Radiosensitization of colon cancer cell lines by docetaxel: mechanisms of action

The radiation-modifying action of docetaxel in experimental systems is well established. Docetaxel is also an increasingly important drug for the treatment of cancer in concurrent radiotherapy protocols. However, the mechanisms of docetaxel radiosensitization are not fully understood. We have investigated the magnitude and mechanisms of docetaxel radiosensitization in vitro in four human colorectal cancer cell lines (SW480, SW707, SW48, and HT29) with widely differing radiosensitivities. Cell survival curves were generated for a range of docetaxel concentrations (5-20 nM) alone and for X-rays (1-5 Gy) +/- 10 or 20 nM docetaxel (for 24 h before irradiation). Cell cycle distributions and apoptotic frequencies were measured during the treatments. Sensitivity to docetaxel alone was similar in all cell lines and could be attributed to massive induction of apoptosis (60-80% by 24 h). Radiosensitivity varied widely; the surviving fractions at 2 Gy in the most resistant (HT29) and most sensitive (SW28) lines were 0.81 and 0.13, respectively. Exposure to 10 nM docetaxel induced a progressive accumulation of SW480, SW707, and SW48 cells in G2/M. After 24 h, 55-70% of the cells were in G2/M. It is likely, therefore, that accumulation in this radiosensitive phase of the cell cycle contributes significantly to radiosensitization by the drug.     

Clinical and molecular epidemiology of erythromycin-resistant beta-hemolytic lancefield group G streptococci causing bacteremia

Among 100 patients with group G beta-hemolytic streptococcal bacteremia in a 6-year period (1997 to 2002), seven had bacteremia caused by erythromycin-resistant strains. Five of the seven patients had cellulitis and/or abscesses. The two isolates resistant to erythromycin and clindamycin possessed erm genes, one ermTR and the other ermB. The five isolates resistant to erythromycin but sensitive to clindamycin and one of those resistant to both erythromycin and clindamycin possessed mef genes.     

Treatment of recurrent ovarian cancer: a retrospective analysis of women treated with single-agent carboplatin originally treated with carboplatin and paclitaxel. The Memorial Sloan-Kettering Cancer Center experience

OBJECTIVE: There is no standard treatment for recurrent epithelial ovarian cancer (EOC). As there are no curative options, many oncologists choose to treat women who recur with carboplatin, particularly if they are deemed to have platinum-sensitive disease. However, particularly in the era of platinum-taxane treatment as primary therapy, the utility of this treatment has not been established, nor is it clear whether the results of single-agent treatment are equivalent to that of combination therapy. We sought to determine the outcomes for patients with platinum-sensitive EOC who were treated with carboplatin-taxane therapy and received single-agent carboplatin (C) as second chemotherapy. In addition, we sought to compare these results to the outcomes in women who received carboplatin and paclitaxel (C + T) at first relapse. PATIENTS AND METHODS: We identified 24 patients using our electronic institutional database with a histologically confirmed diagnosis of ovarian cancer that had a complete response to platinum-paclitaxel chemotherapy, relapsed greater than 6 months after treatment, and received single-agent carboplatin as second-line chemotherapy. We performed a subsequent comparison between a subgroup of this cohort and one that met the same inclusion criteria but received C + T at relapse between January 1998 and December 2000. RESULTS: Eighteen patients were evaluable for response, and all were available for analysis of survival end points. For evaluable patients, the overall response rate was 39% (complete, 11%; partial, 28%). Twenty-two percent had stable disease. Six (25%) patients experienced a hypersensitivity reaction, including 1 who required hospitalization. The median overall survival was 22 months. The 2-year overall survival rate was 49%. Stratification by treatment-free interval (TFI) showed a 25% for a TFI between 6 and 12 months and 43% for a TFI > 12 months. When a subgroup of these women (18/24) was compared to a cohort that received C + T (29), the combination was associated with a higher complete and overall response rate, 7 and 36% for C versus 45 and 71% for C + T (P = 0.02). The overall survival in women who received C was 26 months versus 42 months in the women who received C + T (P < 0.02). CONCLUSION: Carboplatin as a single agent is effective therapy for recurrent ovarian cancer in women who recur following treatment with carboplatin and paclitaxel, and the treatment-free interval predicts response to single-agent carboplatin. However, our secondary analysis suggests that carboplatin and paclitaxel may produce a higher response rate and a survival benefit compared to C alone. This supports the conclusions of ICON4, which recently reported both overall and progression-free survival benefits with C + T over C in women with platinum-sensitive recurrent disease.     

Utility of decision support tools for assessing acute risk of violence

The authors evaluated the utility of 3 decision support tools for assessing acute risk of violence in patients undergoing behavioral emergencies that warranted hospitalization. Information available at the time of admission to a short-term psychiatric unit was coded from the medical charts of 100 patients using the Historical, Clinical, Risk Management-20 (HCR-20), the Hare Psychopathy Checklist-Screening Version (PCL-SV), and the McNiel-Binder Violence Screening Checklist (VSC). Nurses rated violence that later occurred during hospitalization with the Overt Aggression Scale. Scores on all 3 instruments were associated with the likelihood of violence. The strongest predictive relationships were obtained for indices of clinical risk factors rather than historical risk factors. The results suggest that decision support tools, particularly those that emphasize clinical risk factors, have the potential to improve decision making about violence risk in the context of behavioral emergencies.     

Do changes in cognitive factors influence outcome following multidisciplinary treatment for chronic pain? A cross-lagged panel analysis

Changes in maladaptive cognitions may constitute therapeutic processes of multidisciplinary pain programs. A cross-lagged panel design was used to determine whether (a) early-treatment cognitive change predicted late-treatment outcome index change, but not vice versa; and (b) these effects remained significant with depression change controlled. Ninety chronic pain patients, in a 4-week multidisciplinary program, completed measures of catastrophizing, pain helplessness, depression, pain, interference, and activity level at pre-, mid-, and posttreatment. With depression changes controlled, early-treatment catastrophizing and pain helplessness changes predicted late-treatment outcome index changes, but not vice versa; early-treatment depression changes predicted late-treatment activity changes, but not vice versa. Findings advance understanding of pain treatment process and suggest that negative cognition changes may indeed affect improvements in treatment outcome.     

Marijuana use among adolescents

More than half of US adolescents will experiment with marijuana. Of those who try marijuana more than once, approximately one third will subsequently use marijuana regularly, although most will have stopped by their late 20s. Although genetic predisposition plays the most important role in determining who will develop dependence, environmental factors influence who will initiate marijuana use. One of the challenges for prevention and treatment programs is that the immediate adverse effects of marijuana use are not extreme, and many adolescents have difficulty in making decisions based on future risks. Therefore, the consequences of leaving school early, having unprotected sex, and driving while intoxicated are often insufficient to deter adolescents from using marijuana. Thus, it is not surprising that current prevention and treatment programs have had limited success in decreasing the rates of initiation and regular use of marijuana among adolescents. However, the accumulation of data about marijuana use in adolescents has the potential to enable the development of more effective prevention and treatment programs.     

Hypothalamic Y2 receptors regulate bone formation

Neuropeptide Y (NPY) is a downstream modulator of leptin action, possibly at the level of the arcuate nucleus where NPY neurons are known to express both leptin receptors and Y2 receptors. In addition to the well-described role of NPY and leptin in energy balance and obesity, intracerebroventricular administration of NPY or leptin also causes bone loss. Here we show that Y2 receptor-deficient mice have a twofold increase in trabecular bone volume as well as greater trabecular number and thickness compared with control mice. We also demonstrate that central Y2 receptors are crucial for this process, since selective deletion of hypothalamic Y2 receptors in mature conditional Y2 knockout mice results in an identical increase in trabecular bone volume within 5 weeks. This hypothalamus-specific Y2 receptor deletion stimulates osteoblast activity and increases the rate of bone mineralization and formation, with no effect on osteoblast or osteoclast surface measurements. The lack of any changes in plasma total calcium, leptinemia, or hypothalamo-pituitary-corticotropic, -thyrotropic, -somatotropic, or -gonadotropic output suggests that Y2 receptors do not modulate bone formation by humoral mechanisms, and that alteration of autonomic function through hypothalamic Y2 receptors may play a key role in a major central regulatory circuit of bone formation.     

In vivo penicillin MIC drift to extremely high resistance in Serotype 14 Streptococcus pneumoniae persistently colonizing the nasopharynx of an infant with chronic suppurative lung disease: a case study

This is the first report of in vivo pneumococcal penicillin MIC drift from 4.0 to 16.0 mg/liter, possibly associated with alterations in the pbp1a gene. The case presented here is of an infant with early onset recurrent pneumonia and chronic bronchitis requiring repeated antibiotics.     

UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes

OBJECTIVE: To determine the role of hyperglycemia in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors. RESEARCH DESIGN AND METHODS: Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. PVD was defined as two of the following: ankle-arm blood pressure index < 0.8, absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs, and intermittent claudication. Logistic regression was used to estimate the association between potential risk factors measured 3-4 months after diagnosis of diabetes and incident PVD. The prevalence of PVD at 3-year intervals to 18 years was determined. RESULTS: Hyperglycemia, assessed as HbA(1c), was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1% increase in HbA(1c) was associated with a 28% increased risk of PVD (95% CI 12-46), and each 10-mmHg increase in systolic blood pressure with a 25% increase in risk (95% CI 10-43). CONCLUSIONS: Hyperglycemia, as well as smoking, dyslipidemia, and blood pressure are potentially modifiable risk factors for the development of PVD.