Buccal mucosa micronuclei counts in relation to exposure to low dose-rate radiation from the Chornobyl nuclear accident and other medical and occupational radiation exposures.

BACKGROUND: Ionizing radiation is a well-known carcinogen. Chromosome aberrations, and in particular micronuclei represent an early biological predictor of cancer risk. There are well-documented associations of micronuclei with ionizing radiation dose in some radiation-exposed groups, although not all. That associations are not seen in all radiation-exposed groups may be because cells with micronuclei will not generally pass through mitosis, so that radiation-induced micronuclei decay, generally within a few years after exposure. METHODS: Buccal samples from a group of 111 male workers in Ukraine exposed to ionizing radiation during the cleanup activities at the Chornobyl nuclear power plant were studied. Samples were taken between 12 and 18 years after their last radiation exposure from the Chornobyl cleanup. The frequency of binucleated micronuclei was analyzed in relation to estimated bone marrow dose from the cleanup activities along with a number of environmental/occupational risk factors using Poisson regression adjusted for overdispersion. RESULTS: Among the 105 persons without a previous cancer diagnosis, the mean Chornobyl-related dose was 59.5 mSv (range 0-748.4 mSv). There was a borderline significant increase in micronuclei frequency among those reporting work as an industrial radiographer compared with all others, with a relative risk of 6.19 (95% CI 0.90, 31.08, 2-sided p = 0.0729), although this was based on a single person. There was a borderline significant positive radiation dose response for micronuclei frequency with increase in micronuclei per 1000 scored cells per Gy of 3.03 (95% CI -0.78, 7.65, 2-sided p = 0.1170), and a borderline significant reduction of excess relative MN prevalence with increasing time since last exposure (p = 0.0949). There was a significant (p = 0.0388) reduction in MN prevalence associated with bone X-ray exposure, but no significant trend (p = 0.3845) of MN prevalence with numbers of bone X-ray procedures. CONCLUSIONS: There are indications of increasing trends of micronuclei prevalence with Chornobyl-cleanup-associated dose, and indications of reduction in radiation-associated excess prevalence of micronuclei with time after exposure. There are also indications of substantially increased micronuclei associated with work as an industrial radiographer. This analysis adds to the understanding of the long-term effects of low-dose radiation exposures on relevant cellular structures and methods appropriate for long-term radiation biodosimetry.

Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep-wakefulness.

The orexinergic neurons of the lateral hypothalamus (LH) are critical for wakefulness [McCarley RW (2007) Neurobiology of REM and NREM sleep. Sleep Med 8:302-330]. Recent evidence suggests that adenosine (AD), a homeostatic sleep factor, may act via A1 receptor (A1R) to control orexinergic activity and regulate sleep-wakefulness [Thakkar MM, Winston S, McCarley RW (2002) Orexin neurons of the hypothalamus express adenosine A1 receptors. Brain Res 944:190-194; Liu ZW, Gao XB (2006) Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol]. To evaluate the role of AD in the orexinergic LH and its influences on sleep-wakefulness, we designed two experiments in freely behaving rats: First, we bilaterally microinjected 1,3-dipropyl-8-phenylxanthine (DPX) (1.5 pmol and 15 pmol), a selective A1R antagonist into the LH during the light cycle and examined its effect on spontaneous sleep-wakefulness. Second, we performed 6 h of sleep deprivation. Thirty minutes before the animals were allowed to enter recovery sleep, 15 pmol of DPX was bilaterally microinjected into the LH and its effects on recovery sleep were monitored. Microinjection of DPX into the orexinergic LH produced a significant increase in wakefulness with a concomitant reduction in sleep, both during spontaneous bouts of sleep-wakefulness and during recovery sleep. Local administration of DPX into the LH produced a significant increase in the latency to non-REM sleep during recovery sleep. However, total slow wave (delta) activity during non-REM sleep phase of recovery sleep remained unaffected after DPX treatment. This is the first study that implicates endogenous adenosine to have a functional role in controlling orexinergic tone and influencing the homeostatic regulation of sleep-wakefulness.

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.

Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus.

Fibrosing cholestatic hepatitis (FCH) is a severe clinical and histological variant of hepatitis B virus (HBV) infection seen most commonly in the HBV infected allograft after liver transplantation. Without treatment, FCH is fatal, rapidly and universally. Remission has been reported with lamivudine but is associated with evolving resistance to lamivudine. Adefovir dipivoxil has recently been reported to be a potent and highly effective inhibitor of HBV replication in both wild-type and lamivudine resistant HBV infection. We report a case of FCH 15 months after liver transplantation for HBV related cirrhosis despite therapy with lamivudine and hepatitis B immunoglobulin (HBIg). Within two weeks of commencing treatment with adefovir dipivoxil 10 mg once daily, the patient had made a remarkable recovery with resolution of jaundice and normalisation of liver biochemistry. HBV DNA and hepatitis B e antigen were lost from serum subsequently and liver histology had improved at four months. This case report suggests firstly, that advanced FCH can be reversed and secondly, that addition of adefovir dipivoxil to lamivudine and HBIg may be an effective antiviral strategy.

Spontaneously occurring hepatocellular neoplasia in adolescent cynomolgus monkeys (Macaca fascicularis).

Spontaneous hepatic neoplasms were identified in two adolescent (<5 years of age) male cynomolgus monkeys (Macaca fascicularis). Monkey No. 1 had a solitary hepatocellular carcinoma (HCC). Monkey No. 2 had multiple discrete tumors consisting of several poorly circumscribed HCCs and a mixed hepatocholangiocellular carcinoma (MHC). Metastases were not evident in either monkey. Histochemical and immunohistochemical stains were used to assess phenotypic alterations in the tumors. Many or most neoplastic hepatocytes (NHs) of both monkeys stained positive for low-molecular-weight cytokeratin (LMWCK), cytokeratin (CK) 8, and CK 18. In monkey No. 1, small aggregates of NHs were positive for carcinoembryonic antigen (CEA), glutathione S-transferase-pi (GST), and alpha-fetoprotein (AFP), but NHs were uniformly negative for CK 7. NHs in monkey No. 2 were negative for CEA and AFP but were multifocally positive for GST and CK 7. Broad-spectrum cytokeratin (BSCK), high-molecular-weight cytokeratin (HMWCK), and CK 19 did not react with NHs of either animal. Neoplastic cells forming ductlike structures in the MHC of monkey No. 2 stained with LMWCK, CK 7, CK8, CK 18, BSCK, and GST but not with HMWCK or CK 19. Tumors in both monkeys had enhanced pericellular fibronectin staining. Nonneoplastic parenchyma of both monkeys contained multiple discrete foci of cellular alteration and scattered aggregates of hepatocytes with strong cytoplasmic staining for fibronectin. Staining patterns of these tumors demonstrate immunophenotypic heterogeneity of the neoplastic cells within individual tumors and variability among tumors. This information may serve as a useful reference for others encountering similar lesions in primates.

Basement membrane peptides as markers of liver disease in chronic hepatitis C.

BACKGROUND/AIM: Chronic hepatitis C is characterised by slow progression to liver fibrosis. In liver fibrosis, basement membrane components are increasingly deposited around the vessels and in the portal tracts. Serum assays can measure the two major components of the basement membrane, type IV collagen and laminin. The aim of this study was to determine whether serum levels of type IV collagen and laminin are related to severity of liver injury in chronic hepatitis C. METHODS: Thirty-seven patients with chronic hepatitis C (CHC) and five healthy controls were studied. Serum type IV collagen was measured by a one-step sandwich EIA kit (Fuji, Japan) and serum laminin was measured by RIA (CIS, UK). Liver biopsies in patients with CHC were scored using a previously described grading and staging system. Liver biopsy scores were compared to serum levels of laminin, type IV collagen and alanine aminotransferase (ALT). Receiver operating characteristic (ROC) analysis was used to compare the ability of the assays to detect advanced liver injury. RESULTS: The median serum concentration of type IV collagen was 127.1 ng/ml (range 17.7 to 317.4) in CHC patients compared to a median of 61.3 ng/ml (range 11.5 to 102.3) in controls, p=0.006. The median serum concentration of laminin was 1.12 U/ml (range 0.74 to 2.46) in CHC compared to a median of 0.87 U/ml (range 0.83 to 1.06) in controls, p=0.07. Both serum type IV collagen and laminin were significantly correlated with the fibrotic stage and also with the necroinflammatory injury scores- histological activity index, portal inflammation and periportal hepatitis. Serum ALT was significantly correlated with portal inflammation. Using ROC analysis, the area under the curve for type IV collagen and laminin was 0.83 (p=0.001) and 0.82 (p=0.0017), respectively, while the area under the curve for ALT was 0.54 (p=0.1). CONCLUSIONS: Serum assays of basement membrane peptides are accurate non-invasive markers of liver fibrosis and liver inflammation in chronic hepatitis C. These markers are superior to serum ALT in reflecting liver injury and they have high specificity and sensitivity in detecting advanced liver disease in chronic hepatitis C.

National athletic trainers' association position statement: lightning safety for athletics and recreation.

OBJECTIVE: To educate athletic trainers and others about the dangers of lightning, provide lightning-safety guidelines, define safe structures and locations, and advocate prehospital care for lightning-strike victims. BACKGROUND: Lightning may be the most frequently encountered severe-storm hazard endangering physically active people each year. Millions of lightning flashes strike the ground annually in the United States, causing nearly 100 deaths and 400 injuries. Three quarters of all lightning casualties occur between May and September, and nearly four fifths occur between 10:00 AM and 7:00 PM, which coincides with the hours for most athletic or recreational activities. Additionally, lightning casualties from sports and recreational activities have risen alarmingly in recent decades. RECOMMENDATIONS: The National Athletic Trainers' Association recommends a proactive approach to lightning safety, including the implementation of a lightning-safety policy that identifies safe locations for shelter from the lightning hazard. Further components of this policy are monitoring local weather forecasts, designating a weather watcher, and establishing a chain of command. Additionally, a flash-to-bang count of 30 seconds or more should be used as a minimal determinant of when to suspend activities. Waiting 30 minutes or longer after the last flash of lightning or sound of thunder is recommended before athletic or recreational activities are resumed. Lightning- safety strategies include avoiding shelter under trees, avoiding open fields and spaces, and suspending the use of land-line telephones during thunderstorms. Also outlined in this document are the prehospital care guidelines for triaging and treating lightning-strike victims. It is important to evaluate victims quickly for apnea, asystole, hypothermia, shock, fractures, and burns. Cardiopulmonary resuscitation is effective in resuscitating pulseless victims of lightning strike. Maintenance of cardiopulmonary resuscitation and first-aid certification should be required of all persons involved in sports and recreational activities.

The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females.

BACKGROUND: Sibutramine, an inhibitor of serotonin and noradrenaline uptake, reduces appetite to cause weight loss. This study tested the hypothesis that an increase in energy expenditure also contributes to this weight loss. In addition, the effects of sibutramine on adrenaline induced changes in heart rate and cardiac output were determined METHODS: Nineteen obese females randomly received either sibutramine 15 mg daily or placebo for 12 weeks along with dietary advice. Resting energy expenditure (REE) was measured and then energy expenditure was measured during a 30 min infusion of adrenaline (25 ng/min/kg IBW). Cardiac output and heart rate, measured by Duplex Colour Doppler ultrasonography, were similarly measured in the basal state and post adrenaline. All measurements were recorded at baseline and then after 12 weeks. RESULTS: Ten patients who received sibutramine reduced their weight by 8.1+/-3.8% while 9 placebo treated subjects reduced their weight by 5.1+/-4.4%, P=0.13. In absolute terms, REE decreased in placebo subjects from 1500+/-201 kcal/24 h to 1357+/-231 kcal/24 h (9.4+/-9.9%) and in sibutramine subjects from 1540+/-184 kcal/24 h to 1444+/-128 kcal/24 h (5.3+/-12.0%), P=0.77. The increased weight loss in the sibutramine group was associated with an increase in the FFM adjusted REE (2.2+/-16.1%) unlike the expected decrease (5.8+/-9.5%) in the placebo group (P=0.11). There was some suggestion (P=0.09) that the usual positive correlation between loss of weight and decline in REE was lost in the sibutramine group (r=-0.30) compared with placebo (r=0.35). There was a negative correlation between loss of FFM and decline in REE/kg FFM and (P=0.029) which was not evident in placebo (P=0.83). Adrenaline induced energy expenditure was similar in the two groups at the end of the 12 week period and there were no significant cardiovascular changes between the two groups. CONCLUSIONS: Sibutramine limits the decline in REE associated with weight loss, equivalent to about 100 kcal/d. This could allow greater numbers of people to maintain a greater degree of weight loss.

Comparison of assays for N-amino terminal propeptide of type III procollagen in chronic hepatitis C by using receiver operating characteristic analysis.

OBJECTIVE: During the process of liver fibrosis, type III procollagen is converted to type III collagen by cleavage of its amino terminal and carboxy terminal propeptides. Serum levels of amino terminal propeptide of type III procollagen (PIIINP) are a marker of collagen turnover in liver fibrosis. Two assays for PIIINP are available, one which measures both Col 1-3 (collagen synthesis) and Col 1 (collagen degradation) peptides, and one which measures Col 1-3 only. Using receiver operating characteristic analysis, the two PIIINP assays were compared with serum ALT as markers of liver disease in chronic hepatitis C. METHODS: Serum PIIINP was measured using both assays in 33 patients with chronic hepatitis C and five healthy controls. Liver biopsies in chronic hepatitis C patients were scored using a previously described grading and staging system. RESULTS: Serum PIIINP was significantly elevated in chronic hepatitis C compared to controls using both the combined Col 1-3 and Col 1 (median 0.61 vs 0.33 U/ml, P=0.001) and Col 1 assays (median 6.5 vs 3.5 microg/l, P=0.006). Serum PIIINP measured by the combined assay was significantly related to liver fibrosis, periportal necrosis and histological activity index (P<0.05). The area under the curve for specificity and sensitivity in detecting advanced liver disease was only significant for the combined assay (P=0.017). Serum PIIINP measured by the Col 1 assay was not related to these indices of disease severity while serum ALT was only related to portal inflammation. CONCLUSION: A serum PIIINP assay which measures both Col 1-3 and Col 1 peptides instead of Col 1-3 peptide alone is more predictive of severity of liver disease and should be used in preference as a non-invasive marker of liver injury in chronic hepatitis C.

Hepatic effects in beagle dogs administered atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 2 years.

The chronic toxicity of atorvastatin (AT), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was evaluated in beagle dogs. Dogs were treated with 0, 10, 40, or 120 mg/kg of AT daily. Treatment lengths were 52 wk, 52 wk followed by 12 wk without drug, or 104 wk. Decreases in cholesterol levels were dose related and stable throughout the treatment period. Increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were transient and dose related in severity at > or = 40 mg/kg. Two dogs administered 120 mg/kg of AT daily were sacrificed moribund during the first 9 wk of treatment. Hepatic lesions were reversible with or without continued treatment and dose related in severity and distribution. Hepatic microgranulomas and hepatocellular degeneration were seen at the 120-mg/kg dose in dogs sacrificed before 53 wk. Before 53 wk, hepatocellular lipofuscin deposits were increased in dogs given > or = 40 mg/kg of AT daily but were similar to controls after 12 wk without drug and after 104 wk of continuous treatment. Bile stasis occurred in dogs given > or = 40 mg/kg of AT daily at all time points but was less severe after reversal and at week 104 compared with week 52.

Immunotoxicity of the anticancer drug CI-994 in rats: effects on lymphoid tissue.

CI-994 (acetyldinaline) is an investigative oral anticancer drug currently in clinical trials. To characterize the effects of CI-994 on lymphoid tissue, male rats were administered single oral doses at 0 (vehicle control), 10, 23, and 45 mg/kg and killed up to 7 days after dosing for evaluation of white blood cell differentials, bone marrow differentials, lymphoid tissue weights, and selected histopathology of lymphoid tissue. Statistically significant dose-related reductions in blood lymphocytes (CD-3+, CD-4+, CD-8+, CD-20+), monocytes, neutrophils, and bone marrow lymphoid cells were observed in all drug-treated groups on days 1 and/or 3. Statistically significant reductions in bone marrow myeloid cells were also observed on days 1 and 3 at 23 and 45 mg/kg. Complete or partial reversal of most parameters was evident on day 7. Spleen and/or thymus weights were significantly decreased in the groups administered 23 and 45 mg/kg on days 1, 3, and/or 7. Minor reductions in lymphoid organ weights were noted at 10 mg/kg. Minimal to moderate lymphoid depletion of the spleen and thymus was noted on day 3 in animals dosed at 23 mg/kg. In vitro, CI-994 inhibited mitogen-stimulated blood lymphocyte proliferation with a 50% inhibitory concentration (IC50) value of 3 microM. The results demonstrate that CI-994 can effect lymphoid tissue in rats within 1 day of a single oral dose, that effects are generally reversible within 7 days, and that inhibition of lymphocyte proliferation is a sensitive indicator of CI-994 immunotoxicity in vitro.

Plasma levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis.

As chronic liver disease progresses, an imbalance occurs between synthesis and breakdown of extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are involved in degrading ECM while tissue inhibitors of metalloproteinases (TIMPs) prevent their fibrolytic action. We determined if plasma levels of MMP-2, TIMP-1 and TIMP-2 are related to liver histology in patients with chronic hepatitis C. Plasma MMP-2, TIMP-1 and TIMP-2 levels were measured in 43 patients with chronic hepatitis C. Plasma levels of MMP-2, TIMP-1 and TIMP-2 and serum ALT were correlated with liver biopsy score and specificity and sensitivity of the assays in detecting advanced liver disease were calculated from ROC analysis. Plasma TIMP-1 was significantly correlated with histological activity index (r = 0.45), portal inflammation (r = 0.48), periportal necrosis (r = 0.34) and focal necrosis (r = 0.38). Plasma TIMP-2 was significantly correlated with fibrosis (r = 0.43) and confluent necrosis (r = 0.41). Using ROC analysis both TIMP-1 and TIMP-2 had significant diagnostic ability in detecting advanced liver disease (Area under the curve 0.73 for both, p 0.015 and 0.036 respectively). A normal plasma TIMP-1 excluded advanced liver disease. Neither plasma MMP-2 or serum ALT were related to fibrosis or to histological activity index. With increased severity of liver disease in chronic hepatitis C there is increased plasma levels of TIMPs -1 and -2. Plasma TIMP-1 and TIMP-2 are sensitive and to a lesser extent specific in detecting advanced liver disease in chronic hepatitis C and could be used in preference to serum ALT.

Nasal toxicity of CI-959, a novel anti-inflammatory drug, in Wistar rats and Beagle dogs.

CI-959, 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thio phene-2-carboxamide, an anti-inflammatory agent, was considered for development as a treatment for rhinitis. Two-week topical nasal studies in Wistar rats and Beagle dogs were performed to assess nasal toxicity of CI-959. Rats were given daily doses in the right nostril of 0.05 ml of solutions of varying concentrations (0.5, 2, 10, 20, 30, 60, and 90 mg/ml; doses of 0.08, 0.3, 1.6, 3.2, 4.8, 9.6, and 14.6 mg/kg) of CI-959. Beagle dogs were given daily doses in the right nostril of 0.5 ml of 10, 20, 30, 60, and 90 mg/ml solutions (doses of 0.5, 0.8, 1.2, 2.8, and 3.7 mg/kg) of CI-959. Rats given > or = 60 mg/ml either lost weight or had decreased weight gain. Salivation at dosing was seen in both species. Four sections of nasal cavity were examined from each animal. In rats, 0.5 mg/ml was the "no effect" dose; minimal changes were seen at 2 mg/ ml, and significant changes were dose related in severity at > or = 10 mg/ml in all 4 nasal levels. Degeneration and necrosis of respiratory and olfactory epithelia were minimal to moderate in severity. Adhesions and fibro-osseous proliferation of ethmoturbinates, epithelial hyperplasia, squamous metaplasia, and exudate were also seen. In dogs, 10 mg/ml was the no effect dose; respiratory epithelium was affected at > or =20 mg/ml. Respiratory epithelial degeneration was minimal to mild, with loss of ciliated and goblet cells and thinning of mucosa. Distribution of degeneration increased with increased concentrations. In both species, in accordance with the suggested action of CI-959, infiltration with neutrophils was not significant. CI-959 was locally toxic to nasal cavity respiratory and olfactory epithelia in rats and respiratory epithelium in dogs.

Spontaneous neoplasms in control Wistar rats: a comparison of reviews.

Spontaneous neoplasms in 930 control Wistar rats from five carcinogenicity bioassays conducted between 1990 and 1995 were reviewed and compared with review findings in studies between 1980 and 1990. Mean survival at 104 weeks was 55% for males and 60% for females, similar to that of the previous review. A total of 1599 neoplasms was diagnosed in 361 (78%) male and 415 (89%) female rats; 1293 (81%) of these were benign and 306 (19%) were malignant (11% with metastases). Sixty-eight percent of all neoplasms were in endocrine and integumentary systems, similar to 74% seen in the previous review. Most common neoplasms (affecting > 7% of either sex) were pituitary adenoma (34% of males, 50% of females), benign adrenal pheochromocytoma (10% of males, 1% of females), thyroid C cell adenoma (6% of males, 8% of females), mammary fibroadenoma (3% of males, 36% of females), keratoacanthoma (11% of males, 0.6% of females), testicular interstitial cell tumor (11% of males), uterine stromal polyp (16% of females), pancreatic acinar cell adenoma (13% of males, 0.6% of females), and benign thymoma (3% of males, 8% of females). Seventeen neoplasms affecting 2 to 6.9% of either sex included adrenal cortical adenoma, thyroid follicular adenoma, pancreatic islet cell adenoma, pituitary carcinoma, mammary adenoma, mammary adenocarcinoma, fibroma, fibrosarcoma, dermal papilloma, uterine schwannoma, uterine granular cell tumor, pancreatic acinar cell carcinoma, hepatocellular adenoma, lymphoma, granular cell meningioma, renal mesenchymal tumor, and hemangiosarcoma. Remaining neoplasms occurred in fewer than 2% of animals. Mean tumor incidence did not differ significantly between our two reviews. Ratios of benign to malignant neoplasms were similar in both reviews and percentages of survival at 104 weeks were similar. Between the two reviews, greater than threefold increase in frequency of some neoplasms occurred only in males and included keratoacanthomas, pancreatic acinar cell adenomas/carcinomas, and astrocytomas. Frequencies of remaining neoplasms were within twofold or within 10% of previous frequencies. Some neoplasms diagnosed in this review but not in the previous review included cardiac schwannoma, pilomatrixoma, parathyroid adenoma, and prostatic adenoma but incidence was approximately 1% for any one tumor. Based on these reviews, Wistar rats appear to have a predilection to pituitary neoplasms and mammary fibroadenomas (females).

Viral kinetics can predict early response to alpha-interferon in chronic hepatitis C.

AIMS/BACKGROUND: Response rates to alpha-interferon therapy for chronic hepatitis C are poor. An early indication of efficacy would reduce the need for prolonged therapy, leading to significant cost savings. It was established that a change in quantitative hepatitis C virus RNA (HCV-RNA) titre at 4 weeks could predict the outcome of alpha-interferon therapy in chronic hepatitis C. METHODS: Serum HCV-RNA titres were quantified using branched chain DNA (bDNA) assay in 26 patients who responded to alpha-interferon (serum HCV-RNA negative after 12 weeks therapy) and 11 age and sex matched non-responders. Quantitative bDNA and qualitative RT-PCR assays for HCV-RNA were measured pretreatment and at 4 weeks. The change in quantitative HCV-RNA titre between pre-therapy and after 4 weeks was compared in the two groups. RESULTS: Seventeen of the 37 patients had become RT-PCR negative at 4 weeks (early responders) and had an undetectable HCV-RNA titre on bDNA assay. Nine patients were RT-PCR positive at 4 weeks but negative by 12 weeks (delayed responders), and of these, 8 had an undetectable viral titre at 4 weeks on bDNA assay. The patient with a detectable HCV titre did become RT-PCR negative after 12 weeks, but subsequently became RT-PCR positive again at 24 weeks. All the non-responders had a detectable bDNA titre (> 0.2 Meq/ml) at 4 weeks. CONCLUSIONS: Change in quantitative HCV-RNA titre measured by bDNA assay at 4 weeks predicts response to alpha interferon. If HCV-RNA remains detectable on bDNA assay at 4 weeks, no sustained response to treatment is found and alpha-interferon can be discontinued.

Flow cytometric evaluation of bone marrow differentials in rats with pharmacologically induced hematologic abnormalities.

Previously, flow cytometric determination of peroxidase activity, cell size, and reactivity to lymphocyte antibodies were used to produce bone marrow differentials in untreated rats. In the present study, abnormal hematologic profiles were induced with erythropoietin (EPO), recombinant murine stem cell factor (rm-SCF), granulocyte-macrophage stimulating factor (GM-CSF), and cyclophosphamide (CP). Manual and flow cytometric data showed comparable levels of erythroid and myeloid hyperplasia in EPO- and rm-SCF/GM-CSF-treated animals, respectively. In CP-treated animals, flow cytometric data revealed significant decreases in cellularity at concentrations of CP > or = 5 mg/kg. In contrast, 20 mg/kg CP were necessary to induce microscopically apparent hypoplasia in histologic bone sections, showing that the automated methodology was a more sensitive indicator of bone marrow hypocellularity than was the more conventional manual method. Megakaryocyte counts were consistently higher by flow cytometer than by manual counts performed on cytocentrifuge preparations made from the same cell suspensions but were similar to megakaryocyte counts performed on histologic sections of femur, indicating that the automated methodology produced a more accurate reflection of true megakaryocyte numbers. Induction of hematologic abnormalities in the present study showed that manual bone marrow differentials can be replaced with the more efficient and reliable flow cytometric method in most preclinical toxicology studies.

Influences on adrenaline-induced thermogenesis in obese women and relationship to cardiovascular responses.

1. In order to evaluate factors influencing thermogenesis in obesity, energy expenditure was measured before and during an adrenaline infusion (25 ng min-1 kg-1 ideal body weight for 30 min) in 22 obese females. 2. Thermogenic responses were related to body morphology, age and biochemistry. In addition, thermogenic responses were related to cardiovascular responses by simultaneously measuring blood pressure, pulse rate and cardiac output using Doppler sonography. 3. Resting energy expenditure was predicted by body weight, lean body mass and fat mass. 4. Adrenaline-induced thermogenesis was predicted by fasting insulin, low basal respiratory quotient and body fat. 5. There was a significant relationship between the cardiac output and thermogenic responses to adrenaline (r = 0.63 P < 0.015) but there was no relationship to the heart rate or blood pressure responses. For every 1% increase in energy expenditure, there was a 5% increase in cardiac output. 6. In conclusion, the factors predicting resting energy expenditure and adrenaline-induced thermogenesis are different. Increased lipid oxidation and central fat distribution (with hyperinsulinaemia) are associated with a greater thermogenic response. The proportionately greater cardiac output responses may have implications for thermogenic agents designed to induce weight loss.