AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival

Amplification or overexpression of the HER-2/neu gene in breast cancers is associated with aggressive behavior and resistance to therapeutic regimens. The molecular mechanisms that contribute to therapeutic resistance/survival of HER-2/neu-overexpressing tumor cells have not been well defined. To determine if phosphatidylinositol 3-kinase/AKT signaling contributes to cell survival in HER-2/neu-positive breast cancers, we performed immunohistochemical analyses to evaluate expression of HER-2/neu and AKT in a series of 52 breast carcinomas. Elevated expression of HER-2/neu was found to correlate with overexpression of AKT2 protein and activation of AKT kinase. HER-2/neu-overexpressing breast cancer cell lines were resistant to apoptosis induced by UV treatment and hypoxia, which was suppressed in the presence of the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin, indicating a link between AKT activation and stress resistance in HER-2/neu-overexpressing cells. These observations suggest that AKT signaling augments resistance to stress-induced apoptosis in breast cancer cells overexpressing HER-2/neu.     

Bioactivity studies on beta-sitosterol and its glucoside

Beta-sitosterol and beta-sitosteryl-beta-D-glucoside were isolated as analgesic constituents from the leaves of Mentha cordifolia Opiz. The acetic acid-induced writhing test showed that beta-sitosterol and beta-sitosteryl-beta-D-glucoside decreased the number of squirms induced by acetic acid by 70.0% and 73.0%, respectively, at a dose of 100 mg / kg mouse. Statistical analysis using the Kruskall Wallis one-way analysis of variance by ranks showed that these isolates approximate the analgesic activity of mefenamic acid at a 0.001 level of significance. The hot plate method confirmed their analgesic activities, as beta-sitosterol and beta-sitosteryl-beta-D-glucoside exhibited a 300% and 157% increase in pain tolerance, respectively, while mefenamic acid, a known analgesic, showed a 171% increase. Neither isolate exhibited antiinflammatory activity using the carrageenan-induced mouse paw oedema assay. Beta-sitosterol also exhibited anthelminthic and antimutagenic activities. In vitro tests using live Ascaris suum as test animals showed that the behaviour of worms treated with beta-sitosterol approximated that of the positive controls, Combantrin and Antiox. An in vivo micronucleus test showed that beta-sitosterol inhibited the mutagenicity of tetracycline by 65.3% at a dose of 0.5 mg /kg mouse. At the same dose, it did not exhibit chromosome-breaking activity.     

Trastuzumab-associated cardiotoxicity

Trastuzumab is a monoclonal antibody used for the treatment of metastatic breast carcinoma in women whose tumors overexpress the HER2 protein. Cardiotoxicity has been reported to occur with trastuzumab when administered alone and in combination with antineoplastic agents, particularly anthracyclines. The risk of cardiotoxicity with trastuzumab has been reported to be 4% with monotherapy and 27% when administered in combination with an anthracycline and cyclophosphamide, but to the author's knowledge severe outcomes, such as death or permanent disability, are uncommon. The majority of reported cardiac effects are mild to moderate, nonspecific, and medically manageable. Signs and symptoms are similar to those observed in patients who develop anthracycline-induced cardiomyopathy and include tachycardia, palpitations, and exertional dyspnea, which may progress to congestive heart failure. The pathogenesis and histologic changes responsible for trastuzumab-associated cardiotoxicity currently are under investigation. Unlike anthracycline-induced toxicity, trastuzumab-associated toxicity usually responds to standard treatment or the discontinuation of trastuzumab, and there is no evidence that the toxicity is dose related. Current methods for the early detection of cardiotoxicity in trastuzumab-treated patients are similar to those used in anthracycline-treated patients. Cardiac function is established at baseline and monitored regularly during treatment by physical examination and measurement of left ventricular ejection fraction. The majority of patients improve with proper treatment, and some are able to continue to receive trastuzumab.     

Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil

AIMS: To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction. METHODS: In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m(2), orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods. RESULTS: In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (C(max)) of 5-FU was decreased by 21% and the time to C(max) was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods. CONCLUSIONS: Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU C(max), but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.     

History of childhood attention deficit/hyperactivity disorder symptoms and borderline personality disorder: a controlled study

To evaluate the association between history of childhood attention deficit/hyperactivity disorder (ADHD) symptoms and the diagnosis of borderline personality disorder (BPD) in adulthood, the Wender Utah Rating Scale (WURS) was administered to 42 consecutively admitted BPD subjects, 94 consecutively admitted controls with any cluster B personality disorder (PD) diagnosis other than BPD, 38 consecutively admitted controls with any cluster A or cluster C PD diagnosis but no cluster B PD diagnosis, and 69 consecutively admitted controls with no PD diagnosis. A fourth control group was composed by 201 nonclinical volunteers. According to Dunn-Bonferroni contrasts, BPD subjects showed a significantly higher mean WURS total score compared to all control groups (minimum t = 7.93, maximum t = 11.63, all Ps <.001). These contrasts remained significant even controlling for potential confounders such as antisocial personality disorder (ASPD) diagnosis, gender, inpatient status, and axis I diagnoses. The results of this study seem to support the hypothesis of an association between history of childhood ADHD symptoms and adult BPD diagnosis.     

Influences of maternal mental illness on psychological outcomes for adolescent children

The research literature associating maternal mental illness with problematic mental health outcomes of adolescent children typically controls for neither the effects of family stresses and lack of support, nor the effects of parenting style. To address this gap, we explore the effects of maternal psychiatric symptoms and community functioning on child outcomes in a diverse sample of seriously mentally ill women caring for their teenaged children. In hierarchical multiple regression, for youth depression, we find effects for parenting style and maternal mental health; for youth anxiety and efficacy, effects involve the interplay between maternal symptoms and community functioning.     

Positive parenting and child psychosocial adjustment in inner-city single-parent African American families. The role of maternal optimism

The primary purposes of this study were to examine whether maternal optimism is related to positive parenting and child adjustment and whether it contributes beyond maternal depressive symptoms to our understanding. The participants were 141 African American single mothers and one of their children. Findings revealed that maternal optimism was associated with positive parenting and this association was only partially mediated by maternal depressive symptoms. Maternal optimism was not associated with child psychosocial adjustment, but positive parenting was associated with lower levels of both internalizing and externalizing difficulties. The utility of understanding the link between maternal optimism and parenting for prevention and intervention efforts aimed at enhancing quality of life and subsequent child adjustment is discussed, as well as directions for future research on maternal optimism.     

Glutamate infusion coupled with hypoxia has a neuroprotective effect in the rat

Traumatic brain injury leads to a rise in glutamate, interference with oxygen supply and secondary neuronal death in the region surrounding the primary lesion. In the present experiments we have examined the effect of combining glutamate infusion with hypoxia on both brain metabolism and neuronal death. We have used microdialysis in unanaesthetised rats with a novel dual assay for glucose and lactate to monitor the temporal relation of changes in these metabolites resulting from infusion of 100 mM glutamate alone or combined with a reduction of inspired oxygen to 8%. In a parallel series of experiments we have compared the size of neuronal lesions under the same experimental conditions. We have used MAP2 antibody staining to measure the size of the neuronal lesion. Our results demonstrate that a 30 min glutamate infusion causes an immediate increase in neuronal glucose utilisation and a rise in lactate production. When hypoxia is added during the last 15 min of glutamate infusion there is a small rise in glucose and a large additional increase in lactate. The size of the neuronal lesions produced by infusion of 100 mM glutamate is reduced by the addition of hypoxia.     

Behavioral change in persons with dementia: relationships with mental and physical health of caregivers

The purpose of this study was to examine the effects that changes in behavioral and psychological symptoms of dementia of persons with Alzheimer's disease have on their caregivers' mental health and physical health. The research design was a prospective, longitudinal follow-up study conducted in a major medical center and in participants' homes. Longitudinal analysis linking change in behavior to caregiver outcomes was based on 64 cases. Care recipients were assessed at the time of diagnosis with the Mini-Mental State Examination (MMSE). To provide information on the care recipient's behaviors, caregivers participated in an interview with the Modified Neuropsychiatric Inventory at diagnosis and at follow-up. Caregivers also completed a battery of established instruments to measure stress appraisal, mental health, and perceptions of their physical health at follow-up. Results showed that increases in problem behaviors among persons living with dementia, along with residence status, were significant predictors of caregivers' mental health and also their physical health. However, these relationships were mediated through stress appraisal. Variables such as MMSE score of the person with dementia, number of years caregiving, relationship status, and education level were not significant predictors of caregivers' health when behavior change was in the model.