Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease

Aims   To examine the hypothesis that increases in UK liver deaths are a result of episodic or binge drinking as opposed to regular harmful drinking.
Design   A prospective survey of consecutive in-patients and out-patients.
Setting   The liver unit of a teaching hospital in the South of England.
Participants   A total of 234 consecutive in-patients and out-patients between October 2007 and March 2008.
Measurements   Face-to-face interviews, Alcohol Use Disorders Identification Test, 7-day drinking diary, Severity of Alcohol Dependence Questionnaire, Lifetime Drinking History and liver assessment.
Findings   Of the 234 subjects, 106 had alcohol as a major contributing factor (alcoholic liver disease: ALD), 80 of whom had evidence of cirrhosis or progressive fibrosis. Of these subjects, 57 (71%) drank on a daily basis; only 10 subjects (13%) drank on fewer than 4 days of the week—of these, five had stopped drinking recently and four had cut down. In ALD patients two life-time drinking patterns accounted for 82% of subjects, increasing from youth (51%), and a variable drinking pattern (31%). ALD patients had significantly more drinking days and units/drinking day than non-ALD patients from the age of 20 years onwards.
Conclusions   Increases in UK liver deaths are a result of daily or near-daily heavy drinking, not episodic or binge drinking, and this regular drinking pattern is often discernable at an early age.     

Role of COX-2 in epithelial–stromal cell interactions and progression of ductal carcinoma in situ of the breast

Epithelial–stromal cell interactions have an important role in breast tumor progression, but the molecular mechanisms underlying these effects are just beginning to be understood. We previously described that fibroblasts promote, whereas normal myoepithelial cells inhibit, the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinomas by using a xenograft model of human DCIS. Here, we report that the tumor growth and progression-promoting effects of fibroblasts are at least in part due to increased COX-2 expression in tumor epithelial cells provoked by their interaction with fibroblasts. Up-regulation of COX-2 in DCIS xenografts resulted in increased VEGF and MMP14 expression, which may contribute to the larger weight and invasive histology of COX-2-expressing tumors. Administration of celecoxib, a selective COX-2 inhibitor, to tumor-bearing mice decreased xenograft tumor weight and inhibited progression to invasion. Coculture of fibroblasts with DCIS epithelial cells enhanced their motility and invasion, and this change was associated with increased MMP14 expression and MMP9 protease activity. We identified the NF-κB pathway as one of the mediators of stromal fibroblast-derived signals regulating COX-2 expression in tumor epithelial cells. Inhibition of NF-κB and COX-2 activity and down-regulation of MMP9 expression attenuated the invasion-promoting effects of fibroblasts. These findings support a role for COX-2 in promoting the progression of DCIS to invasive breast carcinomas, and suggest that therapeutic targeting of the NF-κB and prostaglandin signaling pathways might be used for the treatment and prevention of breast cancer.     

Utilization of radiotherapy for rectal cancer in Greater Western Sydney 1994–2001

Background and purpose: Despite evidence for the efficacy of radiotherapy in stages II and III rectal cancer, utilization rates remain low. The aim of this study is to examine patient, provider and service factors affecting utilization of radiotherapy in rectal cancer patients. Materials and methods: Patients with a diagnosis of curable rectal cancer were identified from the colorectal tumor databases of three Sydney Area Health Services between 1994 and 2001. Data were collected on tumor characteristics such as site and stage, provider factors such as type of surgery and surgeon caseload, and patient factors including socioeconomic status and access to radiotherapy. Results: Thirty‐five percent of stage II and 57% of stage III rectal cancer patients received radiotherapy. Independent determinants of utilization were age less than 70 years (odds ratio, 2.96; 95% confidence interval, 1.75–5.03), high‐volume surgeons (OR, 1.95; 95% CI, 1.17–3.24), stage III disease (OR, 2.06; 95% CI, 1.25–3.41) and abdominoperineal resections (OR, 3.67; 95% CI, 1.94–6.94). Conclusion: Radiotherapy utilization rates remain low. Age, and being referred to a surgeon with a high caseload, has a greater impact on radiotherapy utilization than other provider, socioeconomic or service factors.     

Oncogenic Collaboration of the Cyclin D1 (PRAD1, bcl-1) Gene with a Mutated p53 and an Activated ras Oncogene in Neoplastic Transformation

Cyclin D1 is one of the key regulators in G1 progression in the cell cycle and is also a candidate oncogene (termed PRAD1 or bcl -1) in several types of human tumors. We report a collaboration of the cyclin D1 gene with ras and a mutated form of p53 (p53-mt) in neoplastic transformation. Transfection of cyclin D1 alone or in combination with ras or with p53-mt was not sufficient for focus formation of rat embryonic fibroblasts. However, focus formation induced by co-transfection of ras and p53-mt was enhanced in the presence of the cyclin D1-expression plasmid. Co-transfection of ras - and p53-mt-transformants with the cyclin D1-expression plasmid resulted in reduced serum dependency in vitro , Furthermore, the transformants expressing exogenous cyclin D1 grew faster than those without the cyclin D1 plasmid when injected into nude mice. These observations strengthen the significance of cyclin D1 overexpression through gene rearrangement or gene amplification observed in human tumors as a step in multistep oncogenesis; deregulated expression of cyclin D1 may reduce the requirement for growth factors and may stimulate in vivo growth.     

Understanding the basis of CD4(+) T-cell depletion in macaques infected by a simian-human immunodeficiency virus

The efficacy of candidate AIDS vaccines to mediate protection against viral infection and pathogenesis is evaluated, at a preclinical stage, in animal models. One model that is favored because the infecting virus is closely related to HIV-1 and because of the rapidity of pathogenic outcomes is the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae. We investigated the basis for the depletion of CD4(+) T lymphocytes in a SHIV-macaque model. Molecularly cloned SHIVs, SHIV-89.6 and SHIV-KB9, differ in the ability to cause CD4(+) T-cell loss at a given level of virus replication in monkeys. The envelope glycoproteins of the pathogenic SHIV-KB9 mediate membrane-fusion in cultured T lymphocytes more efficiently than the envelope glycoproteins of the non-pathogenic SHIV-89.6. The minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity was sufficient to convert SHIV-89.6 into a virus that causes profound CD4(+) T-cell depletion in monkeys. Conversely, two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins also attenuated the CD4(+) T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4(+) T lymphocytes in vivo.     

The New Injury Severity Score: Better Prediction of Functional Recovery after Musculoskeletal Injury

OBJECTIVES: Injury Severity Score (ISS) is the most widely used method of assessing severity of injury in blunt trauma. It has been recognized that, by only allowing the score to consider the worst injury for each body system, ISS underestimates the problems of multiple musculoskeletal injuries. The New ISS (NISS) allows the three most severe injuries to be scored, irrespective of region affected, and may give better prediction of functional recovery in these patients. METHODS: A prospective cohort study of 200 patients with musculoskeletal injuries, examining the predictive value of ISS and NISS on functional recovery as measured by patient-derived outcome measures (Short Form-36, Sickness Impact Profile, and Musculoskeletal Function Assessment). RESULTS: NISS was greater than ISS in 34 patients (17%). NISS showed closer correlation with total scores and subscores of the outcomes measures than did ISS (Spearman's rho ranked test, P < 0.05). CONCLUSIONS: NISS, a simple modification from ISS, better predicts functional outcomes in survivors of musculoskeletal trauma, and offers an improvement in the assessment of effectiveness of trauma care delivery.     

Should Orbscan pachometry be performed before or after Goldmann applanation tonometry?

PURPOSE: To compare the Orbscan central corneal thickness (CCT) values before and after intraocular pressure (IOP) measurement with Goldmann applanation tonometry in young normal adults. MATERIALS AND METHODS: Fifty-three eyes of 53 subjects who were free from any ocular problems were studied. The measurements included optical pachometry by the Orbscan II system, followed by Goldmann applanation tonometry, and finally Orbscan optical pachometry again. Standard Goldmann technique was adopted with the application of one drop of 0.4% benoxinate and fluorescein sodium prior to the measurement. The same operator was involved in the Orbscan pachometry before and after Goldmann tonometry. Another investigator was responsible for Goldmann tonometry. Three readings were obtained in each case, and the means were used for analysis. RESULTS: The mean IOP of the sample was 14.6 +/- 2.6 mmHg. There was no significant difference (paired t-test: p = 0.50) in the mean CCT values before and after the Goldmann tonometry (551 +/- 32 and 552 +/- 35 microm respectively). CONCLUSION: Standard Goldmann applanation tonometry does not affect the Orbscan CCT values. Measurement of CCT for the adjustment of true IOP can be carried out either before or after Goldmann tonometry.     

Are High-Quality Cardiac Surgeons Less Likely to Operate on High-Risk Patients Compared to Low-Quality Surgeons? Evidence from New York State

Context. It is unknown whether high-risk cardiac surgical patients have less access to high-quality surgeons compared with lower-risk patients.
Objective. To determine whether high-quality surgeons are less likely to perform coronary artery bypass graft (CABG) surgery on high-risk patients compared with low-quality surgeons.
Design, Setting, and Patients. Retrospective cohort study using the New York State (NYS) CABG Surgery Reporting System (CSRS) of all patients undergoing CABG surgery in NYS who were discharged between 1997 and 1999 (51,750 patients; 2.20 percent mortality). Regression modeling was used to estimate the association between surgeon quality and patient risk of death. Surgeon quality was quantified using the observed-to-expected mortality ratio (O-to-E ratio).
Results. Higher-risk patients are more likely to receive CABG surgery from higher-quality surgeons. For every 10 percentage point increase in patient risk of death (e.g., from 5 to 15 percent), there is an absolute reduction of 0.034 in the surgeon O-to-E ratio ( p < .001).
Conclusion. This study suggests that high-risk CABG patients are significantly more likely to receive care from high-quality surgeons compared with lower risk patients.     

Genetic and Environmental Influences on the Covariation Between Hyperactivity and Conduct Disturbance in Juvenile Twins

Structural equation models were applied to the maternal ratings of 265 MZ and 163 DZ male-male, 347 MZ and 160 DZ female-female, and 262 male-female twin pairs, aged 8-16 years, who participated in the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). Substantial additive genetic influences and contrast effects were found for hyperactivity, and additive genetic and shared environmental effects or positive comparison effects (particularly for the girls) for oppositional/conduct disturbance. Bivariate model fitting showed that the covariation between hyperactivity and oppositional/conduct problems in both younger and older boys and girls is almost entirely attributable to genetic factors. However, whereas in the younger males and females the same set of genes explain all the variation in hyperactivity and conduct disturbance, in the older cohort at least some of the genetic effects are behavior- and gender-specific.