Fixed dose-rate gemcitabine infusion as first-line treatment for advanced-stage carcinoma of the pancreas and biliary tree

BACKGROUND: Gemcitabine infusion at the fixed dose rate of 10 mg/m(2) per minute (FDR-gemcitabine) has pharmacokinetic advantages and may result in improved therapeutic efficacy. METHODS: Between April 2002 and September 2003, 40 patients with advanced-stage pancreatic adenocarcinoma (PDAC; n = 27) or biliary tree carcinoma (BTC; n = 13) were treated with weekly FDR-gemcitabine (1000 mg/m(2)). The primary end point was the response rate. The secondary end points were progression-free and overall survival (PFS and OS), tumor marker response, and clinical benefit response (CBR). RESULTS: The overall response rate (ORR) on an intent-to-treat basis was 15% (95% confidence interval [95% CI], 4-26%). A positive CBR was obtained in 14 of 29 (48%) patients. Seventeen of 25 (68%) patients had a reduction in carbohydrate antigen 19-9 (CA 19-9) of > 25%. The median time to treatment failure and the median PFS were 17 weeks (95% CI, 13-22 weeks) and 19 weeks (95% CI, 15-23 weeks), respectively. The median OS was 40 weeks (95% CI, 36-45 weeks) and the 1-year actuarial survival rate was 25.8%. Multivariate analysis showed that a performance status score of 0-1 at study entry and locally advanced disease were the only independent predictors of longer PFS and OS, whereas a reduction in CA 19-9 serum levels > 75% was an independent predictor of longer PFS, but had no impact on OS. Toxicity was mild with Grade 3-4 neutropenia (according to the National Cancer Institute-Common Toxicity Criteria [version 2.0]) in 18 of 427 treatment weeks (4.2%), and Grade 3 anemia and thrombocytopenia in 6 of 427 treatment weeks (1.4%) and 9 of 427 treatment weeks (2.1%), respectively, and asymptomatic Grade 3-4 transaminase elevation in 21 of 427 treatment weeks (4.9%). CONCLUSIONS: FDR-gemcitabine at the weekly dose of 1000 mg/m(2) demonstrated promising activity, despite negligible toxicity, in patients with advanced-stage PDAC and BTC.     

Income inequality and mortality in Italy

BACKGROUND: The relationship between income inequality and health remains controversial in terms of whether or not it exists and, if so, its extent and the mechanisms involved. This study examines the relationship between income inequality, as indicated by the Gini coefficient, and mortality in Italy. METHODS: Cross-sectional ecological study on the 57,138,489 inhabitants living in the 95 provinces existing in Italy in 1994. Multivariate weighted regression analysis of total and age-specific mortality, income inequality, gender, and interaction between income inequality and median income or geographical area. RESULTS: A positive association between income inequality and total mortality was observed for both genders in provinces with a low per capita income and in Southern and Central Italy. The effect was present for infants and for persons over 24 years of age; it was marked for the elderly, particularly women. A negative association with mortality was observed for males living in the North-west. Interactions between income inequality and median income, and between income inequality and geographical area were found. CONCLUSION: In Italy, the relationship between income inequality and health is mixed and not universal, in so far as a positive association was observed only in provinces with lower absolute income. Elderly persons living in Southern Italy represent the population subgroup most vulnerable to unequal income distribution. Income inequality can, in part, explain the historically higher mortality among women in Southern Italy compared to women in the North. These results indicate that income inequality affects the health of population subgroups differentially.     

In vivo modulation of soluble "antagonistic" IL-6 receptor synthesis and release in ESRD

Soluble gp130 (sgp130) is a soluble circulating receptor of IL-6 with "antagonistic" biologic activity. It is generated independently by either shedding of the extracellular domain of membrane gp130 or alternative mRNA splicing. This study was addressed to clarify the mechanisms underlying sgp130 synthesis and release in patients who undergo regular dialysis treatment (RDT) using dialytic membranes with different biocompatibility. Two groups of RDT patients were enrolled: 11 patients who were treated with cellulosic membranes (C) and 10 patients who were treated with synthetic membranes (S). Ten healthy subjects constituted the control group. Serum samples and peripheral blood mononuclear cells (PBMC) were harvested in all groups (before dialysis in RDT patients). PBMC were cultured for 24 h in the absence or presence of LPS. The serum levels of sgp130 were significantly higher in C group than in control and S patients (C, 603.1 +/- 89.9; control, 396 +/- 49.5; S, 423.4 +/- 27.7 ng/ml; P < 0.01). PBMC from C patients, in the absence of any mitogenic stimulation, released a significantly greater amount of sgp130 as compared with S and control groups (C, 532.6 +/- 161.2; S, 332.4 +/- 148.6; control, 341.4 +/- 125.4 pg/ml; P < 0.01). The sgp130 release was positively correlated with the release of both IL-6 (r = 0.336, P < 0.05) and sIL-6R receptor (r = 0.324, P < 0.05). A significantly higher gp130 gene expression was also observed in unstimulated PBMC from C patients when compared with control and S groups. It is interesting that the expression of the 85-bp exon characteristic of the alternative splicing mRNA for sgp130 was low in all groups. Finally, confocal microscopy analysis showed an increased expression of gp130 on cell surface in unstimulated PBMC from C patients as compared with control and S groups. Our results demonstrate that in patients on RDT with C membranes, the synthesis and release of sgp130 "antagonistic" receptor is significantly increased. This release is seemingly due to a shedding of membrane-bound gp130 receptor. The increased sgp130 release may partially counteract the inflammatory effects caused by IL-6.     

Evidence that parathyroid hormone is not required for phosphate homeostasis in renal failure

Varying degrees of renal failure were produced by surgical reduction of renal mass in normal dogs and in thyroparathyroidectomized dogs (TPTX) in whom serum calcium levels were maintained in the normal range by the administration of vitamin D. Both groups of dogs maintained normal serum phosphate levels in spite of progressive decreases in glomerular filtration rates (GFR). Furthermore, both groups of dogs were able to increase the fractional excretion of phosphate as GFR decreased. Thus the same renal response to loss of GFR was maintained in the complete absence of parathyroid tissue. Finally, stable serum phosphate levels and increased fractional excretion of phosphate in response to a decrease in GFR were also demonstrated in acutely TPTX dogs who were not receiving vitamin D. These results indicate that phosphate homeostasis can be maintained in renal failure in the total absence of parathyroid hormone secretion.     

Ultrastructural histochemical and autoradiographic studies on the developing chick notochord

Summary The author examines by means of ultrastructural, histochemical and autoradiographic techniques the development of the notochord of the chick embryo in the period between Hamburger-Hamilton's Stages 9 and 26. The interest in this research is that, during this period, the notochord is transformed from an apparently undifferentiated organ into an organ with secretory activity, and at the same time becomes an inductive organ in the development of the axial skeleton.The study shows that, starting from Stage 10, the notochord cells become hypertrophic and acquire the characteristics of secretory elements, with the production of chondroitin sulphate (A and/or C) and probably of collagen microfibrils. Such substances not only cluster densely around the notochord, thus contributing to the formation of the perichordal sheath, but they also diffuse outwards, becoming distributed among the sclerotomic cells; the latter, on the other hand, start to differentiate into cartilaginous cells only after the halo deriving from the notochord has enlarged and diffused among them.It is also pointed out that there is a close temporal connection between the high degree of secretory activity of the notochord and the start of its inductive activity on the sclerotomes.     

Amantadine in chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare genetically determined immunodeficiency. Neutrophils from CGD patients show a defective killing of phagocytosed fungi and bacteria, due not only to an impairment in oxidative burst, but also to absence of normal pH value within phagocytic vacuole following phagocytosis. Because a weak base such as amantadine could potentially reverse these pH abnormalities, the authors used this drug to treat 2 CGD patients. They observed modifications of both phagosomal pH and killing activity on their neutrophils compared to those of healthy controls. Since the drug has been employed, the patients have not developed new infections, suggesting a role of amantadine as a part of CGD prophylactic regimen. These results suggest the opportunity of testing the drug in larger studies.     

Potential risk factors for the development of acute renal failure in preterm newborn infants: a case-control study

AIMS: To determine in a case-control study possible associations between the development of acute renal failure in preterm newborns and therapeutic interventions, particularly drug treatments. METHODS: The study population was 172 preterm infants of <38 weeks gestation; 71 had acute renal failure and 101 were controls closely matched for gestational age and birth weight. Maternal and neonatal information was collected for both groups through questionnaires and interviews. Routine data on renal variables were also collected. Univariate and multivariate logistic regression analyses were performed. RESULTS: Very low birthweight infants were at high risk of acute renal failure (79% of cases were <1500 g). However, the acute renal failure was transient. Mothers of infants with acute renal failure received more drugs during pregnancy and delivery (mainly antibiotics and non-steroidal anti-inflammatory drugs). Of the possible therapeutic interventions, intubation, catheterisation, and phototherapy were mainly applied to case subjects. A low Apgar score and patent ductus arteriosus were diagnosed in a greater percentage of neonates with acute renal failure. Moreover, in the first few days of life and before diagnosis of acute renal failure, case subjects received more drugs (antibiotics, non-steroidal anti-inflammatory drugs, and diuretics) and for a longer time. In the multivariate logistic analysis, medullary hyperechogenicity (odds ratio (OR) 4.491; 95% confidence interval (CI) 1.879 to 10.731) and ceftazidime administration (OR 5.082; 95% CI 1.493 to 17.297) were associated with a greater risk of acute renal failure. CONCLUSIONS: The results suggest the need for careful monitoring of very low birthweight infants and attention to drug treatments, as it is difficult to differentiate between normality and renal failure in the first few days of life.     

Factor solution of the BPRS-expanded version in schizophrenic outpatients living in five European countries

RATIONALE: The expanded version of the Brief Psychiatric Rating Scale (BPRS-E) has improved the instrument's coverage and interrater reliability, but there is little knowledge on its subsyndromes. OBJECTIVES: To assess: (1) whether there are common underlying BPRS-E subscales in patients living in different countries and (2) if this is the case, whether these subscales behave the same in all populations and, if not, what are the differences over these populations. METHODS: Data are part of the EPSILON study, a collaborative project carried out in Denmark, England, Holland, Italy and Spain. A random representative sample of 404 adult patients with a ICD-10 diagnosis of schizophrenia who have been in contact with mental health services of a defined catchment area in each site were assessed. Simultaneous component analysis (SCA) was used to find component weights that optimally explain the variance of the variables in different populations simultaneously. RESULTS: Symptom severity differed significantly among the five EPSILON sites in 12 out of 24 BPRS-E items, but a common component solution could be found. It explained 48.8% of the variance and gave four well-interpretable components: manic excitement/disorganization, depression/anxiety, negative and positive symptoms. Each component's internal consistency and intercomponent correlation matrix differed significantly among sites. The four components mean score differed significantly among sites for negative symptoms and depression/anxiety. CONCLUSIONS: In spite of the heterogeneity of symptom's severity in the various countries, the way symptoms cluster in schizophrenia is rather stable cross-culturally. Data demonstrate that to explore schizophrenia a third component, including mania/disorganization items, is necessary beside the positive-negative symptom dimensions. The subscales derived from these analyses can be readily used in clinical trials and epidemiological studies.