Input dysfunction and beyond--an evaluation of CPT components

The aim of our project is to analyze the functional meaning of neurocognitive components of the Continuous Performance Tests (CPT), which may be responsible for the well-documented performance deficit. Since the CPT can be considered as a vulnerability marker for schizophrenia, this question is of special interest. We set up a test battery testing five different cognitive processing modes: perceptual organization, selective attention, short-term memory (storing component), working memory (rehearsal component), and vigilance/sustained attention. In order to avoid the pitfall of interpreting results confounded by psychometric differences within tasks, we created psychometrically parallel versions within each experimental block (following the proposals of Chapman and Chapman [J. Nerv. Ment. Dis. 171 (1983) 658]). At the main experimental session, we tested newly admitted patients with a DSM diagnosis of schizophrenia during remission (N=30), patients with major depressive disorder (MD) (N=18), and healthy controls (N=20). Results showed that differences specific for schizophrenia are seen at the experimental block, which tests perceptual organization. However, all levels of perceptual organization performance were concerned, i.e., from processing organized to non-organized patterns. The regression analysis showed that 3-7 CPT version performances could be explained by problems with short-term memory, sustained attention, and perceptual organization. In light of these findings, we discussed whether etiology of schizophrenia could be conceptualized as a circumscribed neurocognitive deficit or a multifunctional, multilocal deficit.     

Tumor necrosis factor-alpha (TNF) regulates the expression of ICAM-1 predominantly through TNF receptor 1 after chronic constriction injury of mouse sciatic nerve

Proinflammatory cytokines like tumor necrosis factor-alpha (TNF) contribute to Wallerian degeneration by enhancing the adhesion of leukocytes to the endothelium through increased expression of adhesion molecules. Here we studied the influence of TNF and TNF receptors (TNFR) on intercellular adhesion molecule-1 (ICAM-1) and macrophage influx following chronic constrictive injury (CCI) in mice by three different paradigms: (1) C57BL/Wld mice with delayed TNF up-regulation, (2) in vivo inhibition of TNFR1 and TNFR2 by neutralizing antibodies, and (3) three different types of mice with a genetic deficiency for TNFR. C57BL/Wld mice with a delayed macrophage influx had a delayed increase of ICAM-1 compared to control mice. In vivo inhibition of both TNFR significantly impaired macrophage recruitment; however, treatment with anti-TNFR1 antibodies increased endoneurial ICAM-1 expression. In TNFR1 and TNFR1+2, but not TNFR2-deficient mice, endoneurial ICAM-1 expression was significantly reduced, which correlated with prolonged Wallerian degeneration in TNFR1-deficient mice 2 weeks after CCI. Our data support the hypothesis that TNF regulates the expression of ICAM-1 predominantly through TNFR1.     

Contribution of solid-state properties to the aqueous solubility of drugs.

This study investigates the influence of the solid-state properties melting point (T(m)), enthalpy of melting (DeltaH(m)) and entropy of melting (DeltaS(m)) of a drug on its intrinsic solubility (S(0)). For this purpose, 26 chemically and structurally diverse drugs covering the oral drug space were selected and the S(0), T(m), DeltaH(m) and DeltaS(m) were determined experimentally. The influence of T(m), DeltaH(m) and DeltaS(m) on S(0) was studied using regression analysis. The overall improvement of the predictions were 0.3 log units, however, five compounds (astemizole, glyburide, fenbufen, gliclazide and griseofulvin) were improved by more than one log unit. T(m) and DeltaH(m) had a larger effect than DeltaS(m) on the solubility predictions. The well-known general solubility equation (GSE) and the Dannenfelser semi-empirical equation for the calculation of DeltaS(m) were evaluated using our data set. While predictions of drug solubility obtained using the GSE were acceptable, the use of the experimental DeltaS(m) values instead of the constant 56.5 J mol(-1)K(-1) improved the accuracy of the prediction. The Dannenfelser equation underestimated the DeltaS(m) for most compounds with on average 15 J mol(-1)K(-1). Our results show that solid-state properties should be considered for improved performance of future models for prediction of drug solubility. In addition our study provides accurate experimental data on intrinsic solubility for 26 compounds, supplying a useful external data set for validation of drug solubility models.     

Photocarcinogenesis in human adult skin grafts.

It has been demonstrated previously that the exposure to 7,12-dimethyl[a]benzanthracene (DMBA) and UVB radiation leads to the development of epidermal cysts, squamous cell carcinomas (SCC), melanocytic hyperplasia and melanoma in human foreskins from newborns grafted to immunodeficient mice. Improved techniques in grafting full-thickness skin from adults have enabled us to study photocarcinogenesis in human skin from different body sites and from older donors. One hundred and fifty-five normal white skin specimens from the trunk and face of 53 adult individuals were grafted onto severe combined immunodeficient (SCID) and recombinase activating gene-1 (Rag-1) knockout mice and irradiated two to three times weekly with 40 mJ/cm(2) UVB or solar-simulated UV (SSUV) over a period of up to 10 months with or without one prior topical application of DMBA. Over an observation period of 2-22 months, histopathological and immunohistochemical analyses of 134 specimens revealed actinic keratoses in 30% of the DMBA- + UV-treated grafts, in 18% of the grafts exposed to SSUV only, and in 10% of the grafts exposed to UVB only. Actinic keratoses were absent in grafts treated with DMBA only. One SCC was found in an abdominal skin graft 3 months after exposure to DMBA followed by UVB. Point mutations in codon 61 of the human Ha-ras gene were detected in the SCC, five of six analyzed actinic keratoses and in non-lesional epidermis of DMBA- and UVB-treated grafts, indicating that DMBA as well as UVB alone can induce these mutations in human skin. In contrast to the previous experience with neonatal foreskin grafts, melanocytic lesions were not found except for mild hyperplasia in few cases. The data suggest that melanocytes from young individuals are more susceptible to the transforming effects of genotoxic agents than melanocytes from adults.     

Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer

Background:studies of bimonthly 48-hour regimens of high-doseleucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusioncombined with OXaliplatin (FOLFOX) in pretreated patients with metastaticcolorectal cancer suggest that oxaliplatin dose intensity is an importantprognostic factor for response rate and progression-free survival (PFS). Tohelp define the optimal dose schedule for oxaliplatin in pretreated metastaticcolorectal cancer, we retrospectively analyzed data from three phase IIstudies using different FOLFOX regimens (FOLFOX2, 3 and 6). Patients and methods:Data on 126/161 patients were analyzed.FOLFOX2 included oxaliplatin 100 mg/m²; FOLFOX3, 85mg/m²; and FOLFOX6, 100 mg/m² (added to a simplifiedLV–5-FU regimen), all as two-hour infusions. A total of 47 patientsreceived low dose intensity oxaliplatin (LDI: 85 mg/m²/2 weeks)and 79 patients high dose intensity oxaliplatin (HDI: >85mg/m²/2 weeks). Results:Objective responses occurred in 31 (39%) HDIpatients and 9 (19%) LDI patients (P = 0.03). Median PFS was28 weeks, with 52% of HDI patients progression free at 6 months, and26 weeks with 36% of LDI patients progression free at six months(P = 0.02). Increased oxaliplatin dose intensity was not associatedwith increased neurotoxicity or other toxicities. FOLFOX are among the mosteffective regimens for treating LV–5-FU-resistant metastatic colorectalcancer. Conclusions:This study shows that oxaliplatin doseintensification significantly improves response rate and PFS in pretreatedmetastatic disease without increasing severe toxicity.     

Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRS-IV

Purpose

To better understand outcomes in children with rhabdomyosarcoma (RMS) and lung-only metastatic disease, the authors reviewed the experience from Intergroup Rhabdomyosarcoma Studies IV Pilot and IV.

Methods

Patients with lung-only (n = 46) vs other sites of metastatic disease (n = 234) were reviewed using patient charts and the database of Children's Oncology Group (COG).

Results

Sixteen percent of patients with RMS and metastatic disease had isolated lung metastases. Thirty-one (67%) had more than 5 metastatic lung lesions. These were bilateral in 34 (74%). Only 6 patients were biopsied at diagnosis. Sixteen children (35%) did not receive any lung radiotherapy. Patients that received lung radiotherapy had fewer lung recurrences (P = .04), although this has no significant impact on overall survival (OAS, 47% radiotherapy vs 31% no radiotherapy). Compared with patients with other sites of metastatic disease, patients with lung-only metastases have a greater proportion of favorable histology (67% vs 39%, P = .0017), negative nodal involvement (67% vs 32%, P = .0013), and parameningeal primaries (39% vs 12%) and a smaller proportion of extremity primaries (20% vs 33%, P = .0005 for site of primary tumor). Overall survival at 4 years for lung-only metastases was not significantly different from other single-site metastasis (42% vs 34%). Survival was not improved for unilateral disease or fewer than 5 metastatic lesions. Factors associated with diminished OAS include unfavorable histology (P = .0001) and age >10 years (P = .015).

Conclusions

Children with RMS and lung-only metastases usually present with extensive bilateral disease that is frequently not biopsied nor given protocol-recommended radiotherapy (XRT). However, outcome is comparable, although slightly better, than patients with other single-site metastasis.     

Renal replacement therapy for diabetic end-stage renal disease: data from 10 registries in Europe (1991-2000)

BACKGROUND: There is concern about the rising prevalence of type 2 diabetes mellitus and of the resultant nephropathy. This study uses data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry to provide information on the epidemiology and outcome of renal replacement therapy (RRT) for end-stage renal disease (ESRD) due to diabetic nephropathy (DN). METHODS: Data from the following 10 registries: Austria, French-speaking Belgium, Denmark, Finland, Greece, Norway, Scotland (UK), Catalonia (Spain), Sweden, and The Netherlands were combined. Average annual changes (%) were estimated by Poisson regression. Analyses of mortality were performed by Cox regression. RESULTS: An increase in patients with type 2 DN entering RRT has been observed (+11.9% annually, P < 0.05), while large differences in RRT incidence in this disease continue to exist between countries in Europe. There was a reduction in mortality during the first 2 years on dialysis therapy among patients with type 2 DN (AHR 0.96, 95%CI 0.94-0.97 annually). The mortality among transplant recipients decreased for both type 1 DN and nondiabetic ESRD (non DN) within the 1995-1998 cohort (type 1 DN: AHR 0.49, 95% CI 0.35-0.68; non DN: AHR 0.79, 95% CI 0.69-0.90) compared to the 1991-1994 cohort. CONCLUSION: This report has shown that during the last decade there has been a marked increase in the incidence of RRT for type 2 DN. Survival analysis showed that over the period 1991-1999 the mortality rates of all dialysis patients and of type 1 diabetic and nondiabetic renal transplant recipients have fallen.     

Sentence intelligibility in noise for listeners with normal hearing and hearing impairment: influence of measurement procedure and masking parameters

Speech intelligibility measurements strongly depend on several procedural parameters. In order to obtain comparable results from different test procedures, these parameters must be investigated as to which should be standardized and which could be set freely. This study investigates the influence of noise level, noise type, and presentation mode on speech reception thresholds (SRTs), and intelligibility function slopes in noise for normal-hearing and hearing-impaired subjects. The noise presentation level had no significant influence on either SRTs or slope values, provided that the presentation level exceeded hearing threshold. Two stationary, speech-shaped noises produced identical results. Speech-simulating fluctuating noise yielded about 14 dB lower SRTs for normal-hearing subjects and about 10 dB lower SRTs for 20% of the heating-impaired subjects. Of the hearing-impaired subjects, 30% did not benefit from the modulations and showed similar SRTs as for stationary noise. Using continuous noise yielded lower SRTs compared to gated noise. However, the difference between the results in continuous and gated noise was not significant for the hearing-impaired subjects. A presentation level of 65 dB SPL (normal-hearing subjects) or 80 dB SPL (hearing-impaired subjects) and an interfering noise with a spectrum similar to the mean long-term average speech spectrum (LTASS) is suggested for comparable adaptive measurement procedures. A fluctuating, speech-shaped noise is recommended to differentiate between subjects.     

Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation

Rhesus monkey embryonic stem (rhES) cells were grown on mouse embryonic fibroblast (MEF) feeder layers for up to 10 days to form multilayered colonies. Within this period, stem cell colonies differentiated transiently into complex structures with a disc-like morphology. These complex colonies were characterized by morphology, immunohistochemistry, and marker mRNA expression to identify processes of epithelialization as well as epithelial-mesenchymal transition (EMT) and pattern formation. Typically, differentiated colonies were comprised of an upper and a lower ES cell layer, the former growing on top of the layer of MEF cells whereas the lower ES cell layer spread out underneath the MEF cells. Interestingly, in the central part of the colonies, a roundish pit developed. Here the feeder layer disappeared, and upper layer cells seemed to ingress and migrate through the pit downward to form the lower layer while undergoing a transition from the epithelial to the mesenchymal phenotype, which was indicated by the loss of the marker proteins E-cadherin and ZO-1 in the lower layer. In support of this, we found a concomitant 10-fold upregulation of the gene Snail2, which is a key regulator of the EMT process. Conversion of epiblast to mesoderm was also indicated by the regulated expression of the mesoderm marker Brachyury. An EMT is a characteristic process of vertebrate gastrulation. Thus, these rhES cell colonies may be an interesting model for studies on some basic processes involved in early primate embryogenesis and may open new ways to study the regulation of EMT in vitro.