Strategies for cytokine utilisation in tumor therapy

The state of the art with regard to the employment of various cytokine-based tumor immunotherapy strategies and their mechanisms of action are critically reviewed. As matters now stand, adoptive transfer of LAK cells or tumor infiltrating lymphocytes together with high doses of IL-2 constitutes the only immunologic way to hinder tumor growth in advanced stages of cancer. On the other hand, many experimental data show that the local presence of cytokines, either injected repeatedly at tumor site or released by cytokine-gene engineered tumor cells, arouses immunogenicity in apparently nonimmunogenic spontaneous tumors. By strengthening the notion that most tumors are potentially immunogenic, these f'mdings offer substantial evidence to stres~ the potential use ofcytoklnes as a component of new tumor vaccines.     

Survival and Prognostic Factors of Cirrhotic Patients with Ascites: A Study of 134 Outpatients

Ascites is a complication of chronic liver disease that is associated with decreased survival. The purpose of the present study was to identify some prognostic factors easily obtainable by the clinician in a large group of cirrhotic patients with ascites, possibly useful for first screening of outpatients as candidates for liver transplantation. We studied 134 ambulatory patients with cirrhosis who came to our outpatient clinic between July 1983 and March 1989 because of an episode of ascites. These patients were then followed up for an average period of 31 ± 23 months and survival was determined. Thirty-one variables determined at the time of inclusion were analyzed with a Cox proportional hazards model to identify predictors of mortality. Cumulative mortality as of June 30, 1991, was 59%. Factors independently correlated with death were: refractory ascites (relative risk, 4.78), low albumin levels (3.77), high Child-Pugh score (3.31), encephalopathy (2.71), high bilirubin levels (2.03), high γ-glutamyl-transferase levels (1.87), and old age (1.57). The results show that 1 ) the occurrence of refractory ascites has a prognostic value superior to those of other variables, and 2 ) simple clinical and biochemical parameters, most of them components of the Child-Pugh score, are useful for a first screening of ascitic cirrhotic patients as candidates for liver transplantation.     

An outbreak of Salmonella hadar associated with food consumption at a building site canteen

A biphasic outbreak of gastroenteritis caused by Salmonella hadar affected canteen employees and workers at a construction site in central Italy in September 1994. There were 448 symptomatic cases, from 61 of whom group C Salmonella was isolated. Six cases were canteen employees. Twenty-two other individuals were asymptomatic excreters. There were 10 secondary cases. Working as a food handler at the canteen constituted an increased risk of infection, independently of ingestion of the food (odds ratio: 62.1; 95% confidence interval (CI): 9.5– 406.6). Having eaten at the canteen on the 19th and 20th September was identified as risk factor for subjects symptomatic within 72 hours (relative risk (RR): 17.0, 95% CI: 2.3–124.3), and cooled meat salad was identified as the vehicle of infection (RR: 36.6, 95% CI: 14.3–93.8). The use of portable toilets was another possible route of transmission of infection for all cases (RR: 1.3, 95% CI: 1.0–1.6). The index case was a cook who had symptoms five days before the peak of the outbreak. From 27 individuals both symptomatic and asymptomatic excreters group B, group D and not-typed Salmonellas were isolated. This study underlines the problem of improper food handling in salmonellosis outbreaks and emphasizes the role of several vehicles in the transmission of salmonellosis in a community.     

Evaluating health-related quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications

Although numerous paediatric-based health-related quality-of-life (HR-QOL) instruments are currently in use, there still remain conceptual, methodological and developmental issues to address. This paper provides an up-to-date critical review of the HR-QOL literature in paediatric medicine.Our analysis indicates that there is no consensus on how HR-QOL and overall QOL should be defined and measured in children. It is recommended that future studies focus on operationalising and distinguishing these constructs from each other and from traditional health-status measures. A clear empirical basis for generating instrument items and for prioritising specific domains must be described. Researchers should consider using the data gathered during their first interviews as a springboard from which to test their ideas of HR-QOL and QOL, reformulate concepts and subsequently retest their notions before developing instruments.Related to methodological challenges, consistency and agreement are still used interchangeably when comparing child and parent reports of children's HR-QOL. The Pearson correlation is a measure of co-variation in scores, and not a measure of agreement. We recommend that researchers focus on determining agreement as opposed to consistency. Few, if any, attempts have been made to account for the possibility that a response shift may have occurred in the evaluation of HR-QOL. Most studies have compared HR-QOL scores of children with illness with their healthy peers. As such, there is a dearth of knowledge regarding the normative process of adaptation within the context of illness. It is recommended that researchers focus on gathering data using a relative standard of comparison. We further recommend that researchers interpret HR-QOL data in line with their intended purpose. Regarding developmental consideration, particular attention ought to be paid to developing instruments that consider children's emerging sense of self, cognitive capacity and emotional awareness. Instruments that include items that are age appropriate are more likely to maximise reliability and validity of reports.The results of many HR-QOL instruments are applied in pharmacotherapeutic and pharmacoeconomic assessments. However, there has been relative infrequent application of economically valid HR-QOL tools (utility scales) and the use of HR-QOL scales as outcome measures in paediatric drug trials. As such, few cost-utility analyses have been performed to inform paediatric decision making. In addition, many of the concerns in the development of HR-QOL instruments should also be applied to the utility scales such that they reflect adequately children's preferences for health states.     

Synthesis and chemiluminescent high throughput screening for inhibition of acetylcholinesterase activity by imidazo[2,1-b]thiazole derivatives

The synthesis of a new series of imidazo[2,1-b]thiazole derivatives is described. They were tested as acetylcholinesterase inhibitors by means of a chemiluminescent method suitable for high throughput screening. The compounds without quaternization had no appreciable inhibitory potency probably because they are poorly soluble in water. The corresponding quaternized compounds were good inhibitors with activity related to the spacer employed.     

Cx26 gene mutations in idiopathic progressive hearing loss

OBJECTIVE: The present study evaluated the frequency and type of mutations throughout the entire GJB2 region in a population of 39 patients affected with sporadic progressive "idiopathic" hearing loss. MATERIAL: A large series of patients suffering from progressive hearing loss underwent a systematic screening program to identify the etiology of the hearing loss. Of these patients, 39 presented with sporadic idiopathic progressive hearing loss and were included in this study. METHOD: We performed molecular analysis of GJB2 in each patient sequencing the genomic deoxyribonucleic acid (DNA) in both directions for detection of GJB2 mutations. Furthermore, in all patients bearing a Cx26 mutation, a search was also conducted for mutations or deletions of GJB6 (Cx30 gene) and for the A1555G mutation of the mitochondrial DNA. A control group was also considered to evaluate the frequency of Cx26 mutations in the normal population. RESULTS: A Cx26 gene mutation was detected in nine cases. One subject was found to bear a homozygous genotype for the 35delG mutation, another subject was compound heterozygous for 35delG and E47X, and the remaining patients showed heterozygous genotypes (35delG, L90P, R127H, M34T, V153I, V37I). No mutation or delection of the Cx30 gene was observed in these nine patients, and none of them presented with the A1555G mutation in the mitochondrial DNA. In the control group (40 individuals), a Cx26 mutation was detected in two cases (5%). CONCLUSIONS: About 23% of our patients (nine subjects) presented with mutations in GJB2, and 18% (seven subjects) were heterozygous. However, most of the described mutations are recessive, so a monogenic model of inheritance cannot explain the deafness phenotype. On the basis of these findings, we can speculate that the heterozygote Cx26 genotype could be a cause of progressive hearing loss, probably in association with mutations in other alleles. Thus, we recommend carefully following all hearing-impaired subjects with GJB2 mutations, even if they present with only mild hearing loss, because the hearing deficit could worsen. Furthermore, molecular analysis of the Cx26 gene should also be performed in adult patients affected with idiopathic progressive hearing loss.     

Immunological mechanisms elicited at the tumour site by lymphocyte activation gene-3 (LAG-3) versus IL-12: sharing a common Th1 anti-tumour immune pathway

The experimentally induced TS/A murine mammary carcinoma is poorly immunogenic and mainly infiltrated by antigen-presenting cells (APCs), namely macrophages and immature dendritic cells (DCs). Human (h) and mouse (m) lymphocyte activation gene-3 (LAG-3 or CD233) is a physiological MHC class II ligand and powerful APC activator. A gene transfer approach has revealed its anti-tumour activity in this model: hLAG-3 was more effective than mLAG-3. To obtain a clearer picture of the immunoregulatory mechanisms associated with the rejection dynamics of h- and m-LAG-3 transfectants, immunohistochemistry and confocal microscopy analyses of TS/A-hLAG-3, TS/A-mLAG-3, and control TS/A-pc tumours were performed. The immune events elicited by mLAG-3 and m-interleukin (IL)-12 were also compared, since their rejection kinetics were quite similar, and LAG-3 enables IL-12 production by macrophages and DCs. Both the TS/A-h- and, to a lesser extent, the m-LAG-3 rejection areas were characterized by an impressive recruitment of APCs, granulocytes, NK cells, CD4+ T lymphocytes and CD8+ IFNgamma-expressing cells. In both cases, infiltration by APCs was accompanied by strong CD80 and CD86 expression and macrophage nitric oxide (NO) synthase up-regulation. Distinct expression of IL-12 and CXCL9 was also found, especially in the draining lymph nodes. T lymphocytes and CD86-expressing APCs were significantly prevalent in both the TS/A-h- and the m-LAG-3 compared with the TS/A-mIL-12 rejection area. Production of IFNgamma, TNFalpha and IL1beta, and chemokines, namely CXCL5, CXCL9, CXCL10, CXCL11, CCL5, and CCL2, by infiltrating leukocytes and signs of defective neovascularization were detected in tumours expressing h-LAG-3-, m-LAG-3-, and m-IL-12. However, IFNgamma, CCL2, and CCL5 production prevailed in the TS/A-hLAG-3 rejection area. Taken together, these results indicate that LAG-3 expression by engineered tumour cells efficiently promotes intra-tumoural recruitment, activation, and Th1 commitment of APCs, and leads to a wide intra-tumoural influx of non-specific and specific reactive cells, and the release of immunoregulatory and cytotoxic mediators. Many of LAG-3's anti-tumour activities are shared with IL-12.     

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.     

Novel quantitative immunofluorescent technique reveals improvements in epidermal cell populations after mild treatment of psoriasis

A novel antibody labelling technique, the Zenon technique, was used in fluorescent immunohistochemistry for a better characterization of epidermal cell populations in a quantitative approach. With this technique, differences in proliferation and differentiation characteristics were shown between psoriatic and normal epidermis. The sensitivity of the method was investigated by assessing the effect of a mild topical treatment versus an emollient.Frozen sections of non-treated psoriatic epidermis and psoriatic epidermis treated once daily with either an emollient or betamethasone-17-valerate for only 2 weeks were compared immunohistochemically. Antibodies against keratin 6, 10 and 15 were labelled with the Zenon technique, whereas antibodies against the Ki-67 antigen and beta-1 integrin were covalently FITC-labelled. Using image analysis, these markers were measured in the epidermis in a standardized manner.Treatment of psoriasis with short-term topical steroid resulted towards normalization of Ki-67 antigen, beta-1 integrin, keratin 10 and keratin 6 expression, which are parameters for proliferation and differentiation. Although treatment with an emollient showed hardly any clinical response, changes towards a more normal phenotype could already be detected in several epidermal markers using this method.     

A Cardiac Depression Visual Analogue Scale for the brief and rapid assessment of depression following acute coronary syndromes

OBJECTIVE: A Cardiac Depression Visual Analogue Scale (CD-VAS) was developed as a rapid and easy method of assessing depressed mood in a cardiac population. The CD-VAS was contrasted against the Cardiac Depression Scale (CDS) and the Beck Depression Inventory-II (BDI-II). METHOD: Depression was assessed in 58 participants, 2 weeks postacute coronary syndrome (ACS), using the BDI-II and the CDS. Participants then completed the six-item CD-VAS for 14 consecutive days. RESULTS: Using mean weekly scores, the CD-VAS had strong internal reliability (.91) and strong test-retest reliability that ranged from .85 to .97. Principal components analyses found that the CD-VAS only measured one component. The CD-VAS had strong concurrent validity with the BDI-II (r=.81) and the CDS (r=.82) and was able to differentiate between depressed and nondepressed participants. CONCLUSION: The CD-VAS is a valid and reliable measure for brief and rapid repeated assessments of depressive symptoms in a cardiac population.