Thermoresponsive Reversible Unimer Micelles of Amphiphilic Fluorinated Copolymers

Amphiphilic fluorinated copolymers PEGMAx-co-FAy and TEGMAx-co-FAy are prepared by activators regenerated by electron transfer atom transfer radical polymerization (ARGET-ATRP). All polymers present a reversible thermoresponsive lower critical solution temperature-type behavior, and a cloud point temperature (T_c) in the range of 30–60 °C strictly dependent on the length of the oxyethylene side chain, the content of the hydrophobic counits, and the concentration of the solution. Combined small angle X-ray scattering (SAXS) and dynamic light scattering measurements are used to study the self-assembly behavior in water, organic solvents (tetrahydrofuran [THF] and dimethylformamide [DMF]), and a fluorinated solvent (hexafluorobenzene [HFB]). SAXS confirms the formation of compact-globular single-chain self-folded unimer micelles in water below T_c, which generally presents small hydrodynamic diameters (D_h ≤ 8 nm) as a result of the folding of the hydrophobic perfluorohexylethyl acrylate counits. The copolymers are also able to form reverse unimer micelle in HFB. The copolymers are not able to self-assemble in unimer micelles in THF or DMF solutions, in which they adopt conventional random coil conformations.     

Postzygotic instability of the myotonic dystrophy p[AGC]n repeat supported by larger expansions in muscle and reduced amplifications in sperm

We have analysed the [AGC] expansion in leucocytes, muscle and sperm from 17 individuals affected by myotonic dystrophy (DM). Skeletal muscle showed a larger repeat number than leucocytes in the same patient. A similar degree of expansion was detected in differently affected muscles of a single patient. The germline mutation ( 350 repeats) was expanded in somatic cells of the progeny in all patients examined. Our results provide evidence of an early postzygotic instability of the [AGC] repeat in DM.     

Preparation and local anaesthetic activity of benzotriazinone and benzoyltriazole derivatives

Two sets of benzotriazinone and benzoyltriazole derivatives were prepared and tested for local anaesthetic activity in comparison with lidocaine. Several of the prepared compounds exhibited a fairly good activity comparable or superior to that of lidocaine. The presence of a benzotriazinone or a benzoyltriazole moiety as an aromatic system was quite profitable for both the intensity and duration of activity. The acute toxicity in mice of the four most potent compounds of the series was also assessed. Compound 1b, which has an anaesthetic activity comparable to that of lidocaine, was also characterized by a more favourable therapeutic index. All compounds were tested in vitro to evaluate their negative chronotropic action in isolated rat right atria.     

Changes in plasma iron levels following Carboplatin administration

Carboplatin-induced changes in plasma iron levels and the related erythropoiesis impairment were investigated in 32 neoplastic patients for a total of 64 courses of chemotherapy. Iron showed a significant increase over pretreatment levels starting from day 1 after carboplatin administration (p< 0.001). Return to pre-treatment levels was achieved on day 14. Hemoglobin decreased significantly on day 7 (p< 0.05) and further on days 14 and 21 (p< 0.001). In patients undergoing 3 consecutive cycles of chemotherapy, basal hemoglobin before the 2nd cycle was significantly lower than before the 1st (p< 0.05), whereas before the 3rd cycle the levels were similar to those before the 2nd. Hemoglobin time-course did not differ among the three cycles. No relationship was observed between maximum iron levels and hemoglobin at minimum levels, nor between pre-treatment hemoglobin levels and severity of chemotherapy-induced subacute anemia. These results suggest that neither pre-treatment hemoglobin nor the entity of iron increase are predictive of the need of blood transfusion. Moreover, the absence of correlation between iron increase and hemoglobin decrease suggests that the toxic block on erythroid maturation is not the only mechanism with which platinum compounds interfere with iron metabolism. It is possible that the bivalent platinum ion may displace competitively iron from its binding sites, either on proteins or on cells.     

Effect of aluminum adjuvants on safety and immunogenicity of Haemophilus influenzae type b-CRM197 conjugate vaccine

OBJECTIVE: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM197 (Hib-CRM197) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO4). METHODS: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Gülveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days. RESULTS: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO4 vaccine (19, 10, 11% in Chiron Hib/AlPO4, VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 micro g/mL, respectively (P < 0.05). CONCLUSIONS: The use of aluminum compounds adjuvants in Hib-CRM197 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.     

Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines.

PURPOSE: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines. EXPERIMENTAL DESIGN: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5'-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination. RESULTS: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed-->gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (+227.9, +86.0, and +135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2'-deoxycytidine. CONCLUSIONS: These data demonstrate that the gemcitabine and pemetrexed combination displays schedule-dependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.     

Socioeconomic and contextual determinants of reproductive activity among adolescent women in Colombia]

OBJECTIVE: To contribute to a better understanding of the problems of pregnancy among adolescent women, including proximate and socioeconomic determining factors, in two large, culturally different cities in Colombia: Santa Fe de Bogotá and Cali. METHODS: This longitudinal study combined quantitative and qualitative research methods, using information generated by a survey of adolescents conducted in 2003. The survey included 550 adolescents in Bogotá and 550 adolescents in Cali, from all socioeconomic strata. To analyze the determinants, discrete-time proportional hazards models were used. For the qualitative study, 72 in-depth interviews and four focus groups were done. With the information organized by subjects and categories that were defined in relation to the purposes of the study, categories were identified that arose from the patterns and recurrences in the data, in order to see sociocultural trends by sex, stratum, and city. RESULTS: The patterns of sexual activity, union (married or unmarried relationship), and maternity differ considerably among the socioeconomic strata, in both of the cities. The adolescent women in the low stratum begin having sexual relations, form unions, and become mothers earlier in life and with greater frequency than do adolescent women in the medium or high strata. The main determinant of the reproductive behavior of adolescent women is the set of contextual and socioeconomic factors in the home, mainly the family context (environment and supervision) and the educational climate (the average number of years of formal education of the family members over the age of 15). CONCLUSIONS: Sex education has been provided in the schools in Colombia since 1993, but our results clearly indicate that it has had only a limited impact on the reproductive behavior of adolescent women.     

Parents' reports of barriers to care for children with special health care needs: development and validation of the barriers to care questionnaire.

OBJECTIVE: To describe the development and validation of the Barriers to Care Questionnaire (BCQ). METHODS: The 39-item BCQ was developed through review of the literature, focus groups, and cognitive interviews of Spanish- and English-speaking parents of children with chronic health conditions. Barriers to care are conceptualized as a multidimensional construct consisting of pragmatics, health knowledge and beliefs, expectations about care, skills, and marginalization. The BCQ was field tested in 3 samples of children with special health care needs (CSHCN). RESULTS: Response rate for the field test was 77.2%. There were minimal missing data (0.08%), no floor effects, and minimal ceiling effects (3.8%, total scale). Internal consistency reliability (alpha) for the BCQ total scale was.95 and subscale alpha ranged from.75 to.91. The BCQ total scale and subscales correlated in the expected direction with validated measures of primary care characteristics and health-related quality of life. BCQ scores were higher (fewer barriers) for children with a primary care physician and for those who reported no problems getting care or foregone care. CONCLUSION: The BCQ is a feasible, reliable, and valid instrument for measuring barriers to care for CSHCN. Its use may inform efforts to support consumer choice, enhance provider accountability, and spur quality improvement.     

Taurine inhibition of metal-stimulated catecholamine oxidation

Taurine is an abundant amino acid found in mammalian tissues and it has been suggested to have cyto-protective functions. The aim of the present study was to determine if taurine had the potential to reduce oxidative stress associated with metal-stimulated catecholamine oxidation. Taurine and structural analogs of taurine were tested for their ability to inhibit metal-stimulated quinone formation from dopamine or L-dopa. Oxidative damage to proteins and lipids were also assessedin vitro and the effects of taurine were determined. Taurine (20 mM) was found to decrease significantly ferric iron (50–500 μM)- and manganese (10 μM)-stimulated L-dopa or dopamine oxidation. Taurine had no effect on zinc-induced dopamine oxidation and slightly potentiated copper- and NaIO₄-stimulated quinone formation. Ferric iron-stimulated lipid peroxidation was not affected by taurine (1–20 mM). Protein carbonyl formation induced by ferric iron (500 μM) and L-dopa (500 μM) was significantly reduced by 10 mM taurine. The cytotoxicity of L-dopa (250 μM) and ferric chloride (75 μM) to LLC-PK₁ cells was attenuated by 10 mM taurine or hypotaurine. Homotaurine alone stimulated L-dopa oxidation and potentiated the cytotoxic effects of ferric iron. Homotaurine was found to be cytotoxic when combined with L-dopa or L-dopa/iron. In contrast, hypotaurine inhibited quinone formation and protected LLC-PK₁ cells. These studies suggest that taurine may exhibit cytoprotective effects against the oxidation products of catecholamines by acting as a scavenger for free radicals and cytotoxic quinones.     

Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group.

PURPOSE: Although tumor resection is the mainstay of treatment for localized neuroblastoma, there are no established guidelines indicating which patients should be operated on immediately and which should undergo surgery after tumor reduction with chemotherapy. In an effort to develop such guidelines, the LNESG1 study defined surgical risk factors (SRFs) based on the imaging characteristics. PATIENTS AND METHODS: A total of 905 patients with suspected localized neuroblastoma were registered by 10 European countries between January 1995 and October 1999; 811 of 905 patients were eligible for this analysis. RESULTS: Information on SRFs was obtained for 719 of 811 patients; 367 without and 352 with SRFs. Of these 719 patients, 201 patients (four without and 197 with SRFs) underwent biopsy only. An attempt at tumor excision was made in 518 patients: 363 of 367 patients without and 155 of 352 patients with SRFs (98.9% v 44.0%). Complete excision was achieved in 271 of 363 patients without and in 72 of 155 patients with SRF (74.6% v 46.4%), near-complete excision was achieved in 81 and 61 patients (22.3% v 39.3%), and incomplete excision was achieved in 11 and 22 patients (3.0% v 14.2%), respectively. There were two surgery-related deaths. Nonfatal surgery-related complications occurred in 45 of 518 patients (8.7%) and were less frequent in patients without SRFs (5.0% v 17.4%). Associated surgical procedures were also less frequent in patients without SRFs (1.6% v 9.7%). CONCLUSION: The adoption of SRFs as predictors of adverse surgical outcome was validated because their presence was associated with lower complete resection rate and greater risk of surgery-related complications. Additional studies aiming to better define the surgical approach to localized neuroblastoma are warranted.