Parapharyngeal neuroglial heterotopia extending through the skull base in a neonate with airway obstruction

We present a neonate with heterotopic nasopharyngeal brain tissue causing airway obstruction. Preoperative imaging showed extension of the mass along major neurovascular pathways into the cranial vault. Preoperative identification of intracranial extension is essential for planning surgery to prevent postoperative cerebrospinal fluid leaks or possible meningitis.     

'UroMaix' scaffolds: novel collagen matrices for application in tissue engineering of the urinary tract

Reconstruction of bladder and ureter tissue is indicated in cases of injury, stenosis, infection or tumor. Substitution by ileum, colon or pure synthetic polymers generates a variety of complications. Biohybrid tissue mimicking structural and functional attributes of the multilayered wall architecture of the urinary conduit may be the solution to current problems. This study reports on porcine urinary tract cells isolated and placed on UroMaix matrices with different degrees of cross-linking produced from highly purified type I collagen from medically approved porcine tissue. A patented procedure revealed membrane structures composed of a dense fibrous side and an open fibrous side. These scaffolds with the porcine urinary tract cells were incubated in a batch culture system for up to 14 days. Cell growth and topographical orientation were examined. Urothelial cells showed maximum attachment and a significant increase of living cells on the dense fiber layer of UroMaix-1. No attachment of urothelial cells occurred on the other prototypes. Smooth muscle cells showed similar behavior within the open fiber layer of all UroMaix matrices. Both urothelial and smooth muscle cells retained their phenotypes as demonstrated by the immunostaining of epithelial cytokeratin 18 and the smooth muscle myosin heavy chain respectively. Thus we could show that UroMaix scaffolds support the attachment and proliferation of urinary tract cells. The elastomeric properties of the collagenous matrices promise attractive applications in the tissue engineering of the urinary tract with its high mechanical demands.     

Neuromodulation of associative and organizational plasticity across the life span: empirical evidence and neurocomputational modeling

Developmental plasticity is the key mechanism that allows humans and other organisms to modify and adapt to contextual and experiential influences. Thus, reciprocal co-constructive interactions between behavioral and neuronal plasticity play important roles in regulating neurobehavioral development across the life span. This review focuses on behavioral and neuronal evidence of lifespan differences in associative memory plasticity and plasticity of the functional organization of cognitive and cortical processes, as well as the role of the dopaminergic system in modulating such plasticity. Special attention is given to neurocomputational models that help exploring lifespan differences in neuromodulation of neuronal and behavioral plasticity. Simulation results from these models suggest that lifespan changes in the efficacy of neuromodulatory mechanisms may shape associative memory plasticity and the functional organization of neurocognitive processes by affecting the fidelity of neuronal signal transmission, which has consequences for the distinctiveness of neurocognitive representations and the efficacy of distributed neural coding.     

Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling

Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1-mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.     

Permanent 125I-seed brachytherapy or radical prostatectomy: a prospective comparison considering oncological and quality of life results

OBJECTIVE: To assess the quality of life in patients with prostate cancer after permanent brachytherapy (BT) or radical perineal prostatectomy (RP). PATIENTS AND METHODS: The American Brachytherapy Society recommends the permanent implantation of radioactive seeds as a monotherapy for patients with T1-T2aN0M0 prostate cancer and a prostate-specific antigen (PSA) level of < or = 10 ng/mL, a Gleason score of <7 and a prostate volume of <60 mL. Using these criteria, 132 patients with low-risk prostate cancer were selected; 52 had BT with 125I-seed implantation, 38 had RP with unilateral nerve-sparing (RP + NS) and 42 extended RP (RP group). Only patients with unilateral tumour on biopsy were considered. Before therapy and 6, 12 and 24 months afterward, patients completed questionnaires to assess perceived health and function. PSA relapse was diagnosed with a PSA of >0.1 ng/mL for patients in the RP groups, and three consecutive PSA increases for those after BT. RESULTS: Extraprostatic tumours were found in 18% of specimens taken during RP, and bilateral tumours in 63% of patients. After a mean follow-up of 27 months, there was PSA relapse in two of the 80 patients in the RP and RP + NS groups, and six of the 52 patients in the BT group; a significant difference, with a hazard ratio of 5.2. The acute morbidity was low in all groups. At 1 year, more than two incontinence pads were used by 5% of patients after RP and by 4% after BT. Similarly, at 1 year 15% of patients after RP and 13% after BT were bothered by urinary incontinence. Newly-developed fecal soiling was reported by 4%, 5% and 11% of the RP, RP + NS and BT groups respectively; none of the patients after RP and 4% after BT were bothered by this symptom. The duration and stiffness of erection was assessed after 1 year and reported to be equal or slightly decreased by a third after RP + NS and 38% after BT. Taking a 5-10 point difference as clinically relevant, role, emotional and social functioning were improved considerably after RP + NS than after BT, but sexual activity was impaired significantly after RP + NS than after BT. CONCLUSIONS: Both therapies showed typical acute and late morbidity; the most bothersome late symptoms were urinary incontinence for patients after RP and fecal soiling after BT. Sexual function was impaired significantly in patients who were potent before RP + NS, whereas after BT men reported only a minor change in sexual performance at 1 year. Tumour control after a median follow-up of 27 months was better after RP but biochemical recurrence may still occur after > or = 5 years; therefore the present results are not mature enough and there were too few patients to provide a more definitive statement. As approximately 18% of patients considered to be appropriate candidates for BT had tumours extending beyond the prostate capsule or invading the seminal vesicles, nomograms are needed for more accurate information before therapy.     

Evaluation of kinase inhibitor selectivity by chemical proteomics

Small-molecule inhibitors of protein kinases constitute a novel class of drugs for therapeutic intervention in a variety of human diseases. Most of these agents target the relatively conserved ATP-binding site of protein kinases and have only been tested against a rather small subset of all human protein kinases. Therefore, the selectivity of protein kinase inhibitors has remained a widely underestimated, but highly important issue in drug development programs. In this review, we focus on the recent advancement of chemical proteomic methods to evaluate drug selectivity in an unbiased, comprehensive way. Efficient affinity purification procedures using immobilized kinase inhibitors combined with the sensitivity of mass spectrometry detection permit the mapping of drug targets on a proteome-wide scale. Data from this type of assessment can be used to set up tailor-made selectivity panels, which guide compound development in the context of the most relevant off-targets during lead optimization. In cases in which identified alternative targets are of validated clinical relevance, chemical proteomics provides the opportunity to repeatedly exploit a once established kinase inhibitor principle for additional target kinases and can thereby dramatically shorten the time toward highly selective, preclinical candidates. Moreover, the identification of alternative targets for preclinical or clinical drugs can provide new insights into their cellular modes of action, which might help to define those disease settings in which the most beneficial therapeutic effect is likely to occur.     

Incidence of endomycoses in the autopsy material of the Berlin Charité Hospital

From 1970 to 1993, a total of 93 endomf1p4es confirmed by post-mortem examination was diagnosed in the autopsy material of the Berlin Charité, a large hospital with an average of 1,500 hospital beds and maximum medical care. These comprised 51 candidoses (54.8%), 24 aspergilloses (36.6%), five cryptococcoses (5.4%), one zygomycosis, 1 trichosporosis and one coccidioidomycoses. This corresponded to 0.7% of the 13,375 decreased persons autopsied during this period. The frequency of autopsy was 85.3%. In 3,770 cases (2,418 adults and 1,352 children), brain dissection was performed. An adequate clinical putative diagnosis was made in only six out of 28 patients (18 adults, 10 children) with histologically confirmed cerebral mycosis [11 candidoses (39.3%), 10 aspergilloses (35.7%), five cryptococcoses (17.9%), one trichosporosis and one coccidioidomycosis]. About 80% of the mycoses of the CNS thus remained undetected while the patients were alive. Against the background of the continuing reduction in the frequency of autopsy in the Federal Republic of Germany, the observations made in the present paper underscore the demand for improved efficiency of mycological in-vivo diagnoses in the hospital and laboratory.     

Stimulation of chemiluminescence by synthetic muramyl dipeptide and analogs.

The effect on respiratory burst of murine splenic cells after in vitro exposure to synthetic muramyl dipeptide (MDP) and 6-O-acyl and quinonyl derivatives was studied at an early phase of interaction by luminol-dependent chemiluminescence (CL) in response to stimulation by zymosan. The MDP molecule enhanced CL, but the degree of CL response varied with the kinds of fatty acids introduced in the chemical structure of synthetic glycopeptide analogs. A 6-O-acyl derivative possessing an alpha-branched fatty acid chain, B30-MDP, stimulated maximum levels of CL activity. High CL responses were obtained with L8-MDP having a short chain of linear fatty acids and with QS-10-MDP-66 containing a ubiquinone compound. CL was also stimulated by MDP and its analogs in the spleen cells of nude mice lacking mature T lymphocytes, but the extent of stimulation was decreased compared with that of normal spleen cells.