Genetic and epigenetic alterations of the EGFR and mutually independent association with BRCA1, MGMT,and RASSF1A methylations in Vietnamese lung adenocarcinomas

Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.     

The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Changing prevalence and knowledge of urinary incontinence among Hong Kong Chinese women

A territory-wide telephone survey was conducted in Hong Kong to assess the prevalence, knowledge, and treatment-seeking behaviour of Chinese women with urinary incontinence, using validated Chinese version of Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7). Women, 540, aged between 17 to 77 years were interviewed. Of the respondents, 40.8% reported stress urinary incontinence, 20.4% had urge incontinence and 15.9% had mixed incontinence. Among these, 16.0% reported quality of life impairment; 9.3% felt frustrated with low morale, and 15.2% had nervous and anxiety problems. However, as many as 78.3% of the respondents did not know that stress urinary incontinence is a disease entity, and 60.6% thought that leakage of urine was a normal aging process. For those respondents having stress urinary incontinence, the first treatment of choice was physiotherapy. The second choice was medication, and surgical treatment was the last option. Respondents with stress urinary incontinence showed higher education level.     

Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years.

OBJECTIVES: To evaluate the efficacy of the combination of annual screening with mammography, physical examination of the breasts and the teaching of breast self-examination in reducing the rate of death from breast cancer among women aged 40 to 49 years on entry. DESIGN: Individually randomized controlled trial. SETTING: Fifteen urban centres in Canada with expertise in the diagnosis and treatment of breast cancer. PARTICIPANTS: Women with no history of breast cancer and no mammography in the previous 12 months were randomly assigned to undergo either annual mammography and physical examination (MP group) or usual care after an initial physical examination (UC group). The 50,430 women enrolled from January 1980 through March 1985 were followed for a mean of 8.5 years. DATA COLLECTION: Derived from the participants by initial and annual self-administered questionnaires, from the screening examinations, from the patients' physicians, from the provincial cancer registries and by record linkage to the Canadian National Mortality Data Base. Expert panels evaluated histologic and death data. MAIN OUTCOME MEASURES: Rates of referral from screening, rates of detection of breast cancer from screening and from community care, nodal status, tumour size, and rates of death from all causes and from breast cancer. RESULTS: Over 90% of the women in each group attended the screening sessions or returned the annual questionnaires, or both, over years 2 to 5. The characteristics of the women in the two groups were similar. Compared with the Canadian population, the participants were more likely to be married, have fewer children, have more education, be in a professional occupation, smoke less and have been born in North America. The rate of screen-detected breast cancer on first examination was 3.89 per 1000 in the MP group and 2.46 per 1000 in the UC group; more node-positive tumours were found in the MP group than in the UC group. During years 2 through 5 the ratios of observed to expected cases of invasive breast cancer were 1.26 in the MP group and 1.02 in the UC group. Of the women with invasive breast cancer through to 7 years, 191 and 157 women in the MP and UC groups respectively had no node involvement, 55 and 43 had one to three nodes involved, 47 and 23 had four or more nodes involved, and 38 and 49 had an unknown nodal status. There were 38 deaths from breast cancer in the MP group and 28 in the UC group. The ratio of the proportions of death from breast cancer in the MP group compared with those in the UC group was 1.36 (95% confidence interval 0.84 to 2.21). The survival rates were similar in the two groups. The highest survival rate occurred among women whose cancer had been detected by mammography alone. CONCLUSION: The study was internally valid, and there was no evidence of randomization bias. Screening with yearly mammography and physical examination of the breasts detected considerably more node-negative, small tumours than usual care, but it had no impact on the rate of death from breast cancer up to 7 years' follow-up from entry.     

The glaucoma suspect: Differentiation of the future glaucoma eye from the non-glaucomatous suspect eye

Visual-field areas to a I_2e stimulus were measured planimetrically using an X-Y digitizer and a computer program. Sampling of normal subjects and patients suspected of having glaucoma was done at two points in time. Calculations of eye-wall stress were done using ultrasonic data and intra-ocular pressure (IOP) measurements from patient records. For those suspected of having glaucoma who developed chronic open-angle glaucoma (COAG), the time of transition was the second point in time. The visual field area was regressed against patient age at the two points in time. No difference in the regression slopes was found for the normal subjects and unchanged patients. The patients who did develop glaucoma were significantly different. The mean annual rate of visual-field change (rate of decay) was calculated and found to be 28.5 mm²/year for the normals, 153.5 mm²/year for the suspects, and 376.4 mm²/year for those patients who developed glaucoma. The rate of visual-field decay only correlated with patient age (P = 0.03) and eye-wall stress (P < 0.01) in the patients who developed glaucoma.