Thyroid hormone receptor beta-1 expression in early breast cancer: a validation study.

PURPOSE: Preliminary data suggest that high expression of the TRß1 tumor suppressor is associated with longer survival among women with early breast cancer. We undertook this study to validate these findings. METHODS: In this prospective cohort study, we analyzed the prognostic significance of TRß1 protein expression in the breast tumors of 796 women who had undergone breast surgery in the Henrietta Banting Breast Cancer database. All women were recruited after undergoing primary surgical therapy at Women's College Hospital (Toronto, ON, Canada) between January 1987 and December 2000. Details regarding patient age at diagnosis, systemic, and local therapies, as well as pathological features of their tumor have been systematically recorded. Clinical outcomes including breast cancer recurrence and death have been updated at least once each year with a median follow-up of 9.6 years (range 0.1-21 years). RESULTS: High TRß1 expression (> 4 on the Allred score) was associated with a longer breast cancer-specific survival with a HR 0.45 (95% CI 0.33-0.61), p < 0.0001 in a univariable Cox regression model. This was maintained in a multivariable model adjusted for age, tumor size, nodal status, chemotherapy, hormone therapy, radiotherapy, surgery, and ER status with a HR of 0.61 (95% CI 0.44-0.85), p = 0.004. CONCLUSIONS: High expression of TRß1 is associated with longer breast cancer-specific survival independent of other prognostic factors. Given that low TRß expression is associated with chemotherapy resistance in-vitro, TRß1 may also serve as a predictive biomarker or even a therapeutic target given the availability of TRß agonists.

Historical epidemiology of hepatitis C virus in select countries-volume 4.

Due to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country-specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

Strategies to manage hepatitis C virus infection disease burden-Volume 4.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets-"WHO Targets" (65% reduction in HCV-related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm: Volume 4.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.

Tumor factors predictive of response to hypofractionated radiotherapy in a randomized trial following breast conserving therapy.

PURPOSE: To determine whether tumor grade, molecular subtype and hypoxia predict response to hypofractionated versus standard radiotherapy (RT) following breast-conserving surgery (BCS) for node-negative breast cancer in a randomized controlled trial (RCT). PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor blocks were available on 989 of 1234 patients enrolled in the Hypofractionation Whole Breast Irradiation (HWBI) Trial. A central pathology review and assessment of tumor grade using the Nottingham grading system was carried out. Tumors were classified by molecular subtype as luminal A, luminal B, HER2 enriched, basal-like or unclassified using a six-biomarker panel; ER, PR, HER-2, Ki67, CK5/6 and EGFR. Tumors were also classified as hypoxic based on the expression of HIF1α, CAIX or GLUT-1. The primary end point was local recurrence (LR). RESULTS: Median follow-up was 12 years. In the multivariable Cox model, molecular subtype was the only factor predictive of LR, the 10-year cumulative incidence was 4.5% for luminal A and basal-like, 7.9% for luminal B and 16.9% for HER-2 enriched tumors (P < 0.01). Tumor grade, molecular subtype or hypoxia did not predict response to hypofractionation. CONCLUSIONS: In women enrolled in the HWBI trial following BCS tumor molecular subtype predicted LR. However tumor grade, molecular subtype and hypoxia did not predict response to hypofractionation suggesting that patients with node-negative breast tumors of all grades and molecular subtypes may be safely treated with hypofractionated RT regimens.

An update on apocrine lesions of the breast.

Apocrine change occurs in a spectrum of benign lesions in the female breast and is also demonstrated in a subgroup of in situ and invasive carcinomas. Recent research has focused on the molecular phenotype of both benign and malignant apocrine lesions. This review will briefly summarize the morphological characteristics and risk associations of the spectrum of apocrine proliferations, but will focus on the updated molecular studies of both in situ and invasive apocrine carcinomas.

The spectrum of apocrine lesions of the breast.

Apocrine change is seen in a wide spectrum of breast lesions, ranging from microscopic cysts to invasive carcinoma. This article reviews the range of apocrine lesions and discusses the clinical significance of these lesions. Although apocrine change in many cases does not present any diagnostic difficulty, apocrine proliferations demonstrating cytologic atypia can be particularly challenging. The histologic criteria that have been proposed to foster reproducibility in categorizing such lesions are reviewed. This review attempts to clarify the terminology that has been applied to a range of benign lesions, including sclerosing adenosis and complex sclerosing lesions, containing foci of apocrine change. Malignant apocrine lesions, including both in situ and invasive carcinoma, are also discussed.

Massive perivillous fibrinoid causing recurrent placental failure.

OBJECTIVE: To establish the incidence, recurrence rate and consequences of massive perivillous fibrinoid. DESIGN: Retrospective analysis of the histology of all placentas with a diagnosis of massive perivillous fibrinoid between 1991 and 1998, together with the maternal case records. SETTING: The histopathology department of the Rotunda Hospital, Dublin, Ireland. POPULATION: A relatively homogeneous group of pregnant women in the northern part of Dublin City, which is the catchment area for the Rotunda Hospital, delivered between 1991 and 1998. METHODS: Retrospective review of archival placental pathology and maternal charts. MAIN OUTCOME MEASURES: The incidence of massive perivillous fibrinoid, perinatal outcome and recurrence rate. RESULTS: The incidence of massive perivillous fibrinoid was 0.028%, with a recurrence rate of approximately 18%. All the infants suffered intrauterine growth restriction; there was a 31% fetal loss rate and a 33% preterm delivery rate. CONCLUSIONS: Massive perivillous fibrinoid is associated with intrauterine death, intrauterine growth restriction and preterm delivery. It has a significant recurrence rate and both the clinical findings of intrauterine growth restriction and the postmortem findings imply a syndrome of chronic placental insufficiency.

Case of tuberous sclerosis.

Tuberous Sclerosis (TSc) is a benign multi-system hamaertomatosis and is one of the neurocutaneous syndromes (2, 3, 7). The first case of tuberous sclerosis in a 27 years old female patient is reported from Ethiopia. The importance of meticulous evaluation of a patient as a whole to reach at the right diagnosis is stressed. The clinicopathological features of tuberous sclerosis are discussed with literature review.

Chronic myelomonocytic leukemia revealed by uncontrollable hematuria.

Nephrectomy was performed for uncontrollable unilateral hematuria in an apparently healthy 72-year-old man. The suburothelial connective tissue of the kidney was infiltrated by primitive myeloid cells with associated acute vasculitis and foci of extramedullary hematopoiesis. Subsequently, the patient was shown to have chronic myelomonocytic leukemia. Although renal involvement and vasculitis have been recorded previously in chronic myelomonocytic leukemia, this is the first occasion, to our knowledge, where their concurrence resulted in such a spectacular presentation.

TC-2559: a novel orally active ligand selective at neuronal acetylcholine receptors.

TC-2559 [(E)-N-Methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine] is a novel nicotinic agonist markedly more selective than recently reported novel nicotinic receptor ligands (selectivity ratio for central nervous system (CNS) to peripheral nervous system (PNS)>4000). TC-2559 competes effectively with [3H]-nicotine binding (K(i)=5 nM) but not with [125I]-bungarotoxin (>50,000 nM). Dopamine release from striatal synaptosomes and ion flux from thalamic synaptosomes indicate that TC-2559 is potent and efficacious in the activation of CNS receptors and significantly reduced glutamate-induced neurotoxicity in vitro. TC-2559 has no detectable effects on muscle and ganglion-type nicotinic acetylcholine receptors at concentrations up to 1 mM. TC-2559 significantly attenuates scopolamine-induced cognitive deficits in a step-through passive avoidance task. Acute and repeated oral dosing of TC-2559 enhances performance in a radial arm maze task. In contrast to the effects of equimolar concentrations of (-) nicotine, TC-2559 does not induce hypothermia and locomotor activity is not enhanced following repeated daily administration of 14 days. TC-2559 has a markedly enhanced CNS-PNS selectivity ratio and an intra-CNS selectivity as evidenced by the improved cognition without increased locomotor activity. The in vitro and in vivo studies in the present study suggest that TC-2559 has the desired profile to be further evaluated as a potential therapeutic agent for neurodegenerative diseases.

Adverse effects of dextromethorphan on the spatial learning of rats in the Morris water maze.

The effects of the non-competitive NMDA receptor antagonist dextromethorphan on spatial learning were assessed using the Morris water maze. Dextromethorphan was administered to 4 groups of rats in 10, 20, 30, and 40 mg/kg doses. An additional group of rats was administered saline to serve as a vehicle control group. Dextromethorphan impaired learning dose dependently in the initial training phase of the experiment. During the probe trial, dose-dependent performance deficits were noted in the first 15 s of the trial only. Search strategy differences between the lowest and highest dose groups were also observed during the probe trial. During the reversal training phase, when the platform was moved to a new location, the dose-dependent impairment was seen again, but the 40 mg/kg group perseverated to the former location longer than the other groups. A cued control trial indicated that in addition to the learning impairment produced, the highest dose of dextromethorphan may also impair sensory-motor coordination.

Food deprivation does not influence body or selection temperature in rats receiving intraventricular bombesin.

Bombesin (BBS), a tetradecapeptide, has been found to have potent hypothermic effects when centrally administered. This study was designed to investigate the relationship between food-deprivation and BBS-induced hypothermia in a temperature selection paradigm. Food-deprived and satiated male Sprague-Dawley rats were given intracerebroventricular (ICV) injections of several doses of BBS and control vehicle. Selection temperature data and changes in core body temperature were measured. BBS produced a significant hypothermia and decrease in selection temperatures in all doses but one. No significant differences in body temperature or selection temperatures were found between food-deprived and satiated animals. The results are consistent with the hypothesis that BBS acts centrally to decrease body temperature set point.

Effects of cocaine on dietary self-selection during pregnancy and lactation in the rat.

Previously, we have shown that patterns of food selection are altered by pregnancy and lactation in rats. Reproductive animals increase total food intake during gestation and lactation, and select more carbohydrate and protein during lactation than virginal controls. In other self-selection studies, female rats administered cocaine compensate for decreases in carbohydrate and fat but not protein intake, resulting in a potential protein deficiency. The present study was designed to test the combined effects of cocaine and reproductive period on food intake. Cocaine was administered daily (PO) to 18-h food-deprived rats during the second and third week of gestation and the first week of lactation. Immediately following drug administration, each animal had free access to isocaloric carbohydrate, protein, and fat in a dietary self-selection situation. Intake of each component was measured at 30 min, 60 min, 2 h, and 6 h following the drug treatment. The results of this study indicate that cocaine administration during gestation and lactation disrupts normal patterns of food intake. Altered patterns of food intake may be responsible for some of the deleterious effects of maternal cocaine use on offspring.

The effects of cocaine on dietary self-selection in female rats.

Cocaine was administered via an oral route to 18-h food deprived female rats for 14 consecutive days. Following administration of the drug or vehicle control each animal was presented with separate isocaloric rations of protein, fat, and carbohydrate in a dietary self-selection situation. Amounts consumed of each component were measured at 30 min, 60 min, 2 h, and 6 h following the drug treatment. The intake of all three macronutrients was suppressed by cocaine for 1 h. Between 2 and 6 h after administration, there was a compensatory increase in fat and carbohydrate, but not protein consumption. The results are discussed in terms of protein deficiency caused by cocaine in pregnant and/or lactating females being a causal factor in the deleterious effects on offspring.

Capsaicin does not attenuate bombesin-induced suppression of operant responding for food reward.

Systemic treatment with capsaicin, a neurotoxin which damages unmyelinated peptide-containing sensory neurons, has been shown to attenuate bombesin (BBS)-induced suppression of food intake. To determine whether capsaicin-sensitive fibers mediate the effect of BBS on appetitive motivation, we examined BBS-induced suppression of operant responding in rats pretreated neonatally with capsaicin (50 mg/kg; SC) or control vehicle. At 8-10 weeks of age, rats were trained to bar press for food. After achieving a stable level of performance, the animals were injected with BBS (10 micrograms/kg), normal saline, or prefed with 20 Noyes 45-mg pellets. Animals were then tested in an operant chamber on an FR 5 schedule of reinforcement for one hour. The results indicated that BBS suppressed bar pressing, regardless of whether animals were pretreated with capsaicin or control vehicle. These findings are inconsistent with the hypothesis that BBS induces satiety via capsaicin-sensitive neurons. The results suggest the possibility that more than one mechanism may mediate the effects of BBS: a neural mechanism involved in consummatory responses and a humoral mechanism involved in the operant response.

Abnormal spermatozoa, testicular degeneration, and varicocele in a ram.

A 4-year-old Corriedale ram, with a history of infertility, had 50% abnormal acrosomes in the ejaculate resembling knobbed spermatozoa. Electron microscopic profiles of the apical segment of the affected acrosomes revealed a membrane-enclosed inclusion or cyst filled with particulate matter. The abnormal acrosomes were combined with a high prevalence of other degenerative changes such as head abnormalities, proximal droplets, and loose heads. Spermatozoa were examined from 9 ejaculates collected over an 8-month period. Abnormal acrosomes decreased to 5% after 4 months, but increased to 83% a month later. Examination of the testes after castration revealed bilateral varicocele and degeneration of seminiferous epithelium.

Changes in the morphology of spermatozoa during their passage through the genital tract in dairy bulls with normal and impaired spermat ogenesis.

An investigation was conducted on changes in sperm morphology along the excurrent duct of bulls. The study comprised 20 bulls with proven fertility and normal semen picture, and 10 bulls with pathologic semen. The morphology of spermatozoa was evaluated on ejaculates and on postslaughter collected contents from the excurrent duct. The incidence of pathologic sperm heads decreased along the duct in both groups of bulls. The main decrease generally occurred in caput epididymidis. In bulls with pathologic semen, the decrease continued in lower regions of epididymis and was deferens. The rate and pattern of sperm removal seem to primarily depend on the quality of spermatozoa entering the excurrent duct. The removal was clearly selective and is assumed to be associated with phagocytosis of spermatozoa mainly in the efferent ductules and proximal part of caput epididymis. Proximal cytoplasmic droplets were present on almost all sperm in the efferent ductules. The incidence decreased during passage along the genital tract. Migration of cytoplasmic droplets from a proximal to a distal position took place between regions C and D of the caput epididymidis. The incidence of middle-piece abnormalities decreased during passage along the genital tract, while the incidence of sperm tail abnormalities increased in the corpus and cauda epididymidis in all bulls.