methods in the patient group were positively correlated (r = 0.89, P < 0.001). Abnormalities of left ventricular contraction were detected in nine patients by PET and 10 patients by SPECT imaging. The discrepancy was in a patient with a previous inferior myocardial infarction. Blood pool imaging with 11CO PET can be used to assess left ventricular ejection fraction and regional wall motion.

Rapid myoglobin analysis to assess coronary artery reperfusion after acute myocardial infarction.

BACKGROUND: Coronary artery reperfusion significantly improves outcome in patients with acute myocardial infarction. A noninvasive method for assessing reperfusion in the early stage of infarction should be helpful in patient management. HYPOTHESIS: We sought to assess whether release pattern of myoglobin is helpful in identifying patients with and without reperfusion following thrombolytic therapy for myocardial infarction. METHODS: Myoglobin was measured before thrombolysis, half hourly for 4 h, then every 2 h for 10 h. Myoglobin was analyzed using a ward-based "rapid" and automated analyzer that yielded quantitative results within 10 min of blood collection. RESULTS: In the 15 patients with coronary reperfusion, the time from thrombolysis to peak myoglobin levels (mean +/- SD, 2.4 +/- 1.5 h) was significantly lower than in nonreperfused patients (5.1 +/- 2.9, p < 0.01). As an indicator for reperfusion, a doubling of myoglobin 1 h after streptokinase achieved a sensitivity of 80%, a specificity of 80%, and a predictive accuracy of 80%. CONCLUSIONS: The difference in myoglobin release kinetics is useful in identifying patients without coronary reperfusion and should aid in their management.

Hypothermia in the north east of Scotland.

The aim of the study was to establish the incidence of hypothermia in the Grampian region, and to examine the accuracy of routine reporting of hypothermia on hospital discharge records. From 1990-1994, 167 patients were admitted with an SMRI diagnosis of hypothermia. An admission temperature of under 35 degrees C was recorded in 47 (28%); rectal in 37 (confirmed hypothermia) and not specified on non-rectal in 10 (possible hypothermia). Most admissions were during the winter months in only 18 cases of the 47 patients with confirmed or possible hypothermia was a secondary cause not apparent. Isolated hypothermia is rare in Grampian. In most cases other disease is the underlying cause.

Two coronary artery fistulae in a patient with temporal arteritis and chest pain.

A 59-year-old woman with a history of cardiac sounding chest pain was investigated by coronary arteriography. Two unsuspected fistulae were found. The fistulae originated from the distal right coronary artery and the diagonal branch of the left coronary artery. Both drained into the left ventricle. She was also found to have temporal arteritis, treatment of which abolished the chest pain.

Coronary artery ectasia: is it associated with myocardial ischaemia and infarction?

Coronary artery ectasia is an uncommon finding during coronary angiography. There may be associated stenoses of the affected arteries. We report three cases, which illustrate that ectasia, in the absence of obstructive disease, can result in myocardial ischaemia and infarction.

Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Phenotyping of human complement component C4, a class-III HLA antigen.

The plasma complement protein C4 is encoded at two highly polymorphic loci, A and B, within the class-III region of the major histocompatibility complex. At least 34 different polymorphic variants of human C4 have been identified, including non-expressed or 'null' alleles. The main method of identification of C4 polymorphic allotypes is separation on the basis of charge by agarose-gel electrophoresis of plasma. On staining by immunofixation with anti-C4 antibodies, each C4 type gives three major bands, but, since individuals can have up to five allotypes, the overlapping banding pattern is difficult to interpret. We show that digestion of plasma samples with carboxypeptidase B, which removes C-terminal basic amino acids, before electrophoresis, produces a single, sharp, distinct band for each allotype and allows identification of the biochemical basis of the multiple banding pattern previously observed in C4 phenotype determination.

Adhesion and the cell cycle in cultured L929 and CHO cells.

The adhesiveness of L929 and CHO-K1 cells was monitored throughout their respective cell cycles. The cell cycle stages were identified by a combination of measuring, histochemical and autoradiographic techniques. Adhesiveness was shown to be maximal during the S and late G2 phases, and minimal at mitosis. S cells adhered selectively to other S cells, while late G2 phase cells adhered selectively to other late G2 cells. Mixing of the two cell lines, L929 and CHO-K1, resulted in the S phase cells adhering to each other irrespective of the cell line to which they belonged. The phases of increased adhesiveness and selectivity coincided with a decrease in cell surface negative charge, corresponding to well documented changes in the morphology of the cells.

DNA polymorphism of the C2 and factor B gene.

C2 and factor B are encoded by very closely linked loci in the class III region of the human major histocompatibility complex on chromosome 6. The factor B gene is divided into 18 exons, and is 6 kb in length whereas the C2 gene is much larger being 18 kb in length. Sequence and Southern blot analysis has defined 5 DNA polymorphisms in the DNA encompassing the C2 and factor B loci. The most interesting of these are the SstI multi-allelic polymorphism at the 5' end and the TaqI polymorphism at the 3' end of the C2 gene. Together these allow the subdivision of haplotypes carrying the C2C and factor B F alleles. A novel combination of SstI and TaqI RFLPs is reported here.

Effects of beta-(N-methylamino)-L-alanine on cytoskeletal proteins of erythrocyte membranes.

The interaction of the amino acid beta-(N-methylamino)-L-alanine, a neurotoxin found in the seed of the false sago palm, with erythrocyte membranes has been monitored by electron paramagnetic resonance techniques of spin labeling. This neurotoxin did not alter the motion or order of bilayer lipids, but a highly-significant and dose-dependent alteration in the physical state of cytoskeletal proteins was observed. These results are discussed in reference to potential mechanisms involved in the neurotoxicity produced by beta-(N-methylamino)-L-alanine and in reference to the unusual neurological disorders among the Chamorro population of Guam and other Marianas Islands.