Mutation and protein expression of p53 in acquired immunodeficiency syndrome-related lymphomas

p53 mutations are found in a variety of neoplasia. B-immunoblastic lymphoma (BIBL) is a rapidly progressive, aggressive lymphoma. As patients with acquired immunodeficiency syndrome (AIDS) live longer, BIBL is becoming an increasing problem. We asked three questions in our study. What is the frequency of p53 mutations in BIBL? Is it more frequent in patients with AIDS? Can immunohistochemical staining of lymph nodes for expression of p53 substitute for mutational analysis of p53 to detect lymphomas with mutated p53? Exons 5, 6, 7, 8 of the p53 gene (hot-spots for mutations) were amplified and examined for mutations by single-strand conformation polymorphism (SSCP) analysis. Altered migration was observed in 7 of 52 BIBL samples. Of these, 4 of 25 were from individuals infected with human immunodeficiency virus (HIV) and 3 of 27 were not infected with HIV. Direct sequencing of amplified material confirmed the presence of mutations in exons 5, 7, 8 of p53. A total of 26 BIBL as well as other lymphoma/leukemia samples, stained strongly by immunohistochemistry with three antibodies directed against human p53. Five of 6 BIBL samples with p53 mutations stained strongly for p53, but 20 lymphoma samples with no detectable p53 mutations also stained strongly for p53. Of note, however, 10 hyperplastic, nonmalignant lymph nodes from individuals either infected or not infected with HIV had negligible staining for p53 protein. In conclusion, p53 mutations occur in about 14% BIBL samples; the frequency of p53 mutations in BIBL in individuals with and without AIDS was similar. Positive p53 immunohistochemistry did not correlate with detectable p53 mutations in the same tissue, but positive immunohistochemical staining for p53 was only found in neoplastic lymph nodes. This latter finding provides a strong warning that p53 immunochemistry with available reagents cannot be used to determine which tumors have mutations of p53.     

Liver complications of haemoglobin H disease in adults

Haemoglobin H (HbH) disease is a type of non‐transfusion‐dependent thalassaemia. This cross‐sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24–79) years, male 34%, non‐deletional HbH disease 24%]. Patients underwent ‘observed’ T2‐weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate‐to‐severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non‐deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52–17·50; P = 0·047] and moderate‐to‐severe liver iron overload (OR 3·47, 95% CI 1·01–12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.     

Depressive symptoms and smoking among Hong Kong Chinese adolescents

AIMS: To examine associations among depressive symptoms, smoking, smoking trajectories and quitting smoking in Hong Kong. DESIGN: Prospective longitudinal design, with wave 1 at baseline (T1) and wave 2 (T2) 12 months later. SETTING AND PARTICIPANTS: Form 1 (equivalent to 7th grade in the United States) students, mean age = 12.7 years, n = 1894. MEASUREMENTS: Self-reported smoking status, attempts to quit and depressive symptoms. FINDINGS: At both waves, current as well as ex-smokers had higher depressive symptoms than never smokers. T1 smoking predicted T2 depressive symptoms among those with low baseline depressive symptoms. Depressive symptoms at T1 predicted smoking at T2 among non-smokers at T1. Trajectories were defined by separating participants who were never smokers at both waves ('non-smokers'), those who smoked at both waves ('persistent smokers'), those who smoked at one time but were not smoking at either wave ('past smokers), and those who had never smoked at T1 but reported smoking a year later ('new smokers'). Persistent, past and new smokers had higher depressive symptoms at both waves than non-smokers. Smokers who reported not wanting or trying to quit and those who had been unsuccessful at quitting had higher depressive symptoms at T2 than those who successfully quit. CONCLUSION: Our results suggest that depressive symptoms promote tobacco use in Asian adolescents by making it more likely that an adolescent will begin smoking and less likely that she or he will quit. These findings elucidate risk factors in Hong Kong for two important public health concerns for adolescents: smoking and depression.     

Experimental infection of the leaf-monkeys, Presbytis cristata and Presbytis melalophos with subperiodic Brugia malayi

The leaf-monkeys, Presbytis cristata and Presbytis melalophos, experimentally infected with subperiodic Brugia malayi, have been used for studies on the pathoimmunology of the infection and the screening of potential filaricides during the last 6-8 years, and considerable information on the pattern of microfilaraemia and adult worm recoveries have been obtained. The prepatent periods in 97 P. cristata and 45 P. melalophos, each infected with about 200 infective larvae, were similar, these being approximately 70 and 68 days respectively. Although all infected animals became microfilaraemic, the peak geometric mean count was much higher in P. cristata than in P. melalophos, this being 182.0 and 65.8 per ml blood respectively. Mean adult worm recovery expressed as the percentage of the infective dose was 4.7% and 2.5%, respectively. Most worms were recovered from the sacral nodes/thoracic duct or inguinal lymph nodes in these animals. In view of the higher worm recovery and the higher peak microfilaraemia attained, it is concluded that P. cristata is a better model for the infection than P. melalophos.     

Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy

Journal of Gastroenterology - We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development. This is a case–control study of 104 patients [52 HCC and...     

Occupational inhalant exposure and respiratory disorders among never-smokers referred to a hospital pulmonary function laboratory

BACKGROUND: Multiple reports have described associations between occupational inhalant exposure and lung disease. Previous occupational lung disease investigations have studied populations consisting of both smokers and nonsmokers. Smoking complicates interpretation of toxicant exposure-response relationships. The objective of this study was to determine whether, among never-smokers, occupational exposure to gases, dusts, or fumes is associated with a history of respiratory disorders and pulmonary function test defined obstructive lung disease. METHODS: We performed a retrospective analysis of 517 never-smoker patients who underwent pulmonary function testing in our clinical laboratory between 1986 and 1999. We calculated the relative risks of developing adverse respiratory health outcomes given a history of exposure to occupational inhalants. RESULTS: Compared with persons with a negative occupational exposure history, exposed persons had an increased risk of reporting a history of bronchitis [relative risk (RR), 1.59; 95% confidence interval (CI), 1.20-2.12], recurrent lung infections (RR, 2.09; 95% CI, 1.14-3.82), and bronchodilator use (RR, 1.61; 95% CI, 1.26-2.06). There was also a statistically significant association between a history of inhalant exposure and the finding of an obstructive ventilatory defect on pulmonary function testing (RR, 1.79; 95% CI, 1.12-2.85). A history of inhalant exposure was not associated with self-reported asthma (RR, 1.08; 95% CI, 0.83-1.41). The population attributable risk estimates for respiratory disorders due to inhalant exposure were: bronchitis, 23.6%; recurrent lung infection, 36.3%; bronchodilator use, 24.3%; and obstructive lung disease, 29.6%. CONCLUSIONS: Occupational inhalant exposure is a strong risk factor for lung disease in this population of never smokers. A significant burden of respiratory disease in this population may be attributable to occupational inhalant exposure.     

Early and late clinical and angiographic outcomes following terumo coronary stent implantation

The Terumo stent is a new, balloon-expandable, stainless-steel device with a unique multicellular design to provide robust radial force and end-stoppers to prevent dislodgement. We evaluated the early and late clinical and angiographic outcomes of Terumo coronary stent implantation in native coronary arteries using an open, nonrandomized 3-center registry. From July 1998 to June 1999, a total of 118 Terumo stents were implanted in 105 patients (mean age, 58 +/- 10 years). A significant proportion of patients suffered from diabetes (34%), prior myocardial infarction (MI; 43%) and unstable angina (31%). Most target lesions (48%) had unfavorable morphological characteristics (type B2 or C); mean reference luminal diameter was 2.76 +/- 0.41 mm and lesion length was 11.4 +/- 5.3 mm. Primary success in stent deployment was achieved in 103 patients (98%). There was 1 patient with acute stent thrombosis in whom 2 overlapping stents were deployed. Following stenting, the minimal luminal diameter increased from 1.04 +/- 0.48 mm to 2.39 +/- 0.33 mm. Six-month angiography was performed in 97 patients (92%), and the binary angiographic restenosis (> or = 50% narrowing) rate was 16%. Late loss index was 0.50 +/- 0.43. By 6 months, two patients (1.9%) died, two patients (1.9%) had Q-wave MI and 9 patients (8.4%) required repeat coronary interventions. Therefore, our study shows that the Terumo stent is potentially safe and efficacious in the treatment of coronary narrowings, even in the presence of unfavorable clinical conditions and complex lesion morphological characteristics.     

Immunohistochemical Determination of Hepatic Cytochrome P-4502E1 in Formalin-Fixed, Paraffin-Embedded Sections

Cytochrome P-4502E1 (2E1) is inducible by chronic ethanol consumption that results in enhanced activation of anesthetics and commonly used drugs (such as acetaminophen) to hepatotoxins. Therefore, assessment of hepatic 2E1 is needed in prescribing these drugs for the management of alcoholic patients. Currently, measurement of 2E1 requires either immunohistochemistry on frozen sections or Western blot (WB) analysis of homogenized tissue in excess of that needed for pathology. To obtain a more widely applicable method, we developed a procedure to detect 2E1 by immunohistochemistry in formalin-fixed, paraffin-embedded liver biopsies obtained routinely for diagnosis. Data were collected from rats fed ethanol-containing or control liquid diets for 3 weeks. lmmunostaining was performed using anti-human rabbit 2E1 antibody as the primary antibody, and the immunoreaction was detected by the avidin-biotin immunoperoxidase method after treating sections with target unmasking fluid, an antigen retrieval buffer that enhanced the staining of 2E1. In control rats, 2E1 staining was weak and perivenular. After ethanol feeding, it showed a lobular gradient, strongest perivenular and weakest periportal, similar to that seen in frozen sections. The staining intensity was scored as: 0 (no staining) to 3 (strong staining). The zonal staining was scored as follows: 1 = perivenular zonal staining, 2 = midzonal, and 3 = panlobular. With the product of the two scores, a significant difference was found between alcohol-fed and control rats (5.1 ± 0.3 vs. 0.8 ± 0.2, p < 0.001). 2E1 assessments by WB were also significantly different for these rat pairs (68.5 ± 2.1 vs. 7.9 ± 0.8 arbitrary units/mg protein, p < 0.001), with a parallel increase of immunostaining scores and WB measurement of 2E1 content. This immunohistochemical method was then validated in 14 paraffin-embedded percutaneous human liver biopsy samples. In livers of nonalcoholics, 2E1 staining was seen in the perivenular zone only, whereas in samples of alcoholics, the staining was perivenular to midzonal and sometimes periportal. A significant correlation between the zonal staining scores (r_s= 0.67, p < 0.005) or intensity ± zonal staining scores (r_s= 0.79, p < 0.001) and WB analysis was found. The immunohistochemical assessments of 2E1 expression in formalin-fixed, paraffin-embedded sections from livers of alcoholics was found to correlate with WB analysis, and lobular distribution was consistent with that seen in frozen sections. The proposed method should therefore be useful for the assessment of 2E1 content in paraffin-embedded liver samples, thereby aiding in the management of heavy drinkers.     

Elevated levels of transforming growth factor-beta(1) in serum of patients with stable bronchiectasis

Bronchiectasis is a chronic inflammatory and infective airway disease characterized by irreversible dilatation of the bronchi and persistent purulent sputum. Transforming growth factor-beta(1) (TGF-beta(1)) has been found to be increased in the lungs or bronchoalveolar lavage fluid of patients with inflammatory lung diseases. However, little is known on the serum TGF-beta(1) levels in patients with bronchiectasis. We aimed to determine the serum TGF-beta(1) concentrations in 95 patients with stable bronchiectasis (63 women; mean+/-sd age, 58.9+/-14.1 years) and 68 control subjects (23 women; 48.9+/-12.8 years) by ELISA, and to correlate with clinical parameters. The serum TGF-beta(1) levels were significantly higher in bronchiectatic patients compared with control subjects (median [range], 1812.5 pg/ml [1226.4-4114.5 pg/ml] vs. 1342.4 pg/ml [940.3-2371.7 pg/ml]; P<0.001). There was, however, no correlation between serum TGF-beta(1) levels with FEV(1) (% predicted), FVC (% predicted), 24h sputum volume, the number of bronchiectatic lung lobes or total white blood cell count (P>0.05). Our findings support previous indications that TGF-beta(1) may contribute to bronchiectatic airway inflammation. Further studies on the potential mechanisms and pathogenesis implications of this elevation should also be pursued in future.