Mechanism of UV-related carcinogenesis and its contribution to nevi/melanoma

Melanoma consists 4-5 % of all skin cancers, but it contributes to 71-80 % of skin cancers deaths. UV light affects cell and tissue homeostasis due to its damaging effects on DNA integrity and modification of expression of a plethora of genes. DNA repair systems protect cells from UV-induced lesions. Several animal models of melanoma have been developed (Xiphophorus, Opossum Monodelphis domestica, mouse models and human skin engrafts into other animals). This review discusses possible links between UV and genes significantly related to melanoma but does not discuss melanoma genetics. These include oncogenes, tumor suppressor genes, genes related to melanocyte-keratinocyte and melanocyte-matrix interaction, growth factors and their receptors, CRH, ACTH, α-MSH, glucocorticoids, ID1, NF-kappaB and vitamin D3.     

An Automated Self‐Similarity Analysis of the Pulmonary Tree of the Sprague–Dawley Rat

We present the results of an automated analysis of the morphometry of the pulmonary airway trees of the Sprague–Dawley rat. Our work is motivated by a need to inform lower‐dimensional mathematical models to prescribe realistic boundary conditions for multiscale hybrid models of rat lung mechanics. Silicone casts were made from three age‐matched, male Sprague–Dawley rats, immersed in a gel containing a contrast agent and subsequently imaged with magnetic resonance (MR). From a segmentation of this data, we extracted a connected graph, representing the airway centerline. Segment statistics (lengths and diameters) were derived from this graph. To validate this MR imaging/digital analysis method, airway segment measurements were compared with nearly 1,000 measurements collected by hand using an optical microscope from one of the rat lung casts. To evaluate the reproducibility of the MR imaging/digital analysis method, two lung casts were each imaged three times with randomized orientations in the MR bore. Diameters and lengths of randomly selected airways were compared among each of the repeated imaging datasets to estimate the variability. Finally, we analyzed the morphometry of the airway tree by assembling individual airway segments into structures that span multiple generations, which we call branches. We show that branches not segments are the fundamental repeating unit in the rat lung and develop simple mathematical relationships describing these structures for the entire lung. Our analysis shows that airway diameters and lengths have both a deterministic and stochastic character. Anat Rec, 2008. © 2008 Wiley‐Liss, Inc.     

Hypoxic pulmonary vasoconstriction is heterogeneously distributed in the prone dog

Hypoxic pulmonary vasoconstriction (HPV) is thought to protect gas exchange by decreasing perfusion to hypoxic regions. However, with global hypoxia, non-uniformity in HPV may cause over-perfusion to some regions, leading to high-altitude pulmonary edema. To quantify the spatial distribution of HPV and regional PO2 (PRO2) among small lung regions (approximately 2.0 cm3), five prone beagles (approximately 8.3 kg) were anesthetized and ventilated (PEEP approximately 2 cm H2O) with an F1O2 of 0.21, then 0.50, 0.18, 0.15, and 0.12 in random order. Regional blood perfusion (Q), ventilation (VA) and calculated PRO2 were obtained using iv infusion of 15 microm and inhalation of 1 microm fluorescent microspheres. Lung pieces were clustered by their relative blood flow response to each F1O2. Clusters were shown to be spatially grouped within animals and across animals. Lung piece resistance increased as PRO2 decreased to 60-70 mmHg but dropped at PRO2's < 60mmHg. Regional ventilation changed little with hypoxia. HPV varied more in strength of response, rather than PRO2 response threshold. In initially homogeneous VA/Q lungs, we conclude that HPV response is heterogeneous and spatially clustered.     

Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke

Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)⁺ and CD105⁺ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ⁺ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.     

Antioxidants do not explain the disparate longevity between mice and the longest-living rodent, the naked mole-rat

The maximum lifespan of naked mole-rats (NMRs; Heterocephalus glaber) is greater than that of any other rodent. These hystricognaths survive in captivity >28 years, eight-times longer than similar-sized mice. The present study tested if NMRs possess superior antioxidant defenses compared to mice and if age-related interspecies changes in antioxidants were evident. Activities of Cu/Zn superoxide dismutase (Cu/Zn, SOD), Mn SOD, catalase and cellular glutathione peroxidase (cGPx) were measured in livers of physiologically equivalent age-matched NMRs (30, 75 and 130 months) and CB6F1 mice (4, 12 and 18 months). In mice, Mn SOD activity increased with age, while the activity of catalase and cGPx declined. None of the antioxidants changed with age in mole-rats. cGPx activity of NMRs was 70-times lower (p < 0.0001) than in mice, and resembled that of cGPx knock-out animals. NMRs may partially compensate for the lower cGPx when compared to mice, by having moderately higher activities of the other antioxidants. It is nonetheless unlikely that antioxidant defenses are responsible for the eight-fold longevity difference between these two species. Maintenance of constant antioxidant defenses with age in NMRs concurs with previous physiological data, suggesting delayed aging in this species.     

Malaysian siblings with friedreich ataxia and chorea: a novel deletion in the frataxin gene

BACKGROUND: Friedrich ataxia (FRDA1) is most often the result of a homozygous GAA repeat expansion in the first intron of the frataxin gene (FRDA gene). This condition is seen in individuals of European, North African, Middle Eastern and Indian descent and has not been reported in Southeast Asian populations. Approximately 4% of FRDA1 patients are compound heterozygotes. These patients have a GAA expansion on one allele and a point mutation on the other and have been reported to have an atypical phenotype. OBJECTIVE: To describe a novel dinucleotide deletion in the FRDA gene in two Malaysian siblings with FRDA1. SETTING: Tertiary referral university hospital setting. PATIENTS AND METHODS: A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period. His neurological exam revealed evidence of dysarthria and ataxia, mild generalized weakness and choreoform movements of the tongue and hands. His reflexes were absent and Babinski sign was present bilaterally. A nine-year-old sister was found to have mild ataxia but was otherwise neurologically intact. RESULTS: Molecular genetic studies demonstrated that both siblings were compound heterozygotes with a GAA expansion on one allele and a novel dinucleotide deletion on the other allele. CONCLUSIONS: We describe a novel dinucleotide deletion in the first exon of the FRDA gene in two siblings with FRDA1. Additionally this is the first report of FRDA1 occurring in a family of southeast Asian descent, it demonstrates intrafamilial phenotypic variability, and confirms that atypical phenotypes are associated with compound heterozygosity.     

Acetylsalicylic acid is compounding to antiplatelet effect of C-reactive protein

The contribution of inflammatory process to the modulation of platelet response to acetylsalicylic acid (ASA) remains obscure. In our study, we examined the in vitro effect of C-reactive protein (CRP) on the ASA-mediated inhibition of collagen-stimulated platelet reactivity. Influence of CRP on platelet responsiveness to ASA was analysed using classical turbidimetric aggregation and flow cytometry. When acting alone, both C-reactive protein and ASA inhibited collagen-dependent platelet aggregation and reduced the expressions of two platelet surface membrane activation markers: P-selectin and activated GPIIbIIIa complex. Compared to the effects observed for ASA alone, the simultaneous action of both agents lead to further reductions in platelet aggregation (by 56.7+/-1.0% vs. 14.9+/-0.6%, p<0.0001) and lowered the expressions of platelet surface membrane P-selectin (by 72.1+/-5.3% vs. 65.0+/-6.0%, p<0.01) and activated GPIIbIIIa (by 67.0+/-5.6% vs. 47.7+/-8.3%, p<0.01). In general, our findings showed for the first time the augmenting effect of native C-reactive protein in the antiplatelet action of acetylsalicylic acid. Thus, we conclude that the effectiveness of aspirin therapy may strongly depend upon the presence of native CRP in circulation.     

Predictors of carotid atherosclerotic plaque progression as measured by noninvasive magnetic resonance imaging

The purpose of this in vivo MRI study was to quantify changes in atherosclerotic plaque morphology prospectively and to identify factors that may alter the rate of progression in plaque burden. Sixty-eight asymptomatic subjects with >or=50% stenosis, underwent serial carotid MRI examinations over an 18-month period. Clinical risk factors for atherosclerosis, and medications were documented prospectively. The wall and total vessel areas, matched across time-points, were measured from cross-sectional images. The normalized wall index (NWI=wall area/total vessel area), as a marker of disease severity, was documented at baseline and at 18 months. Multiple regression analysis was used to correlate risk factors and morphological features of the plaque with the rate of progression/regression. On average, the wall area increased by 2.2% per year (P=0.001). Multiple regression analysis demonstrated that statin therapy (P=0.01) and a normalized wall index >0.64 (P=0.001) were associated with a significantly reduced rate of progression in mean wall area. All other documented risk factors were not significantly associated with changes in wall area. Findings from this study suggest that increased normalized wall index and the use of statin therapy are associated with reduced rates of plaque progression amongst individuals with advanced, asymptomatic carotid atherosclerosis.     

Endovenous laser treatment of the small [corrected] saphenous vein: efficacy and complications

OBJECTIVE: The study was conducted to assess the efficacy and rate of complications of endovenous laser treatment (EVLT) of the short saphenous vein (SSV). METHODS: During a 17-month period, 210 (187 patients) with SSV incompetence documented by duplex ultrasound studies were treated with EVLT using a 980-nm diode laser. Duplex ultrasound examinations were performed on the day of the procedure, within the first week, and 2 to 11 months after the procedure (mean follow-up, 4 months). Clinical examinations were performed at 2 weeks and 6 weeks. Patients were assessed for deep venous thrombosis (DVT), nerve injury, and resolution of symptoms. RESULTS: All procedures were technically successful, and in the 126 patients (60%) who completed final follow-up scanning, 96% of SSVs remained closed. Three patients (1.6%) had numbness at the lateral malleolus at the 6-week follow-up. DVT, defined as a tail of thrombus protruding into the popliteal vein, was not detected in any limbs at the initial duplex study, but was noted in 12 limbs (5.7%) at the 1-week follow-up examination. Nine patients were treated with 3 days to 3 months of fractionated heparin and Coumadin (Bristol-Myers Squibb, Princeton, NJ), and there were no DVT extensions or pulmonary emboli. The anatomic configuration of the saphenopopliteal junction was the only factor predictive of DVT. CONCLUSIONS: Intermediate-term results of EVLT of the SSV demonstrate that the technique is effective at eliminating SSV reflux and affording symptomatic relief. The incidence of nerve injury is low, but the incidence of DVT is higher than reported for the great saphenous vein. Anatomic features of the SSV may predict patient risk for DVT.