The effect of bariatric surgery type on cardiac reverse remodelling.

INTRODUCTION: Bariatric surgery is effective in reversing adverse cardiac remodelling in obesity. However, it is unclear whether the three commonly performed operations; Roux-en-Y Gastric Bypass (RYGB), Laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Adjustable Gastric Band (LAGB) are equal in their ability to reverse remodelling. METHODS: Fifty-eight patients underwent CMR to assess left ventricular mass (LVM), LV mass:volume ratio (LVMVR) and LV eccentricity index (LVei) before and after bariatric surgery (26 RYGB, 22 LSG and 10 LAGB), including 46 with short-term (median 251-273 days) and 43 with longer-term (median 983-1027 days) follow-up. Abdominal visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) were also assessed. RESULTS: All three procedures resulted in significant decreases in excess body weight (48-70%). Percentage change in VAT and EAT was significantly greater following RYGB and LSG compared to LAGB at both timepoints (VAT:RYGB -47% and -57%, LSG -47% and -54%, LAGB -31% and -25%; EAT:RYGB -13% and -14%, LSG -16% and -19%, LAGB -5% and -5%). Patients undergoing LAGB, whilst having reduced LVM (-1% and -4%), had a smaller decrease at both short (RYGB: -8%, p < 0.005; LSG: -11%, p < 0.0001) and long (RYGB: -12%, p = 0.009; LSG: -13%, p < 0.0001) term timepoints. There was a significant decrease in LVMVR at the long-term timepoint following both RYGB (-7%, p = 0.006) and LSG (-7%, p = 0.021), but not LAGB (-2%, p = 0.912). LVei appeared to decrease at the long-term timepoint in those undergoing RYGB (-3%, p = 0.063) and LSG (-4%, p = 0.015), but not in those undergoing LAGB (1%, p = 0.857). In all patients, the change in LVM correlated with change in VAT (r = 0.338, p = 0.0134), while the change in LVei correlated with change in EAT (r = 0.437, p = 0.001). CONCLUSIONS: RYGB and LSG appear to result in greater decreases in visceral adiposity, and greater reverse LV remodelling with larger reductions in LVM, concentric remodelling and pericardial restraint than LAGB.

Assessing Meaningful Improvement: Focus on the Tinnitus Functional Index.

Many studies have attempted to determine methodology for interpreting change on outcome instruments that result from an intervention. The objective of these studies has been to devise methods to identify the minimal level of change that would be consistent with actual benefit perceived by the patient, and not just statistically significant change. With respect to intervention for bothersome tinnitus, the authors of the original study to develop and validate the Tinnitus Functional Index (TFI) suggested that a minimum 13-point reduction in the TFI score was likely to reflect a change perceived as meaningful to an individual. The 13-point estimation of meaningful change for an individual is appropriate for use with any adult seeking care for tinnitus. However, it cannot be relied upon in isolation to determine if an individual believes that there has been a noticeable, or meaningful improvement in their quality of life. It is important to use subjective impressions elicited from the patient to assist in interpreting the meaning of TFI data for an individual. For clinicians engaging in care for tinnitus, we recommend using the TFI and pairing it with the patient's belief/impression as to whether they are doing better than they were before care for tinnitus was provided. Ideally, the outcome assessment would be conducted by someone other than the clinician who provided the intervention.

Changes in epicardial and visceral adipose tissue depots following bariatric surgery and their effect on cardiac geometry.

Introduction: Obesity affects cardiac geometry, causing both eccentric (due to increased cardiac output) and concentric (due to insulin resistance) remodelling. Following bariatric surgery, reversal of both processes should occur. Furthermore, epicardial adipose tissue loss following bariatric surgery may reduce pericardial restraint, allowing further chamber expansion. We investigated these changes in a serial imaging study of adipose depots and cardiac geometry following bariatric surgery. Methods: 62 patients underwent cardiac magnetic resonance (CMR) before and after bariatric surgery, including 36 with short-term (median 212 days), 37 medium-term (median 428 days) and 32 long-term (median 1030 days) follow-up. CMR was used to assess cardiac geometry (left atrial volume (LAV) and left ventricular end-diastolic volume (LVEDV)), LV mass (LVM) and LV eccentricity index (LVei - a marker of pericardial restraint). Abdominal visceral (VAT) and epicardial (EAT) adipose tissue were also measured. Results: Patients on average had lost 21kg (38.9% excess weight loss, EWL) at 212 days and 36kg (64.7% EWL) at 1030 days following bariatric surgery. Most VAT and EAT loss (43% and 14%, p<0.0001) occurred within the first 212 days, with non-significant reductions thereafter. In the short-term LVM (7.4%), LVEDV (8.6%) and LAV (13%) all decreased (all p<0.0001), with change in cardiac output correlated with LVEDV (r=0.35,p=0.03) and LAV change (r=0.37,p=0.03). Whereas LVM continued to decrease with time (12% decrease relative to baseline at 1030 days, p<0.0001), both LAV and LVEDV had returned to baseline by 1030 days. LV mass:volume ratio (a marker of concentric hypertrophy) reached its nadir at the longest timepoint (p<0.001). At baseline, LVei correlated with baseline EAT (r=0.37,p=0.0040), and decreased significantly from 1.09 at baseline to a low of 1.04 at 428 days (p<0.0001). Furthermore, change in EAT following bariatric surgery correlated with change in LVei (r=0.43,p=0.0007). Conclusions: Cardiac volumes show a biphasic response to weight loss, initially becoming smaller and then returning to pre-operative sizes by 1030 days. We propose this is due to an initial reversal of eccentric remodelling followed by reversal of concentric remodelling. Furthermore, we provide evidence for a role of EAT contributing to pericardial restraint, with EAT loss improving markers of pericardial restraint.

Intra-operative frozen section analysis for suspected early-stage ovarian cancer: 11 years of Gateshead Cancer Centre experience.

OBJECTIVE: In centres in which intra-operative frozen section (FS) analysis is not performed, 'apparent' early-stage ovarian cancer diagnosed after surgery on paraffin section may require further restaging laparotomy or adjuvant chemotherapy. Previous studies on FS analysis have reported high sensitivity, specificity and overall accuracy. The objective of this article is to present the largest published dataset on the accuracy of FS analysis over an 11-year period from a single institution. DESIGN: Diagnostic test accuracy. SETTING: Northern Gynaecological Oncology Centre and Department of Cellular Pathology, Gateshead, UK. POPULATION: 1439 intra-operative FS analyses performed between January 2000 and December 2010 for suspected ovarian cancer. METHODS: Prospectively collected data on FS analysis were compared with gold standard paraffin section. MAIN OUTCOME MEASURES: Sensitivity, specificity, likelihood ratios and post-test probability. RESULTS: The overall sensitivity and specificity of FS analysis were 91.2% and 98.6%, respectively. Positive and negative likelihood ratios were 64.7% and 0.09%, respectively. The pre-test probability of an ovarian tumour being borderline or malignant was 45.8%. When FS analysis was reported to be positive, the post-test probability increased to 98% (confidence interval, 97-99%). Conversely, when FS analysis was reported to be negative, the post-test probability decreased to 7% (confidence interval, 6-9%). The majority of false test results were either borderline tumours or of mucinous differentiation. CONCLUSIONS: Intra-operative FS analysis has excellent diagnostic test accuracy and assists gynaecological oncologists to perform the appropriate surgery in 95% of cases, thereby preventing the morbidity of surgical staging in benign cases and the morbidity of restaging procedures or chemotherapy in early-stage malignant tumours.

Laparoscopic assisted radical vaginal hysterectomy versus radical abdominal hysterectomy--a randomised phase II trial: perioperative outcomes and surgicopathological measurements.

OBJECTIVE: To evaluate perioperative surgical outcomes and resection size for laparoscopically assisted radical vaginal hysterectomy (LARVH) compared with radical abdominal hysterectomy (RAH). DESIGN: A prospective randomised phase II trial. POPULATION: Early stage IB cervical cancer requiring radical surgical treatment. SETTING: Northern Gynaecological Oncology Centre, Gateshead, UK. METHODS: Fifteen women were randomised to LARVH and to RAH. MAIN OUTCOME MEASURES: Outcomes included requirement in days for bladder catheterisation after surgery, operating time, blood loss, hospital stay, opiate pain relief, complication rate, time to normal activities and resection size of major ligaments and vaginal cuff. Results Statistically significant differences were found between LARVH and RAH, respectively: median duration of bladder catheterisation, 4 days versus 21 days (P = 0.003); median operating time, 180 minutes versus 138 minutes (P = 0.05); median blood loss, 400 ml versus 1000 ml (P = 0.05), median hospital stay, 5 days versus 7 days (P = 0.04) and median opiate requirement in the first 36 hours postoperatively, 30 mg versus 53 mg (P = 0.004). The mean resected lengths for LARVH versus RAH, respectively, were: mean resected vaginal cuff, 1.26 cm versus 2.16 cm (P = 0.014); mean resected cardinal ligament length, 1.30 cm versus 2.79 cm (P = 0.013) and mean resected uterosacral ligament length, 1.47 cm versus 4.68 cm (P = 0.034). CONCLUSIONS: This study confirms the short-term surgical benefits of LARVH. In addition, LARVH has been shown to be a less radical procedure than RAH, supporting the need for strict patient selection and to restrict the procedure to small tumours.

Assessment of tinnitus: measurement of treatment outcomes.

There is a wide range of assessment techniques for tinnitus, but no consensus has developed concerning how best to measure either the presenting features of tinnitus or the effects of tinnitus treatments. Standardization of reliable and valid tinnitus measures would provide many advantages including improving the uniformity of diagnostic and screening criteria between clinics and facilitating comparison of treatment outcomes obtained at different sites. This chapter attempts to clarify issues involved in developing self-report questionnaires for the assessment of tinnitus. While the tinnitus questionnaires that are currently available provide valuable information on which to base diagnostic and screening decisions, they were not originally developed in such a way as to maximize their sensitivity to treatment-related changes in tinnitus. As a result, their construct validity for measuring treatment benefit has not received appropriate attention. In this paper, special emphasis is devoted to the use of effect sizes as an estimate of the ability of questionnaires (and their individual items) to measure changes associated with treatment. We discuss the criteria relevant to evaluating the effectiveness of a questionnaire for diagnostic purposes vs. for treatment-evaluation purposes, and we present a detailed illustration of how the various criteria have been applied in a recent questionnaire development effort.

Audiologic characteristics in a sample of recently-separated military Veterans: The Noise Outcomes in Servicemembers Epidemiology Study (NOISE Study).

Military Service Members are often exposed to high levels of occupational noise, solvents, and other exposures that can be damaging to the auditory system. Little is known about hearing loss and how it progresses in Veterans following military service. This epidemiology study is designed to evaluate and monitor a cohort of Veterans for 20 years or more to determine how hearing loss changes over time and how those changes are related to noise exposure and other ototoxic exposures encountered during military service. Data reported here are from baseline assessments of the first 100 study participants (84 males; 16 females; mean age 33.5 years; SD 8.8; range 21-58). Each participant was asked to complete a comprehensive audiologic examination and self-report questionnaires regarding sociodemographic characteristics, noise and solvent exposures, health conditions common among post-deployment Veterans, and the social and emotional consequences of hearing loss. For this relatively young cohort, 29% exhibited hearing loss, defined as average hearing threshold >20 dB HL in the conventional audiometric range. Forty-two percent exhibited hearing loss in the extended-high-frequency audiometric range using the same criterion (average hearing threshold >20 dB HL). Certain factors were found to be associated with poorer hearing in both conventional and extended-high-frequency ranges, including age, type of military branch, years of military service, number of military deployments, noise exposure, tinnitus, and a positive screen for post-traumatic stress disorder. Although the majority of participants had hearing within normal limits, 27% reported a self-perceived mild/moderate hearing handicap and 14% reported a significant handicap. Further research is needed to identify a cause for this discrepancy in audiologic results versus self-report. The information obtained from this longitudinal study could be used in future resource planning with the goal of preventing, as much as possible, the development of hearing loss during military service, and the exacerbation of prevalent hearing loss after military service and over Veterans' lifetimes.

The in utero passage of meconium by very low birth weight infants: a marker for adverse outcomes.

OBJECTIVES: To determine the incidence of in utero meconium passage and the rate of associated complications among VLBW infants. STUDY DESIGN: Retrospective review of medical records and prospective evaluation of placental samples from 431 VLBW infants who survived >24 h. Cases with histologic evidence of meconium were re-examined and hemosiderin excluded by a negative iron stain. Statistical analysis included chi2, logistic regression, Student's t-test and Kruskal-Wallis. RESULTS: The 70 infants (16.2%) who had placental evidence of in utero meconium passage were younger, weighed less, and more likely to be delivered by C-section (P = 0.006), intubated in the delivery room (P = 0.02), receive chest compressions (P = 0.003), require volume resuscitation (P = 0.001) and develop grade III-IV intraventricular hemorrhages (P = 0.011) than were control infants. CONCLUSION: Microscopic evaluation of the placental membranes reveals that the in utero passage of meconium occurs in about 16% of premature infants and is associated with adverse perinatal outcomes, including the need for resuscitation at delivery and an increased risk for grade III-IV intraventricular hemorrhages.

Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis.

The nm23 gene was identified in murine melanoma cells, in which its expression is associated with the cells' metastatic potential. Expression of nm23 has been detected in human breast tumors by means of hybridization and immunocytochemistry. We measured nm23 mRNA in 71 patients with primary breast cancer and found variable levels of nm23 expression. The nm23 gene was expressed at higher levels in well-differentiated tumors (P less than .02). There was a significant inverse relationship between nm23 expression and nodal status (P less than .02). Expression of nm23 was positively associated with longer disease-free survival and overall survival, and the relationships were significant (P less than .002 and P less than .003, respectively). This study showed that nm23 expression in human breast cancer was associated with good prognosis and a lack of lymph node metastasis and suggests that the nm23 gene product may play an important role in suppressing the metastatic phenotype.

Treatment of poisoning induced cardiac impairment using cardiopulmonary bypass: a review.

Severe poisoning can cause potentially fatal cardiac depression. Cardiopulmonary bypass (CPB) can support the depressed myocardium, but there are no clear indications or guidelines available on its use in severe poisoning. A review was conducted of relevant papers in the available literature (seven single case reports of both deliberate and accidental ingestion of cardiotoxic drugs and two animal studies). Although CPB is rarely used in the management of poisoning, it may have potential benefits for haemodynamic instability not responding to conventional measures. At present there is insufficient evidence concerning the use of CPB as a treatment for severe cardiac impairment due to poisoning (grade C). This review suggests that in patients with severe and potentially prolonged reversible cardiotoxicity there is potential for full survival with CPB, provided that the patient has not already sustained hypoxic cerebral damage due to resistant hypotension prior to its use.

Determination of the prognostic value of cyclin D1 overexpression in breast cancer.

Cyclin D1 plays a critical role in the timing of the initiation of DNA synthesis in the normal cell cycle of mammalian cells. Deregulated expression of this protein has been seen in a variety of tumours either as a result of gene amplification or chromosomal translocation, in breast cancer and B cell malignancies respectively. In order to determine the role this putative oncoprotein plays in breast cancer, we have applied a new monoclonal antibody, recently produced in our laboratory, in an immunohistochemical study of 93 primary breast carcinomas. We show that approximately 28% of the cases displayed enhanced expression of the cyclin D1 protein. Furthermore, either cyclin D1, cyclin D3, or both, were expressed in 69% of cases, suggesting that overexpression of any one member of this family may relieve cancer cells of their mitogenic stimulatory requirement. In addition, we show that those patients whose breast cancers co-express cyclin D1 with either epidermal growth factor receptor (EGFR) or the retinoblastoma protein (pRB) have a significantly poorer prognosis in comparison to those expressing cyclin D1 alone. Our observations indicate that, in a subset of breast cancers, aberrant cyclin D1 expression is a contributory factor to tumorigenesis and in association with EGFR or pRB expression, identify those tumours which may require more aggressive therapy.

Assessment of a point-of-care test for paracetamol and salicylate in blood.

BACKGROUND: Paracetamol and salicylate are commonly taken in acute overdose. Clinicians have a low threshold for excluding the presence of these two drugs, by ordering laboratory tests in any patient suspected of ingesting an overdose or with an altered mental state. AIM: To test the effectiveness of a new point of care test that qualitatively detects paracetamol and salicylate in blood and to examine the potential time saved by its use. DESIGN: Prospective multicentre trial. METHODS: The new test was compared with laboratory analysis in a routine blood sample taken from patients presenting to emergency departments with suspected overdose. RESULTS: The test had sensitivities of 98.5% and 88.5%, and specificities of 74.7% and 92%, for paracetamol and salicylate, respectively, at cut-off levels of 25 mg/l and 100 mg/l, respectively The point of care test results were available 2 h before the laboratory result. DISCUSSION: This point-of-care test could be used to rule out an overdose with either of these two drugs, and could thus lead to earlier clinical decisions for suspected overdose patients. Recommendations have been made following this trial that the cut-off value for paracetamol should be reduced from 25 mg/l to 12.5 mg/l in order to increase its usefulness. To prevent the test being misread, we also suggest that each device should be embossed to remind users that the presence of a line indicates there is no drug present.

Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors.

Carboplatin is effective in the treatment of malignant brain tumors. However, when administered in conjunction with osmotic opening of the blood-brain barrier (BBB), carboplatin is ototoxic. The purpose of this study was to determine whether delayed administration of sodium thiosulfate (STS), given after BBB closure, provided protection against carboplatin ototoxicity. Patients underwent monthly treatment with intra-arterial carboplatin (200 mg/m2/day x 2) in conjunction with osmotic opening of the BBB, for up to 1 year. Audiological assessment was conducted at baseline and within 24 h before each monthly treatment. STS was administered i.v. as one (20 g/m2) or two (20 g/m2 and 16 g/m2) 15-min doses, depending on baseline hearing status. The initial group received the first STS dose 2 h (or 2 and 6 h) after carboplatin (STS2) and a subsequent group received STS 4 h (or 4 and 8 h) after carboplatin (STS4). Audiological data were compared with a historical comparison group (HCG) treated with carboplatin without STS. Spearman correlation coefficients comparing STS 2 (n = 24), STS4 (n = 17), and HCG (n = 19) indicated significantly lower rates of ototoxicity with increased delay in STS (P = 0.0006). On the basis of the analysis of hearing levels, there were significant differences among the two STS groups and HCG at 8000 Hz (P = 0.0010) and at 4000 Hz (P = 0.0075). The log-rank test for time to ototoxicity indicated a significant difference between STS4 and HCG (P = 0.0018). Delayed STS was effective in protecting against carboplatin-induced hearing loss. STS delayed to 4 h after carboplatin significantly decreased time to development of ototoxicity and rate of ototoxicity when compared with HCG.

Thromboxane A2 receptor antagonism and synthase inhibition in essential hypertension.

Short-term effects of ridogrel, a combined thromboxane synthase inhibitor and receptor antagonist, were investigated in 16 patients with uncomplicated essential hypertension. After a 2-week placebo period without antihypertensive medication, patients were admitted to the hospital overnight on two occasions 3 weeks apart. On each occasion, they received two doses of either placebo or ridogrel (300 mg) 12 hours apart according to a double-blind crossover protocol. Renal and systemic thromboxane A2 and prostacyclin biosynthesis were investigated by measuring urinary excretion of thromboxane B2, 6-oxo-prostaglandin F1 alpha, and their respective 2,3-dinor metabolites using gas chromatography/mass spectrometry. Responses of platelets to a thromboxane A2 mimetic and to adenosine diphosphate were studied turbidometrically. Blood pressure was measured automatically at 20-minute intervals. Ridogrel reduced excretion of 2,3-dinor-thromboxane B2 and thromboxane B2 compared with placebo (21 +/- 6 versus 279 +/- 28 and 14 +/- 4 versus 39 +/- 9 ng/g creatinine, respectively; P < .0001 and P < .05). Excretion of 2,3-dinor-6-oxoprostaglandin F1 alpha and 6-oxoprostaglandin F1 alpha was increased by ridogrel compared with placebo (184 +/- 20 versus 146 +/- 11 and 86 +/- 9 versus 58 +/- 6 ng/g creatinine, respectively; P < .05). Ridogrel selectively antagonized platelet aggregation to the thromboxane mimetic (P < .0001). Blood pressure did not differ significantly between ridogrel and placebo treatment periods. Thus, in patients with essential hypertension, acute administration of ridogrel reduces renal and extrarenal thromboxane A2 biosynthesis, increases renal and extrarenal prostacyclin biosynthesis, inhibits thromboxane receptor-activated platelet aggregation, but has no effect on systemic arterial pressure.

Influence of time of administration on verapamil pharmacokinetics.

The plasma concentration-time profile of verapamil was studied in eight healthy drug-free volunteers after oral administration of a single 80 mg dose of the drug on six separate occasions at different times of day (4 AM, 8 AM, noon, 4 PM, 8 PM, and midnight). The median maximum plasma concentration of verapamil was significantly higher after the 8 AM and noon administrations (p less than 0.05) than at any other time. The median area under the concentration-time curve was also significantly higher (p less than 0.05) after administration at 8 AM and noon than at other times. The median time to maximum concentration was not significantly different at any time point (p greater than 0.05). It is possible that concentration-related adverse effects of verapamil could be avoided by choosing the time of day when the drug is prescribed. This concept may also apply to other drugs that have circadian effects in their pharmacokinetic profiles.

Relationships between pharmacokinetics and nonpulmonary pharmacodynamic effects of theophylline.

Concentration-effect relationships between oral theophylline and its nonpulmonary pharmacodynamic effects were examined in a double-blind, randomized, two-way crossover study in which 10 healthy subjects received a single dose of 500 mg ordinary-release theophylline or placebo. Mean plasma theophylline concentrations rose to 16.1 mg.L-1 at 1 hour and 16.8 mg.L-1 at 2 hours. Maximum decreases in plasma potassium (0.33 mmol.L-1) and magnesium (0.039 mmol.L-1) and increases in supine (11.1 mm Hg) and standing (8.0 mm Hg) diastolic blood pressure and plasma total cholesterol (0.59 mmol.L-1) occurred after the achievement of peak plasma theophylline concentrations (negative hysteresis). This delay is consistent with the intracellularly mediated effects of theophylline and with compartmental shifts of electrolytes. Discrepancies between the pharmacokinetic profile and pharmacodynamic effects should be borne in mind when assessing the duration of action of a drug.

Relatively greater increase of oxytocin than vasopressin in the supraoptic nucleus of rats after hypophysectomy.

The vasopressor and milk ejection activities were estimated in the supraoptic region of the hypothalamus of rats which had been hypophysectomized 30 min, 4 and 8 days earlier. Both pressor and milk ejection activities were significantly greater 4 days after hypophysectomy than those in sham-operated control rats. Eight days after hypophysectomy, pressor activity decreased below control values but milk ejection activity was still significantly raised. Increased biological activity after hypophysectomy is thus associated with the previously observed increase in neurosecretory material within the supraoptic nucleus so these results provide additional evidence that neurosecretory material represents stored hormone. Milk ejection activity increased relatively more than pressor activity which supports the suggestion that the final stage in the formation of neurohypophysial hormones occurs as they pass from the hypothalamus to the neural lobe. If this final maturation normally occurs more slowly for oxytocin than for vasopressin, the obstruction to the flow of hormones down the neural stalk caused by hypophysectomy would result in a greater increase in milk ejection than pressor activity.

Oestrogen receptor and oestrogen regulated proteins in human breast cancer: a review.

Breast growth and development is influenced by oestrogens and the growth of many breast cancers is driven by oestrogens, an effect which is utilised in the endocrine treatment of breast cancer. Oestrogens act by binding to the oestrogen receptor, a specific protein which in turn binds to specific regulatory regions of DNA, thereby altering gene expression. The effects of oestrogens may be mediated by growth factors and other substances under oestrogen regulation. Oestrogen receptor status in breast tumours can be determined by cytosolic radioligand binding assays, enzyme linked immunoassay, immunohistochemistry and measurement of messenger RNA levels. Tumour oestrogen receptor content is an established but not absolute predictor of both response to endocrine therapy and prognosis in breast cancer. Paradoxically, a small proportion of apparently oestrogen receptor negative tumours do respond to endocrine therapy, perhaps reflecting expression of low and unmeasurable levels of receptor or tumour heterogeneity with respect to receptor expression. A larger proportion of oestrogen receptor positive tumours unexpectedly fail to respond to endocrine therapy; in these cases it is possible that oestrogen receptor has become dissociated from the transcriptional and translational events which it normally regulates. Determination of levels of expression of substances regulated by oestrogens can provide information regarding the functional integrity of the oestrogen response pathway and such substances include the progesterone receptor, plasminogen activator, cathepsin D and a variety of messenger RNA sequences.

Increase in alcohol related deaths: is hepatitis C a factor?

AIM: To evaluate recent trends in alcohol related deaths in the UK and to consider possible causative factors. DESIGN: Observational retrospective study of the database of the Office for National Statistics, alcohol consumption data reported by the General Household Survey, and other published data. SETTING: England, 1993-9. RESULTS: Deaths for each million of the population from alcohol related illness increased by 59% in men and 40% in women over the years 1993 to 1999. One subgroup of alcohol related deaths, ICD 571.3 (alcoholic liver damage unspecified), showed a 243% increase in men aged 40 to 49 years over the same period. Figures for younger men, and women in all age groups, showed less pronounced increases. There has been no associated rise in alcohol intake. There has been an increase in the incidence of hepatitis C virus (HCV) infection in recent years, and alcohol consumption in HCV positive individuals accelerates the progression to cirrhosis. Circumstantial evidence links the rise in HCV infection to the use of illicit drugs in the 1970s and 1980s, among those currently aged 40 to 59 years. CONCLUSIONS: The recent increase in alcohol related deaths cannot be solely explained by a change in drinking habits. It is suggested that this probably results from the rapid progression of alcoholic cirrhosis in people who have acquired HCV infection through intravenous drug use. Alcohol consumption in HCV positive individuals is firmly linked with a poor outcome.

Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release.

3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause hyponatraemia, which appears to result from inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). After administration of a low dose of (R,S)-MDMA (40 mg) to eight healthy drug-free male volunteers, concentrations of AVP in plasma increased significantly at 1, 2, and 4 hours. Although no relation between plasma MDMA and AVP was found on an examination of the entire data set over the 24-hour study period, a statistically significant negative correlation was observed at 1 hour. As this occurred at a time when both AVP and MDMA concentrations were rising, it was postulated that a metabolite, or metabolites, could primarily be responsible for the increase in AVP. To test this hypothesis we examined the effect of MDMA and five of its metabolites, in the dose range 0.1-1,000 nM, on AVP release from the isolated rat hypothalamus. All compounds tested were found to increase AVP release (using 10 nM and 1,000 nM concentrations), with 4-hydroxy-3-methoxymethamphetamine (HMMA), the major metabolite of MDMA, being the most potent, and 3,4-dihydroxymethamphetamine (DHMA) the least potent. Each compound (1,000 nM), with the exception of DHMA, also enhanced the response to 40-mM potassium stimulation. Our findings confirm that metabolites of MDMA, in addition to the parent drug, contribute to AVP secretion in vitro. Further work will demonstrate whether this is also true in vivo.