Structure of a synthetic fragment of the lipopolysaccharide (LPS) binding protein when bound to LPS and design of a peptidic LPS inhibitor

Peptidic lipopolysaccharide (LPS) antagonists are the subject of intensive research. We report an NMR and modeling study of LBP-14 (RVQGRWKVRASFFK), a synthetic fragment of the LPS binding protein (LBP). In a mixture with LPS we observed the transferred nuclear Overhauser effect and determined the LPS-bound structure of LBP-14 that was used for docking calculations to LPS. The derived complex was used to design a peptide that displayed more than 50% increase in LPS inhibition in vitro.     

Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been recognized as important events in squamous cell carcinoma of the head and neck (HNSCC), suggesting involvement of both suppressor and mutator pathways. We analyzed 153 HNSCC with 8 Bethesda reference panel markers and 14 microsatellite markers selected from chromosomal regions known to harbor either tumor-suppressor genes or oncogenes. A combination of multiplex fluorescence-based polymerase chain reaction and automatic fragment analysis was performed. LOH was observed in 78% of all tumors. 2% to 17% LOH frequency was observed with Bethesda reference panel markers comparing to higher 8% to 48% LOH in chromosomal areas 3p, 9p, 11q, and 17p. LOH of 11q14.3 correlated with tumor grade. The proportions of high- and low-MSI tumors were 3% and 10%, respectively, but no mutation was identified in MLH1 and MSH2 mismatch repair genes. These results indicate the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis.     

Intramuscular electrical stimulation: Tissue damage

Coiled wire electrodes have been evaluated for intramuscular electrical stimulation. Monophasic cathodal stimulation at average current densities not exceeding 10 μamp/mm² (0.2 μC/mm²/stimulus pulse at 50 Hz) shows no increased tissue trauma over that incurred by passive implant. At average current densities greater than 50 μamp/mm² (1.0 μC/mm² /stimulus pulse at 50 Hz), extensive tissue damage occurs. The muscle tissue damage appears to be secondary to blood vessel damage. With balanced charge biphasic stimulation, greater charge densities could be used without the effect of increased tissue damage. However, to avoid electrode corrosion, the maximum charge injection during the cathodic phase should be less than 0.4 μC/mm² at 50 Hz. Balanced charge biphasic stimulation is considered safer than monophasic stimulation, and is recommended for chronic use. Department of Neuropathology Institute of Pathology Case Western Reserve University This research was supported by The Neural Prostheses Program, NIH-NINCDS contract No. N01-NS-2-2314 (USA). Support during the writing phase was provided by The Alexander von Humboldt-Stiftung Senior US Scientists Program (Federal Republic of Germany), while Dr. Mortimer was a guest at the Institut fur Biokybernetik, Universitat Karlsruhe, Karlsruhe BRD (Federal Republic of Germany). We thank Ms. Millicent Johnstone for her technical assistance in preparing the histology.     

Aging impairs collateral sprouting of nociceptive axons in the rat

Sprouting of uninjured nociceptive axons was examined in young adult, middle aged and aged rats. Axon sprouting from the spared sural nerve, both into adjacent denervated skin and into end-to-side coapted nerve graft, was significantly higher in young rats than in aged rats. Cross-transplantations of the end-to-side coapted nerve grafts between young and aged rats demonstrated that axon sprouting from young recipient nerves into aged donor nerve grafts was significantly deteriorated, whereas the axon sprouting from aged recipient nerves into young donor nerve grafts was not statistically significantly affected. The levels of laminin polypeptides in peripheral nerves were 50-100% higher in young adult than in aged rats. However, the levels of peripherin, NGF isoforms and TrkA in skin, peripheral nerves and DRG, respectively, were not significantly reduced in aged rats. Therefore, impaired sprouting of nociceptive axons in aged rats is due rather to the alterations in peripheral neural pathways, than to the limited sprouting capacity of aged sensory neurons. Decreased levels of extracellular matrix components might be important in this respect.     

Experimental evaluation of infection,dissemination, and transmission rates for two West Nile virus strains in European Aedes japonicus under a fluctuating temperature regime

Parasitology Research - West Nile virus (WNV) is continuously spreading in Eastern and Southern Europe. However, the extent of vector competence of Aedes japonicus (Theobald, 1901) is...     

Upper urinary tract transitional cell carcinoma: location is not correlated with prognosis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Tumour location has been shown to be of prognostic importance in UUT‐TCC, with tumours of renal pelvis having a better prognosis than ureteral tumours. Patients from Balkan Endemic Nephropathy (BEN) areas had a higher frequency of pelvis tumours. Also, we found that belonging to a BEN area is an independent predictor of disease recurrence.

OBJECTIVE

• ? To identify the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for upper urinary tract transitional cell carcinoma (UUT‐TCC).

PATIENTS AND METHODS

• ? A single‐centre series of 189 consecutive patients who were treated surgically for UUT‐TCC between January 1999 and December 2009 was evaluated.
• ? Patients who had previously undergone radical cystectomy, preoperative chemotherapy or contralateral UUT‐TCC were excluded.
• ? In all, 133 patients were available for evaluation. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour.
• ? Recurrence‐free probabilities and cancer‐specific survival were estimated using the Kaplan–Meier method and Cox regression analyses.

RESULTS

• ? The 5‐year recurrence‐free and cancer‐specific survival estimates for the cohort in the present study were 66% and 62%, respectively.
• ? The 5‐year bladder‐only recurrence‐free probability was 76%. Using multivariate analysis, only pT classification (hazard ratio, HR, 2.46; P= 0.04) and demographic characteristics (HR, 2.86 for areas of Balkan endemic nephropathy, vs non‐Balkan endemic nephropathy areas; 95% confidence interval, 1.37–5.98; P= 0.005) were associated with disease recurrence
• ? Tumour location was not associated with disease recurrence in any of the analyses.
• ? There was no difference in cancer‐specific survival between renal pelvis and ureteral tumours (P= 0.476).
• ? Using multivariate analysis, pT classification (HR, 8.04; P= 0.001) and lymph node status (HR, 4.73; P= 0.01) were the only independent predictors associated with a worse cancer‐specific survival.

CONCLUSION

• ? Tumour location is unable to predict outcomes in a single‐centre series of consecutive patients who were treated with radical nephroureterectomy for UUT‐TCC.

     

Intensity inhomogeneity correction of multispectral MR images

Intensity inhomogeneity in MR images is an undesired phenomenon, which often hampers different steps of quantitative image analysis such as segmentation or registration. In this paper, we propose a novel fully automated method for retrospective correction of intensity inhomogeneity. The basic assumption is that inhomogeneity correction could be improved by integrating spatial and intensity information from multiple MR channels, i.e., T1, T2, and PD weighted images. Intensity inhomogeneities of such multispectral images are removed simultaneously in a four-step iterative procedure. First, the probability distribution of image intensities and corresponding spatial features is calculated. In the second step, intensity correction forces that tend to minimize joint entropy of multispectral image are estimated for all image voxels. Third, independent inhomogeneity correction fields are obtained for each channel by regularization and normalization of voxel forces, and last, corresponding partial inhomogeneity corrections are performed separately for each channel. The method was quantitatively evaluated on simulated and real MR brain images and compared to three other methods.     

Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability

Altered expression of P-glycoprotein (P-gp) encoded by the multidrug resistance (MDR1/ABCB1) gene, as well as somatic mutations and hypermethylation in the MDR1/ABCB1 gene, were identified in a proportion of previously untreated colorectal cancers (CRC) exhibiting high microsatellite instability (MSI-H), which suggested that MDR1/ABCB1 acts as a candidate gene contributing to the initiation and progression of MSI-H tumors. Here we report germline functional single nucleotide polymorphisms (SNPs) and haplotypes in the MDR1/ABCB1 gene, which could contribute to genetic risk or increase susceptibility to MSI-H cancers. We have confirmed disease association by comparing the MDR1/ABCB1 genotype, allele, and haplotype frequencies between healthy controls and patients with MSI-H tumors. In particular, carriers of the T/T genotype in exon 12 (1236 C→T) SNP and the T/T genotype in exon 21 (2677G→T) SNP were most significantly associated with a higher risk for developing MSI-H CRC compared to controls (P=0.01, OR=3.182 and P=0.005, OR=3.594, respectively). The most significant MSI-H–associated risk haplotypes include the most frequent haplotype H1 (T-C-T-T) defined by SNPs in exon 12, intron 13 (rs2235035), exon 21, and exon 26 (3435 C→T; P=0.004, OR= 0.476). Our results suggest that ABCB1/MDR1 is a novel low-penetrance gene for susceptibility to MSI-H tumors. The present study provides additional evidence for the role that the MDR1/ABCB1 gene plays in the initiation and progression of MSI-H CRC development. ©2008 Elsevier Inc. All rights reserved.