First radiotherapy of human metastatic brain tumors delivered by a computerized tomography scanner (CTRx)

Purpose: This Phase I study was designed to evaluate the computed tomography (CT) scanner as a device for radiation therapy of human brain tumors (CTRx). This first use in humans of a modified CT for treatment was founded on extensive research experience with canine tumors. An additional objective was to increase the therapeutic radiation dose to tumors compared to normal tissue by concentration of infused contrast material in tumors, an effect available at diagnostic x-ray energies but not at megavoltage energies.

Methods and Materials: A small metastatic brain tumor in each of eight patients received 3–5-weekly fractions of 5 Gy equivalent per fraction from a CT scanner modified to deliver radiation therapy. In each patient, one additional tumor, lying completely outside the volume treated by CTRx, served as a control. The tumor receiving CTRx was treated after infusion of iodinated x-ray contrast media (CM) for dose enhancement. Many of these patients also received conventional 40 Gy whole brain radiation, before, during, or after CTRx treatment.

Results: None of the patients showed adverse reactions to the CM or necrosis of the normal brain from the CTRx boost radiation. Monte Carlo calculations of the radiation dose distributions in a model tumor showed that the CTRx irradiation of tumors carrying 10 mg or more of iodine per gram of tumor was as good or better than the dose distribution from conventional 10-MV X-rays. The treated tumor in two of the patients vanished after four treatments, whereas a control tumor in one patient remained constant and grew 4-fold in another patient.

Conclusion: The CTRx concept effectively combines a modified CT scanner as a diagnostic device, as a simulator dedicated to radiotherapy, and as a treatment machine. Thus, CTRx could be very useful for radiation oncologists in controlling CM-enhanced and other small brain tumors.     

Role of lipopolysaccharide in the induction of type I interferon-dependent cross-priming and IL-10 production in mice by meningococcal outer membrane vesicles

We investigated the contribution of lipopolysaccharide (LPS) to adjuvant properties of native outer membrane vesicles (NOMV), a vaccine candidate for meningococcal B disease. NOMV induce the maturation of and cytokine production by murine bone marrow-derived dendritic cells through both toll-like receptors (TLR) 2 and 4 which are mostly dependent on the signalling adaptor MyD88. NOMV are also able to induce B cell proliferation in splenocytes from LPS-hyporesponsive mice. However, induction of IL-10 and type I interferon-dependent, antigen-specific and IFN_γ-secreting CD8⁺ cytotoxic T lymphocyte responses in vivo by NOMV requires LPS. The importance of LPS in the induction of IL-10 and functional cross-priming has implications for NOMV-based vaccine and adjuvant development.     

Effects of addition of policosanol to omega-3 fatty acid therapy on the lipid profile of patients with type II hypercholesterolaemia

BACKGROUND: Policosanol is a mixture of higher aliphatic primary alcohols purified from sugar-cane wax. The mixture has cholesterol-lowering efficacy, its specific effects being to reduce serum total (TC) and low-density lipoprotein cholesterol (LDL-C), and to increase high-density lipoprotein cholesterol (HDL-C). The effects of policosanol on triglycerides (TG) are modest and inconsistent. Omega-3 fatty acids (FA) from fish oil protect against coronary disease, mainly through antiarrhythmic and antiplatelet effects. Omega-3 FA also have lipid-modifying effects, mostly relating to TG reduction. Thus, potential benefits could be expected from combined therapy with omega-3 FA and policosanol. OBJECTIVE: To investigate whether combined therapy with omega-3 FA + policosanol offers benefits compared with omega-3 FA + placebo with respect to the lipid profile of patients with type II hypercholesterolaemia. METHODS: This randomised, double-blind study was conducted in 90 patients with type II hypercholesterolaemia. After 5 weeks on a cholesterol-lowering diet, patients were randomised to omega-3 FA + placebo, omega-3 FA + policosanol 5 mg/day or omega-3 FA + policosanol 10 mg/day for 8 weeks. Omega-3 FA was supplied as 1g capsules (two per day); placebo and policosanol were provided in tablet form. Physical signs and laboratory markers were assessed at baseline and after 4 and 8 weeks on therapy. Drug compliance and adverse experiences (AEs) were assessed at weeks 4 and 8. The primary efficacy variable was LDL-C reduction; other lipid profile markers were secondary variables. RESULTS: After 8 weeks, omega-3 FA + policosanol 5 and 10 mg/day, but not omega-3 FA + placebo, significantly reduced LDL-C by 21.1% and 24.4%, respectively (both p < 0.0001). Omega-3 FA + policosanol 5 mg/day also significantly lowered TC (12.7%; p < 0.01) and TG (13.6%; p < 0.05), and significantly increased HDL-C (+14.4%; p < 0.001). Omega-3 FA + policosanol 10 mg/day significantly decreased TC (15.3%; p < 0.001) and TG (14.7%; p < 0.01), and significantly increased HDL-C (+15.5%; p < 0.0001). Omega-3 FA + placebo significantly reduced TG (14.2%; p < 0.05) but had no significant effect on other lipid profile variables. The proportion of randomised patients in the omega-3 FA + policosanol 5 or 10 mg/day groups that achieved LDL-C targets or reductions 15% was significantly greater than in the omega-3 FA + placebo group (p < 0.001). Combined therapy with omega-3 FA + policosanol 5 or 10 mg/day resulted in significantly greater changes in LDL-C, TC and HDL-C than treatment with omega-3 FA + placebo, but did not modify the TG response compared with the omega-3 FA + placebo group. Four patients (two in the omega-3 FA + placebo group and two in the omega-3 FA + policosanol 10 mg/day group) withdrew from the study; none of these withdrawals was due to AEs. Two patients reported mild AEs, namely nausea/headache (one in the omega-3 FA + placebo group) and heartburn (one in the omega-3 FA + policosanol 5 mg/day group). CONCLUSIONS: Policosanol 5 or 10 mg/day administered concomitantly with omega-3 FA 1 g/day improved LDL-C, TC and HDL-C, maintained the reduction in TG attributable to omega-3 FA monotherapy, and was well tolerated. Treatment with omega-3 FA + policosanol could be useful for regulating lipid profile in patients with type II hypercholesterolaemia, but further studies involving larger sample sizes are needed before definitive conclusions can be drawn.     

The effect of D-003 (10 mg/day) on biochemical parameters of bone remodelling in postmenopausal women: a randomized, double-blind study

Biphosphonates, which are antiresorptive agents used to treat osteoporosis, inhibit the mevalonate pathway, preventing protein prenylation and inhibiting osteoclast activity. Statins decrease cholesterol biosynthesis by blocking the mevalonate pathway and have been reported to have beneficial effects on bone. D-003 is a mixture of high molecular weight acids purified from sugarcane wax that inhibits cholesterol biosynthesis before mevalonate production. D-003 prevents bone loss and resorption in rats with osteoporosis induced with ovariectomy or corticoids. Biochemical markers of bone turnover are used to monitor the short-term efficacy of antiosteoporotic therapy. This randomized, double-blind, placebo-controlled study was undertaken to investigate the short-term effects of D-003 (10 mg/day) on biochemical markers of bone turnover in postmenopausal women with low bone mineral density (BMD). After 4 weeks on a low-fat diet, 34 women were randomized to D-003 (10 mg/day) or placebo for 6 months. Pre- and post-treatment samples were analyzed for urinary excretion of deoxypyridinoline (DPD)/creatinine (Cr), a marker of bone resorption, and serum bone specific alkaline phosphatase (BSAP), a marker of bone formation. The effects on lipid profile and safety indicators, as well as adverse events (AE), were investigated. D-003 (10 mg/day) lowered urinary excretion of tDPD/Cr versus baseline (20.6%) (p < 0.001) and placebo (33.7%) (p < 0.01), but did not modify serum BSAP. D-003 decreased low-density lipoprotein-cholesterol (LDL-C) (32.8%), total cholesterol (TC) (16.4%) and the TC/high-density lipoprotein-cholesterol (HDL-C) ratio (34.7%), increased HDL-C (30.3%) (p < 0.001) and did not modify triglycerides. The effects on these variables were significant as early as 3 months after treatment initiation. D-003 was well tolerated. Three patients (one in the placebo group and two in the D-003 group) withdrew from the study. Two of these withdrawals were due to AE: abdominal pain (placebo) and heartburn (D-003). Five patients (four in the placebo group [22.2%] and one in the D-003 group [6.3%]) reported mild AE. In conclusion, D-003 (10 mg/day) reduced urinary excretion of tDPD/Cr, a bone resorption marker and did not change serum BSAP, a bone formation marker, while it lowered cholesterol in study patients. These preliminary results suggest that D-003 could be useful in treating postmenopausal women with low BMD. However, the potential value of D-003 in treating or preventing osteoporosis deserves further clinical investigation.     

Postprandial glucose, insulin and gastrointestinal hormones in healthy and diabetic subjects fed a fructose-free and resistant starch type IV-enriched enteral formula

Background

Reducing the dietary glycaemic response has been proposed as a means of reducing the risk of diabetes.

Aim

To evaluate the effects of a new diabetes-specific formula (DSF) enriched with resistant starch type IV and fructose-free on postprandial glycaemia, insulinaemia and gastrointestinal hormones in healthy volunteers and in outpatient type 2 diabetics.

Methods

(1) Twenty-four healthy volunteers were divided into two groups: Group 1 ( n = 10) was provided 50 g of the carbohydrate (CHO) constituent of the new product and 50 g of glucose separated by 1 week; Group 2 ( n = 14) was provided 400 ml of the new DSF (T-Diet Plus^® Diabet NP) and 400 ml of a control product separated by 1 week. (2) Ten type 2 diabetic patients received 400 ml of the new DSF and two other commercially available DSF (Glucerna^® SR and Novasource^® Diabet) on three occasions separated by 1 week. Venous blood samples were drawn at time 0 and at different times until 120 min. Glucose, insulin and gastrointestinal hormones were determined. Glycaemic and insulinaemic indices and glycaemic load were calculated.

Results

The CHO constituent and the new DSF showed low glycaemic index and glycaemic load. In healthy subjects, insulin and C-peptide release were lower after administration of the CHO constituent as well as after the new DSF (P < 0.001). Ghrelin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) production were lower after intake of the CHO constituent (P ranging from <0.001 to 0.019) compared with glucose, and GIP was lower after ingestion of the new DSF (P = 0.002) than after the control product. In type 2 diabetic patients, glucose AUC was lower after the administration of the new DSF (P = 0.037) compared with the others.

Conclusions

Our results indicate that this new product could be beneficial for diabetic patients.     

Motivations for tobacco consumption among adolescents in an urban high school

Objective

To determine the motivations (attitudes, beliefs and experiences) for tobacco consumption among adolescents.

Methods

This study was based on qualitative methodology using six 50-minute discussion groups with 6-8 adolescents per group during the 2008/09 school year. Purposive sampling was performed of 12-18 year-old adolescents attending a middle-class urban school (Jaén, Spain). The sample was stratified by educational level as the homogeneity criterion and gender and tobacco consumption as the heterogeneity criterion. Content analysis consisted of coding, triangulation of categories and obtaining and verifying the results.

Results

There were 44 adolescents (54% male). The participants reported that smoking relaxed and improved self-image, providing security (boys) and improving relations with the opposite sex, as well as weight control (girls). The family encouraged smoking by providing a model to imitate, although many adolescents hid their smoking from their families. Friends constituted a pressure group to start or continue smoking. Starting secondary school marked the beginning of experimental use. Society tended to accept consumption and buying tobacco was easy for minors. University students were a role model and were free to smoke. The adolescents looked to their parents and educators/health workers to provide a model of abstinence and reported that they were well informed but only remembered powerful messages. Participants unanimously indicated that tobacco causes addiction, but in proportion to the duration of consumption, and were concerned only with the immediate symptoms caused by smoking. Teenage smokers associated multiple drug use with leisure time.

Conclusions

This study provides useful data on motivation that could be used to improve smoking prevention interventions among adolescents. The most important factors seem to be peer influence, parental attitudes, easy access to tobacco and symptoms of dependence.     

Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type II hypercholesterolaemia

BACKGROUND: Hypercholesterolaemia is a risk factor for coronary heart disease (CHD). Clinical studies have shown that lowering elevated serum total cholesterol (TC) levels, and particularly low density lipoprotein-cholesterol (LDL-C) levels, reduces the frequency of coronary morbidity and deaths, whereas high serum levels of high density lipoprotein-cholesterol (HDL-C) protect against CHD. Policosanol is a cholesterol-lowering drug purified from sugar cane wax with a therapeutic dosage range from 5-20 mg/day. Atorvastatin is an HMG-CoA reductase inhibitor which across its dosage range (10-80 mg/day) has shown significantly greater lipid-lowering effects than all previously marketed statins. OBJECTIVE: This study was undertaken to compare the efficacy and tolerability of policosanol with atorvastatin in older patients with type II hypercholesterolaemia. PATIENTS AND METHODS: This randomised, single-blind, parallel-group study was conducted in older patients (60-80 years) with type II hypercholesterolaemia. After 4 weeks on a cholesterol-lowering diet, 75 patients were randomised to policosanol or atorvastatin 10mg tablets taken once daily with the evening meal for 8 weeks. An interim and final check-up were performed at 4 and 8 weeks, respectively, after treatment was initiated. RESULTS: At 4 (p < 0.0001) and 8 (p < 0.00001) weeks, policosanol 10 mg/day significantly lowered serum LDL-C levels by 17.5 and 23.1%, respectively compared with baseline; corresponding values for atorvastatin were 28.4 and 29.8%. At study completion, policosanol significantly (p < 0.0001) reduced serum TC (16.4%), LDL-C/HDL-C ratio (25.5%) and TC/HDL-C ratio (19.3%), as well as (p < 0.001) triglyceride levels (15.4%). Atorvastatin significantly (p < 0.0001) decreased serum TC (22.6%), LDL-C/HDL-C (26.2%) and TC/HDL-C (19.8%) ratios, as well as (p < 0.001) triglyceride levels (15.5%). Atorvastatin was significantly more effective than policosanol in reducing LDL-C and TC, but similar in reducing both atherogenic ratios and triglyceride levels. Policosanol, but not atorvastatin, significantly (p < 0.05) increased serum HDL-C levels by 5.3%. Both treatments were well tolerated. At study completion, atorvastatin mildly, but significantly (p < 0.05) increased creatine phosphokinase (CPK) and creatinine, whereas policosanol significantly reduced AST and glucose (p < 0.01) and CPK (p < 0.05) levels. All individual values, however, remained within normal limits. Three atorvastatin but no policosanol patients withdrew from the study because of adverse events: muscle cramps (1 patient), gastritis (1 patient) and uncontrolled hypertension, abdominal pain and myalgia (1 patient). Overall, no policosanol and seven atorvastatin patients (18.9%) reported a total of nine mild or moderate adverse events during the study (p < 0.01). CONCLUSIONS: This study shows that policosanol (10 mg/day) administered for 8 weeks was less effective than atorvastatin (10 mg/day) in reducing serum LDL-C and TC levels in older patients with type II hypercholesterolaemia. Policosanol, but not atorvastatin, however, significantly increased serum HDL-C levels, whereas both drugs similarly reduced atherogenic ratios and serum triglycerides. Policosanol was better tolerated than atorvastatin as revealed by patient withdrawal analysis and overall frequency of adverse events. Nevertheless, further studies must be conducted in larger sample sizes and using dose-titration methods to achieve target lipid levels in order to reach wider conclusions.     

Massive thrombosis of the left atrium. Surgical experience with a series of 117 patients

From 1975 to 1988 we have operated 117 patients with left arterial thrombosis associated with rheumatic mitral valve disease. Seventy-seven were female and 40 male, with ages ranging from 22 to 69 years. In 75 cases (64.1%) the valvular lesion was mitral stenosis. Embolic antecedents were present in 38 cases (32.4%) and 95 patients (81.1%) were in class III or IV of the NYHA functional classification. In 48 cases we performed a mitral commissurotomy and in 51 cases mitral valve replacement, associated to left artrial thrombectomy. In the remaining 18 patients we made other valve procedures. The hospital mortality was 15 cases (12.8%), eight because low cardiac output, four because severe brain injury and three because posterior atrioventricular sulcus disruption. In 41.1% of the survivors there was serious hospital complications, standing out the incidence of 8 cases of transient neurologic accidents. We have followed 98 of the 102 hospital survivors between 10 and 140 months (mean 57 months). Three patients died in the follow-up, two of them during a reintervention because bioprosthesis disfunction and the third one during a reintervention because prosthetic infective endocarditis. Nine additional patients were reoperated because recidivant valvular lesions or because prosthetic disfunction, and two patients suffered embolic events during the follow-up. The antithrombotic therapy was abandoned in 19.6% of patients. At present 73.6% are in functional class I and 26.3% in class II. The association of left atrial thrombosis with with mitral valve disease induce a surgical morbimortality greater than usual for isolated valvular lesions, being mandatory a watchfull surgical technic.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complications of Bothrops, Porthidium, and Bothriechis snakebites in Colombia. A clinical and epidemiological study of 39 cases attended in a university hospital.

The clinical and epidemiological features, as well as complications presented by 39 patients with Bothrops, Porthidium and Bothriechis snakebites, are described. Patients were admitted during 1 year in 25 hospitals of Antioquia and Chocó and then, they were transferred to the Hospital Universitario San Vicente de Paúl in Medellín, 30 of them because of the presence of complications, eight because of lack of antivenoms and another one because of the desire of his relatives. Thirty--one (79.5%) of the patients were male, 13 (33.3%) children, 59% of them were bitten at the lower extremities, the majority (74.4%) by Bothrops asper. Twenty-one (53.8%) of the patients were initially attended by traditional healers and sought medical attention at the local hospitals after 2h in 87.2% of the cases. Edema (100%), hemorrhage (74.4%), blistering (38.5%) and necrosis (38.5%), were the local signs of envenomation, while blood coagulation alteration (79.5%), hematuria (74.4%), gingival bleeding (43.6%), hypovolemic shock (23.1%) and oliguria (23.1%), were the systemic signs of envenomation. The final grade of envenomation was severe in 29 patients (74.4%). Thirty patients (76.9%) had one or more complications of the envenomation: acute renal failure (ARF), 15 (38.5%); soft-tissue infection, 12 (30.8%); central nervous system (CNS) hemorrhage, 5 (12.8%); compartment syndrome, 3 (7.7%); soft--tissue hematomas, 6 (15.4%); and Abruptio placentae, one (2.6%). There were four deaths (10.3%), two from ARF and two from cerebral hemorrhage. Fourteen other patients (35.9%) had sequelae. The onset of serotherapy after 2h of the bite was associated with the occurrence of ARF and CNS hemorrhage (p=0.02), as well as the risk of death and sequelae (RR=2.5).