Effects of short-term and subchronic lead poisoning on nitric oxide metabolites and vascular responsiveness in rat

Chronic exposure to low levels of lead results in sustained hypertension in humans and experimental animals. The mechanism of lead-induced hypertension remains unclear. We investigated the short-term (4 and 8 weeks) and subchronic (12 weeks) effects of lead treatment on responsiveness of vascular adrenergic system and level of nitric oxide metabolites, that is, total nitrates and nitrites (NOx). Male Sprague-Dawley rats were treated with lead acetate (100 ppm in drinking water) for 12 weeks. Short-term lead administration resulted in marked elevation of blood pressure accompanied by significant reduction in serum NOx levels. In contrast, after subchronic lead administration the trend of decrease in NOx levels somehow reversed despite further increase in blood pressure. Both short-term and subchronic lead administration resulted in significant differences in vascular reactivity with respect to either vasoconstrictor (phenylephrine and clonidine) or vasodilator (isoproterenol) agents. We conclude that vascular adrenergic system and nitric oxide pathway change in short-term and subchronic phases of lead poisoning.     

Genetic polymorphisms in three Iranian populations with different risks of esophageal cancer, an ecologic comparison

The age-standardized incidence of esophageal cancer (EC) varies from 3 to >100/100,000 per year in different provinces of Iran. This striking variation of incidence is associated with differences in ethnic backgrounds, raising the possibility that genetic factors are involved in the pathogenesis of EC. We compared the frequencies of polymorphisms in ten genes that have been hypothesized to have a role in risk of EC (CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTP1, GSTT1, ADH2, ADH3, ALDH2, and O6-MGMT) among three Iranian ethnic groups with highly varying rates of EC. These three groups included high-risk Turkomans, medium-risk Turks, and low-risk Zoroastrian Persians. Compared to Zoroastrians, Turkomans had higher frequency of four alleles that are speculated to favor carcinogenesis (CYP1A1 m1, CYP1A1 m2, CYP2A6*9, and ADH2*1); these results are consistent with an influence of these allele variants on the population risk of EC. However, none of these four alleles had a high enough prevalence in Turkomans to explain the high rates of EC in this group. Three of these four alleles (CYP1A1 m1, CYP1A1 m2, CYP2A6*9) were less frequent among Turkomans than in some Asian populations with lower risks of EC. We conclude that it is unlikely that variations in these polymorphic genes are major contributors to the high incidence of EC among Turkomans in Iran.     

Analysis of interfraction and intrafraction variation during tangential breast irradiation with an electronic portal imaging device

PURPOSE: To evaluate the daily setup variation and the anatomic movement of the heart and lungs during breast irradiation with tangential photon beams, as measured with an electronic portal imaging device. METHODS AND MATERIALS: Analysis of 1,709 portal images determined changes in the radiation field during a treatment course in 8 patients. Values obtained for every image included central lung distance (CLD) and area of lung and heart within the irradiated field. The data from these measurements were used to evaluate variation from setup between treatment days and motion due to respiration and/or patient movement during treatment delivery. RESULTS: The effect of respiratory motion and movement during treatment was minimal: the maximum range in CLD for any patient on any day was 0.25 cm. The variation caused by day-to-day setup variation was greater, with CLD values for patients ranging from 0.59 cm to 2.94 cm. Similar findings were found for heart and lung areas. CONCLUSIONS: There is very little change in CLD and corresponding lung and heart area during individual radiation treatment fractions in breast tangential fields, compared with a relatively greater amount of variation that occurs between days.     

Clinical course of ulcerative colitis in patients with and without primary sclerosing cholangitis

BACKGROUND AND AIM: We noticed in our practice that patients with ulcerative colitis (UC) who have developed primary sclerosing cholangitis (PSC) experience a milder course of colonic disease. Our objective in this study was to define whether or not there is any difference between UC activity and its course in patients with and without PSC. METHODS: Nineteen patients with UC and PSC (eight male, mean age 25 years) were enrolled. To every patient with UC and PSC, three patients with UC alone (total of 57 patients, 28 male, mean age 24 years) matched for age at onset, duration of the disease and extension of colonic disease were selected as the control group. We used number of hospitalizations due to activity of UC and number of short corticosteroid administrations in various years of follow-up as variables indicating course and severity of the colonic disease in this period. For comparing trends of UC activity between two groups, we used repeated measures two-way analysis of variances. RESULTS: Mean duration of follow up in case and control groups was 12.2 +/- 5.7 and 11.4 +/- 4.9 years, respectively. Two groups had no significant difference in use of sulfasalzine or aminosalicylates. Number of hospitalizations and courses of steroid therapy because of UC activity decreased significantly over time (P < 0.000) in both groups, and it was significantly higher in controls than in cases (P = 0.045 and 0.032, respectively). CONCLUSIONS: Development of PSC in patients with UC might have a positive effect on colonic disease. Further investigations to evaluate the basis of this improvement are warranted.     

Deletion of the 60-loop provides new insights into the substrate and inhibitor specificity of thrombin

Structural data have indicated that the 60-loop of thrombin with 8-9 insertion residues is responsible for the restricted substrate and inhibitor specificity of thrombin. However,previous deletion of 3-4 residues of this loop (des-PPW and des-YPPW) did not widen the specificity of thrombin, but further restricted it. The partial deletion of this loop also dramatically impaired the reactivity of thrombin with antithrombin (AT), protein C and fibrinogen, implicating a role for the productive interaction of the 60-loop with the target macromolecules. To further investigate the role of this loop, a mutant of thrombin was expressed in mammalian cells in which all 8 residues (Tyr-Pro-Pro-Trp-Asp-Lys-Asn-Phe) of the 60-loop were deleted (des-60-loop). In contrast to the partially deleted loop mutants, it was discovered that the des-60-loop mutant cleaved small synthetic substrates, clotted purified fibrinogen, and activated protein C with a near normal catalytic efficiency; however, its activity toward cofactors V and VIII was impaired approximately 2-4-fold. Direct binding and AT inhibition studies in the presence of heparin revealed that the affinity of heparin for interaction with exosite-2 of des-60-loop thrombin was impaired, though the reactivity of the mutant with AT and other plasma serpins was not impaired, but rather improved approximately 2-fold. These results suggest that the 60-loop plays a key role in regulating the specificity of thrombin by shielding the active-site pocket, but its productive interaction with the target molecules may not be as critical as has been speculated in previous reports.     

Alopecia areata in Darier disease and clinical findings in five affected family members

A 32-year-old man known to have keratosis follicularis presented with a new problem of alopecia areata involving his scalp. His Darier disease had been present for 24 years and was manifested by pruritic eruptions that were more severe in the summer months. Other family members, including his father, brother, and two sisters suffered from similar skin manifestations.