Optimization of metabolic activation for four mutagens in a bacterial, fungal and two mammalian cell mutagenesis assays

The optimum concentrations of Aroclor-induced rat liver S9 microsomal fraction for the mutagenic activity of the four standard mutagens 2-aminofluorene (2-AF), acriflavine (ACR), benzo[a]pyrene (BP) and cyclophosphamide (CP) were determined in four mutation assays. The four assays were the Ames test using Salmonella typhimurium strain TA100, cycloheximide resistance in the yeast Saccharomyces cerevisiae, the mouse lymphoma TK assay and the human peripheral lymphocyte cytogenetic assay. BP was the only mutagen to be most active at comparable S9 concentrations, of approximately 1%, for all four assays. The optimum S9 concentrations for each of the remaining three mutagens varied substantially between the four assays. ACR was a potent direct-acting mutagen in both mammalian cell assays. The mouse lymphoma TK assay results showed similar optimal values of 1.5% S9 or below for each of the four test agents. The assay with the largest variation of optimal S9 values for the four mutagens was the Ames test in strain TA100, although it also had the widest peaks of activity over the range of S9 concentrations tested. It is likely that the diversity of findings is due to a variety of metabolites affecting the different genetic endpoints that are measured in these assays. Thus from these results it is not possible for bacterial optimization data to be related to other routine in vitro systems. The use of more than one concentration of S9 would contribute useful information.     

Sodium chlorite administration in Long-Evans rats: reproductive and endocrine effects

Long-Evans rats, 4-6 weeks of age, were given access to 0, 1, 10, or 100 ppm sodium chlorite in deionized water ad libitum as drinking water. Males were exposed 56 days, and females for 14 days prior to breeding and throughout the 10-day breeding period. Males were evaluated for sperm parameters and reproductive tract histopathology following the breeding period. Females were exposed throughout gestation and lactation. Dams and pups were necropsied at weaning. Decreases in serum T3 and T4 were observed on Postnatal Days 21 and 40 in male and female pups exposed to 100 ppm chlorite or above. Additionally, groups of males were exposed to 0, 10, 100, or 500 ppm ad libitum in the drinking water to confirm observed subtle reproductive effects and examine dose-effect relationships. A significant increase in the percentage of abnormal sperm morphology (P less than 0.001) and decrease in sperm direct progressive movement (P less than 0.01) were observed for adult males at chlorite levels of 100 or 500 ppm. Since other clinical and reproductive endpoints were not affected, sperm morphology and sperm direct progressive movement may be two of the more sensitive indicators of reproductive damage.     

Trends in maternal and child health care: implications for research and issues for social work practice

Trends are reviewed in four areas of maternal and child health care: (1) prenatal care; (2) infant mortality; (3) teenage pregnancy; and (4) HIV infected mothers and infants. The purpose of this review is to identify major trends in these programmatic areas, key indicators of physical-social health risk and survival, and central issues relevant to research and social work practice. Attention is directed to the status of research, and the usefulness of existing data sets available to researchers in the four programmatic areas of maternal and child health care under review. Emphasis is given to the importance of the integration of theory, research findings, and practice.     

Serotoninergic and noradrenergic projections to the ventral posterolateral nucleus of the monkey thalamus

In the present study, serotoninergic and noradrenergic varicosities were identified in the ventral posterolateral nucleus of the macaque monkey. Monoaminergic neurons projecting to the ventral posterolateral nucleus of the thalamus were identified by using retrograde labeling with horseradish peroxidase combined with immunocytochemical staining for serotonin or dopamine-beta-hydroxylase. The midbrain nucleus raphe dorsalis was the major site of origin for neurons providing a serotoninergic projection to the ventral posterolateral nucleus. A few retrogradely labeled serotonin-containing neurons were also observed in the central superior and the raphe pontis nuclei. Noradrenergic cells with projections to the thalamus were primarily located in the nucleus locus coeruleus with some projection neurons in the nucleus subcoeruleus, and the A5 catecholamine cell group of the pons.     

Bupropion for the treatment of methamphetamine dependence.

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p=0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.     

Rubratoxin B mycotoxicosis in the Syrian hamster

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Syrian golden hamsters by ip injection was 0.4 (0.2-0.8) mg/kg body weight. The greatest number of deaths occurred 6-24 hr after administration. Gross alterations consisted of congestion of the liver, spleen and kidneys and histopathological alterations involved congestion of the spleen and congestion and mild degenerative changes in hepatocytes. In a second study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Mortality was greatest in the 50 and 75% dose groups. Toxicity was cumulative with multiple doses. Gross alterations were similar to those found in the LD50 study. Histopathological alterations included renal tubular degeneration and necrosis and focal necrosis of hepatocytes. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a third study. Histopathological alterations were limited to the kidney and were characterized by renal tubular degeneration and necrosis. Renal lesions were first seen at 2 hr after administration and increased in severity to a maximum at 20 hr. Tubular regeneration was first seen at 24 hr and was found to the end of the test period (72 hr). Serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum concentrations of total and indirect bilirubin were increased by 8 hr after dosing and returned to control values by the end of the test period. In a fourth study, rubratoxin B was administered ip daily for 1 wk at a dose of 25% of the ip LD50. Gross alterations were similar to those in the other studies. Histopathological alterations included progressive renal tubular degeneration and necrosis. Serum activities of AST and ALT and concentration of blood urea nitrogen (BUN) were progressively increased with increasing numbers of doses. Urinalysis indicated progressive renal tubular damage.     

The injury profile after the 2008 earthquakes in China

The 8.0 magnitude earthquake that struck China on May 12, 2008, was the deadliest earthquake in 30 years. Most hospitals were destroyed and limited facilities were available for medical service in the earthquake regions. Over the first 5 days, three general hospitals and one children's hospital admitted 1770 injured individuals.MethodsWe retrospectively collected data on 1770 injured subjects in three general hospitals (n = 1723) and one children's hospital (n = 47) in the quake-area during the first 5 days after the event. The diagnosis for the injuries was based on the final hospital diagnosis made by the physicians and classified by two-independent researchers using the International Statistical Classification of Diseases and Related Health Problems ICD-10 (WHO ICD-10 Code.1993). To ensure the accuracy of the information, any questionable data was reviewed by phone with hospital staff.ResultsIn three general hospitals, 848 patients (48%) were male and 922 (52%) were female. Nine percent (n = 84) of females and 8.8% (n = 75) of males were over the age of 75. Four (0.4%) females and 5 (0.5%) males were less than 1-year old. The most common injuries were the injuries of the knee, lower leg, ankle and foot (36%), followed by head injuries (18%). In the children's hospital, 31 (65%) of the patients were males and 16 (35%) were females. 40% of the subjects were 10–14, while 21% were less than 1-year old. The most frequently seen injuries were also of the knee, lower leg, ankle or foot (19%), and of the abdomen, lower back, lumbar spine and pelvis, and hip and thigh (15%).ConclusionsWe gathered information from resources in Chinese, which at the time contained more records on this event than any documents in English. The age of the patients ranged from 7 days to 84 years old. Subjects over age 75 and children between 10 and 14 were the largest population in their respective hospitals, indicating that these groups required the greatest medical resources. The injury profile presented here serves as a reference not only for present injury intervention but also for future earthquake disaster response.     

Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer

Introduction: Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease.

Areas Covered: This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease.

A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy.

Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.