Vascular morphometry and micrometry of the orbital region of the human optic nerve

The study aims at providing data on the vascular morphometry and micrometry of the orbital region of the human optic nerve. The disposition of the microcirculatory trunk in the orbital region has been studied on 40 samples taken post-mortem, as well as on 10 pieces from subjects having undergone enucleation. Histological specimens were prepared from the optic nerves using eosinhematoxylin dye-staining, the Romhany-Barzu staining and the Gomory trichromic staining. Functionally active capillaries make up 19.380 per cent (7-14 micro group), respectively 21.318 per cent (15-20 micro group) of the total vessels in the area, having an average diameter of 10.01 +/- 0.0826085 p, respectively 17.9272 +/- 0.0651995 micro, for P = 0.05. There are 169 reserve capillaries (with a diameter between 2-6 micron), representing 32.752 of the total of vessels counted. The existence of reserve capillaries allows, at a certain point, for the supplying of the obstruction or of the vasospasm on the territory of the functionally active capillary     

Comparative study on antioxidant effects and vascular matrix metalloproteinase-2 downregulation by dihydropyridines in renovascular hypertension

The vascular remodeling associated with hypertension involves oxidative stress and enhanced matrix metalloproteinases (MMPs) expression/activity, especially MMP-2. While previous work showed that lercanidipine, a third-generation dihydropyridine calcium channel blocker (CCB), attenuated the oxidative stress and increased MMP-2 expression/activity in two-kidney, one-clip (2K1C) hypertension, no previous study has examined whether first- or second-generation dihydropyridines produce similar effects. We compared the effects of nifedipine, nimodipine, and amlodipine on 2K1C hypertension-induced changes in systolic blood pressure (SBP), vascular remodeling, oxidative stress, and MMPs levels/activity. Sham-operated and 2K1C rats were treated with water, nifedipine 10 mg/kg/day, nimodipine 15 mg/kg/day, or amlodipine 10 mg/kg/day by gavage, starting 3 weeks after hypertension was induced. SBP was monitored weekly. After 6 weeks of treatment, quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin-stained sections. Aortic and systemic reactive oxygen species levels were measured by using dihydroethidine and thiobarbituric acid-reactive substances (TBARs), respectively. Aortic MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Nifedipine, nimodipine, or amlodipine attenuated the increases in SBP in hypertensive rats by approximately 17% (P < 0.05) and prevented vascular hypertrophy (P < 0.05). These CCBs blunted 2K1C-induced increases in vascular oxidative stress and plasma TBARs concentrations (P < 0.05). All dihydropyridines attenuated the increases in aortic MMP-2 levels and activity associated with 2K1C hypertension. These findings suggest lack of superiority of one particular dihydropyridine, at least with respect to antioxidant effects, MMPs downregulation, and inhibition of vascular remodeling in hypertension.     

Evidence of early involvement of matrix metalloproteinase-2 in lead-induced hypertension

Lead exposure increases blood pressure (BP) by unknown mechanisms. Many recent studies have shown the involvement of matrix metalloproteinases (MMPs) in hypertension, particularly MMP-2. In this work, we have examined whether MMP-2 levels increase with lead-induced increase in BP. We have also investigated whether doxycycline (an MMP inhibitor) affects these alterations. To this end, rats were exposed to lead (90 ppm) and treated with doxycycline or vehicle for 8 weeks. Similar aortic and whole blood lead levels were found in lead-exposed rats treated with either doxycycline or vehicle. Lead-induced increases in BP and aortic MMP-2 levels (activity, protein, and mRNA) were blunted by doxycycline. Doxycycline also prevented lead-induced increases in the MMP-2/TIMP-2 mRNA ratio. No significant changes in vascular reactivity or morphometric parameters were found. In conclusion, lead exposure increases BP and vascular MMP-2, which is blunted by doxycycline. This observation suggests that MMP-2 may play a role in lead-induced increases in BP.     

Cardiac autonomic dysfunction in rats chronically treated with anabolic steroid

To date no published data exist regarding the effects of chronic high-dose anabolic-androgenic steroid administration on tonic cardiac autonomic control. The aim of this study was to evaluate, by power spectral analysis of heart rate variability (HRV), the effects of chronic treatment with supraphysiological doses of nandrolone decanoate (DECA) on tonic cardiac autonomic regulation in sedentary rats. Male Wistar rats were treated weekly with 10 mg kg⁻¹ of DECA (n=7) or vehicle (CONTROL, n=7) for 10 weeks. At the 8th week of treatment, electrocardiogram was recorded in the conscious state, for time- and frequency-domain HRV analysis. Parasympathetic indexes were reduced in DECA group: high-frequency power (CONTROL=11.1±3.0 ms2 vs. DECA=3.8±0.6 ms2, P<0.05), RMSSD (CONTROL=5.9±0.9 ms vs. DECA 3.5±0.3 ms; P<0.05) and pNN5 (CONTROL=31.5±7.5 ms vs. DECA=13.2±2.6 ms; P<0.05). The sympathetic index LF/HF tended to be higher in DECA group (CONTROL=0.65±0.15 vs. DECA=1.17±0.26, P=0.0546). In conclusion, chronic treatment with DECA, in rats, impairs tonic cardiac autonomic regulation, which may provide a key mechanism for anabolic steroid-induced arrhythmia and sudden cardiac death.     

Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes

Several recent studies have suggested that the adult bone marrow harbors cells that can influence beta-cell regeneration in diabetic animals. Other reports, however, have contradicted these findings. To address this issue, we used an animal model of type 1 diabetes in which the disease was induced with streptozotocin in mice. Freshly prepared sex-mismatched bone marrow cells (BMCs) and syngeneic or allogeneic mesenchymal stem cells (MSCs) were concomitantly administrated into sublethally irradiated diabetic mice. Blood glucose and serum insulin concentrations rapidly returned to normal levels, accompanied by efficient tissue regeneration after a single injection of a mixture of 10(6) BMCs per 10(5) MSCs. Neither BMC nor MSC transplantation was effective alone. Successful treatment of diabetic animals was not due to the reconstitution of the damaged islet cells from the transplant, since no donor-derived beta-cells were found in the recovered animals, indicating a graft-initiated endogenous repair process. Moreover, MSC injection caused the disappearance of beta-cell-specific T lymphocytes from diabetic pancreas. Therefore, we suggest that two aspects of this successful treatment regimen operate in parallel and synergistically in our model. First, BMCs and MSCs induce the regeneration of recipient-derived pancreatic insulin-secreting cells. Second, MSCs inhibit T-cell-mediated immune responses against newly formed beta-cells, which, in turn, are able to survive in this altered immunological milieu. Thus, the application of this therapy in human patients suffering from diabetes and/or other tissue destructive autoimmune diseases may be feasible.     

Functional and structural analysis of the visual system in the rhesus monkey model of optic nerve head ischemia

PURPOSE: A redistribution of neurochemicals has been identified in the visual cortex of monkeys with laser-induced glaucoma. Examined were functional, structural, and neurochemical changes to the retina, optic nerve, and central visual system in a nonhuman primate model of optic nerve head (ONH) ischemia caused by sustained unilateral administration of endothelin (ET)-1 to the optic nerve. METHOD: ET-1 or sham control solution was delivered by osmotic minipump to the retrolaminar region of one optic nerve of rhesus monkeys (Macaca mulatta) for 1.5 years. ONH topography and blood flow velocity were serially studied with scanning laser tomography and laser Doppler flowmetry, respectively. Retinal and cortical electrophysiologic measurements from pattern-derived stimuli were obtained quarterly. Immunohistochemistry was used to identify the distribution of calbindin (CB) and c-Fos labeled neurons in the visual cortex areas V1 and V2, and lateral geniculate nucleus (LGN). Retinal ganglion cell counts and optic nerve axon density were determined by light microscopy. RESULTS: No significant changes in retinal and ONH morphology, ONH blood flow velocity, and retinal and cortical pattern-derived functional activity were detected. Measurement of CB-positive cell density in V1 and V2 showed a significant decrease in CB labeling to the contralateral side of the ET-1-treated eye (P < 0.04). CB-positive cells were present in the magnocellular layers of the LGN with no differences noticed between the ET-1- and sham-treated eyes. c-Fos-labeled neurons were found in striate area V1 and extrastriateV2 of both groups. No c-Fos labeling was observed in the LGN. CONCLUSIONS: Administering ET-1 to the orbital optic nerve alters neuronal metabolic activity in the visual cortex in rhesus monkeys. Metabolic activity reductions in the visual cortex precede the ability to detect functional and structural alterations in the retina, ONH, and visual cortex in this animal model.     

Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of theophylline can increase HDAC activity. We measured the effect of theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P < 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-alpha, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, theophylline might restore steroid responsiveness in COPD patients.     

Evidence that molecular changes in cells occur before morphological alterations during the progression of breast ductal carcinoma

Introduction  

Ductal carcinoma in situ (DCIS) of the breast includes a heterogeneous group of preinvasive tumors with uncertain evolution. Definition of the molecular factors necessary for progression to invasive disease is crucial to determining which lesions are likely to become invasive. To obtain insight into the molecular basis of DCIS, we compared the gene expression pattern of cells from the following samples: non-neoplastic, pure DCIS, in situ component of lesions with co-existing invasive ductal carcinoma, and invasive ductal carcinoma.