A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias.

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities >or=grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. x 21 days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.

WITHDRAWN: Rice-based oral rehydration solution for treating diarrhoea.

BACKGROUND: Oral rehydration therapy is used to treat dehydration caused by diarrhoea. However the rehydration solution does not reduce stool loss or length of illness. A solution able to do this may lessen the use of ineffective diarrhoea treatments as well as improve morbidity and mortality related to diarrhoea. OBJECTIVES: The objective of this review was to assess the effects of rice-based oral rehydration salts solution compared with glucose-based oral rehydration salts solution on reduction of stool output and duration of diarrhoea in patients with acute watery diarrhoea. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Lilacs and the reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomized trials comparing standard World Health Organization oral rehydration solution with an experimental oral rehydration salts solution in which glucose (20 grams per litre) was replaced by 50-80 grams per litre of rice powder, with the electrolytes remaining unchanged. DATA COLLECTION AND ANALYSIS: Data were extracted independently by a statistician and a clinician. MAIN RESULTS: Twenty-two trials were included. Concealment of allocation was adequate in 15 of these trials. Irrespective of age, people with cholera who were given rice oral rehydration salts solution had substantially lower rates of stool loss than those given oral rehydration salts solution in the first 24 hours. Mean stool outputs in the first 24 hours were lower by 67 millilitres/kg of body weight (weighted mean difference -67.40, 95% confidence interval -94.26 to -41.53) in children, and by 51 millilitres/kg of body weight (weighted mean difference -51.07, 95% confidence interval -65.87 to -36.27) in adults. The rate of stool loss in infants and children with acute non-cholera diarrhoea was reduced by only four millilitres/kg of body weight (weighted mean difference -4.29, 95% confidence interval -9.36 to 0.78). AUTHORS' CONCLUSIONS: Rice-based oral rehydration appears to be effective in reducing stool output in people with cholera. This effect was not apparent in infants and children with non-cholera diarrhoea.

Rice-based oral rehydration solution for treating diarrhoea.

BACKGROUND: Oral rehydration therapy is used to treat dehydration caused by diarrhoea. However the rehydration solution does not reduce stool loss or length of illness. A solution able to do this may lessen the use of ineffective diarrhoea treatments as well as improve morbidity and mortality related to diarrhoea. OBJECTIVES: The objective of this review was to assess the effects of rice-based oral rehydration salts solution compared with glucose-based oral rehydration salts solution on reduction of stool output and duration of diarrhoea in patients with acute watery diarrhoea. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Lilacs and the reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomized trials comparing standard World Health Organization oral rehydration solution with an experimental oral rehydration salts solution in which glucose (20 grams per litre) was replaced by 50-80 grams per litre of rice powder, with the electrolytes remaining unchanged. DATA COLLECTION AND ANALYSIS: Data were extracted independently by a statistician and a clinician. MAIN RESULTS: Twenty-two trials were included. Concealment of allocation was adequate in 15 of these trials. Irrespective of age, people with cholera who were given rice oral rehydration salts solution had substantially lower rates of stool loss than those given oral rehydration salts solution in the first 24 hours. Mean stool outputs in the first 24 hours were lower by 67 millilitres/kg of body weight (weighted mean difference -67.4, 95% confidence interval -94.3 to -41.0) in children, and by 51 millilitres/kg of body weight (weighted mean difference -51.1, 95% confidence interval -65.9 to -36.3) in adults. The rate of stool loss in infants and children with acute non-cholera diarrhoea was reduced by only four millilitres/kg of body weight (weighted mean difference -4.3, 95% confidence interval -9.3 to 0.8). REVIEWER'S CONCLUSIONS: Rice-based oral rehydration appears to be effective in reducing stool output in people with cholera. This effect was not apparent in infants and children with non-cholera diarrhoea.

Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators' Collaborative Group.

OBJECTIVES: This study assessed the effects of zinc supplementation in the prevention of diarrhea and pneumonia with the use of a pooled analysis of randomized controlled trials in children in developing countries. STUDY DESIGN: Trials included were those that provided oral supplements containing at least one half of the United States Recommended Daily Allowance (RDA) of zinc in children <5 years old and evaluated the prevention of serious infectious morbidity through household visits. Analysis included 7 "continuous" trials providing 1 to 2 RDA of elemental zinc 5 to 7 times per week throughout the period of morbidity surveillance and 3 "short-course" trials providing 2 to 4 RDA daily for 2 weeks followed by 2 to 3 months of morbidity surveillance. The effects on diarrhea and pneumonia were analyzed overall and in subgroups defined by age, baseline plasma zinc concentration, nutritional status, and sex. The analysis used random effects hierarchical models to calculate odds ratios (OR) and 95% CIs. RESULTS: For the zinc-supplemented children compared with the control group in the continuous trials, the pooled ORs for diarrheal incidence and prevalence were 0.82 (95% CI 0.72 to 0.93) and 0.75 (95% CI 0.63 to 0.88), respectively. Zinc-supplemented children had an OR of 0.59 (95% CI 0.41 to 0.83) for pneumonia. No significant differences were seen in the effects of the zinc supplement between the subgroups examined for either diarrhea or pneumonia. In the short-course trials the OR for the effects of zinc on diarrheal incidence (OR 0.89, 95% CI 0.62 to 1.28) and prevalence (OR 0.66, 95% CI 0.52 to 0.83) and pneumonia incidence (OR 0.74, 95% CI 0.40 to 1.37) were similar to those in the continuous trials. CONCLUSIONS: Zinc supplementation in children in developing countries is associated with substantial reductions in the rates of diarrhea and pneumonia, the 2 leading causes of death in these settings.

African-American women's perceptions of weight: paradigm shift for advanced practice.

To identify African-American women's definitions and descriptions of body weight, using King's General Systems Framework and Combs and Snygg's concept of perception as a guide, focus group methodology was utilized. These women's frame of reference for "normal body weight" was much larger than the standard indicator for weight and defined weight, normal weight, ideal weight, underweight, overweight, and obesity in terms of their cultural, social, and individual context. By understanding individual perceptions of weight, advanced practice nurses can devise strategies to facilitate weight management in African-American women who may want to lose or need to lose weight for such health-related illnesses as diabetes, cardiovascular disease, or hypertension.

Premenopausal breast cancer patients treated with conservative surgery, radiotherapy and adjuvant chemotherapy have a low risk of local failure.

The use of adjuvant chemotherapy in premenopausal breast cancer patients with positive nodes is now routine, but the optimal local treatment of these patients is uncertain. To determine the effect of adjuvant chemotherapy on the likelihood of local recurrence as the first site of failure in premenopausal patients treated with conservative surgery (CS) and radiotherapy (RT), we examined the outcome of 74 patients treated with CS, RT, and adjuvant chemotherapy and compared it to the outcome in 192 patients treated with CS and RT alone. Adjuvant chemotherapy consisted of four or more cycles of either a doxorubicin-containing regimen or cyclophosphamide, methotrexate, and 5-fluorouracil. All patients were less than 50 years old, had UICC-AJCC Stage I or II breast cancer treated between 1968 and 1981, had gross excision of the primary tumor, and had a total radiation dose to the primary tumor bed of greater than or equal to 6000 cGy. Factors predicting for local recurrence, such as extensive intraductal carcinoma and age less than 35, were equivalent in the two groups. Women treated with adjuvant chemotherapy had significantly worse T- and N-stages than women treated with conservative surgery and radiotherapy alone: 61% versus 36% had T2 tumors (p = 0.0003), 34% versus 6% had clinically positive nodes (p less than 0.0001), and 97% versus 4% had pathologically positive nodes (p less than 0.0001). Despite the poorer prognosis of patients treated with adjuvant chemotherapy, within 5 years of diagnosis, 4% of patients who received adjuvant chemotherapy had their initial relapse in the breast and 24% had initial failure elsewhere, compared with 15% local failure first and 14% failure elsewhere first for those treated without chemotherapy (p = 0.01). We conclude that premenopausal patients with positive nodes treated with combined modality therapy (conservative surgery, radiation therapy, and adjuvant chemotherapy) have a low risk of local recurrence as a first site of failure. These results suggest a possible interaction between radiation therapy and chemotherapy in their effects on local tumor control.

Partition of inorganic ions and phospholipids in isolated cell, membrane and matrix vesicle fractions: evidence for Ca-Pi-acidic phospholipid complexes.

Electrolytes and phospholipids of cartilage fractions were partitioned by extraction with organic and aqueous solvents into six solubility groups: Electrolytes I, II and III, and Lipids I, II and III. Of the total Ca, only 4% was water soluble (Electrolytes I); 4-12% was complexed with lipids (Electrolytes II); while the majority (84-92%) was insoluble (Electrolytes III). In contrast, nearly half of the Mg and Pi were water soluble. Of the neutral phospholipid, 95% was not complexed with mineral ions (Lipids I), but 30-45% of the acidic phospholipid was (Lipids II). Ca/Pi ratios were extremely low in the water-soluble phase, but were in the range of amorphous calcium phosphate (ACP) in the insoluble. Molar ratios of the lipid-mineral complex were: Ca:Mg:Pi:acidic phospholipid, 4:3:2:2. Mg/Ca ratios in the soluble fraction were high (5.5-8.9), sufficient to stabilize ACP. Kinetic studies revealed rapid turnover of soluble Ca, insoluble turning over much more slowly. Labeling of lipid-complexed Ca was rapid in cells, but occurred later in matrix vesicles, suggesting transfer. While lipid-Ca-Pi complexes can nucleate apatite in vitro, those present in vivo inside matrix vesicles apparently do not because of the excess Mg. We conclude therefore, that in vesicle-mediated calcification, lysis of the membrane may be essential to allow release of internal Mg.