CDKN2A germline mutations in familial pancreatic cancer

OBJECTIVE: To evaluate the prevalence of mutations in the CDKN2A gene encoding p16 and p14 in familial pancreatic cancer (FPC). SUMMARY BACKGROUND DATA: The genetic basis of FPC is still widely unknown. Recently, it has been shown that germline mutations in the p16 tumor suppressor gene can predispose to pancreatic cancer. The presence of p14 germline mutations has yet not been determined in this setting. METHODS: Eighteen families with at least two first-degree relatives with histologically confirmed pancreatic cancer and five families with at least one patient with pancreatic cancer and another first-degree relative with malignant melanoma of the German National Case Collection for Familial Pancreatic Cancer were analyzed for CDKN2A germline mutations including p16 and p14 by direct DNA sequencing. All participating family members were genetically counseled and evaluated by a three-generation pedigree. RESULTS: None of 18 FPC families without malignant melanoma revealed p16 mutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16 germline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14 germline mutations. CONCLUSIONS: CDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer-melanoma syndrome associated with CDKN2A germline mutations affecting p16. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16 mutations to identify high-risk family members who should be enrolled in a clinical screening program.     

Association of TP53 mutations with TP53 codon 72 polymorphism and outcome in triple-negative breast cancer

Despite recent improvements, triple-negative breast cancer (TNBC) remains a breast cancer subtype with poor prognosis. TP53 mutations are commonly associated with TNBC, suggesting a role in breast cancer carcinogenesis. In addition to mutations, several reports focused on TP53 polymorphisms and their association with breast cancer risk and outcome. TP53 codon Pro72Arg polymorphism may predict response to anti-cancer therapy as Pro72 is apparently less effective in the induction of apoptosis.Here, we investigated a potential association of TP53 mutations with TP53 codon 72 polymorphism and clinical outcome in a homogeneous cohort of TNBC patients.DNA isolated from formalin-fixed paraffin-embedded tissue of 35 consecutive TNBC patients was investigated for TP53 mutation and TP53 codon 72 polymorphic status by Sanger sequencing.The kind of TP53 mutations were associated with particular polymorphic Pro72Arg genotypes. Frameshift mutations were significantly correlated with Pro/Pro carriers, nonsense mutations showed a trend for Pro/Arg carriers. Despite this observation no association with clinical outcome was observed.Further studies with larger and more homogeneous cohorts are warranted in order to elucidate a potential association of TP53 Pro72Arg polymorphism and particular TP53 mutations with TNBC carcinogenesis and outcome.     

Pharmacological profile of carvedilol as a beta-blocking agent with vasodilating and hypotensive properties

Carvedilol is a new beta-receptor blocking and vasodilating drug that is presently undergoing clinical trials in hypertension and coronary heart disease. In this article, the pharmacodynamic properties of carvedilol are compared with those of standard drugs. The beta-blocking activity was characterized in isolated organs and in conscious rats, rabbits, and dogs. For the beta 1-blockade in guinea pig atria, the pA10 values were 7.44 +/- 0.16 for carvedilol and 6.77 +/- 0.08 for propranolol. Carvedilol is a noncardioselective beta-blocker. The i.v. doses that inhibited the tachycardia by 50% induced by 1 microgram/kg isoprenaline were 62 micrograms/kg in dogs, 138 micrograms/kg in rabbits and 841 micrograms/kg in rats. In rabbits carvedilol was slightly more active and in rats less active than propranolol. In all models, carvedilol was much more active than labetalol or prizidilol. In contrast to propranolol, carvedilol relaxed rat aortic strips. A dose-dependent decrease in arterial blood pressure was seen in different in vivo models. The total peripheral and coronary resistance were decreased in conscious dogs. The doses required for both beta-blockade and decrease in blood pressure were in the same range. The drug was also active after oral administration. There is no hint for development of tolerance.     

Vital Signs: Estimated Effects of a Coordinated Approach for Action to Reduce Antibiotic-Resistant Infections in Health Care Facilities — United States

BackgroundTreatments for health care–associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increasing incidence of these infections than independent facility-based program efforts.MethodsData from CDC’s National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of health care–associated infections from antibiotic-resistant bacteria or C. difficile both with and without a large scale national intervention that would include interrupting transmission and improved antibiotic stewardship. As an example, the impact of reducing transmission of one antibiotic-resistant infection (carbapenem-resistant Enterobacteriaceae [CRE]) on cumulative prevalence and number of HAI transmission events within interconnected groups of health care facilities was modeled using two distinct approaches, a large scale and a smaller scale health care network.ResultsImmediate nationwide infection control and antibiotic stewardship interventions, over 5 years, could avert an estimated 619,000 HAIs resulting from CRE, multidrug-resistant Pseudomonas aeruginosa, invasive methicillin-resistant Staphylococcus aureus (MRSA), or C. difficile. Compared with independent efforts, a coordinated response to prevent CRE spread across a group of inter-connected health care facilities resulted in a cumulative 74% reduction in acquisitions over 5 years in a 10-facility network model, and 55% reduction over 15 years in a 102-facility network model.ConclusionsWith effective action now, more than half a million antibiotic-resistant health care–associated infections could be prevented over 5 years. Models representing both large and small groups of interconnected health care facilities illustrate that a coordinated approach to interrupting transmission is more effective than historical independent facility-based efforts.Implications for Public HealthPublic health–led coordinated prevention approaches have the potential to more completely address the emergence and dissemination of these antibiotic-resistant organisms and C. difficile than independent facility–based efforts.     

Occupational hand dermatitis in food industry apprentices: results of a 3-year follow-up cohort study

Objective: The aim of this prospective follow-up study was to quantify the impact of hand dermatitis (HD) in bakers, confectioners and bakery shop assistants, and to investigate related risk factors. Method: Bakers', confectioners' and bakery-shop assistants were included in a prospective follow-up study in the region of East Thuringia starting in August 1996. At the beginning of their vocational training 91 apprentices were interviewed and examined in a standardised way. Follow-up examinations and interviews were done after 6 months (n=79), 12 months (n=63) and at the end of the training (n=69) after 36 months. Results: In their case histories 3.3% (n=3) of the apprentices reported previous HD in childhood and adolescence. The first assessment after 2 to 4 weeks of vocational training revealed HD in 17.5% (n=16) of the individuals. At the follow-up examination after 6 months, point prevalence of HD was 29.1% (n=23), after 12 months 27.0% (n=17) and after 36 months 27.5% (n=19). Mild to moderate irritant contact dermatitis was the most frequent finding. Finally, an atopic skin diathesis (>10 points, “atopy score”) (OR=4.89; CI 95% 1.15–20.79), previous HD (OR=41.1; CI 95% 4.99–339.13) as well as flexural dermatitis (OR=6.8; CI 95% 1.72–27.22) proved to be predictive factors for the development of HD. No association was found to respiratory atopy (OR=1.29; CI 95% 0.35–4.7) and metal sensitisation (OR=1.1; CI 95% 0.29–4.35). Exogenous irritant factors did not show a strong association towards a risk increase. Wet work in general, as well as distinct occupational tasks showed only a tendency for being a risk factor for HD. However, leisure time activities, especially house building and rebuilding (OR=5.4; CI 95% 1.05–27.81), were associated with an elevated risk. Conclusions: Endogenous and exogenous factors contribute to the development of HD in bakers' and confectioners' apprentices. Received: 25 September 2000 / Accepted: 20 February 2001     

Small inherited terminal duplication of 7q with hydrocephalus,cleft palate,joint contractures,and severe hypotonia

We report a 14-month-old girl with submucous cleft palate, resolving mild hydrocephalus, severe hypotonia and joint contractures. The finding of extreme hydrocephalus, cleft palate and club feet in a fetus of the mother's previous pregnancy suggested an inherited defect. Chromosome analysis and FISH studies in the proband revealed an abnormal homolog 13 resulting in a duplication of distal chromosome 7q, 7q35-qter, and a very small associated deletion of distal chromosome 13q, 13q34-qter. The mother showed the balanced translocation. Similar clinical signs have been described with larger distal 7q duplications. Our findings suggest that 7q35-qter, and possibly the gene for sonic hedgehog (SHH) on 7q36, is the critical region for the typical facial features and the profound hypotonia observed in the 'trisomy of distal 7q' syndrome.     

Predictors of illicit drug use among a national sample of adolescents

Background: Rates of illicit drug use are increasing among adolescents. This study was guided by Jessor’s problem behavior theory and explored the conceptual domains of risk factors for adolescent illicit drug use. The purpose of the present study was to investigate whether sex, age, race/ethnicity, authoritarian parenting, negative school experiences, ever been treated for depression, or legal involvement predicted lifetime illicit drug use, past year illicit drug use, or past month illicit drug use among adolescents nationwide. Method: The present study was a secondary data analysis of the 2012 National Survey on Drug Use and Health including 17,399 youth from 12 to 17 years of age nationwide. Results: Among adolescents, 25.3% reported using illicit drugs in their lifetime, 18.9% reported past year use, and 10.1% reported past month use. Predictors of lifetime illicit drug use were age, race/ethnicity, ever been treated for depression, authoritarian parenting, negative school experiences, and legal involvement. Predictors of past year and past month illicit drug use were age, ever been treated for depression, authoritarian parenting, negative school experiences, and legal involvement. Conclusions: A global approach targeting all problem behavior theory systems may reduce illicit drug use among adolescents nationwide. Recommendations for future studies are included.     

Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients

Nonsteroidal anti-inflammatory drugs (NSAIDs) can regress adenomas in patients with familial adenomatous polyposis (FAP), and the mechanism involves inhibition of cyclooxygenases (COX). Reactive intermediates formed during the arachidonic acid cascade, notably by COX-2, which is upregulated in polyps of FAP patients, may promote various stages of the polyp --> adenoma --> carcinoma sequence. Etheno-DNA adducts can be derived from reactive intermediates generated during arachidonic acid metabolism and lipid peroxidation. We tested this hypothesis in colonic polyps from FAP patients and colorectal tissue from cancer patients to see whether increased formation of etheno-DNA adducts occurs. Using an ultra-sensitive and specific immunoaffinity/(32)P-postlabelling method, 1, N(6)-ethenodeoxyadenosine (straightepsilondA) and 3, N(4)-ethenodeoxycytidine (straightepsilondC) were quantitated in epithelial cell DNA from asymptomatic colon, FAP polyps and colon tumor tissues. Mean adduct levels in FAP polyps were 65 straightepsilondA/10(9) and 59 straightepsilondC/10(9) parent nucleotides, being 2 to 3 times higher than in unaffected colon tissue (p < 0.02 for straightepsilondA; p < 0.05 for straightepsilondC). Adduct levels in colonic epithelia decreased in the order: FAP polyps > tumor-adjacent tissue > tumor, normal and tumor-distal tissue. Based on this study, requiring confirmation in a larger number of patients and in experimental models, we have demonstrated the formation of promutagenic etheno-DNA adducts in adenomatous polyps of FAP patients that may contribute to genetic instability and cancer progression.     

Mutant androgen receptors in prostatic tumors distinguish between amino-acid-sequence requirements for transactivation and ligand binding

Mutant androgen receptors are thought to contribute to hormone resistance in prostate carcinoma. The part they play in this process, however, is ill-defined. Here we report on transactivation by 2 mutant androgen receptors from prostatic tumors with single amino-acid exchanges in their hormone-binding domains. These exchanges enhance the transactivation property of the receptors, particularly to androsterone and androstanediol, 2 metabolized derivatives of testosterone present in the prostate. Additionally, they enhance the transactivation potential of the mutant receptors to hydroxyflutamide, an anti-androgen frequently used in hormone ablation therapy. The increased transactivation by the mutant receptors did not result from altered affinity of the receptors to the inducing ligands nor from measurable changes in conformation of the liganded receptors. Thus the single amino-acid exchanges identify differences in amino-acid-sequence requirements for transactivation and ligand binding in the hormone-binding domain of the androgen receptor. These results provide new insights into ligand-dependent transactivation, and form a framework for the search for effective antagonists to be used in prostate-cancer therapy.     

Correlation between static automated and scanning laser entoptic perimetry in normal subjects and glaucoma patients

OBJECTIVE: To compare the effectiveness of scanning laser entoptic perimetry with static automated perimetry as a noninvasive instrument for screening for glaucomatous damage in visually asymptomatic subjects within the central 60 degrees (diameter) of vision. DESIGN: A masked cross-sectional study comparing entoptic perimetry to achromatic threshold perimetry. PARTICIPANTS: Twenty-three subjects and controls from the Sharp Rees-Stealy Hospital and the Shiley Eye Center at the University of California, San Diego. TESTING: Virtual reality-based entoptic perimetry was compared with achromatic threshold perimetry. MAIN OUTCOME MEASURES: For each testing session, we compared the presence of a disturbance in the entoptic perimetry stimulus with the presence of defects in visual function as measured by Humphrey automated visual field perimetry. RESULTS: Scanning laser entoptic perimetry reasonably estimates the overall visual field loss for moderate-to-severe scotomas as measured by the pattern deviation in standard visual field perimetry. Scanning laser entoptic perimetry has a sensitivity from 27% to 90% and a specificity from 50% to 100% for screening moderate-to-severe visual field defects caused by glaucoma within the central 60 degrees diameter of vision. CONCLUSIONS: Scanning laser entoptic perimetry may be an effective and inexpensive screening test in hospitals and community clinics for diagnosing visual field loss caused by glaucoma.