Considering the role of adolescent sex steroids in schizophrenia.

Schizophrenia is a disabling illness that is typically first diagnosed during late adolescence to early adulthood. It has an unremitting course and is often treatment-resistant. Many clinical aspects of the illness suggest that sex steroid-nervous system interactions may contribute to the onset, course of symptoms and the cognitive impairment displayed by men and women with schizophrenia. Here, we discuss the actions of oestrogen and testosterone on the brain during adolescent development and in schizophrenia from the perspective of experimental studies in animals, human post-mortem studies, magnetic resonance imaging studies in living humans and clinical trials of sex steroid-based treatments. We present evidence of potential beneficial, as well as detrimental, effects of both testosterone and oestrogen. We provide a rationale for the necessity to further elucidate sex steroid mechanisms of action at different ages, sexes and brain regions to more fully understand the role of testosterone and oestrogen in the pathophysiology of schizophrenia. The weight of the evidence suggests that sex steroid hormones influence mammalian brain function, including both cognition and emotion, and that pharmaceutical agents aimed at sex steroid receptors appear to provide a novel treatment avenue to reduce symptoms and improve cognition in men and women with schizophrenia.

Steroid hormone receptor expression in male breast cancer.

AIMS: To investigate expression of the steroid hormone receptors estrogen receptor (ER)-alpha and -beta, progesterone receptor (PR) and androgen receptor (AR) in male breast cancer. METHODS: Specimens from 16 male breast cancers were immunostained for ERalpha, ERbeta, PR and AR. FINDINGS: Eighty-seven percent of tumours expressed ERalpha, 93% PR, 87% ERbeta and 87% AR. Staining for ERalpha and PR was confined exclusively to the nuclei of epithelial cells with some heterogeneity. Nuclear immunoreactivity was also observed with AR. Again this was restricted to epithelial cells but tended to be more uniform. ERbeta was seen in the nuclei of epithelial cells and also in stromal fibroblasts and lymphocytes. Analysis of serial sections revealed a similar pattern of staining with ERbeta and AR in epithelial cells. CONCLUSIONS: In addition to expression of the better known steroid receptors, ERalpha, PR and AR, we have demonstrated a high rate of expression of ERbeta in male breast cancer. This is in keeping with the generally high steroid receptor expression seen in males. However, the abundance of ERbeta expressed in this small series of male breast cancer is in contrast to female breast cancer where ERbeta expression is often reduced.

Angiogenesis in breast cancer: how should we measure this? (Review).

Despite the established importance of angiogenesis in the pathogenesis of solid tumours, there is still no consensus on how this is best measured or which method is the most appropriate in the determination of prognosis. Here we review the pros and cons of current methods of assessing angiogenesis, both clinical and in the laboratory, and discuss with respect to breast cancer.

Surgical excision is warranted following a core biopsy diagnosis of mucocoele-like lesion of the breast.

AIMS: Mucocoele-like lesions (MLLs) of the breast are unusual lesions in which mucin-filled ducts or cysts are accompanied by extrusion of mucin into surrounding stroma. A possible diagnosis of MLL may be suggested by the finding of mucin-filled ducts or cysts and/or stromal mucin in a core biopsy sample. Whether such findings should prompt immediate open diagnostic biopsy to exclude malignancy is currently uncertain, although this represents current practice in our institution. In this study we have reviewed 11 cases of possible MLL on core biopsy correlating both pathological and radiological findings in order to determine the risks of associated malignancy and whether excision is the most appropriate management option. METHODS AND RESULTS: Eleven cases of possible MLL presenting via the Breast Screening and Assessment Unit in Leeds since April 1999 were identified by review of pathological records. Histological slides, mammograms and ultrasound images were reviewed. Ten of the 11 had undergone open surgical biopsy for diagnosis. Three of the 10 (30%) proved to derive from malignant lesions. Two were ductal carcinoma in situ (DCIS) and one was an invasive mucinous carcinoma. All three cases had an associated atypical epithelial proliferation which, in a surgical excision, would be classified as atypical ductal hyperplasia (ADH) at least, as well as mucin in the core biopsy sample. The majority of possible MLLs presented radiologically as coarse calcification, but two of four (50%) which had a radiological mass subsequently proved malignant. Seven cases were without atypia on the core and all subsequently proved benign. Three of these, however, were associated with ADH on the excision biopsy. CONCLUSION: Surgical excision is warranted following a core biopsy suggestion of possible MLL when mucin-filled ducts or cysts and stromal mucin have been seen. The risk of malignancy is high when the core biopsy also contains an atypical epithelial proliferation (100% in our series) and also when there is an associated radiological mass lesion. In cases without atypia on the core a significant proportion of cases (43%) are associated with ADH on excision.

Clostridium difficile toxin: cytoskeletal changes and lactate dehydrogenase release in hepatocytes.

BACKGROUND: We have found that Clostridium difficile toxins can evoke hepatocyte acute-phase protein synthesis, and that this effect is dependent on a functioning interleukin-1 (IL-1) receptor. The present study was undertaken to determine if C. difficile toxicity, as determined by actin rearrangement and lactate dehydrogenase (LDH) release, also requires a functioning IL-1 receptor. METHODS: Primary hepatocyte cultures were prepared from normal mice, knockout mice deficient in the IL-1-converting enzyme (ICE), and knockout mice deficient in the IL-1 p80 receptor. Hepatocytes were treated for 24 h with C. difficile culture extract, purified C. difficile toxin A, or purified C. difficile toxin B. The actin cytoskeleton was examined using confocal microscopy, and LDH release was measured by spectrophotometric analysis. RESULTS: C. difficile culture extract, toxin A, and toxin B induced collapse of the actin cytoskeleton in hepatocytes from normal mice. Hepatocytes from both the ICE-deficient mice and the IL-1 p80 receptor-deficient mice demonstrated similar responses to both toxins. These toxins also induced significant LDH release in a concentration-dependent fashion in the normal hepatocytes and the ICE-deficient hepatocytes. However, no significant increase in LDH release was observed in hepatocytes from IL-1 p80 receptor-deficient mice. CONCLUSIONS: C. difficile toxins induce actin cytoskeletal collapse independent of IL-1 or the IL-1 receptor. In contrast, toxin-stimulated LDH release was dependent on the presence of the IL-1 receptor. Thus, separate pathways appear to mediate toxic effects as manifested by actin rearrangement and LDH release.

Radiostrontium in the Savannah river site environment.

The Savannah River Site has produced plutonium, tritium, and other special nuclear materials for national defense, other government programs, and some civilian purposes. Strontium has been released to the environment during the operation of five reactors, two radiochemical processing facilities, and other supporting facilities. During the period 1954-1996, 110 GBq of 90Sr were released to the atmosphere and 5,400 GBq were released to site streams. The maximum individual effective dose equivalent at the site boundary was estimated to be 72 microSv from atmospheric releases and 25 microSv from liquid releases. The 80-km population dose was 0.3 person-Sv.

K-ABC simultaneous processing, DAS nonverbal reasoning, and Horn's expanded fluid-crystallized theory.

Horn's distinction between--fluid intelligence (Gf) and visualization (Gv) was investigated with two Nonverbal Reasoning subtests from the Differential Ability Scales and three Simultaneous Processing subtests from the Kaufman Assessment Battery for Children. The sample comprised a predominantly Euro-American groups of 57 normal boys and girls between the ages of 6 and 12 years. Principal factor analysis yielded clear-cut Gf and Gv dimensions. The Gf factor was composed both of Differential Ability Scales and Kaufman-ABC subtests, suggesting that the construct of simultaneous processing is not merely a measure of Gv, as researchers have hypothesized, but also measures Horn's Gf fluid intelligence to a considerable extent.

Plutonium in the Savannah River Site environment.

The Savannah River Site has produced plutonium, tritium, and other special nuclear materials for national defense, other government programs, and some civilian purposes. Plutonium has been released to the environment during the operation of five reactors, two radiochemical processing facilities, and other supporting facilities. During the period 1954-1989, 140 GBq of plutonium were released to the atmosphere and 23 GBq were released to site streams and ponds. The maximum individual effective dose equivalent at the site boundary was estimated to be 120 microSv from atmospheric releases and 2.4 microSv from liquid releases. The 80-km population dose was 7.1 person-Sv.

Radiocesium in the Savannah River Site environment.

The Savannah River Site has produced plutonium, tritium, and other special nuclear materials for national defense, other government programs, and some civilian purposes. Radiocesium, a waste product, has been released to the environment during the operation of five reactors, two radio-chemical processing facilities, and a high-level waste storage system. During the period 1955-1989, 130 GBq of 137Cs was released to the atmosphere and 2.2 x 10(4) GBq was released to site streams and ponds. Approximately 65% of the latter remained on the site. The maximum individual effective dose equivalent at the site boundary was estimated to be 3.3 microSv from atmospheric releases and 600 microSv from liquid releases. The 80-km population dose was 1.6 person-Sv.

Tritium transport and cycling in the environment.

The transport and cycling of tritium in the environment can be understood in terms of the role of hydrogen in the environment. Physical and chemical isotopic effects, while present in some transport mechanisms and chemical reactions, are not important factors in environmental tritium dynamics. In addition, because of the role of hydrogen in metabolism and its ubiquitousness in the environment, organisms have not evolved mechanisms to accumulate or concentrate hydrogen or its isotopes in food chains. Therefore, biomagnification of tritium is not a factor in food chain transfer. The lack of significant isotopic effects or biomagnification means that tritium transport and cycling in the environment can be predicted on the basis of the transport processes, hydrogen content, and chemical transformation of hydrogen and its compounds in the environment.

Strategy of acne therapy with long-term antibiotics.

A study of the outcome of conventional antibiotic treatment in 543 patients with acne was performed. All were treated initially with erythromycin 1 g/day and topical 5% benzoyl peroxide. The median improvement at 6 months was 78%, with an interquartile range of 67-90%. Four-hundred and eight of the 492 who completed 6 months' treatment showed over 50% improvement and 247 of the 279 patients treated for a subsequent 6 months with benzoyl peroxide alone, continued to do well. Another subgroup of 174 patients, was continued for 6 months with systemic antibiotic and 5% benozyl peroxide. No significant benefit was gained, however, by maintaining successfully treated patients on a further 6 months of systemic antibiotics. Of the 84 patients who did less well, 18 were given alternative treatment (Diane, isotretinoin). The other 60, subsequently referred to as slow responders, were continued on antibiotics (erythromycin, 31; minocin, 29; cotrimoxazole, 4; trimethoprim, 2) and benzoyl peroxide. Those prescribed minocycline for the second 6 months appeared to have greater benefit (64%) than those receiving erythromycin (57%). This level of improvement was still lower than that seen in those who responded well within 6 months (78%). Of the risk factors analysed, the poorest response occurred in males with truncal acne. Age at presentation, duration and severity did not adversely affect therapeutic outcome. Side-effects were minimal.

Disturbances of calcium and magnesium metabolism occur in most hyperthyroid patients.

The concentrations in serum of total and ionised calcium, phosphate, magnesium, albumin and alkaline phosphatase activity were measured in patients when hyperthyroid and again when euthyroid. Significant declines in the mean values of ionised calcium, phosphate and alkaline phosphatase activity and significant increases in the mean concentrations of magnesium and albumin were observed. Similar changes were observed in most individual patients. Levels of ionised calcium greater than two standard deviations (representing between batch imprecision) above the upper limit of the reference range were present in 15.6% of hyperthyroid patients. The hyperthyroid levels of calcium, ionised calcium and alkaline phosphatase activity were highest in patients with the most severe thyrotoxicosis. Disturbances of calcium and magnesium metabolism are frequent in hyperthyroid patients.

The importance of load-independent analysis in assessment of the inotropic effect of prostaglandin E1 in vivo.

Load-independent pressure-dimension analysis was applied in 13 open-chest, anesthetized dogs during either left atrial (n = 7) or right atrial (n = 6) infusion of prostaglandin E1. Right atrial infusion of prostaglandin E1 in doses from 31 to 500 ng/kg/min resulted in no change in any parameters studied, including mean arterial pressure, cardiac output, and systemic and pulmonary vascular resistances. Left atrial infusion of prostaglandin E1 produced dose-dependent reductions in mean arterial pressure and systemic vascular resistance but no change in the slope of the relationship of left ventricular stroke work to end-diastolic length, a load-independent index of ventricular performance. In contrast to findings obtained with load-dependent parameters, these results suggest that prostaglandin E1 has no positive inotropic effect in vivo.

Ventricular function after atrial cardioplegia.

Continuous retrograde coronary sinus cardioplegia (CSCP) has previously been carefully evaluated experimentally and shown to be efficacious during ischemia, even in the presence of coronary lesions and in the hypertrophied state. A new technique of retrograde cardioplegia delivery through the right atrium, using right ventricular distension and pressures of 60 mm Hg, has recently been described with excellent clinical results. This study was designed to specifically examine right ventricular function after atrial cardioplegia and acute passive right ventricular distension. CSCP (n = 10) was compared with cardioplegia delivered through the right atrium both continuously (n = 10) and intermittently (n = 8). When ventricular function was examined with the use of the load-independent relationship of stroke work vs end-diastolic length, there was a profound deterioration of right ventricular function in both atrial cardioplegia groups (44% and 37% of control values, respectively) after 1 hr of reperfusion. In contrast, biventricular function was fully preserved in the CSCP group 1 hr after reperfusion. Left ventricular function measured at the end of reperfusion was preserved in all three groups. Right ventricular ATP levels were slightly but significantly depressed in all groups and in the atrial cardioplegia groups, this metabolic change was also seen in the left ventricle. These metabolic and hemodynamic data may reflect the inability of atrial cardioplegia to cool the myocardium below 16 degrees C. Postoperative right ventricular dysfunction may be more common than has been previously thought when atrial cardioplegia is used, particularly in the absence of topical cooling.

Quantification of the contractile response to injury: assessment of the work-length relationship in the intact heart.

We used a sonomicrometric determination of ventricular dimension to examine the effect of ischemia and reperfusion on the work-length relationship in the intact heart to develop a useful and precise variable of ventricular contractile response to injury. Twenty anesthetized dogs were instrumented with epicardial ultrasonic dimension transducers to record right ventricular free wall chord length and left ventricular minor-axis length, micromanometers to record ventricular pressures, and an electromagnetic probe to record pulmonary arterial (n = 8) or aortic (n = 7) flow. Dogs were subjected to either 20 min (n = 7) or 30 min (n = 13) of global cardiac ischemia supported by cardiopulmonary bypass. Data were acquired over a range of end-diastolic volumes produced by transient (5 to 10 sec) vena caval occlusion before and after ischemia. In both ventricles, systolic epicardial dimensional shortening correlated with flow probe-measured stroke volume (mean r = .969) and regional stroke work calculated as the integral of instantaneous ventricular pressure and epicardial dimension correlated with measured global stroke work (mean r = .960), confirming the validity of dimensional measurements. Regression analysis demonstrated a highly linear relationship between calculated regional stroke work and end-diastolic length in the right ventricle (mean r = .973) and left ventricle (mean r = .967), quantifiable by a slope (Mw) and x intercept (Lw). Change in afterload produced by pulmonary arterial or aortic constriction resulted in no significant changes in Mw or Lw in either ventricle. Ischemia and reperfusion decreased Mw and shifted Lw to the right in both ventricles. The decrease in Mw with 30 min ischemia exceeded the decrease with 20 min ischemia by 29% in the right ventricle and by 32% in the left (p less than .04) with up to 1 hr of reperfusion. Changes in Lw were not related to severity of injury. After ischemia, infusion of calcium increased Mw by 177% in the right ventricle and by 67% in the left (p less than .03) without significant changes in Lw. Independent of load conditions, the slope Mw, of the linear stroke work vs end-diastolic length relationship is a valid and precise index of right and left ventricular contractile response to global ischemia in the intact circulation. This variable may be useful in evaluating therapies designed to limit myocardial injury and enhance ventricular functional performance.