Extension of a typology of alcohol dependence based on relative genetic and environmental loading

Mild, severe, and dyssocial subtypes of alcohol dependence, previously identified among Caucasian men from the Epidemiologic Catchment Area study, were also identified among Caucasian men and women with DSM-IV alcohol dependence from the National Longitudinal Alcohol Epidemiologic Survey (n = 2,703; 1,746 respectively). These subtypes were not identified among African American and Hispanic American men or women with DSM-IV alcohol dependence. Among Caucasians with alcohol dependence, the subtypes were characterized by differential loading on three dimensions: genetic, general environmental, and dyssocial environmental symptom scales developed in a prior twin study. The mild subtype (60% of men and 66% of women) was distinguished by low mean scores on all three scales; the dyssocial subtype (24% of men and 20% of women) by low mean genetic and general environmental scores but high mean dyssocial environmental scores; and the severe subtype (16% of men and 14% of women) by high scores on the genetic and general environmental scales. These subtypes also showed the expected distinctions in clinical characteristics. The severe subtype showed greater comorbid drug dependence and major depression, more treatment seeking, and a higher prevalence of parental alcoholism. The severe subtype also showed significantly greater genetic influence adjusted for overall severity of alcohol dependence (genetic ratio). Only the severe subtype showed a pattern of scale scores and clinical characteristics suggestive of substantial genetic influence. The present study indicates a robustness of the typology originally developed among DSM-III alcohol-dependent Caucasian men by empirical extension of the subtypes to a different sample of Caucasian men and, separately, Caucasian women. The use of this typology may aid in distinguishing between Caucasian alcohol-dependent individuals on the basis of relative genetic influence, enabling genetic, behavioral, and epidemiological investigations to reduce genetic or environmental "noise" and better focus on specific aspects of alcohol dependence.     

Spinal neurilemmomas and neurofibromas: central dot sign in postgadolinium MRI

The MR studies of three histologically proven spinal neurilemmomas and neurofibromas were reviewed retrospectively. There were two benign neurilemmomas (schwannomas) and one neurofibroma. The common characteristic of these cases was a central low intensity focus ("dot") seen on postcontrast T1-weighted imaging. The low intensity foci corresponded histologically to a congeries of changes including edema, microcysts, foam cells, hyalinization of blood vessels, old hemorrhage, and dystrophic calcification.     

"Indianism" and MMPI scores of men alcoholics

Mean MMPI profiles of 40 Indian and 40 White veterans were similar, but "Indianism," as measured by the Indian Culturalization Test, was significantly related to scores on Hs, Hy, Pt and Sc scales. Caution is advised in using the MMPI in the diagnosis of Indians' psychiatric problems.     

Magnetic resonance imaging of acute stroke

In the investigation of ischemic stroke, conventional structural magnetic resonance (MR) techniques (e.g., T1-weighted imaging, T2-weighted imaging, and proton density-weighted imaging) are valuable for the assessment of infarct extent and location beyond the first 12 to 24 hours after onset, and can be combined with MR angiography to noninvasively assess the intracranial and extracranial vasculature. However, during the critical first 6 to 12 hours, the probable period of greatest therapeutic opportunity, these methods do not adequately assess the extent and severity of ischemia. Recent developments in functional MR imaging are showing great promise for the detection of developing focal cerebral ischemic lesions within the first hours. These include (1) diffusion-weighted imaging, which provides physiologic information about the self-diffusion of water, thereby detecting one of the first elements in the pathophysiologic cascade leading to ischemic injury; and (2) perfusion imaging. The detection of acute intraparenchymal hemorrhagic stroke by susceptibility weighted MR has also been reported. In combination with MR angiography, these methods may allow the detection of the site, extent, mechanism, and tissue viability of acute stroke lesions in one imaging study. Imaging of cerebral metabolites with MR spectroscopy along with diffusion-weighted imaging and perfusion imaging may also provide new insights into ischemic stroke pathophysiology. In light of these advances in structural and functional MR, their potential uses in the study of the cerebral ischemic pathophysiology and in clinical practice are described, along with their advantages and limitations.     

Outbreak of pneumonia in a long-term care facility: antecedent human parainfluenza virus 1 infection may predispose to bacterial pneumonia

OBJECTIVES: To determine the causes of an outbreak of lobar pneumonia. DESIGN: Matched (1:2) case-control study. SETTING: A 70-bed chronic care facility for older people. PARTICIPANTS: Residents of the facility. RESULTS: Ten residents developed pneumonia over a 10-day period. Two residents died. One case-patient had Streptococcus pneumoniae bacteremia; another had polymerase chain reaction evidence of S. pneumoniae infection. No other etiologic agent was identified. Only four of 10 case-patients had received routine diagnostic cultures of blood or sputum before the administration of antibiotics. Symptoms of upper respiratory illness (URI) among residents before the pneumonia outbreak corresponded with elevation of antibodies to human parainfluenza virus 1 (HPIV1). In a matched case-control study, six of 10 case-patients, compared with five of 20 controls, had symptoms of URI during the preceding month (matched odds ratio (MOR) = 4.5, 95% CI = 0.8-33). Nine case-patients had serum available, and five of these had both serologic evidence of recent HPIV1 infection and recent URI, compared with two of 18 controls (MOR = 9.0, 95% CI = 1.2-208). Only three residents had documentation of pneumococcal vaccination. CONCLUSIONS: Noninfluenza viral infections may play a role in the pathogenesis of some bacterial pneumonias. S. pneumoniae was the cause of at least two pneumonias; lack of preantibiotic cultures may have interfered with isolation of S. pneumoniae in others. Recent HPIV1 infection was epidemiologically linked to subsequently developing pneumonia. Spread of HPIV1 in the facility may have contributed to increased susceptibility to S. pneumoniae and, potentially, to other bacterial pathogens.     

Regulation of cardiac myocyte contractile function by inducible nitric oxide synthase (iNOS): mechanisms of contractile depression by nitric oxide

Inflammatory cytokines have been implicated in the reversible depression of cardiac contractile function accompanying local or systemic immune stimulation. Incubation of cardiac myocytes with soluble components in the supernatant from cultured rat lung macrophages activated with endotoxin decreases their contractile response to beta-adrenergic stimulation through the induction of iNOS and the subsequent production of nitric oxide by these cells. In the present study, we characterize the mechanisms underlying NO's attenuation of adrenergic responsiveness in cardiac myocytes. iNOS was induced in cultured ventricular myocytes from adult rats by incubation for 20 h with conditioned medium from lipopolysaccharide (LPS)-activated macrophages. iNOS induction did not induce any alteration in beta-adrenergic receptor density or affinity, Galphai protein abundance, or adenylyl cyclase activity in cultured myocytes. Myocyte exposure to activated macrophage-conditioned medium markedly attenuated the elevation of cAMP in response to isoproterenol (Iso, 2 nM). Induction of iNOS with the macrophage-conditioned medium also potentiated the Iso-induced increase in myocyte cGMP. This cGMP increase was totally abolished by NOS inhibitors. NOS inhibition also returned the attenuated cAMP response to 2 nM Iso to levels observed in control cells. Pre-incubation of the cells in isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, also partly reversed the attenuation of cAMP increase with 2 nM Iso in cells expressing iNOS. Brief (15 min) exposure of myocytes to the NO donor, S-nitrosoacetylcysteine (SNAC, 100 micro M) which produced a three-fold increase in intracellular cGMP, also decreased by half the contractile response of cardiac myocytes to Iso (2 nM). We conclude that NO endogenously produced by iNOS decreases the intracellular levels of cAMP in response to beta-adrenergic stimulation in isolated cardiac myocytes, in part through a cGMP-mediated mechanism. This effect may participate in the NO-dependent depression of cardiac function following cytokine exposure.     

O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases

To modulate the bioavailability and perhaps improve the tumor cell selectivity of O6-alkylguanine-DNA alkyltransferase (AGT) inactivators, pivaloyloxymethyl ester derivatives of O6-benzylguanine (BG) were synthesized and tested as AGT inactivators and as substrates for cellular esterases. The potential prodrugs examined were the 7- and 9-pivaloyloxymethyl derivatives of O6-benzylguanine (7- and 9-esterBG), and of 8-aza-O6-benzylguanine (8-aza-7-esterBG and 8-aza-9-esterBG) and the 9-pivaloyloxymethyl derivative of 8-bromo-O6-benzylguanine (8-bromo-9-esterBG). The benzylated purines were all potent inactivators of the pure AGT and of the AGT activity in HT29 cells and cell extracts. Each ester was at least 75 times less potent than the corresponding benzylated purine against the pure human AGT. In contrast, the activities of esters and their respective benzylated purine were similar in crude cell extracts and in intact cells. The increase in potency of esters in cellular extracts could be explained by a conversion of the respective prodrug to the more potent benzylated purine in the presence of cellular esterases. The apparent catalytic activity (Vmax/Km) of liver microsomal esterase for 8-azaBG ester prodrugs was 70-130 times greater than for BG prodrugs and 10-20 times greater than for 8-bromo-9-esterBG. Tumor cell hydrolysis of the esters varied considerably as a function of cell type and prodrug structure. These data suggest that these or related prodrugs may be advantageous for selective AGT inactivation in certain tumor types.     

Reduction in postprandial lipemia after walking: influence of exercise intensity

Whole-body thermogenesis, substrate utilization (open-circuit ventilated-hood system), and exogenous carbohydrate oxidation were evaluated in 10 healthy lean male volunteers (aged 27.8 +/- 2.5 years) for 6 hours after oral ingestion of 75 g naturally enriched fructose, glucose (both derived from corn starch), cane sugar, and a good digestible corn starch (all mixed with 400 mL water). The integrated areas under the glucose and insulin response curves above baseline were highest with glucose and starch, intermediate with sucrose, and lowest with fructose, whereas there were no significant differences in the integrated nonesterified fatty acid (NEFA) response between carbohydrates. The total increment in energy expenditure (EE) above baseline was similar with fructose (130 +/- 24 kJ/6 h) and sucrose (141 +/- 17 kJ/6 h), was higher with sucrose as compared with starch (108 +/- 24 kJ/6 h, P < .05) and glucose (94 +/- 20 kJ/6 h, P < .05), and tended to be higher with fructose as compared with glucose (P = .059). Both the increment in total carbohydrate oxidation (P < .05) and the increment in exogenous carbohydrate oxidation (P < .01) were significantly higher with fructose and sucrose compared with glucose and starch. The initial inhibition of lipid oxidation was higher with sucrose and fructose than with glucose and starch, whereas the integrated decrement in lipid oxidation over 6 hours was only higher with fructose compared with glucose and starch (P < .05). In conclusion, thermogenesis and substrate utilization vary considerably after ingestion of different types of carbohydrate in young lean males, indicating that the carbohydrate composition of the diet may have important consequences for energy and macronutrient balance.     

Potential and limitations of magnetic resonance imaging for real-time monitoring of interstitial laser phototherapy

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging has been suggested as a method to monitor interstitial laser phototherapy (ILP) in deep tissues. Unfortunately, a reliable relation between temperature and MR parameters has not yet been demonstrated. In this study, we examined whether such a relation exists and whether MR imaging can measure absolute temperature or temperature changes. METHODS: We evaluated, in the range of 21 degrees C to 80 degrees C, the temperature dependence of the MR imaging signal and T1 in samples of liver, water, CuSO4, and oil. Spin-echo and fast low-angle shot (FLASH) sequences were used. RESULTS: The MR imaging signal of liver, CuSO4, and water continuously decreased when the temperature was increased from 21 degrees C to 80 degrees C. By contrast, the MR imaging signal of the oil increased with increasing temperature up to 40-50 degrees C and then decreased at higher temperatures. We observed a reliable linear relation only between T1 and temperature in a range' of 30-60 degrees C for oil and CuSO4. CONCLUSION: MR imaging has the potential to measure thermal variations with an uncertainty of approximately +/- 10 degrees C. However, the use of MR imaging to monitor the real-time thermal effect induced in biologic tissues during laser irradiation requires further investigation before it can be applied clinically.     

Mechanism of irreversible inactivation of phosphomannose isomerases by silver ions and flamazine

Silver ions and silver-containing compounds have been used as topical antimicrobial agents in a variety of clinical situations. We have previously shown that the enzyme phosphomannose isomerase (PMI) is essential for the biosynthesis of Candida albicans cell walls. In this study, we find that PMI can be inhibited by silver ions. This process is shown to be irreversible, and is a two-step process, involving an intermediate complex with a dissociation constant, Ki, of 59 +/- 8 microM, and a maximum rate of inactivation of 0.25 +/- 0.04 min-1 in 50 mM Hepes buffer, pH 8.0 at 37 degrees C. The enzyme can be protected against this inactivation by the substrate mannose 6-phosphate, with a dissociation constant of 0.31 +/- 0.04 mM, close to its Km value. Flamazine (silver sulfadiazine) is a silver-containing antibiotic which is used clinically as a topical antimicrobial and antifungal agent. We compared the ability of silver sulfadiazine and two other silver-containing compounds to irreversibly inactivate C. albicans PMI. The addition of the organic moiety increased the affinity of the compounds, with silver sulfadiazine showing a Ki of 190 +/- 30 nM. In all cases, the maximum inhibition rate was similar, implying a similar rate-determining step. Silver sulfadiazine does not inhibit Escherichia coli PMI, and this suggests a role of the only free cysteine, Cys-150, in the inactivation process. To confirm this, we mutated this residue to alanine in C. albicans PMI. The resultant Cys150 --> Ala mutant protein showed similar Vm and Km values to the wild-type enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)