Effect of age, ethnicity, sex, cognitive status and APOE genotype on amyloid load and the threshold for amyloid positivity.

The threshold for amyloid positivity by visual assessment on PET has been validated by comparison to amyloid load measured histopathologically and biochemically at post mortem. As such, it is now feasible to use qualitative visual assessment of amyloid positivity as an in-vivo gold standard to determine those factors which can modify the quantitative threshold for amyloid positivity. We calculated quantitative amyloid load, measured as Standardized Uptake Value Ratios (SUVRs) using [18-F]florbetaben PET scans, for 159 Hispanic and non-Hispanic participants, who had been classified clinically as Cognitively Normal (CN), Mild Cognitive Impairment (MCI) or Dementia (DEM). PET scans were visually rated as amyloid positive (A+) or negative (A-), and these judgments were used as the gold standard with which to determine (using ROC analyses) the SUVR threshold for amyloid positivity considering factors such as age, ethnicity (Hispanic versus non-Hispanic), gender, cognitive status, and apolipoprotein E ε4 carrier status. Visually rated scans were A+ for 11% of CN, 39.0% of MCI and 70% of DEM participants. The optimal SUVR threshold for A+ among all participants was 1.42 (sensitivity = 94%; specificity = 92.5%), but this quantitative threshold was higher among E4 carriers (SUVR = 1.52) than non-carriers (SUVR = 1.31). While mean SUVRs did not differ between Hispanic and non-Hispanic participants;, a statistically significant interaction term indicated that the effect of E4 carrier status on amyloid load was greater among non-Hispanics than Hispanics. Visual assessment, as the gold standard for A+, facilitates determination of the effects of various factors on quantitative thresholds for amyloid positivity. A continuous relationship was found between amyloid load and global cognitive scores, suggesting that any calculated threshold for the whole group, or a subgroup, is artefactual and that the lowest calculated threshold may be optimal for the purposes of early diagnosis and intervention.

The liver-cytokine-brain circuit in interferon-based treatment of patients with chronic viral hepatitis.

Psychiatric symptoms are commonly identified in patients with viral hepatitis. They may have been present prior to the onset of disease and may include symptoms related to addiction issues. Furthermore, the virus and antiviral therapy, in particular interferon, may induce or modify psychiatric symptoms. Recent data support chronic hepatitis C replication in the brain and subsequent changes of cerebral metabolite spectra and magnetic resonance alterations. In chronic viral hepatitis and in other chronic inflammatory diseases, an alteration of the neuro-endocrine-immune system response has been observed. Catecholamines and glucocorticoids modulate this immune/inflammatory reaction. Psychiatric assessment and monitoring before, during and after antiviral therapy can identify patients whose psychiatric symptoms preclude therapy, and those who may benefit from psychopharmacological therapy and counselling, thereby improving therapeutic results. This review will discuss current insights into the complex interplay between cytokines, liver and brain in chronic viral hepatitis closely associated with psychiatric issues, especially in the case of antiviral therapy, with the aim of indicating future research and possible treatments.

Assessment of psychological distress in cancer patients: a pivotal role for clinical interview.

OBJECTIVE: The evaluation of psychological distress in cancer patients recently entered oncologic clinical practice. The objective of this study was to evaluate the role of clinical interview within psycho-oncologic assessment. METHODS: Questionnaires assessing distress (PDI), psychopathology (MHQ, HADS) and needs (NEQ) and a subsequent clinical interview were proposed to 320 consecutive inpatients from the Oncology Department of Careggi Hospital in Florence. RESULTS: The clinical interview made it possible to evaluate a significant percentage of patients (30%) who did not fill in questionnaires and to detect the presence of distress in 39 (13.7%) patients who would not have received a diagnosis in a protocol for the assessment of distress based only on questionnaires. It also provided the possibility to ask for help or to receive clinical support to a high percentage of patients (44.1%) who had not requested to speak to a psychologist through the questionnaires (NEQ). Moreover, 25% of patients who received prolonged clinical support had a low score in tests detecting distress, indicating that the opportunity for therapeutic support can emerge during a clinical interview, also in the absence of relevant symptoms detected by questionnaires. CONCLUSIONS: The use of more than one questionnaire in the assessment of distress and psychopathology is associated with reduced compliance and redundant information. On the other hand, clinical interview has a pivotal role in clinical evaluation and access to psychological support. We conclude that optimal efficacy of programs assessing distress in cancer patients is reached when a single questionnaire evaluating distress is associated with a clinical interview.

[The effect of age in a planning and arranging task ('Mexican pyramid') among schoolchildren]. / Efecto de la edad en una tarea de planificación y organización ('pirámide de México') en escolares.

AIM: To analyze the influence of age on the performance of a planning and organization task, two skills included in the executive functions. SUBJECTS AND METHODS: Performance of the task 'Mexican pyramid' from the Evaluacion Neuropsicologica Infantil (ENI) were analyzed on 239 school age children from México and Colombia, distributed in six age groups. Five measures were analyzed: number of correct designs, number of movements per design and execution time in the correct designs, number of correct designs built with the minimum of movements and its execution time. RESULTS: There was a significant effect of age on the five measures. Comparison between groups showed that younger children (5 to 6 years old) had a smaller number of correct designs, while children from 5 to 8 years old need more movements. Execution time showed a greater number of differences between groups. Analyzing the 11 items of the task, it was evident that difficulty level is related with the number of movements and the novelty of rules. CONCLUSIONS: Our results suggest that accuracy of performance, the number of moves as well as the speed of performance are useful markers of the development of the executive functions. Our results support the notion that the development of planning and organization; is fast in the first years of the school age, and it slows down on adolescence.

Efecto de la edad en una tarea de planificación y organización (‘pirámide de México’) en escolares / The effect of age in a planning and arranging task (‘Mexican Pyramid’) among school children

Objetivo. Conocer los cambios relacionados con la edad en una tarea de planificación y organización, como componentes de las funciones ejecutivas. Sujetos y métodos. Se analizó la ejecución en la ‘pirámide de México’ de la evaluación neuropsi-cológica infantil en 239 escolares de México y Colombia de 5 a 16 años de edad, distribuidos en seis grupos. Se utilizaron cinco medidas: número de aciertos, número de movimientos y tiempo de ejecución en los diseños correctos, número de aciertos y tiempo de ejecución en los diseños correctos realizados con el mínimo de movimientos. Resultados. Se observó un efecto de la edad sobre las cinco medidas. En comparación con los otros grupos, los niños de 5 a 6 años tienen una menorcantidad de diseños correctos; los de 5 a 8 años requieren mayor número de movimientos. El tiempo de ejecución mostró un mayor número de diferencias intragrupales. El análisis por ensayo reveló que el grado de dificultad se relaciona con la cantidadde movimientos y lo novedoso de las reglas. Conclusiones. Además del número de aciertos y de movimientos invertidos para lograr cada acierto, el tiempo de ejecución es un indicador útil del desarrollo de estas funciones, dado que la rapidez enla ejecución es la que marca diferencias mayores entre los niños. Nuestros resultados apoyan la existencia de un desarrollo acelerado de las funciones de planificación y organización durante los primeros años de la etapa escolar, que sigue un cursomás lento en la adolescencia

Aim. To analyze the influence of age on the performance of a planning and organization task, two skills includedin the executive functions. Subjects and methods. Performance of the task ‘Mexican pyramid’ from the Evaluación Neuropsicológica Infantil (ENI) were analyzed on 239 school age children from México and Colombia, distributed in six age groups.Five measures were analyzed: number of correct designs, number of movements per design and execution time in the correct designs, number of correct designs built with the minimum of movements and its execution time. Results. There was a significant effect of age on the five measures. Comparison between groups showed that younger children (5 to 6 years old) hada smaller number of correct designs, while children from 5 to 8 years old need more movements. Execution time showed a greater number of differences between groups. Analyzing the 11 items of the task, it was evident that difficulty level is related with the number of movements and the novelty of rules. Conclusions. Our results suggest that accuracy of performance, the number of moves as well as the speed of performance are useful markers of the development of the executive functions. Our results support the notion that the development of planning and organization; is fast in the first years of the school age, and it slows down on adolescence

Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients.

Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (TRP) metabolism, is induced in various tissues of patients with bacterial and viral infection or with neoplastic diseases. This induction is considered the main cause of the decreased serum TRP levels, the reduced brain serotonin synthesis and the occurrence of psychopathological disorders often detected in patients with chronic infections or different forms of cancer. We studied 89 subjects including: (a) 39 patients with chronic hepatitis C virus (HCV) infection and mild liver damage (b) 40 healthy controls, and (c) 10 patients with chronic hepatitis B virus (HBV) infection. We measured serum TRP and kynurenine levels and IDO activity in macrophages. Furthermore, each patient had an accurate psychopathological evaluation. HCV-infected patients had lower (-28%) serum TRP concentrations than healthy volunteers or HBV-infected patients with comparable liver damage. Depression and anxiety symptoms were particularly common in HCV patients. Unexpectedly, serum kynurenine levels and IDO activity in cultured macrophages (under both basal or stimulated conditions) were lower in HCV patients than in controls. Our study shows that HCV patients have reduced serum TRP levels and confirms that they frequently suffer from anxiety and depression-related symptoms. The reduced IDO activity found in the macrophages of these patients suggest that HCV infection may hamper macrophage functions.

[Neuropsychological predictors of reading ability in Spanish]. / Predictores neuropsicológicos de la lectura en español.

INTRODUCTION: Learning how to read has been associated with different types of linguistic and non-linguistic skills. However, few studies have looked at the association between neuropsychological test performance and reading skills at different ages during childhood. AIM: To analyze the association between neuropsychological test scores and reading performance, and to investigate the influence of age, gender and type of school (public or private) over reading test performance. SUBJECTS AND METHODS: The sample included 625 6 -to-15 year old children (207 Colombians, 418 Mexicans; 277 boys, 348 girls). The following cognitive abilities were assessed: reading speed and reading comprehension and attention, memory (coding and recall), perception, visuospatial and conceptual abilities and executive functions. RESULTS: The best neuropsychological test predictor for reading speed was Letter Cancellation, and for reading comprehension was Memory for a Story. Children from private schools performed better in most reading tests than children from public schools. Differences between boys and girls were observed in only two reading tests. CONCLUSION: Reading speed correlates mainly with attentional skills and reading comprehension with verbal memory. Reading abilities in school age children are influenced mainly by age and type of school and little by gender.

Predictores neuropsicológicos de la lectura en español / Neuropsychological predictors of reading ability in spanish

Introducción. El aprendizaje de la lectura se ha asociado con el desarrollo de habilidades tanto lingüísticas como no lingüísticas. Sin embargo, pocos estudios han analizado la relación entre las habilidades de lectura y el desempeño en pruebas cognitivas de tipo neuropsicológico en niños de diferentes edades. Objetivos. Correlacionar el desempeño lector con las puntuaciones en diferentes subpruebas neuropsicológicas y analizar el efecto de la edad, el sexo y el tipo de escuela (pública o privada) en pruebas de lectura. Sujetos y métodos. Se estudiaron 625 niños (207 colombianos, 418 mexicanos; 277 niños, 348 niñas) con edades comprendidas entre 6 y 15 años. Se evaluaron, además de las habilidades de lectura, 12 áreas cognitivas diferentes: atención, habilidades construccionales, memoria (codificación y evocación diferida), percepción, lenguaje oral, habilidades metalingüísticas, lectura, escritura, matemáticas, habilidades visuoespaciales, habilidades conceptuales y funciones ejecutivas. Resultados. Un análisis de regresión escalonado mostró que la prueba de cancelación de letras es el mejor predictor de velocidad en la lectura, y la prueba de memoria de una historia la que mejor predice puntuaciones de comprensión de lectura. Los niños de las escuelas privadas se desempeñaron mejor en pruebas de lectura que los niños de escuelas públicas. Las diferencias entre niños y niñas solamente fueron significativas en dos pruebas de lectura. Conclusiones. La velocidad en la lectura se correlaciona especialmente con habilidades atencionales, en tanto que la comprensión en la lectura se correlaciona más con pruebas de memoria verbal. Las habilidades de lectura en niños de edad escolar se ven más influidas por la edad del niño y por el tipo de escuela que por el sexo de los participantes (AU)

Introduction. Learning how to read has been associated with different types of linguistic and non-linguistic skills. However, few studies have looked at the association between neuropsychological test performance and reading skills at different ages during childhood. Aim. To analyze the association between neuropsychological test scores and reading performance, and to investigate the influence of age, gender and type of school (public or private) over reading test performance. Subjects and methods. The sample included 625 6 -to-15 year old children (207 Colombians, 418 Mexicans; 277 boys, 348 girls). The following cognitive abilities were assessed: reading speed and reading comprehension and attention, memory (coding and recall), perception, visuospatial and conceptual abilities and executive functions. Results. The best neuropsychological test predictor for reading speed was Letter Cancellation, and for reading comprehension was Memory for a Story. Children from private schools performed better in most reading tests than children from public schools. Differences between boys and girls were observed in only two reading tests. Conclusion. Reading speed correlates mainly with attentional skills and reading comprehension with verbal memory. Reading abilities in school age children are influenced mainly by age and type of school and little by gender (AU)

Personality profile and neuropsychological test performance in chronic cocaine-abusers.

Little is known about the association between personality disorders and neuropsychological test performance in chronic cocaine users. The aims of the present study were to (1) pinpoint the specific neuropsychological characteristics of chronic cocaine abusers, (2) analyze their personality profile, and (3) explore the association between personality traits and neuropsychological test performance. A sample of 42 drug-abusers (mean age = 34.15; SD = 6.73; mean educational level = 11.44; SD = 2.01) was selected from a state rehabilitation facility and was compared to a control group (mean age = 34.53; SD = 9.01; mean educational level = 12.29; SD = 1.31). The following information was collected for each subject: (1) A clinical history adapted from Horton (1996). (2) The Personality Assessment Inventory (PAI) (Morey, 1991). (3) A neuropsychological test battery including: Arithmetic and Digits subtests from the WAIS-R, California Verbal Learning Test, Trial Making Test, Verbal Fluency tests, Rey-Osterrieth Complex Figure, Wisconsin Card Sorting Test, Benton Visual Retention Test, Stroop Neurological Screening Test and Hooper Visual Organization. Thirty-seven of the drug-dependent subjects obtained an abnormal score in at least one PAI scale. The personality profile of the drug-dependent subjects found via the PAI pointed to a Borderline/Antisocial personality, frequently associated with mania features. In six of the drug-abusers, a normal personality profile was observed. Neuropsychological test performance scores were within the low average or borderline range. The most abnormal scores were observed in attention, memory, and executive functioning tests. The results did not show any robust association between personality profile and neuropsychological test performance.

Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study.

BACKGROUND AND RATIONALE: Non-curative surgical cytoreduction of advanced tumors is associated with increased proliferation of the remaining tumor cells. Thus, appropriate preoperative chemotherapy should prevent both cell proliferation and the increase of resistant cells. The aim of the present study was to evaluate the efficacy and toxicity of primary chemotherapy (P-CT) in previously untreated patients with stage IV ovarian cancer (OC). PATIENTS AND METHODS: Thirty-four patients with stage IV OC were treated from January 1993 to April 2000 with P-CT. Eligibility criteria included: histologically or cytologically confirmed, unresectable stage IV OC and performance status < or = 3. P-CT consisted of four courses of carboplatin, cyclophosphamide and epirubicin until October 1996, and paclitaxel, carboplatin thereafter. Surgery followed P-CT. After the operation patients received two further courses of chemotherapy that were tailored according to their individual response. Median (M) age was 61 years, range 32-73; median performance status was 2. A total number of 197 courses of CT were administered, median 5.7 per patient. RESULTS: Complete or partial response (CR, PR) was observed in 28 patients (response rate 82%, 95% CI: 65.4% to 93.2%), disease stability and progression (SD, PD) was observed in three and three patients, respectively. Median time to progression was 16.45 months (range 4.8-90.4+), median survival time was 28 months (range 4.5 - 90.4+): 1-year survival rate was 94%. Toxicity according to WHO: nausea and vomiting grade (G) 2, 30% of patients; gastrointestinal G 2-3, 20% of patients; alopecia G 3, 88% of patients; hematological G 3-4, 73% of patients; neurologic G 2, 12% of patients. Nine pathological CRs were observed. CONCLUSION: Neoadjuvant treatment with CBDCA with either CTX and EPI or Taxol is feasible and shows activity in OC.

Ifosfamide, cisplatin, and 13-Cis retinoic acid for patients with advanced or recurrent squamous cell carcinoma of the head and neck: a phase I-II study.

BACKGROUND: Ifosfamide (IFO) and cisplatin (CDDP) are active drugs in the treatment of patients with squamous cell carcinoma (SCC) of the head and neck. 13-Cis retinoic acid (RA), along with its antiproliferative and differentiating activity on SCC cell lines, has immunomodulatory and chemopreventive effects. The objective of the current Phase I-II study was to evaluate the combination of CDDP, IFO, and RA in patients with advanced or recurrent SCC of the head and neck. METHODS: Patients with measurable recurrent, metastatic, or locally advanced SCC of the head and neck were eligible. Patients received a fixed dose of 20 mg/m(2) CDDP, and IFO was administered with sodium mercaptoethanesolfonate in three-dose increments (1000 mg/m(2), 1200 mg/m(2), and 1500 mg/m(2)) up to dose limiting toxicity. Both drugs were given for 5 consecutive days every 3 weeks. RA (0.5 mg/kg) was given orally for 5 days per week. RESULTS: Fifty-two patients either with locoregional recurrence or distant metastases (50%) or with locally advanced SCC of the head and neck beyond surgery or radiation therapy (50%) were entered into the trial. Fifteen patients were enrolled in the Phase I study, during which the maximum tolerated dose of IFO was 1500 mg/m(2). In the Phase II study (CDDP 20 mg/m(2) and IFO 1200 mg/m(2)), the response rate was 72% (95% confidence interval, 57-83%). After a median follow-up of 23 months, the median time to disease progression was 10.4 months (range, 2.9-47.2+ months), and the median overall survival was 12.95 months (range, 1.7-47.2+ months). Two patients were converted from a partial response to a complete response with RA. Toxicity was relatively well tolerated and caused no deaths. Grade 3-4 neutropenia was observed in 16 patients, and Grade 2-3 diarrhea toxicity occurred in 9 patients. CONCLUSIONS: The dose and schedule for the combination of CDDP, IFO, and RA that were used in this study are feasible and active in the treatment of patients with SCC of the head and neck, with durable responses and a relatively well tolerated toxicity.

Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer.

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.

Phase II study of epirubicin, mitomycin C, and 5-fluorouracil in hormone-refractory prostatic carcinoma.

Management of metastatic prostatic carcinoma when it becomes refractory to hormonal therapy is controversial, and no standard treatment exists. Nevertheless, chemotherapy for hormone-refractory prostatic carcinoma (HRPC) has shown some advantages compared with the best supportive care. In a prospective phase II study, we evaluated the combination of epirubicin (E), mitomycin C (MMC), and 5-fluorouracil (5-FU) in patients with HRPC. Twenty-eight patients with HRPC were treated with a combination of E (30 mg/m2), 5-FU (750 mg/m2), and MMC (5 mg/m2) day 1 and 2, every 4 weeks. Treatment was continued until evidence of disease progression or excessive toxicity. Patients were monitored with serial measurements of prostate-specific antigen (PSA). Forty-seven percent of the patients exhibited a reduction of serum PSA concentration and an objective response; 38% exhibited disease stability, and 15% had disease progression. Toxicity was substantial. The median time to progression was 7.3 months (range, 1.7-16.8 months) and median survival was 14.5 months (range, 1.6-38.4 months). Performance status improved in 80% of patients, and bone pain was relieved in 70%. Thus the combination of E, MMC, and 5-FU shows activity in the treatment of HRPC, giving substantial palliation of symptoms. In one patient, PSA values remained low even when the tumor had progressed.

Phase 1B study of subcutaneously administered interleukin 2 in combination with 13-cis retinoic acid as maintenance therapy in advanced cancer.

At present, no therapeutic strategy is available to maintain responses achieved in patients treated with chemotherapy. This Phase IB study was aimed at identifying the optimal biological dose of chronic maintenance therapy using s.c. interleukin (IL) 2 and oral 13-cis retinoic acid (RA) in patients with either tumor stabilization or response to chemotherapy. IL-2 has no cross-resistance with chemotherapy and improves cancer-related lymphocytopenia, a factor that determines poor prognosis, whereas RA has immunomodulatory properties, potentially synergistic with IL-2. Eighteen patients with advanced solid tumor who achieved a response or stable disease as a result of standard chemotherapy, received RA (0.5 mg/kg) and IL-2 5 days/week for two cycles of 3 weeks/month for up to 1 year. Three doses of IL-2 were used: 9.0, 4.5, and 1.8 x 10(6) IU/day. Monitoring consisted in a weekly blood differential count and a bimonthly assessment of tumor markers, CD4+, CD8+, and natural killer cells. Patients were evaluated for toxicity, response maintenance, time to progression, and survival. Patients chronically treated with 9 and 4.5 x 10(6) IU of IL-2 developed dose-limiting toxicity grade III or IV, consisting of fever, fatigue, thrombocytopenia, mucositis, and local cutaneous reaction. No grade III or IV toxicity was observed with the 1.8 x 10(6) IU dose, considered as the optimal biological dose. Fifty courses of IL-2 were administered (median, 3 per patient). An increase in total lymphocyte number, CD4:CD8 ratio and natural killer cell count was observed at all of the three dose levels with respect to baseline values. Two patients with a partial response to chemotherapy achieved a complete response after 6 and 7 months, respectively, of IL-2 + RA maintenance therapy. Median time to progression and overall survival were, respectively, 8.1 and 13.7 months (range, 2-48.8+ months). Low-dose IL-2 + RA as maintenance therapy after chemotherapy is, therefore, feasible and well tolerated and improves immunological parameters known to have a prognostic value in cancer.

Advanced colorectal cancer in elderly patients: tolerance and efficacy of leucovorin and fluorouracil bolus plus continuous infusion.

BACKGROUND: Colorectal cancer (CRC) incidence increases sharply with age. In this study we assessed activity, toxicity and both the activity of daily living (ADL) and instrumental activity of daily living (IADL) of the De Gramont schedule in a series of advanced CRC patients aged > or = 70 years. PATIENTS AND METHODS: Sixty-two previously untreated advanced CRC patients entered the study. Median age was 75 (range 70-88). RESULTS: 447 courses were delivered. All of the 62 patients were evaluable for toxicity, 55 for response and ADL-IADL indexes. We recorded 2 complete and 9 partial responses, for an overall response rate of 20%. ADL and IADL indexes improved in 33%, remained stable in 49% and worsened in 18% of evaluable patients. Treatment was very well-tolerated with no serious hematological or non-hematological toxicities. CONCLUSIONS: The De Gramont schedule was very well tolerated in advanced CRC elderly patients, although our work could not confirm the original reported activity. ADL and IADL indexes improved or remained stable in 82% of evaluable patients.

Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism.

Estradiol inhibits endothelin-1 synthesis, an effect that may contribute to the cardiovascular protective effects of estradiol. Recent findings that estradiol inhibits neointima formation in mice lacking estrogen receptors suggests that the cardiovascular protective effects of estradiol may be mediated by means of an estrogen receptor-independent mechanism. Because 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little/no affinity for estrogen receptors, are more potent than estradiol in inhibiting vascular smooth muscle cell growth, we investigated whether these metabolites also inhibit endothelin-1 synthesis by means of an receptor-independent mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 micromol/L of estradiol, 2-hydroxyestradiol, or 2-methoxyestradiol concentration-dependently inhibited basal as well as serum-induced (2.5%), TNFalpha-induced (10 ng/mL), angiotensin II-induced (100 nmol/L), and thrombin-induced (4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol also inhibited serum-induced mitogen-activated protein kinase activity. As compared with estradiol, its metabolites were more potent in inhibiting endothelin-1 secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyestradiol and 2-methoxyestradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 micromol/L), an estrogen receptor antagonist. Our findings indicate that the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol potently inhibit endothelin-1 synthesis by means of an estrogen receptor-independent mechanism. This effect of estradiol metabolites may be mediated by inhibition of mitogen activated protein kinase activity and may contribute to the cardioprotective effects of estradiol.

Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis.

OBJECTIVES: Cytomegalovirus infection has been reported as a cause of refractory inflammatory bowel disease, but no data are available on its prevalence in severe colitis. The aim of this study was to evaluate the prevalence and outcome of cytomegalovirus infection in a consecutive series of patients with severe steroid refractory colitis admitted to our department from 1997 to 1999. METHODS: Among 62 patients with severe colitis, 55 with ulcerative colitis and seven with Crohn's disease, 19 (30%) were resistant to intravenous steroids and bowel rest. In all of them, rectal biopsies were examined for cytomegalovirus (the flexible proctoscopy being performed without air insufflation and limited to the first 10 cm). Buffy coat preparation on leukocytes was also performed to detect systemic infection. If cytomegalovirus was not detected, cyclosporine was started. RESULTS: In seven (five with ulcerative colitis and two with Crohn's disease) out of 19 (36%) patients with refractory disease, cytomegalovirus was diagnosed in the rectal specimens as well as by buffy coat preparation. Five patients went into remission after antiviral treatment (three with ganciclovir and two with foscarnet). One patient did not respond and was operated on. In one patient, cytomegalovirus was found in the surgical specimen. CONCLUSIONS: Cytomegalovirus infection is a frequent cause of severe refractory colitis. Rectal biopsy should always be performed in severe steroid-resistant colitis.

5-fluorouracil-carboplatin continuous infusion as salvage chemotherapy in advanced cancer.

AIMS AND BACKGROUND: 5-fluorouracil given by continuous infusion allows higher dose delivery, causes less myelosuppression and may interfere with repair of DNA damage caused by carboplatin. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-fluorouracil and carboplatin given in continuous infusion to patients with advanced cancer and pretreated with at least two chemotherapy regimens. METHODS: Forty patients with advanced tumors (21 colon, 4 stomach, 3 breast, 3 bladder, 3 ovary, and 6 at other sites) were entered in the trial. 5-fluorouracil (200 mg/m2) and carboplatin (20 mg/m2) were administered by continuous infusion from days 1 to 20, every 4 weeks. RESULTS: All patients were assessable for response and toxicity. A total of 138 courses of chemotherapy were administered, with a mean of 3.5 per patient (range, 2-9). Toxicity, assessed using WHO criteria, was as follows: nausea and vomiting grade 2-3 in 34% of patients, alopecia grade 2-3 in 96%, and neutropenia grade 3-4 in 26%. One patient (2.5%) had a complete response to therapy and 7 (17.5%) had a partial response (response rate 20%; 95% Cl, 9.06-35.68%). Disease stability and progression occurred in 12 (30%) and 20 (50%) patients, respectively. Median time to progression was 5.6 months (range, 2.8-45.9+), with a median survival time of 7.7 months (range, 1.5-45.9+). CONCLUSIONS: Outpatient treatment with a combination of 5-fluorouracil and carboplatin in continuous infusion was active as salvage treatment for advanced tumors and may give prolonged palliation of symptoms with manageable toxicity.

Neuropsychological test scores, academic performance, and developmental disorders in Spanish-speaking children.

Limited information is currently available about performance of Spanish-speaking children on different neuropsychological tests. This study was designed to (a) analyze the effects of age and sex on different neuropsychological test scores of a randomly selected sample of Spanish-speaking children, (b) analyze the value of neuropsychological test scores for predicting school performance, and (c) describe the neuropsychological profile of Spanish-speaking children with learning disabilities (LD). Two hundred ninety (141 boys, 149 girls) 6- to 11-year-old children were selected from a school in Bogotá, Colombia. Three age groups were distinguished: 6- to 7-, 8- to 9-, and 10- to 11-year-olds. Performance was measured utilizing the following neuropsychological tests: Seashore Rhythm Test, Finger Tapping Test (FTT), Grooved Pegboard Test, Children's Category Test (CCT), California Verbal Learning Test-Children's Version (CVLT-C), Benton Visual Retention Test (BVRT), and Bateria Woodcock Psicoeducativa en Español (Woodcock, 1982). Normative scores were calculated. Age effect was significant for most of the test scores. A significant sex effect was observed for 3 test scores. Intercorrelations were performed between neuropsychological test scores and academic areas (science, mathematics, Spanish, social studies, and music). In a post hoc analysis, children presenting very low scores on the reading, writing, and arithmetic achievement scales of the Woodcock battery were identified in the sample, and their neuropsychological test scores were compared with a matched normal group. Finally, a comparison was made between Colombian and American norms.

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in a Mediterranean area.

BACKGROUND: Thromboembolism has been reported to be associated with inflammatory bowel disease. AIM: To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events. PATIENTS AND METHODS: A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls. RESULTS: One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively. CONCLUSIONS: Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.