Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells

Although the existence of a humoral response against tumor-associated antigens is well appreciated, a systematic analysis of its possible induction by the tumor remains missing. We compared the specific IgG response of Stage IV melanoma patients during vaccination. Patients had been treated within 2 clinical trials with autologous tumor cells gene-modified for IL-7 or IL-12. A panel of 27 tumor-associated antigens (HD-MM-01 to HD-MM-27) was isolated by a SEREX screening of a testis cDNA library using a pool of 5 sera from patients after vaccination. All antigens were retested with individual sera of 12 patients both pre- and post-vaccination. A serological response was induced during vaccination against 18 antigens. Remarkably, induction was detected only in patients included in the screening pool. The low overlap between sero-reactivity of the 12 patients suggested a very individualized immunological reaction. Two of 5 sera included in the screening pool exhibited a high frequency of induced humoral responses. The same patients had been shown to have a high Karnovsky index and had generated lytic cytotoxic T cells against the tumor. Besides 2 known cancer-germline genes (SCP-1 and PLU-1), the other isolated antigens were expressed in a non-tumor-specific fashion as analyzed by virtual Northern blot or RT-PCR. The properties of homologues to several of the identified tumor-antigens, especially PLU-1, SCP-1, DNEL2, CLOCK, and PIASx-alpha, suggest further investigation of their possible function in malignant melanoma. We conclude that a strong humoral response against tumor-associated antigens is inducible by tumor cells and that this response is very individual.     

Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis

OBJECTIVE: Lupus nephritis (LN) is a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is evidence that polymorphisms in the genes of inflammatory mediators may predispose to the development of LN in patients with SLE. In this study, we examined the role of a functional monocyte chemoattractant protein 1 (MCP-1) polymorphism in SLE and LN. METHODS: DNA and paired urine and serum samples were obtained from 134 SLE patients (> or =4 American College of Rheumatology criteria for SLE; 49 with and 85 without LN) and 118 controls. MCP-1 genomic variants were detected by polymerase chain reaction followed by restriction enzyme-fragment analysis. Urinary and serum MCP-1 levels and MCP-1 production by peripheral blood macrophages were measured by enzyme-linked immunosorbent assay. RESULTS: The A/A genotype was more common in controls than in SLE patients (P = 0.0002), whereas both the A/G (P = 0.009) and G/G (P = 0.0212) genotypes were more frequent in SLE patients. The A/A genotype was observed in only 23% of the patients with LN compared with 58% of those without LN (P < 0.0001). MCP-1 production by peripheral blood mononuclear cells from patients with the A/G and G/G phenotypes was markedly higher than the production by cells from patients with the A/A genotype. Urinary levels of MCP-1 were significantly higher in patients with LN. CONCLUSION: These results suggest that an A/G or G/G genotype may predispose to the development of SLE and further indicate that SLE patients with these genotypes may be at higher risk of developing LN. Moreover, measurement of urinary levels of MCP-1 may be a useful tool for the detection and management of LN.     

Effects of verteporfin therapy on central visual field function

PURPOSE: To evaluate the effect of photodynamic therapy with verteporfin on the maintenance of central visual field function. DESIGN: Randomized controlled clinical trial. PARTICIPANTS: Forty-six consecutive patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration including a classic component were randomly assigned. Thirty-three participants received standard verteporfin therapy, and 13 received placebo and laser treatment. METHODS: The trial was performed as a single-center, double-masked study. Patients were examined before therapy and continuously in 3-month intervals during 2 years of follow-up. A scanning laser ophthalmoscope (SLO) was used to perform macular microperimetry. Absolute and relative scotomas were documented at each visit, and size was measured in square millimeters. MAIN OUTCOME MEASURES: The change in size of central scotoma in the verteporfin group compared with the placebo group. RESULTS: An absolute scotoma was seen in 88%, and a relative scotoma was seen in 100% of eyes before therapy. Absolute defects were associated with the classic CNV component localized angiographically. In the verteporfin group, the absolute scotoma grew from 2.5 mm(2) at baseline to a final size of 7.3 mm(2) at month 24. In the placebo group, the mean lesion size of the absolute scotoma enlarged from an initial size of 2.7 mm(2) to 31.5 mm(2) after 24 months. The relative scotoma increased from 7.9 mm(2) at baseline to 20.8 mm(2) at month 24 in the verteporfin group, whereas a progression from 8.5 mm(2) initially to 48.3 mm(2) at the final presentation was measured in the placebo group. Statistical analysis showed that both the mean absolute and relative scotoma sizes were significantly smaller in the verteporfin group than the placebo group for all intervals from 6 to 24 months (P<0.001). CONCLUSIONS: Documentation of macular function with SLO perimetry demonstrated a significant benefit of verteporfin therapy for the preservation of the central visual field. Absolute and relative scotoma sizes remained smaller after therapy. This may influence reading ability and visual rehabilitation.     

Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour

The suppression and eradication of malignant tumours by targeting the endothelial cells of the tumour is one of the rapidly evolving new approaches to cancer therapy. Head and neck tumours, because of their high levels of vascularization, present themselves as ideal candidates for such antiangiogenic strategies. We report a heavily pretreated patient with a tumour 15 cm in diameter representing fourth relapse of squamous cell carcinoma, which had its origin in the upper left jaw. The patient was treated with the antiangiogenetic, cyclic peptide, EMD 121974 [cilengitide] (600 mg/m2 over 60 minutes i.v.) on day 1 and 4 in combination with gemcitabine (1000 mg/m2 over 30 minutes) administered days 1 and 8 every 3 weeks for five months, and a partial remission was achieved. This resulted in a clinical improvement in the ability of the patient to eat and smell. The patient remained stable for 12 months on cilengitide mainenance therapy, with no tendency towards spontaneous bleeding. This clinical case demonstrates the clinical efficacy of the antiangiogenetic agent cilengitide, in combination with gemcitabine, in inhibiting rapid growth of highly vascularized tumour and highlights the potential of this new therapeutic agent     

Anterior cruciate reconstruction combined with autologous osteochondral transplantation

The purpose of this prospective study was to evaluate the results of simultaneous anterior cruciate ligament (ACL) reconstruction and osteochondral autograft transplantation performed in patients suffering an anterior instability associated with symptomatic full-thickness cartilage defects. Our clinical report includes the first 21 patients (six women, 15 men) who have been followed up for 32 months or longer. The average patient age was 29 years (range 22–44 years), and mean time from injury to the combined reconstructive surgery was 10 months (range 4–27 months). The cartilage defects had a mean area of 3.5 cm² (range 2.0–5.0 cm²). All patients were evaluated according to the IKDC, Lysholm and Tegner scoring scales by an independent observer. A visual analogue scale (VAS) reflecting patient pain was evaluated. Assessment using the IKDC knee scoring scale revealed 81% of the patients with a normal or nearly normal knee joint. There was a significant improvement in subjective discomfort, and the KT-1000 arthrometric evaluation showed a reduction of the ventral tibial translation (5.9 to 1.9 mm). All but two patients had returned to full activities without restriction and were asymptomatic. The results of this study suggest that symptomatic full-thickness articular cartilage defects associated with ACL instability can be effectively treated by performing ACL reconstruction and osteochondral autologous grafts in one procedure. However, only the years which follow will show the long-term outcome of the patients.     

Prospect of therapeutic approaches to tauopathies

Alois Alzheimer described the concurrence of two conspicuous proteinacious aggregates in 1906. Today it is clear that the two types of protein aggregates are fundamentally different. One consists of a short fragment (Abeta peptide) of a membrane protein APP and is found mainly outside of cells and the other is formed from a biochemically modified cytoskeleton-associated protein known as tau. The latter is found exclusively inside cells. Aggregated tau in all tauopathies including AD is abnormally modified by the excess incorporation of chemical groups called phosphates (hyperphosphorylation), and the appearance of this biochemical change coincides with the onset all tauopathies, suggesting that it is both a necessary and sufficient cause for such diseases. Data indicate that the basis for tau hyperphosphorylation is the dysregulation of key enzymes known as kinases. These enzymes are therapeutic targets for AD and other neurodegenerative diseases, which feature pathological tau structures in brain     

The identification of trends in the utilisation of mental health services by elderly: a Dutch case register study

OBJECTIVE: In view of the rapid ageing of the population any changes in the use of mental health services by the elderly became increasingly important for policy development. This study aimed at the supply of information about trends in the numbers of elderly clients, the services they used and the volume and pattern of service utilisation. METHODS: Details of elderly users and their use of community- and hospital-based services between 1990 and 1999 were retrieved from the Groningen case register. Developments in population size and age distribution in the register area were taken into account, as were the unit costs of mental health services. RESULTS: Large age specific changes were found that caused only the expenditures on the oldest elderly to increase due to a shift from outpatient clinics to prolonged psychogeriatric day treatment and inpatient care. Comparatively young elderly used fewer inpatient services and more community care. The number of new elderly clients declined progressively. In some age groups treated prevalence also decreased, but to a lesser extent, because of a prolonged use of mental health services. CONCLUSIONS: Study results seemed well in accordance with mental health policy as to deinstitutionalization and active ageing. Research on the effect of mental health care on life expectancy and the time lag between the intake of mental health providers and treated prevalence was proposed in order to improve the prediction of future service use by elderly.     

Dietary fat content alters insulin-mediated glucose metabolism in healthy men

BACKGROUND: A high dietary fat intake is involved in the pathogenesis of insulin resistance. OBJECTIVE: The aim was to compare the effect of different amounts of dietary fat on hepatic and peripheral insulin sensitivity. DESIGN: Six healthy men were studied on 3 occasions after consuming for 11 d diets with identical energy and protein contents but different percentages of energy as fat and carbohydrate as follows: 0% and 85% [low-fat, high-carbohydrate (LFHC) diet], 41% and 44% [intermediate-fat, intermediate-carbohydrate (IFIC) diet], and 83% and 2% [high-fat, low-carbohydrate (HFLC) diet]. Insulin sensitivity was quantified by using a hyperinsulinemic euglycemic clamp (plasma insulin concentration: approximately 190 pmol/L). RESULTS: During hyperinsulinemia, endogenous glucose production was higher after the HFLC diet (2.5 +/- 0.3 micromol x kg(-1) x min(-1); P < 0.05) than after the IFIC and LFHC diets (1.7 +/- 0.3 and 1.2 +/- 0.4 micromol x kg(-1) x min(-1), respectively). The ratio of dietary fat to carbohydrate had no unequivocal effects on insulin-stimulated glucose uptake. In contrast, insulin-stimulated, nonoxidative glucose disposal tended to increase in relation to an increase in the ratio of fat to carbohydrate, from 14.8 +/- 5.1 to 20.6 +/- 1.9 to 26.2 +/- 2.9 micromol x kg(-1) x min(-1) (P < 0.074 between the 3 diets). Insulin-stimulated glucose oxidation was significantly lower after the HFLC diet than after the IFIC and LFHC diets: 1.7 +/- 0.8 compared with 13.4 +/- 2.1 and 19.0 +/- 2.1 micromol x kg(-1) x min(-1), respectively (P < 0.05). During the clamp study, plasma fatty acid concentrations were higher after the HFLC diet than after the IFIC and LFHC diets: 0.22 +/- 0.02 compared with 0.07 +/- 0.01 and 0.05 +/- 0.01 mmol/L, respectively (P < 0.05). CONCLUSION: A high-fat, low-carbohydrate intake reduces the ability of insulin to suppress endogenous glucose production and alters the relation between oxidative and nonoxidative glucose disposal in a way that favors storage of glucose.