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.     

Epidemiologic aspects of pediatric multiple trauma in a Spanish urban population

BACKGROUND/PURPOSE: Trauma is still the most frequent cause of mortality and disability in childhood and adolescence. An epidemiologic prospective study on children under 16 years of age with multiple trauma (MT) was conducted in a large Spanish urban university hospital over a 6-year period. METHODS: Of 1,937 children admitted at the pediatric trauma unit for musculoskeletal injuries from March 1988 until March 1994, 56 patients including 37 boys and 19 girls had MT. MT was considered when at least 2 long bones were fractured or there was a fracture of 1 long bone combined with an injury of 4 other major anatomic regions (face and neck, thorax, abdomen, or neural system). The severity of injuries was evaluated according to the modified injury severity score (MISS). RESULTS: Injury to pedestrians was the most frequent cause of MT (54%). The overall mortality rate of the series, including those children dying during transport to the hospital was 11.5%. The average MISS for the whole group was 15 (range, 5 to 59). Head trauma was the most frequent associated injury (52%), two thirds of which were considered minor injuries (Glasgow Coma Scale >15). Seventy-seven fractures were registered, 10% of which were open fractures. External fixation was the most common surgical technique among operated fractures. The average hospitalization period was 16 (median, 13; range, 1 to 150) days. Children with a MISS above 18 points showed a significant longer hospitalization period (mean, 31 +/- 45 days) as compared with those with MISS below 18 points (mean, 10 +/- 7 days; P < .05). There was a strong correlation between the MISS and both the period of hospitalization at the pediatric intensive care unit and the total length of hospital stay. CONCLUSIONS: Pedestrian accidents caused by motor vehicles in children playing at the street contributed most significantly to MT in the urban pediatric population. Special care for prevention must be taken in the age group of 6 to 10 years. Head injury was the main cause of death in children with multiple trauma. MISS was found to be a good predictor of survival and duration of hospital stay in pediatric MT.     

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.     

Osteomyelitis of the pubic symphysis, abscess and late disjunction after delivery. A case report

Infection of the pubic symphysis after delivery is rare, and probably occurs through a small vaginal laceration and is usually silent in the early phase: as the disease progresses, bone infection, sequestra formation and septicemia man occur. This report presents one case of staphylococcal osteomyelitis of the symphysis in a twenty five years old woman, with onset of symptoms 2 months after delivery. Staphylococcus Aureus was collected from pus and blood. Bone sequestra and a large abscess extending in the rectus abdominis fascia were present. Drainage and curettage resolved infection, but sourapubic pain persisted because of symphysis disjunction, and was treated by external pelvic fixation.     

Are preoperative parameters of unilateral pyelo-ureteric junction obstruction in children predictive of postoperative function improvement?

OBJECTIVES: Surgery on the pyelo-ureteric junction obstruction (PUJO) has long been thought to affect postoperative renal function. However, preoperative assessment of which kidneys will benefit from such surgery remains unreliable. MATERIAL AND METHODS: Pre- and postoperative data relating to renal function were obtained by renal scan for 69 patients who were operated upon for PUJO. These patients were divided into two groups: group A (improved differential renal function) and group B (unimproved or decreased differential renal function). The two groups were then compared with regard to age at operation and presence or absence of clinical symptoms. Ultrasound (anteroposterior diameter of the pelvis, parenchymal thickness) and renal scan (glomerular filtration rate, differential renal function of the affected kidney, obstructive pattern) parameters were also taken into consideration. Some variables were also made dichotomous (pelvic diameter < or > 15 mm, parenchymal thickness < or > 5 mm, differential renal function < or > 40%). Statistical correlation was sought with parametric and non-parametric tests. RESULTS: No correlation whatsoever was found between the two groups for any of the parameters under consideration, so that any attempt at logistical regression analysis failed. CONCLUSIONS: None of the currently adopted diagnostic tests can be used to indicate which renal units will benefit from surgery through an improved renal function. The presence or absence of clinical symptoms does not appear to affect renal function either. There is evidence that parents should be provided with such information when giving their informed consent to pyeloplasty.     

Stress and hippocampal abnormalities in psychiatric disorders.

The hippocampus plays a main role in regulating stress response in humans, but is itself highly sensitive to neurotoxic effects of repeated stressful episodes. Hippocampal atrophy related to experimental stress has been reported in laboratory studies in animals. Several controlled brain imaging studies have also shown hippocampal abnormalities in psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and borderline personality disorder (BPD). This paper reviews the physiological role of the hippocampus in stress circuitry and the effects of stress on cognitive functions mediated by the hippocampus. We also review brain imaging studies investigating hippocampus in PTSD, MDD, and BPD. This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders. Prospective, longitudinal studies will be needed in high-risk offspring and first-episode subjects to explore the relationship between stress and hippocampal atrophy in these neuropsychiatric illnesses.