A dose-escalation study of irinotecan (CPT-11) in combination with gemcitabine in patients with advanced non-small cell lung cancer previously treated with a cisplatin-based front line chemotherapy

PURPOSE: CPT-11 and gemcitabine are both active agents against non-small cell lung cancer (NSCLC). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of their combination in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: Twenty-seven patients with histologically confirmed NSCLC, who had failed cisplatin-based front-line chemotherapy, were enrolled. The patients' median age was 56 years, 24 were male and 22 had a performance status (WHO) 0-1. Gemcitabine was administered on days 1 and 8, as a 30-minute i.v. infusion, at escalated doses ranging from 900 to 1200 mg/m2. CPT-11 was given over a 60-minute i.v. infusion on day 8 at escalated doses ranging from 200 to 350 mg/m2, following gemcitabine administration. The treatment was repeated every three weeks. RESULTS: The MTD was exceeded at dose-level 7 with CPT-11 350 mg/m2 and gemcitabine 1200 mg/m2, where all three enrolled patients presented DLTs (one patient grade 4 thrombocytopenia, one grade 3 diarrhea and one grade 3 asthenia). The recommended doses for future phase II studies are CPT-11 300 mg/m2 on day 8 and gemcitabine 1200 mg/m2 on days 1 and 8. A total of 107 treatment cycles were administered. Grade 3/4 neutropenia was observed in 13 (13%) cycles, febrile neutropenia in 3 (3%) and grade 3/4 thrombocytopenia in 2 (2%). Grade 2/3 diarrhea was seen in 6 (6%) cycles, grade 2/3 nausea and vomiting in 13 (13%) and grade 2/3 asthenia in 8 (8%). Other toxicities were mild. Among 23 patients evaluable for response, PR was achieved in one (4.5%), SD in 12 (52.5%) and PD in 10 (43%). CONCLUSION: The results of this phase I study clearly demonstrate that gemcitabine and CPT-11 can be efficiently combined in a low-toxicity regimen with doses equal or near monotherapy levels. Further studies are needed to evaluate the efficacy of this combination in both chemotherapy-naive and pre-treated patients with advanced NSCLC.     

Mood disorder with mixed features due to vitamin B(12) and folate deficiency

Vitamin B(12) and folate deficiency is often associated with affective disorders mainly of the depressive type. We report a case of a 42-year-old woman with a mood disorder with mixed depressed/manic features that was due to vitamin B(12) and folate deficiency. The psychopathology developed over a five-year period without hematologic or other overt clinical characteristics of pernicious anemia. Replacement treatment with vitamin B(12) and folate was rapidly followed by full clinical remission, electroencephalographic normalization and neuropsychological improvement. At a one-year follow-up this condition was stable. Consequently, patients who respond poorly to psychopharmacologic treatment and/or present with atypical mood symptoms would warrant determination of vitamin B(12) and folate serum levels.     

The cytoprotective effect of amifostine in acute radiation dermatitis: a retrospective analysis

To study the impact of amifostine as a cytoprotective agent against acute radiation dermatitis, we reviewed 220 patient records. One hundred cancer patients, with tumors localised in the pelvis (bladder, rectum, prostatic carcinomas, or gynecological cancer), who received radiotherapy and cytoprotective treatment with intravenous infusion of amifostine (group A) were included in this study. Retrospectively, we randomly selected from a database in our hospital 120 historical controls, who received only radiotherapy without cytoprotection (group B). Mean gross dermatitis score (MGDS) was the mean value of recorded acute radiation dermatitis according to common toxicity criteria. In group A versus B patients, a significantly reduced severity of dermatitis (P < 0.001, Fisher's exact test) and significant reduction of MGDS as well as mean interruption treatment time (P < 0.001, Mann-Whitney U test) was observed. The relative risk of the outcome of the two study groups was 0.23 (95% CI: 0.15 to 0.34). The significant dermato-cytoprotective effect of amifostine noticed in our retrospective analysis warrants further investigation with randomised trials.     

Transition to the open state of the TolC periplasmic tunnel entrance

The TolC channel-tunnel spans the bacterial outer membrane and periplasm, providing a large exit duct for protein export and multidrug efflux when recruited by substrate-engaged inner membrane complexes. The sole constriction in the single pore of the homotrimeric TolC is the periplasmic tunnel entrance, which in its resting configuration is closed by dense packing of the 12 tunnel-forming alpha-helices. Recruitment of TolC must trigger opening for substrate transit to occur, but the mechanism underlying transition from the closed to the open state is not known. The high resolution structure of TolC indicates that the tunnel helices are constrained at the entrance by a circular network of intra- and intermonomer hydrogen bonds and salt bridges. To assess how opening is achieved, we disrupted these connections and monitored changes in the aperture size by measuring the single channel conductance of TolC derivatives in black lipid bilayers. Elimination of individual connections caused incremental weakening of the circular network, accompanied by gradual relaxation from the closed state and increased flexibility of the entrance. Simultaneous abolition of the key links caused a substantial increase in conductance, generating an aperture that corresponds to the modeled open state, with the capacity to allow access and passage of diverse substrates. The results support a model in which transition to the open state of TolC is achieved by an iris-like realignment of the tunnel entrance helices.     

Developing and testing an instrument for identifying performance incentives in the Greek health care sector

Background  

In the era of cost containment, managers are constantly pursuing increased organizational performance and productivity by aiming at the obvious target, i.e. the workforce. The health care sector, in which production processes are more complicated compared to other industries, is not an exception. In light of recent legislation in Greece in which efficiency improvement and achievement of specific performance targets are identified as undisputable health system goals, the purpose of this study was to develop a reliable and valid instrument for investigating the attitudes of Greek physicians, nurses and administrative personnel towards job-related aspects, and the extent to which these motivate them to improve performance and increase productivity.     

Prevalence of allergic symptoms among children with diabetes mellitus type 1 of different socioeconomic status

Abstract:  The aim of the study was to assess the possible associations between allergies and type 1 diabetes mellitus (DM1), stratified by social class. We studied 127 children with DM1 with a median age of 10.8 yr and 150 controls of comparable age and sex distribution. The parents completed questionnaires on their education and occupation and on their children's history of allergic symptoms, breast-feeding, viral infections, and measles–mumps–rubella (MMR) vaccination. Lower family's social class was more frequently encountered among the DM1 families than in the controls (OR = 0.56, 95% CI: 0.35–0.92). The occurrence of any allergic symptoms among children with DM1 (35.45%) was not significantly different from the controls (38.78%), neither in the total group (OR = 0.87, 95% CI: 0.52–1.45) nor in the stratified analysis by social class. Similar findings were observed regarding the different types of allergic symptoms. In the univariate analysis, breast-feeding, the experience of viral infections, and MMR vaccination were found to be protective of DM1 presentation in both upper and lower social classes. In the multiple logistic regression analysis, the experience of more than 2 infections/yr (OR = 0.12, 95% CI: 0.04–0.34), the origin from middle and upper social classes (OR = 0.42, 95% CI: 0.22–0.80) and breast-feeding (OR = 0.58, 95% CI: 0.31–1.07) were protective of DM1 occurrence. In children with DM1, the presence of allergic symptoms was not associated with the development of DM1. Among the environmental factors, the origin from middle or upper social classes, breast-feeding, the experience of viral infections, and MMR vaccination were found to have a protective effect on DM1 presentation.     

The value of computed tomography-derived coronary artery calcification score in coronary artery disease detection in asymptomatic hemodialysis patients

BACKGROUND: We evaluated the value of coronary artery calcification (CAC) score in coronary artery disease (CAD) detection in asymptomatic hemodialysis (HD) patients by evaluating the association among CAC score, exercise electrocardiography (EECG), and Thallium-201 dipyridamole scintigraphy. Correlation between aortic pulse wave velocity (PWV) and CAC score was also evaluated. METHODS: CAC score was assessed with conventional computed tomography in 40 patients. Thirty patients completed EECG and 25; those with a positive CAC score and/or a positive EECG performed Thallium dipyridamole scintigraphy. Carotid-femoral PWV was assessed in all patients. RESULTS: There was no association among CAC score and EECG or Thallium dipyridamole scintigraphy. In contrast, CAC score was correlated with aortic PWV. CONCLUSION: The previous results question the role of CAC score in the detection of CAD in asymptomatic HD patients. The correlation between CAC score and aortic PWV raises the possibility that CAC score represents more an indicator of coronary artery medial wall calcification than a marker of CAD.     

Verbal fluency in institutionalized patients with schizophrenia: age-related performance decline

Several studies have reported a relatively stable level of cognitive deficits among patients with schizophrenia regardless of age, while others have suggested continued deterioration with age. We compared the performance of 42 institutionalized patients with schizophrenia and 42 age- and education-matched healthy controls on a semantic and phonemic verbal fluency test. Each group was divided into young participants (<65 years old) and elderly participants (> or =65 years old). We found a fluency condition x diagnostic group x age group interaction on total words produced, a fluency condition x diagnostic group interaction on the number of cluster-related words, and a fluency condition x age group interaction on the number of switches. Patients with schizophrenia generally used similar strategies (i.e., semantic or phonemic cluster-related words and switches) as healthy individuals when generating words, but to a lesser degree. We found a disproportionate decline in the elderly schizophrenic patients relative to that of healthy controls only on the phonemic, relative to the semantic test. This decline in performance appears related to the effects of aging rather than severity or chronicity of illness, duration of institutionalization, or a progressive degenerative process associated with the disorder.     

Octreotide regulates CC but not CXC LPS-induced chemokine secretion in rat Kupffer cells

Kupffer cells (KC) and lipopolysaccharide (LPS) interaction is the initial event leading to hepatic inflammation and fibrosis in many types of liver injury. We studied chemokine secretion by KC activated with LPS and the possible effect of the somatostatin analogue octreotide, in the regulation of this process. KC isolated from Sprague-Dawley rats were cultured in the presence of LPS added alone or with different concentrations of octreotide for 24 and 48 h, and chemokine production was assessed in culture supernatants by ELISA. CC chemokine mRNA expression was assessed by semiquantitative RT-PCR. Vehicle-stimulated KC produced a basal amount of CC and CXC chemokines. LPS-stimulated KC secreted significantly increased amounts of IL-8 (GRO/CINC-1) (P<0.001), MIP-2 (P<0.001), MCP-1 (P<0.001), and RANTES (P<0.01). Octreotide inhibited LPS-induced secretion of the CC chemokines MCP-1 (P<0.05) and RANTES (P<0.05), but not the CXC chemokines IL-8 (GRO/CINC-1) and MIP-2, in a concentration-dependent manner. Downregulation of basal and LPS-induced mRNA expression of the CC chemokines was also observed in the presence of octreotide. Pretreatment with phosphatidylinositol 3 (PI3)-kinase inhibitors reduced chemokine production by LPS-treated KC in both the mRNA and protein level. Furthermore, it prevented the octreotide inhibitory effect on LPS-induced chemokine secretion, indicating a possible involvement of the PI3-kinase pathway. In conclusion, these data demonstrate that chemokine secretion by KC can be differentially regulated by octreotide, and suggest that this somatostatin analogue may have immunoregulatory effects on resident liver macrophages.British Journal of Pharmacology (2004) 141, 477-487. doi:10.1038/sj.bjp.0705633     

1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a bioisostere of a carboxylic acid aldose reductase inhibitor

[1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone (6) was synthesized as a putative bioisostere of the known aldose reductase (AR) inhibitor (3-benzoylpyrrol-1-yl)acetic acid (I). It was found that 6 is approximately 5 times more potent as an in vitro inhibitor of AR than I, with an IC(50) value in the submicromolar range. Furthermore, 6 showed considerable activity in an in vitro experimental glycation model of diabetes mellitus. Our results support the notion that 6 might become a useful lead structure.