Long-term viability and mechanical behavior following laser cartilage reshaping

OBJECTIVE: To investigate the long-term in vivo effect of laser dosimetry on rabbit septal cartilage integrity, viability, and mechanical behavior. METHODS: Nasal septal cartilage specimens (control and irradiated pairs) were harvested from 18 rabbits. Specimens were mechanically deformed and irradiated with an Nd:YAG laser across a broad dosimetry range (4-8 W and 6-16 seconds). Treated specimens and controls were autologously implanted into a subperichondrial auricular pocket. Specimens were harvested an average +/- SD of 208 +/- 35 days later. Tissue integrity, histology, chondrocyte viability, and mechanical property evaluations were performed. Tissue damage results were compared with Monte Carlo simulation models. RESULTS: All laser-irradiated specimens demonstrated variable tissue resorption and calcification, which increased with increased dosimetry. Elastic moduli of the specimens were significantly either lower or higher than controls (all P<.05). Viability assays illustrated a total loss of viable chondrocytes within the laser-irradiated zones in all treated specimens. Histologic examination confirmed these findings. Experimental results were consistent with damage profiles determined using numerical simulations. CONCLUSION: The loss of structural integrity and chondrocyte viability observed across a broad dosimetry range underscores the importance of spatially selective heating methods prior to initiating application in human subjects.     

The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases

Coffin-Siris syndrome (CSS) is a rare, clinically heterogeneous disorder often considered in the setting of cognitive/developmental delay and 5th finger/nail hypoplasia. Due to the clinical variability of facial and other features, this diagnosis is often difficult to confirm clinically and the existence of this disorder as a specific diagnosis has been at times an issue of debate. In an effort to further delineate the spectrum and key phenotypic features, we reviewed 80 previously reported cases to define features in patients that most closely correlated with a convincing diagnosis. There appear to be two subtypes of CSS, one which displays the "classic" coarse facial features previously described; another displays "variant" facial features which are less striking. Using these features, we defined an algorithm to rank the confidence of diagnosis and applied it to 15 additional patients who had been previously characterized by chromosome microarray. This approach will also facilitate uniform categorization for whole-exome analysis.     

Eosinophilic Fasciitis associated with Mycoplasma arginini infection

Eosinophilic fasciitis (EF) with generalized sclerodermiform skin lesions developed over a 19-month period in a previously healthy 23-year-old man. Although we confirmed EF by skin histology and laboratory tests, the recurrent fevers and the clinical observation of sclerotic prepuce with urethritis indicated further bacteriological analysis by conventional microbiological and DNA-based tests. Urethra cultures were positive for an arginine-hydrolyzing mycoplasma and Ureaplasma urealyticum. The patient also had serum IgM antibodies to Mycoplasma pneumoniae using enzyme-linked immunosorbent assay (ELISA)-based qualitative detection. Mycoplasma arginini was isolated from two independent venous blood serum samples and was identified by conventional microbiological tests and sequencing of the 16S rRNA and rpoB genes (GenBank sequence accession numbers HM179555 and HM179556, respectively). M. arginini genomic DNA also was detected by species-specific PCR in the skin lesion biopsy sample. Treatment with corticosteroids and long-term courses of selected antibiotics led to remission of skin symptoms and normalization of laboratory values. This report provides the first evidence of EF associated with mycoplasma infection and the second report of human infection with M. arginini and therefore suggests that this mycoplasma infection might have contributed to the pathogenesis of the disease.     

Biophysical mechanisms of phase contrast in gradient echo MRI

Recently reported contrast in phase images of human and animal brains obtained with gradient-recalled echo MRI holds great promise for the in vivo study of biological tissue structure with substantially improved resolution. Herein we investigate the origins of this contrast and demonstrate that it depends on the tissue “magnetic architecture” at the subcellular and cellular levels. This architecture is mostly determined by the structural arrangements of proteins, lipids, non-heme tissue iron, deoxyhemoglobin, and their magnetic susceptibilities. Such magnetic environment affects/shifts magnetic resonance (MR) frequencies of the water molecules moving/diffusing in the tissue. A theoretical framework allowing quantitative evaluation of the corresponding frequency shifts is developed based on the introduced concept of a generalized Lorentzian approximation. It takes into account both tissue architecture and its orientation with respect to the external magnetic field. Theoretical results quantitatively explain frequency contrast between GM, WM, and CSF previously reported in motor cortex area, including the absence of the contrast between WM and CSF. Comparison of theory and experiment also suggests that in a normal human brain, proteins, lipids, and non-heme iron provide comparable contributions to tissue phase contrast; however, the sign of iron and lipid contributions is opposite to the sign of contribution from proteins. These effects of cellular composition and architecture are important for quantification of tissue microstructure based on MRI phase measurements. Also theory predicts the dependence of the signal phase on the orientation of WM fibers, holding promise as additional information for fiber tracking applications.     

NH-1,2,3-Triazole Inhibitors of the VIM-2 Metallo-β-Lactamase

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Angiographic pattern of restenosis following implantation of overlapping sirolimus-eluting (Cypher) stents

Sirolimus-eluting stents (Cypher) have been shown to reduce the frequency of neointimal hyperplasia and restenosis compared with bare metal stents. However, the clinical implication of overlapping stents with regard to the pattern of restenosis is unclear. All patients who underwent angiography at our institution from May 2003 to March 2005 who had previously received 2 overlapping Cypher stents in native coronary lesions and had binary restenosis were included in our study. Quantitative coronary analysis was performed to determine the degree and location of the restenotic lesion with respect to the overlapping stented segment. The primary end point was to determine how often restenotic lesions occurred at the overlapped segment versus the nonoverlapped stented segments. During the study, 11 patients fit the inclusion criteria for our study; 91% were men and 55% had diabetes mellitus. The mean total stent length was 33.7 +/- 8.2 mm. The mean length of the overlapped segment was 5.9 +/- 3.8 mm, equating to 19 +/- 16% of the total stented area. The average time to follow-up angiography was 277 +/- 126 days. All 11 lesions exhibited type 1 (focal) restenosis. Of these 11 lesions, 10 had focal restenosis at the overlapped segment (p = 0.01, binomial test). The single case involving in-stent restenosis in the nonoverlapped segment occurred at the proximal stent edge. In conclusion, the pattern of restenosis observed in our study suggests a higher relative incidence of binary restenosis in the overlapped stented segment in patients who receive 2 overlapping Cypher stents.     

A methyldiazene (HN=N-CH3)-derived species bound to the nitrogenase active-site FeMo cofactor: Implications for mechanism

Methyldiazene (HN=N-CH3) isotopomers labeled with 15N at the terminal or internal nitrogens or with 13C or 2H were used as substrates for the nitrogenase alpha-195Gln-substituted MoFe protein. Freeze quenching under turnover traps an S = (1/2) state that has been characterized by EPR and 1H-, 15N-, and 13C-electron nuclear double resonance spectroscopies. These studies disclosed the following: (i) a methyldiazene-derived species is bound to the active-site FeMo cofactor; (ii) this species binds through an [-NHx] fragment whose N derives from the methyldiazene terminal N; and (iii) the internal N from methyldiazene probably does not bind to FeMo cofactor. These results constrain possible mechanisms for reduction of methyldiazene. In the Chatt-Schrock mechanism for N2 reduction, H atoms sequentially add to the distal N before N-N bond cleavage (d-mechanism). In a d-mechanism for methyldiazene reduction, a bound [-NHx] fragment only occurs after reduction by three electrons, which leads to N-N bond cleavage and the release of the first NH3. Thus, the appearance of bound [-NHx] is compatible with the d-mechanism only if it represents a late stage in the reduction process. In contrast are mechanisms where H atoms add alternately to distal and proximal nitrogens before N-N cleavage (a-mechanism) and release of the first NH3 after reduction by five electrons. An [-NHx] fragment would be bound at every stage of methyldiazene reduction in an a-mechanism. Although current information does not rule out the d-mechanism, the a-mechanism is more attractive because proton delivery to substrate has been specifically compromised in alpha-195Gln-substituted MoFe protein.