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Notes: Abstract  Background: Controversy exists whether transmyocardial laser revascularization (TMR) is associated with angiogenesis or neuromodulation and whether these are time-dependent phenomena. Accordingly, we performed a time-course analysis of the expression of angiogenic and neuronal factors following experimental percutaneous TMR. Methods and Results: Five weeks after placing ameroid constrictors on the circumflex coronary artery, 16 pigs underwent left ventricular mapping guided TMR using Ho:YAG laser (2 J × 1 pulse) at 30 sites directed at the ischemic zones and 11 animals were ischemic controls. Histology and immunostaining were obtained at 1 and 2 weeks (4 TMR and 3 controls at each time point) and at 4 weeks (8 TMR and 5 controls) for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), nerve growth factor (βNGF), substance P (SP), and monocyte chemoattractant protein-1 (MCP-1). Immunoreactivity was scored using a digital image analysis system. Factor VIII staining was used for blood vessel counting. Enhanced regional expression of VEGF, bFGF and MCP-1 in the TMR group was noted at 1 and 2 weeks with a threefold increase at 4 weeks following TMR compared to controls. βNGF expression in the TMR group was enhanced at 1 and 2 weeks with subsequent decline at 4 weeks to the controls level. SP expression was not significantly different between groups at all time points. There was a twofold increase in the number of blood vessels in the TMR group at 4 weeks, which was not apparent earlier. Conclusions: These immunohistological findings suggest that cytokines expression compatible with angiogenesis and neuromodulation occurs early after TMR. Up-regulation of angiogenic and inflammatory cytokines may be more sustained than neuromodulation.

Notes: Coronary flow reserve (CFR) and fractional flow reserve (FFRmyo) are two guidewire-based methods currently used to assess the functional severity of coronary artery lesions. Acquiring both measurements simultaneously may provide complementary information, but would require the passage of two different guidewires and complex instrumentation for their calculation. This study assessed the procedural safety and performance of a novel personal computer-based algorithm, the SmartFlow Intravascular Processor (SFIP), which utilizes a single conventional pressure wire for obtaining simultaneous CFR and FFRmyo measurements for the assessment of coronary artery lesion severity. In 20 consecutive patients with 21 lesions, pressure-derived CFR, FFRmyo and SFIP-FFRmyo measurements were obtained during adenosine-induced hyperemia. Intravascular ultrasound and quantitative coronary angiography lesion analysis was done off-line at the Washington Core Laboratory. Mean FFRmyo was 0.83 ± 0.11, SFIP-FFRmyo was 0.86 ± 0.06, and CFR was 1.74 ± 0.46. Pairwise correlation analysis showed excellent correlation between the FFRmyo and the FFRmyo-SFIP (r2= 0.83, P 〈 0.0001) and a fair degree of relationship between the CFR and minimal lumen diameter (r2= 0.43, P = 0.07). We could not find a correlation between CFR and FFRmyo (r2= 0.22, P = 0.37), between CFR and FFR-SFIP (r2= 0.05, P = 0.86), or between the hemodynamic measurements and any of the IVUS-derived measurements. In conclusion, the SFIP is u novel algorithm for obtaining simultaneous CFR and FFRmyo that may provide valuable information for the assessment of lesion severity and clinical decision making.

Notes: Background: Patient and procedural characteristics associated with major adverse cardiac events following balloon angioplasty have been identified. Factors predictive of angiographic restenosis following coronary stent implantation have been reported, although patient variables associated with adverse clinical outcome are not well defined. Hypothesis and Methods: To identify predictors of adverse clinical outcome following NIR stent implantation, clinical and angiographic characteristics of patients enrolled in the FINESS Trial were subjected to stepwise logistic regression analysis. From December 1995 through March 1996, NIR stent implantation was attempted in 255 patients (341 lesions) enrolled prospectively in a multicenter registry with broad entry criteria. Results: On stepwise logistic regression analysis, the presence of multivessel disease, diabetes, and the total length of the stented segment were predictive of major adverse cardiac events during 6-month follow-up. For every 1 mm increase in stent length, the risk for the combined end point of death or myocardial infarction increased by 3%. Lesion length was not predictive of clinical events on multivariate analysis. Conclusions: Our data raise the possibility that an attempt to use shorter stents to cover significant stenoses, but not adjacent areas of visible narrowing, may improve outcome.

Notes: The small G-protein superfamily is an evolutionarily conserved group of GTPases that regulate diverse signalling pathways including pathways for growth and development in eukaryotes. Previously, we showed that dominant active mutation in the unique Ras gene (DARas) of the fungal phytopathogen Colletotrichum trifolii displays a nutrient-dependent phenotype affecting polarity, growth and differentiation. Signalling via the MAP kinase pathway is significantly impaired in this mutant as well. Here we describe the cloning and functional characterization of Rac (Ct-Rac1), a member of the Rho family of G proteins. Ct-Rac1 expression is downregulated by DARas under limiting nutrition. Co-expression of DARas with dominant active Rac (DARac) stimulates MAPK activation and restores the wild-type phenotype. Inhibition of MAPK activation suppresses phenotypic restoration suggesting Rac-mediated MAPK activation is responsible for reversion to the wild-type phenotype. We also examined the role of reactive oxygen species (ROS) in these genetic backgrounds. The DARas mutant strain generates high levels of ROS as determined by DCFH-DA fluorescence. Co-expression with DNRac decreases ROS generation to wild-type levels and restores normal fungal growth and development. Pretreatment of DARas with antioxidants or a cytosolic phospholipase A2 inhibitor also restores the wild-type phenotype. These findings suggest that Ras-mediated ROS generation is dependent on a Rac–cPLA2-linked signalling pathway. Taken together, this study provides evidence that Rac functions to restore the hyphal morphology of DARas by regulating MAPK activation and intracellular ROS generation.

Notes: A 44-year-old Caucasian man was admitted in December 1995 for the treatment of generalized skin pruritus. The patient had a history of cirrhosis felt to be caused by chronic ethanol abuse and renal insufficiency. He had undergone orthotopic liver transplantation in January 1991. Physical examination revealed numerous, fleshy, nontender nodules protruding from the face ( 〈link href="#f5-1"〉Fig. 1), trunk, and extremities, as well as axillary freckling. The patient was certain that the lesions had appeared 2–-3 months after his liver transplant. Wood's lamp examination revealed several café-au-lait macules. Ophthalmic examination was remarkable for Lisch nodules ( 〈link href="#f5-2"〉Fig. 2).〈figure xml:id="f5-1"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD841-5:IJD_841_f5-1"/〉A representative clinical lesion as a fleshy, non-tender nodule on the neck. Also a few very small lesions are barely visible on the mandible line〈figure xml:id="f5-2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD841-5:IJD_841_f5-2"/〉Iris hamartomas (Lisch nodules) in our patientTwo skin nodules on contralateral sides of the body were biopsied. Histologic examination of the nodules revealed a normal epidermis and a nonencapsulated dermal mass composed of thin, wavy eosinophilic fibers lying in loosely textured strands. Interdispersed among these strands were cells with spindle-shaped or oval nuclei and an increased number of mast cells. The histology was typical of a neurofibroma ( 〈link href="#f5-3"〉Fig. 3).〈figure xml:id="f5-3"〉3〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD841-5:IJD_841_f5-3"/〉Histopathologic features of a cutaneous nodule demonstrating normal epidermis overlying a non-encapsulated dermal mass (left panel), with loosely-textured thin wavy eosinophilic fibers and strands, containing cells with spindle-shaped or oval nuclei (right panel)Computed tomography (CT) scans of the chest, abdomen, and pelvis taken before and after the transplant surgery did not reveal any internal plexiform neurofibromas.A thorough review of the patient's medical record dating to shortly after birth made no mention of any skin nodules or hyperpigmentation prior to the transplant. There was no family history of neurofibromatosis.The patient's pruritus resolved with UVB light therapy and hemodialysis. Currently, the patient is on hemodialysis with no clinical progression of his neurofibromatosis.

Notes: A 34-year-old woman with systemic lupus erythematosus and high titres of antiphospholipid antibodies was admitted to hospital suffering a viral illness but developed haemorrhagic and necrotic areas on the neck and anterior chest 7 days following cessation of warfarin. Anticoagulation had been initiated following a retinal vein thrombosis, but was ceased on day 4 of admission when she was found to be excessively anticoagulated (international normalized ratio (INR) 〉 10). However, at the time of developing the cutaneous lesions, the INR was sub-therapeutic. Histology of a skin biopsy from the neck revealed thrombosis of upper dermal blood vessels without vasculitis, consistent with antiphospholipid antibody-related skin necrosis. This case illustrates one of the cutaneous features that can occur in patients with elevated titres of antiphospholipid antibodies and the importance of closely monitoring anticoagulation in such patients.

Notes: Aims : The World Health Organization classification of bronchial intraepithelial neoplastic lesions has been shown to be reproducible. However little is known about its biological value. The aim of this study was to assess the proliferative activity of mild (MiD), moderate (MoD), severe (SD) dysplasia and carcinoma in situ (CIS) by the expression of Ki67 on biopsy specimens obtained during fluorescence bronchoscopy.Methods and results : The percentage of Ki67+ lesional nuclei was calculated in each lesion. In addition, the presence of Ki67 clusters (defined as a group of at least two strongly Ki67+ nuclei located in the upper third of the epithelium) and a Ki67 score were evaluated. The Ki67 score depended on the proportion of the stained nuclei and on the intensity of staining. MiD, MoD, SD and CIS showed increased Ki67 staining (respectively, 10%, 20%, 30% and 40% median values of positive cells). Thirty-one percent MiD, 77% MoD, 91% SD and 100% CIS showed one or more positive clusters. When only multiple clusters were considered the difference between high- and low-grade lesions was accentuated. Ki67+ clusters were more frequent in SD (91%) and CIS (94%) compared with MiD (15%) and MoD (22%). This difference was statistically significant (P 〈 0.01). Evaluation of the Ki67 score was in line with the above results: high grade lesions (SD and CIS) more often showed scores 〉4 (P = 0.05 between MiD plus MoD versus SD plus CIS).Conclusions : Ki67 expression increases from MiD to CIS with a statistically significant difference between MiD plus MoD and SD plus CIS. These results suggest that, in terms of Ki67 positivity, SD behaves like CIS rather than like MiD or MoD.

Notes: [Auszug] Börjeson–Forssman–Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not ...