A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma.

The incidence of oesophageal adenocarcinoma is rising; to date, no susceptibility genes have been identified. p73, a novel p53 homologue, maps to chromosome 1p36, a region commonly deleted in oesophageal cancers. p73 shares some p53-like activity, but in addition, may also play a role in gastrointestinal epithelial inflammatory responses. A non-coding p73 polymorphism (denoted AT or GC) may be functionally significant. We investigated whether this polymorphism might play a role in the aetiopathogenesis of oesophageal cancer. This was a case-control, retrospective study. 84 cases of oesophageal cancer (25 squamous and 59 adenocarcinoma) and 152 normal population controls were genotyped for this polymorphism. Informative cases were examined for p73 LOH within the tumour. AT/AT homozygotes were significantly less prevalent in the oesophageal cancer population (1/84 = 1.2%) compared to controls (15/152 = 9.9%) (P < 0.02), corresponding to an odds ratio of 0.11 (95% C.I. 0.02-0.6, P < 0.02), or 9-fold reduced risk. Moreover, AT/AT homozygotes were significantly less frequent in the cancer population than would be expected under the Hardy-Weinberg hypothesis (P = 0.0099). LOH at the p73 locus was observed in 37.8% (14/37) of the AT/GC heterozygotes studied; in all cases there was loss of the AT allele. Our findings indicate that p73 AT/AT homozygotes appear to be protected against the development of oesophageal cancer. Clinically, this observation could have implications in aiding identification of high-risk Barrett's oesophagus patients.     

Current smoking, occupation, N-acetyltransferase-2 and bladder cancer: a pooled analysis of genotype-based studies.

The aim of this study was to investigate the association of NAT2 gene polymorphism with bladder cancer using the data derived from the International Project on Genetic Susceptibility to Environmental Carcinogens. Four case control studies conducted in four European countries, plus two case series, one from England and one from Germany, for a total of 1530 cases and 731 controls (all Caucasian) were included. The interaction between NAT2 and bladder cancer considering smoking habits and occupational exposure was studied. There was a significant association between NAT2 and bladder cancer (odds ratio: 1.42, 95% confidence interval: 1.14-1.77), with a slightly significant heterogeneity among studies. However, heterogeneity disappeared when smokers were divided into current and ex-smokers. The risk of cancer was elevated in smokers and occupationally exposed subjects, with the highest risk among slow acetylators. The increase in risk was limited, in fact, to current smokers (odds ratio = 1.74, 95% confidence interval: 0.96-3.15). This analysis confirms that the NAT2 genotype is a risk factor for bladder cancer by interacting with smoking or occupational exposures. Our observation suggests that NAT2 is not a risk factors per se but modulates the effect of carcinogens contained in tobacco smoke (probably arylamines) or associated with occupational exposures.     

Genetic epidemiology of environmental toxicity and cancer susceptibility: human allelic polymorphisms in drug-metabolizing enzyme genes, their functional importance, and nomenclature issues.

Pharmacogenetics is the study of idiosyncratic drug responses that have an hereditary basis and usually reflect differences in drug-metabolizing enzymes (DMEs) and the receptors that control DME levels. The purpose of this review is to provide a brief overview of recent findings concerning more than a dozen clinically important polymorphisms and to emphasize the need to standardize the nomenclature of these alleles in each polymorphism, as quickly as possible. This nomenclature system should be consistent with the Human Gene Nomenclature Guidelines. Because DMEs have existed before divergence of prokaryotes and eukaryotes more than 2 billion years ago, it is clear that DME genes first must have evolved for critical life functions and that, more recently in animals, DME genes expanded to include the role of detoxification of dietary products, evolving plant metabolites, and, of course, pharmaceutical drugs. Many human DME polymorphisms are relevant to clinical problems in that they represent the basis of risk factors in the development of cancer, toxicity, and other diseases associated with drug, chemical, or dietary exposure. The study of the relationship among human genetic polymorphisms, cancer susceptibility, toxicity, and environmental exposure is a new and exciting area of research--which will undoubtedly have increasingly important implications for risk assessment and the prevention, early diagnosis, and intervention of clinical disease.     

Pharmacological analysis of postjunctional alpha-adrenoceptors mediating contractions to (-)-noradrenaline in the rabbit isolated lateral saphenous vein can be explained by interacting responses to simultaneous activation of alpha 1- and alpha 2-adrenoceptors.

1. The pharmacological characteristics of the alpha-adrenoceptor population in the rabbit isolated saphenous vein has been examined with (-)-noradrenaline (NA), as principal agonist, and a number of antagonists with selectivity for either alpha 1- or alpha 2-adrenoceptors. 2. The rank order of potency of various agonists is consistent with a population of alpha 2-adrenoceptors; UK-14304 greater than (-)-noradrenaline = (-)-adrenaline greater than B-HT 920 = cirazoline greater than phenylephrine greater than amidephrine, but the rank order of pA2 values for the antagonists against (-)-noradrenaline: BDF-6143 greater than rauwolscine = prazosin greater than CH-38083 = YM-12617 greater than Wy-26703 = phentolamine greater than corynanthine, is indicative of a mixed population of alpha 1- and alpha 2-adrenoceptors or, alternatively, a new subtype with characteristics of both the alpha 1- and alpha 2-subtypes. 3. Further evidence for two discrete populations of alpha-adrenoceptors is provided by, (a) the potent but non-competitive effect of prazosin against (-)-noradrenaline, (b) the presence of a component of the contractions elicited by NA and phenylephrine which is resistant to the selective alpha 2-adrenoceptor antagonists rauwolscine and CH-38083: these responses were inhibited by the selective alpha 1-adrenoceptor antagonists prazosin and YM-12617, but not by the selective alpha 2-adrenoceptor antagonist BDF-6143 and, (c) the relative potency of the yohimbine diastereoisomers rauwolscine and corynanthine against NA, phenylephrine and UK-14304. 4. In spite of the overwhelming evidence for a population of postjunctional alpha 2-adrenoceptors, prazosin was similarly effective against all agonists and failed to discriminate between those with putative selectivity for alpha 1- and alpha 2-adrenoceptors. This suggests an interaction of the effects of agonists at the two alpha-adrenoceptor subtypes. 5. An attempt has been made to reconcile a number of paradoxical observations with regard to the identification of postjunctional alpha 2-adrenoceptors in vitro, and it is suggested that in many of the isolated blood vessels presently available for examination both subtypes reside on the same smooth muscle cell. The pharmacological consequences of multiple subtypes of receptors mediating the same response is considered.     

Acute corneal calcification following chemical injury

PURPOSE: To describe the clinical and ultrastructural features of 3 cases of acute corneal calcification following accidental chemical injury. METHODS: Three men presented over an 18-month period with unilateral eye injuries sustained when applying an industrial fire retardant. This product is predominantly a gypsum aggregate (calcium sulfate dihydrate) plaster combined under pressure with a set-time accelerator (aluminum sulfate). In each case the tear pH was initially alkaline, and the eyes were irrigated with phosphate-buffered saline according to protocol. Within hours a dense corneal opacity had developed that showed only minor resolution over 3 years of follow-up. Two eyes required corneal graft surgery for visual rehabilitation. Light and electron microscopy and energy dispersive analysis of x-rays (EDAX) was performed on excised tissue. RESULTS: Light and electron microscopy showed dense mineralization of the anterior stroma with discrete crystalline deposits in the deeper stroma. EDAX of the crystals showed high emission peaks for calcium and phosphorus. CONCLUSIONS: The insolubility, elemental composition, and ultrastructural appearance suggest that the opacity was caused by calcium phosphate deposition. The absence of phosphorus from the listed components of the fire retardant suggests that the use of phosphate-buffered irrigation fluid or the subsequent use of phosphate-buffered drops may have contributed to the deposition of this insoluble crystalline deposit.     

Operative correction of an unstable total hip arthroplasty.

We reviewed the results of reoperation in ninety-five patients who had acute subluxation (ten patients) or dislocation (eighty-five patients) of the hip after conventional cemented total hip-replacement arthroplasty. Postoperatively, fifty-eight patients (61 per cent) had no subsequent dislocation or subluxation. Seven of thirty-seven patients who had had recurrent dislocation had occasional subluxation during follow-up. Of the remaining thirty patients in whom instability persisted after the reoperation, twenty-eight had at least one dislocation, and nine had bothersome subluxation. Ten of these thirty-seven patients had another operation for the persistent instability. The causes of instability were classified as malrotation of the component, disruption of the trochanteric-abduction mechanism, impingement, or multiple and unknown, and appropriate treatment was provided. The component was revised in forty-five patients, revision and advancement of the trochanteric component was done in twenty-five patients, and impinging bone or cement was removed from six patients; a combination of these procedures was done in nineteen patients. Over-all, fifty-eight procedures (61 per cent) were successful (no additional subluxations or dislocations). We concluded that the results of operative treatment for an unstable total hip replacement can be optimized when a precise determination of the cause of the instability is made and appropriate measures are applied.     

Trauma deaths in the south west Thames region.

This is an epidemiological study based on Coroners' records analysing mode of injury and place and cause of death. The aim of the study is to provide data on the incidence and patterns of death from trauma and to assess the need for changes in trauma management. All traumatic deaths occurring in the South West Thames Region during 1988 were studied. We analysed 434 of these deaths (mean age 52 years) in some detail. Of the deaths, 59 per cent occurred before arrival at hospital. Road traffic accidents are the commonest cause of death from trauma, being most prevalent in the areas containing major trunk roads. The majority of deaths due to chest injury (79 per cent) and multiple injuries (70 per cent) occurred before arrival at a hospital, whereas the majority of deaths due to head injury (63 per cent) occurred after admission. The majority of deaths from trauma occur before arrival at a hospital, particularly in the semi-rural areas. Improvements in hospital trauma care could have only a limited effect on the death rate in existing circumstances. If important reductions in deaths from severe injury are to be made then prevention and prehospital care need to be improved.     

The relationship between adverse events during selective serotonin reuptake inhibitor treatment for major depressive disorder and nonremission in the suicide assessment methodology study

Little is known about the association between antidepressant treatment-emergent adverse events and symptom nonremission in major depressive disorder. The objective of the current analysis was to determine whether particular baseline symptoms or treatment-emergent symptoms (adverse events) during the first 2 weeks are associated with nonremission after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI).Outpatients clinically diagnosed with nonpsychotic major depressive disorder were recruited from 6 primary and 9 psychiatric care sites. Participants (n = 206) were treated with an SSRI antidepressant (citalopram [20-40 mg/d], escitalopram [10-20 mg/d], fluoxetine [20-40 mg/d], paroxetine [20-40 mg/d], paroxetine CR [25-37.5 mg/d], or sertraline [50-150 mg/d]) for 8 weeks. Remission was defined as having a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology-Clinician-Rated at week 8, or using last observation carried forward. Adverse events were identified using the 55-item Systematic Assessment for Treatment Emergent Events-Systematic Inquiry completed by participants at baseline and week 2.Findings indicated that the emergence of adverse events of weakness/fatigue, strange feeling, and trouble catching breath/hyperventilation at week 2 were independently associated with lack of remission even after controlling for the potential confounders of baseline depressive severity, anxious symptoms, antidepressant medication, chronic depression, race, burden of general medical comorbidity, and time in study. Hearing/seeing things appeared to have a protective effect. In conclusion, during SSRI treatment, the adverse events of weakness/fatigue, feeling strange, and trouble catching breath/hyperventilation are associated with nonremission, possibly due to lower adherence, early attrition, difficulty increasing the dose, and reduced efficacy.     

Low penetrance breast cancer predisposition SNPs are site specific

Large scale association studies have identified low penetrance susceptibility alleles that predispose to breast cancer. A locus on chromosome 8q24.21 has been shown to harbour variants that predispose to breast, ovarian, colorectal and prostate cancer. The finding of risk variants clustering at 8q24 suggests that there may be common susceptibility alleles that predispose to more than one epithelial cancer. The aim of this study was firstly to determine whether previously identified breast cancer susceptibility alleles are associated with sporadic breast cancer in the West of Ireland and secondly to ascertain whether there are susceptibility alleles that predispose to all three common epithelial cancers (breast, prostate, colon). We genotyped a panel of 24 SNPs that have recently been shown to predispose to prostate, colorectal or breast cancer in 988 sporadic breast cancer cases and 1,016 controls from the West of Ireland. We then combined our data with publicly available datasets using standard techniques of meta-analysis. The known breast cancer SNPs rs13281615, rs2981582 and rs3803662 were confirmed as associated with breast cancer risk (P _{allelic test} = 1.8 × 10⁻², OR = 1.17; P _{allelic test} = 2.2 × 10⁻³, OR = 1.22; P _{allelic test} = 5.1 × 10⁻², OR = 1.15, respectively) in the West of Ireland cohort. For the remaining five breast cancer SNPs that were studied there was no evidence of an association with breast cancer in the West Ireland population (P _{allelic test} > 6.5 × 10⁻²). There was also no association between any of the prostate or colorectal susceptibility SNPs, whether at 8q24 or elsewhere, with breast cancer risk. Meta-analysis confirmed that all susceptibility SNPs were site specific, with the exception of rs6983269 which is known to predispose to both colorectal and prostate cancer. This study confirms that susceptibility loci at FGFR2, 8q24 and TNCR9 predispose to sporadic breast cancer in the West of Ireland. It also suggests that low penetrance susceptibility SNPs for breast, prostate and colorectal cancer are distinct. Although 8q24 harbours variants that predispose to all three cancers, the susceptibility loci within the region appear to be specific for the different cancer types with the exception of rs6983269 in colon and prostate cancer. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.