Brain activation measured with fMRI during a mental arithmetic task in schizophrenia and major depression

OBJECTIVE: The authors used functional magnetic resonance imaging (fMRI) to investigate brain activation in patients with schizophrenia and major depression while they performed two tasks-a vigilance task and a mental arithmetic task-that differed in cognitive complexity. METHOD: In the vigilance task, the participants had to press a response button whenever a specific number was seen on a screen inside the MR scanner. In the mental arithmetic task, the participants had to add two consecutive numbers and press the response button whenever the sum was 10. fMRI was performed with a 1.5-T MR scanner. Twelve patients with recurrent nonpsychotic unipolar major depression, 12 patients with schizophrenia, and 12 healthy comparison subjects were included in the study. RESULTS: Performance data showed that the patients were impaired relative to the comparison subjects and showed no difference in performance between the patient groups. The patients with schizophrenia, but not those with major depression, had less activation in prefrontal brain regions, relative to the comparison participants. However, subtracting brain activation during the vigilance task from activation during the mental arithmetic task showed that the schizophrenia patients had activation in parietal areas. CONCLUSIONS: A double dissociation of parietal and frontal lobe activation was found for the schizophrenia patients and the depression patients. The greater parietal lobe activation in the patients with schizophrenia may reflect a compensatory strategy for the failure to recruit cognitive processes that involve frontal lobe areas when solving a mental arithmetic task.     

Cell-type-specific responses to chemotherapeutics in breast cancer

Recent microarray studies have identified distinct subtypes of breast tumors that arise from different cell types and that show statistically significant differences in patient outcome. To gain insight into these differences, we identified in vitro and in vivo changes in gene expression induced by chemotherapeutics. We treated two cell lines derived from basal epithelium (immortalized human mammary epithelial cells) and two lines derived from luminal epithelium (MCF-7 and ZR-75-1) with chemotherapeutics used in the treatment of breast cancer and assayed for changes in gene expression using DNA microarrays. Treatment doses for doxorubicin and 5-fluorouracil were selected to cause comparable cytotoxicity across all four cell lines. The dominant expression response in each of the cell lines was a general stress response; however, distinct expression patterns were observed. Both cell types induced DNA damage-response genes such as p21(waf1), but the response in the luminal cells showed higher fold changes and included more p53-regulated genes. Luminal cell lines repressed a large number of cell cycle-regulated genes and other genes involved in cellular proliferation, whereas the basal cell lines did not. Instead, the basal cell lines repressed genes that were involved in differentiation. These in vitro responses were compared with expression responses in breast tumors sampled before and after treatment with doxorubicin or 5-fluorouracil/mitomycin C. The in vivo data corroborated the cell-type-specific responses to chemotherapeutics observed in vitro, including the induction of p21(waf1). Similarities between in vivo and in vitro responses help to identify important response mechanisms to chemotherapeutics.     

Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I

The prevalence of autoantibodies against nine intracellular enzyme autoantigens, namely 21-hydroxylase, side-chain cleavage enzyme (SCC), 17 alpha-hydroxylase, glutamic acid decarboxylase 65, aromatic L-amino acid decarboxylase, tyrosine phosphatase-like protein IA-2, tryptophan hydroxylase (TPH), tyrosine hydroxylase, cytochrome P450 1A2, and against the extracellular calcium-sensing receptor, was assessed in 90 patients with autoimmune polyendocrine syndrome type I. A multivariate logistic regression analysis was performed for the presence of autoantibodies as independent predictors for different disease manifestations. Reactivities against 21-hydroxylase and SCC were associated with Addison's disease with odds ratios (ORs) of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against SCC with an OR of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with insulin-dependent diabetes mellitus with an OR of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, glutamic acid decarboxylase 65, were associated with intestinal dysfunction, with ORs of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an OR of 27.0. Hypoparathyroidism was not associated with reactivity against any of the autoantigens tested. No reactivity against the calcium-sensing receptor was found. Analysis of autoantibodies in autoimmune polyendocrine syndrome type I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease.     

Serum insulinlike growth factor is not elevated in patients with multiple myeloma but is still a prognostic factor

Insulinlike growth factor 1 (IGF-1) has growth-promoting effects on myeloma cells in vitro as well as in vivo. In this study, we measured the concentration of IGF-1 and its major binding protein, IGF- binding protein 3 (IGFBP-3), in serum from 127 patients with multiple myeloma. Serum had been drawn at the time of diagnosis, before treatment with high-dose melphalan. IGFBP-3 in myeloma patients (1.6 +/- 0.73 microg/mL; mean +/- SD) was significantly decreased compared to healthy age- and sex-matched controls (2.2 +/- 0.42 microg/mL). However, IGFBP-3 had no prognostic value in this study. The mean IGF-1 level did not differ between myeloma patients (17.8 +/- 7.7 nM) and controls (17.3 +/- 5.6 nM). Nevertheless, IGF-1 was a strong indicator of prognosis. After 80 months of follow-up, myeloma patients with low levels (< 13 nM) of serum IGF-1 had not reached median survival. In the patient group with IGF-1 levels above 13 nM, median survival was 62 months (P =.006). These findings support the hypothesis of a role for IGF-1 in myeloma disease progression.     

Evaluation of two matrix materials intended for fiber-reinforced polymers

Two matrix resins for fiber composites that remain in a fluid state during storage and handling before polymerization were evaluated. The resin mixtures, based on methyl methacrylate (MMA), were produced with two different cross-linking agent systems: 1,4-butanediol dimethacrylate and ethylene glycol dimethacrylate or diethylene glycol dimethacrylate. Water sorption, water solubility, water uptake and residual MMA monomer were determined. Thermomechanical analysis was used to determine linear dimensional changes as a function of temperature. Flexural strength and modulus as well as fracture work and the maximum stress intensity factor were determined. The results revealed similar values for both matrix polymers regarding water sorption, water solubility, water uptake, residual MMA monomer (0.5 wt% (+/- 0.03)) and coefficient of linear thermal expansion. Flexural strength for polymer B was 68.7 MPa (+/- 9.8) compared to 56.0 MPa (+/- 13.3) for polymer A when tested dry and 64 MPa (+/- 6.1) compared to (54 MPa (+/- 3.3) when water-saturated. Fracture toughness tests showed higher maximum stress intensity factor values for polymer B (0.75 +/- 0.17) MPa x m1/2 than for polymer A (0.55 +/- 0.12) MPa x m1/2. The resin binders showed an appropriate consistency while remaining in a fluid state during storage and manipulation.     

Maternal vaccination against subclinical necrotic enteritis in broilers

The inclusion of antibacterial feed additives has until now been the major strategy for controlling Clostridium perfringens-associated necrotic enteritis in broilers. In the present study, the effect of maternal immunization against the disease was examined. Broiler breeder hens were injected intramuscularly with candidate vaccines based on C. perfringens type A and type C toxoids adjuvanted with aluminium hydroxide. Vaccination resulted in a strong serum immunoglobulin G response to C. perfringens alpha-toxin in parent hens, and specific antibodies were transferred to their progeny. Subclinical necrotic enteritis in broilers was induced under field conditions or in a disease model, and the occurrence of specific enteric and hepatic lesions was evaluated in randomly selected birds. In three experiments, estimates of odds ratio for developing such lesions were 0.23, 0.33 and 0.56 in maternally toxoid C-immunized broilers compared with non-immunized controls. In toxoid A-immunized birds, odds ratios were estimated at 0.41, 0.61 and 0.63. From these results, immunoprophylaxis seems to be an interesting alternative for the control of necrotic enteritis in broilers.     

Pathway based analysis of SNPs with relevance to 5-FU therapy: relation to intratumoral mRNA expression and survival

Genetic factors are thought to play a role in resistance towards chemotherapeutic agents such as 5-fluorouracil (5-FU). Approximately 30 genes are directly or indirectly involved in 5-FU metabolism, and genetic variation in any of these may contribute to anti-tumor response. Polymorphisms in these genes were analyzed in relation to tumoral mRNA levels of 5-FU metabolizing genes, response to chemotherapy and survival. A total of 21 genetic variants were studied in 35 breast cancer patients treated with 5-FluoroUracil, mitomycin (FUMI) and in a similar cohort of 90 doxorubicin treated breast cancer patients. Genotype distributions were compared using 109 healthy controls. No significant association was found between any polymorphisms and response to chemotherapy as measured by shrinkage of tumor. However, carriers of 3 copies of the TYMS 5'UTR repeat had shorter survival than noncarriers (p = .048) in the FUMI treatment group, but not in the doxorubicin treated group. Carriers of 3 copies of the repeat were also more frequently observed in both patients groups than in healthy controls (p = .034). Several highly significant associations were observed between genotypes and expression levels of 5-FU metabolizing genes. A SNP in codon 72 of TP53 was revealed to be a key regulator of 5-FU metabolizing genes such as DHFR and MTHFR, constituting 50% of all significant associations observed after FUMI therapy. These data suggest that 3 copies of the TYMS 5'UTR repeat may give a treatment specific reduced survival in breast cancer patients, and that TP53 may have a direct, allele specific, role in 5-FU mediated response.     

Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma

Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p < 0.001) compared to patients with tumors wild-type for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and <0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01), low BRAF levels were associated with improved overall survival only among patients with tumors wild-type for BRAF (p = 0.013). These findings indicate that BRAF and NRAS expression levels may influence responses to DTIC as well as prognosis in patients with advanced melanoma.