The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine

In this retrospective cephalometric study of mandibular rotational change, we studied 60 cases. All patients were treated with full fixed appliances and exhibited an opening rotation of at least 1.5 degrees during treatment, as measured on the basis of the angle of the Y-axis to the sella-nasion line (SN). Our objective was to determine whether this opening rotation was sustained during retention. Paired t tests were used to test the hypothesis that the treatment change or opening rotation was stable and that these patients did not return to their original mandible-to-cranium relationship in the posttreatment period. Stepwise regression analysis was used to determine which (if any) changes in the independent variables during treatment could predict the subsequent behavior of the angle of the mandibular plane to the SN and the angle of the Y-axis to the SN during retention. During treatment, the mean increase in the angle of the Y-axis to the SN was 2.43 degrees. After an average posttreatment period of 54 months, this angle was reduced on average by only 0.73 degrees. Stepwise linear-regression analysis indicated that none of the treatment changes seen in the independent variables strongly predicted the ensuing closing rotation seen during retention. The correlation coefficient between the Y-axis angle and the mandibular-plane angle during treatment was 0.67. Mandibular opening rotations as a consequence of orthodontic treatment do not invariably return to the pretreatment value, and their negative effects--although sometimes small--cannot be discounted. Because the preponderant evidence of a closing rotation occurs in the terminal pubertal growth stages, the net effect may be even more significant.     

A comparison of gene organization in the zwf region of the genomes of the cyanobacteria Synechococcus sp. PCC 7942 and Anabaena sp. PCC 7120

The region of the genome encoding the glucose-6-phosphate dehydrogenase gene zwf was analysed in a unicellular cyanobacterium, Synechococcus sp. PCC 7942, and a filamentous, heterocystous cyanobacterium, Anabaena sp. PCC 7120. Comparison of cyanobacterial zwf sequences revealed the presence of two absolutely conserved cysteine residues which may be implicated in the light/dark control of enzyme activity. The presence in both strains of a gene fbp, encoding fructose-1,6-bisphosphatase, upstream from zwf strongly suggests that the oxidative pentose phosphate pathway in these organisms may function to completely oxidize glucose 6-phosphate to CO2. The amino acid sequence of fructose-1,6-bisphosphatase does not support the idea of its light activation by a thiol/disulfide exchange mechanism. In the case of Anabaena sp. PCC 7120, the tal gene, encoding transaldolase, lies between zwf and fbp.     

Metabolism of Zidovudine

1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications.     

Accuracy of portable chest radiography in the critical care setting. Diagnosis of pneumonia based on quantitative cultures obtained from protected brush catheter

Sixty-six supine portable chest radiographs done on the day of bronchoscopy in 62 critical care unit patients suspected of having pneumonia were examined in a blinded fashion by two radiologists. Quantitative culture results obtained from protected brush catheter (PBC) specimens were compared with chest radiograph scores. For one observer, the sensitivity of the chest radiograph for predicting the presence of positive culture results was 0.60, specificity was 0.29, overall agreement was 0.41, positive predictive value was 0.34, and negative predictive value was 0.55. For the second observer, the values were as follows: sensitivity, 0.64; specificity, 0.27; overall agreement, 0.41; positive predictive value, 0.35; and negative predictive value, 0.55. The kappa statistic was calculated at 0.27 indicating marginal interobserver reproducibility. We conclude the portable chest radiograph in the critical care setting is not accurate in predicting the presence of pneumonia when the diagnosis is based on quantitative cultures obtained from protected brush catheter specimens.     

Cdc34 and the F-box protein Met30 are required for degradation of the Cdk-inhibitory kinase Swe1

Ubiquitin-mediated proteolysis controls the abundance of many cell cycle regulatory proteins. Recent work in Saccharomyces cerevisiae suggests that a complex consisting of Cdc53, Skp1, and a third component known as an F-box protein (termed SCF) in combination with Cdc34 specifically targets regulatory proteins for degradation, and that substrate specificity is likely to be mediated by the F-box subunit. A screen for genetic interactions with a cdc34 mutation yielded MET30, which encodes an F-box protein. MET30 is an essential gene required for cell cycle progression and met30 mutations interact genetically with mutations in SCF components. Furthermore, physical interactions between Met30, Cdc53, Cdc34, and Skp1 in vivo provide evidence for an SCFMet30 complex. We demonstrate the involvement of Met30 in the degradation of the Cdk-inhibitory kinase Swe1. Swe1 is stabilized in met30 mutants and GST-Met30 pull-down experiments reveal that Met30 specifically binds Swe1 in vivo. Furthermore, extracts prepared from cdc34 or met30 mutants are defective in polyubiquitination of Swe1. Taken together, these data suggest that SCF-mediated proteolysis may contribute to the regulation of entry into mitosis. Our data, in combination with previously published results, also provide evidence for distinct SCF complexes in vivo and support the idea that their F-box subunits mediate SCF substrate specificity.     

Cyclosporin A in patients receiving renal allografts from cadaver donors. 1978

A psychrotrophic yeast, Rhodotorula glutinis KUJ 2731, isolated from soil, effectively produced an extracellular endo-beta-glucanase (EC 3.2.1.4). The enzyme was monomeric, and the molecular mass was about 40,000 Da. The N-terminal amino acid sequence was H-Ser-Leu-Pro- Lys-Leu-Gly-Gly-Val-Asp-Leu-Ala-Gly-Leu-Asp-Ile-Gly-Lys-Asp-Lys-Asn-. alpha-Helix content was calculated to be about 32.6%. The isoelectric point was 8.57. The activation energy was 20.9 kJ/mol, which was much smaller than that of mesophilic enzymes. The enzyme was active at temperatures from 0 to 70 degrees C, with a highest initial velocity at 50 degrees C similar to other psychrotrophic enzymes. The enzyme was inhibited by Hg2+. The enzyme catalyzed hydrolysis of carboxymethyl cellulose with an apparent K(m) of 1.1% and Vmax of 556 mumol/min/mg. Products from the enzymatic hydrolysis of carboxymethyl cellulose by the enzyme were glucose, cellobiose, and cellotriose. The enzyme also catalyzed the transglycosylation of p-nitrophenyl-beta-cellotrioside to cellotetraose.     

Mild hypothermia: therapeutic window after experimental cerebral ischemia

The treatment of cerebral ischemia remains a formidable challenge in neuroscience today. Mild hypothermia has been shown to be an effective neuroprotective agent. Despite the great volume of published research, the therapeutic window of mild hypothermia has not been precisely elucidated. Using a model of reversible focal cerebral ischemia in the rat, this study was undertaken to define the optimal duration of hypothermic application and the maximal postischemic delay in hypothermic application before which optimal therapeutic effect is noted. Focal ischemia was induced by temporary occlusion of the middle cerebral artery and both carotid arteries in Sprague-Dawley rats for a period of 3 hours. In the first study, mild hypothermia (32-33 degrees C) was induced at the onset of ischemia in four groups of rats for varying lengths of time ranging from 1 to 4 hours. The animals were killed after 3 days, and their brains were sliced and stained. Infarcted volume was measured using a computerized image analyzer. The infarct volumes were 211 +/- 4.5, 214.2 +/- 8.0, 199.5 +/- 5.3, 171.3 +/- 9.1, and 169.8 +/- 6.5 mm3 (mean +/- standard error of the mean, n = 6 per group) for the control, 1-hour, 2-hour, 3-hour, and 4-hour groups, respectively. On the basis of the results from the above study, a 3-hour duration of hypothermia was then applied to animals at 0, 15, 30, or 45 minutes after the ischemic onset. The volumes of infarction for these four respective groups were: 171.3 +/- 9.1, 173 +/- 5.7, 179.3 +/- 5.2, and 206.2 +/- 8.4 mm3 (mean +/- standard error of the mean, n = 6 per group). These results demonstrated that optimal duration of mild hypothermia was at least 3 hours (P < 0.001) when applied within the first 30 minutes after the onset of ischemia (P < 0.001).