Structural effects of the binding of GTP to the wild-type and oncogenic forms of the ras-gene-encoded p21 proteins

Molecular dynamics calculations have been performed to determine the average structures of ras-gene-encoded p21 proteins bound to GTP, i.e., the normal (wild-type) protein and two oncogenic forms of this protein, the Val 12- and Leu 61-p21 proteins. We find that the average structures for all of these proteins exhibit low coordinate fluctuations (which are highest for the normal protein), indicating convergence to specific structures. From previous dynamics calculations of the average structures of these proteins bound to GDP, major regional differences were found among these proteins [Monaco et al. (1995), J. Protein Chem., in press]. We now find that the average structures of the oncogenic proteins are more similar to one another when the proteins are bound to GTP than when they are bound to GDP [Monaco et al. (1995), J. Protein Chem., in press]. However, they still differ in structure at specific amino acid residues rather than in whole regions, in contradistinction to the results found for the p21-GDP complexes. Two exceptions are the regions 25-32, in an alpha-helical region, and 97-110. The two oncogenic (Val 12- and Leu 61-) proteins have similar structures which differ significantly in the region of residues 97-110. This region has recently been identified as being critical in the interaction of p21 with kinase target proteins. The differences in structure between the oncogenic proteins suggest the existence of more than one oncogenic form of the p21 protein that can activate different signaling pathways.     

Heat-shock-proteins-antibodies in patients with Helicobacter pylori associated chronic gastritis

Twenty eight patients (15 F, 13 M mean age 37.7 SD +/- 9.93 range 22-55) affected by Helicobacter Pylori infection associated gastritis were studied. HSP 70 Antibodies were found in 21.4% of patients and their mean values were significantly higher in the patients than in the subjects affected by gastritis HP negative used as controls (p = 0.05). This datum was confirmed by Western blotting. The presence of HSP 70 antibodies in the sera of those patients may support the link between the protein and the development and persistence of chronic inflammation in the gastric mucosa.     

A CCG repeat polymorphism adjacent to the CAG repeat in the Huntington disease gene: implications for diagnostic accuracy and predictive testing

STUDY HYPOTHESIS: Concentrated aqueous solutions of hydroxocobalamin (OHCob) are given intravenously for the treatment of cyanide poisoning. Because OHCob solutions are intensely red and have peak light absorptions at 352 nm and 525 nm, we investigated whether the presence of OHCob in serum would interfere with various automated, colorimetric chemistry measurements. DESIGN: Selected serum chemistry colorimetric measurements were compared in seven patients, using their own serum as control, with serum containing OHCob at the following concentrations: 100 mg/L, 500 mg/L, and 1,000 mg/L. These concentrations are in the range achieved with therapeutic doses of OHCob when given for cyanide poisoning. MEASUREMENTS AND MAIN RESULTS: Statistically significant alterations in serum values for aspartate aminotransferase, total bilirubin, creatinine, magnesium, and iron were seen in the presence of OHCob. CONCLUSION: The presence of OHCob in serum interferes with several chemistry methodologies, and such interference should be anticipated when this antidote is used.     

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.     

Finishing of glass-ionomer cement (SEM study)

A total of 12 glass-ionomer cement specimens were utilized in the present study. The specimens were divided into two equal groups. The first group was used after 10 minutes from setting, while the second was utilized after 24 hours from setting. Each group was divided into three equal subgroups (2 specimens each). The first subgroups were finished under wet condition (wet finished). The second subgroups were dry finished. On the other hand, the third subgroups were kept undisturbed (as set) under mylar strips. The specimens surfaces were then examined by a Scanning Electron Microscope (SEM). It was found that, finishing of the specimens after 24 hours from setting demonstrated more acceptable surface topography either in wet or dry conditions than finishing after 10 minutes from setting. Moreover, the dry finished specimens displayed more acceptable surface topography than the wet finished specimens. On the other hand, the as set (undisturbed) specimens the most acceptable surface topography.     

Massive hemorrhage of the digestive system secondary to ulcerated colonic malacoplakia

The presence of an earlier latency of 12 msec of a somato-sensory evoked potential elicited by the stimulation of the median nerve at the wrist was discovered in 1963 by Liberson and Kim. They suggested its origin in the cervical spine or in the brain stem and possibly the cerebellum. Liberson, Voris and Uematsu recorded directly these potentials from the cervical spine and from the mesencephalon during surgery for pain in 1969 and published some of the findings in 1970. Cracco and Bickford confirmed in 1968 the findings of Liberson and Kim.     

HCV and diabetes mellitus: evidence for a negative association

OBJECTIVE: Uncontrolled, retrospective clinical studies have recently claimed that HCV infection could trigger the onset of diabetes mellitus (DM). We sought to verify the association between DM and liver diseases of different etiology, stage, and severity in a prospective study including gender- and age-matched controls. METHODS: Two hundred forty-seven patients with liver cirrhosis (184 men, 116 with an associated hepatocellular carcinoma, 34% in Child-Pugh's class A) were evaluated (group 1). One hundred fifty-seven (63.5) of them were HCV positive, 38 (15.5%) HBV positive, 49 (19.8%) alcohol abusers, and three (1.2%) cryptogenic. Two control groups were also included. The first control group consisted of 138 patients with chronic hepatitis due to HCV infection (73.9%), HBV infection (15.9%), or alcohol abuse (10.2%) (group 2). The second control group included 494 patients with an acute osteoarticular trauma, age- and gender-matched with patients in group 1 (group 3). RESULTS: Diabetes mellitus was present in 32.3%, 3.6%, and 9.7% of patients in groups 1, 2, and 3, respectively. When compared with controls (group 3), DM was significantly less frequent in group 2 (p < 0.004) and significantly more frequent in group 1 (p < 0.0001). The prevalence of DM was not different among patients with HCV, HBV infection, or alcohol abuse. In group 3, the prevalence of DM appeared to increase steadily with age. On the contrary, in patients with liver cirrhosis (group 1) DM was detected in about 20-30% of cases in all decades of age. In group 2, diabetics were found only in the 7th and 8th decades of life. At multivariate analysis cirrhosis and age were the only two factors independently associated with DM; odds ratios were 12.5 (95% confidence interval [C.I.], 6.74-20.4) for cirrhosis, and 1.47 for age (95% C.I. 0.39-2.55). CONCLUSIONS: Our findings disprove HCV infection as a trigger factor for DM, which should not be listed among the various extrahepatic manifestations of this viral infection.     

A signal-detection theory based perspective on design of warning

The effects of warnings are analyzed using a distributed signal-detection theory model. It is established that selectivity always increases effectiveness. The implications to optimal warning design for intermittent versus continuous hazards are discussed. The changes in the behavior of the 6 human subjects in response to changes in the warning levels are consistent with the predictions of the model.