Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol

Because d-alpha-tocopherol (vitamin E) has been shown to decrease diacylglycerol (DAG) levels and prevent the activation of protein kinase C (PKC), which is associated with retinal and renal dysfunctions in diabetes, the study presented here characterized the effect of d-alpha-tocopherol treatment to prevent glomerular hyperfiltration and increased albuminuria as well as PKC activities in streptozotocin (STZ)-induced diabetic rats. Two weeks after the induction of diabetes, total DAG content and PKC activity in glomeruli were significantly increased in diabetic rats by 106.4 +/- 16.8% and 66.4 +/- 8.4%, respectively, compared with control rats. Intraperitoneal injection of d-alpha-tocopherol (40 mg/kg of body weight) every other day prevented the increases in total DAG content and PKC activity in glomeruli of diabetic rats. Glomerular filtration rate (GFR) and filtration fraction (FF) were significantly elevated to 4.98 +/- 0.34 mL/min and 0.36 +/- 0.05, respectively, in diabetic rats, compared with 2.90 +/- 0.14 mL/min and 0.25 +/- 0.02, respectively, in control rats. These hemodynamic abnormalities in diabetic rats were normalized to 2.98 +/- 0.09 mL/min and 0.24 +/- 0.01, respectively, by d-alpha-tocopherol. Albuminuria in 10-wk diabetic rats was significantly increased to 9.1 +/- 2.2 mg/day compared with 1.2 +/- 0.3 mg/day in control rats, whereas d-alpha-tocopherol treatment improved albumin excretion rate to 2.4 +/- 0.6 mg/day in diabetic rats. To clarify the mechanism of d-alpha-tocopherol's effect on DAG-PKC pathway, the activity and protein levels of DAG kinase alpha and gamma, which metabolize DAG to phosphatidic acid, were examined. Treatment with d-alpha-tocopherol increased DAG kinase activity in the glomeruli of both control and diabetic rats, by 22.6 +/- 3.6% and 28.5 +/- 2.3% respectively, although no differences were observed in the basal DAG kinase activity between control and diabetic rats. Because immunoblotting studies did not exhibit any difference in the protein levels of DAG kinase alpha and gamma, the effect of d-alpha-tocopherol is probably modulating the enzyme kinetics of DAG kinase. These findings suggest that the increases in DAG-PKC pathway play an important role for the development of glomerular hyperfiltration and increased albuminuria in diabetes and that d-alpha-tocopherol treatment could be preventing early changes of diabetic renal dysfunctions by normalizing the increases in DAG and PKC levels in glomerular cells.     

Regulation of retinal and optic nerve blood flow

Blood flow to the retina and optic nerve remains constant over a range of elevated intraocular pressure or mean arterial pressure, independent of sympathetic activation (pressure autoregulation). In addition, increased metabolic activity in these tissues proportionally increases blood flow (metabolic autoregulation). At constant metabolic rate, altered arterial oxygen content reciprocally alters blood flow, leaving total oxygen delivery constant, while blood flow rises and falls with the arterial carbon dioxide tension. These responses are similar to those of the cerebral circulation. However, while aging, atherosclerosis, arterial hypotension, and individual variation may profoundly alter blood flow regulation and predispose to the development of illness, these factors remain largely unexplored.     

Reversal of blood flow in experimental branch retinal vein occlusion

BACKGROUND: The consequences and management of asymptomatic Actinomyces-like organisms detected on cervical cytologic smears continue to be controversial. CASE: A unilateral tuboovarian actinomycotic abscess was discovered in a woman who had undergone a hysterectomy for uterine leiomyomas. She had had an intrauterine device in place for many years without any symptoms of pelvic inflammatory disease. CONCLUSION: Ascending infection of the upper genital tract by Actinomyces may be clinically inapparent. When Actinomyces-like organisms aer detected on cervical cytologic smears, removal of an intrauterine device should be considered.     

Optical flow not retinal flow is the basis of wayfinding by foot.

Two experiments were directed at the hypothesis that wayfinding is achieved by a recursive strategy using differential motion parallax (DMP), a property of retinal flow due to near and far objects moving against fixation. Experiment 1 showed that without the changing global optical pattern due to translation of the eye, DMP failed to support wayfinding accuracy in the 2°–4° range assumed necessary for guiding locomotion. Experiment 2 revealed that the requisite accuracy was achievable when displays simulating locomotion violated the conditions for the DMP strategy but included the optical flow pattern due to translation. It was concluded that DMP is neither necessary nor sufficient for wayfinding; the information for wayfinding is in optical flow. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of 0.5% apraclonidine on optic nerve head and peripapillary retinal blood flow

AIMS: To examine the effects of 0.5% apraclonidine on optic nerve head (ONH) and peripapillary retinal blood flow by scanning laser Doppler flowmetry (SLDF). METHODS: ONH and peripapillary retinal blood flow of 17 healthy subjects were measured by SLDF before and 1 hour and 3 hours after unilateral administration of 0.5% apraclonidine. The fellow eyes were treated with balanced salt solution and the examiners were masked as to which eye was treated with apraclonidine. On each occasion, three scans were obtained and haemodynamic variables (volume, flow, and velocity) were analysed at eight locations, four in the neural rim and four in the peripapillary retina, avoiding ophthalmoscopically visible vessels. The statistical significance of changes from the baseline value of variables and the differences in the measured quantities between apraclonidine treated eyes and fellow eyes at each time point were evaluated using Wilcoxon signed rank test. RESULTS: The intraocular pressure was reduced significantly in apraclonidine treated eyes by 15.0% (p = 0.001) at 1 hour and 30.0% (p = 0.000) at 3 hours after administration. In the volume, flow, or velocity of ONH and peripapillary retinal blood flow, there were no significant changes from the baseline values at 1 hour and 3 hours after apraclonidine administration in either apraclonidine treated eyes (p > 0.4) or fellow eyes (p > 0.2). Also, no significant differences were found in the measured quantities between apraclonidine treated eyes and fellow eyes at each time point (p > 0.1). CONCLUSION: A single dose of topical apraclonidine 0.5% in healthy subjects does not have adverse effects on the ONH and peripapillary retinal blood flow.     

Nitric oxide modulation of retinal, choroidal, and anterior uveal blood flow in newborn piglets

The purpose of the present study was to investigate the role of nitric oxide (NO) in modulating the resting vascular tone of the choroidal and anterior uveal circulations and the autoregulatory gain of the retina. Blood flow (ml/min/100 gm dry weight) to tissues was determined in 23 anesthetized piglets (3-4 kg) using radiolabelled microspheres. Ocular Perfusion Pressure (OPP) was defined as mean arterial pressure minus intraocular pressure (IOP) which was manipulated hydrostatically by cannulation of the anterior eye chamber. The OPP was decreased during intravenous infusion (30 mg/kg/hr) of either the NO-synthase inhibitor L-NAME or the inactive enantiomer D-NAME. Blood flows were determined at OPP of 60, 50, 40, 30, and 20 mmHg following initial ocular blood flow measurements. Mean initial choroidal and anterior uveal blood flows with L-NAME showed a 47+/-12% and a 43+/-6% reduction (p <.001), respectively. Mean choroidal blood flows were significantly reduced (p<.01) in the L-NAME treated animals at an OPP of 60 and 50 when compared to D-NAME. Uveal blood flows were linearly correlated with OPP in the L-NAME and D-NAME treated groups. Uveal blood flow was greater following exogenous administration of L-arginine (180 mg/kg). Mean initial retinal blood flow did not differ significantly in either group. Retinal blood flow with L-NAME was reduced at OPP of 60 mmHg and below compared to D-NAME (p<.05). The degree of compensation in the autoregulatory gain of the retinal vasculature was reduced in the presence of L-NAME at an OPP of 50 mmHg and below compared to D-NAME. These data support the hypothesis that NO may be a primary mediator in maintaining resting vascular tone to the choroid and anterior uvea in vivo and that NO blockade reduces the degree of compensation in the autoregulatory gain of the retinal vasculature within a specific range of ocular perfusion pressures.     

Modulation of cochlear blood flow by extracellular purines

Humoral adenosine 5'-triphosphate (ATP), adenosine and uridine 5'-triphosphate (UTP) have been shown to have a role in controlling local blood flow in a variety of tissues. The presence of P1 and P2 receptors in the cochlea, and particularly the highly vascular region, the stria vascularis, implies a vasoactive role for these compounds in the inner ear. To test the effect of extracellular purines and pyrimidines on cochlear blood flow, cochleae from anaesthetised guinea-pigs were perfused with ATP (1 microM-10 mM), adenosine (1 microM-10 mM) and UTP (1 mM) in artificial perilymph while blood flow through the cochlea was measured. An acute perilymphatic perfusion technique was established via tubing placed through a hole in the bone overlying scala tympani of the first cochlear turn, with an outlet hole in scala vestibuli of the fourth turn. Blood flow was measured by placing the probe of a laser Doppler blood perfusion monitor on the bone overlying the stria vascularis in the third cochlear turn. ATP and adenosine produced a significant dose dependent increase in cochlear blood flow (28.8-229.0% and 35.8-258.1%, respectively). The effect of ATP (100 microM) on cochlear blood flow was reduced in the presence of reactive blue 2 (1 mM) and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (1 mM). The blood flow response to adenosine (10 microM) was reduced in the presence of 1,3-dimethylxanthine (theophylline, 100 microM), but not with either 3,7-dimethyl-1-propargylxanthine (10 microM) or 8-cyclopentyl-1,3-dipropylxanthine (10 microM). UTP did not produce any change in the cochlear blood flow. To determine if the ATP effect was also mediated by adenosine derived from ectonucleotidase activity, the perilymphatic compartment was perfused with either ATP plus theophylline (100 microM) or with the non-metabolisable form of ATP, adenosine 5'-O-(3-thiophosphate) (ATPgammaS, 100 microM). The effect of ATP on cochlear blood flow was unaffected with the inclusion of theophylline while ATPgammaS produced an increase in cochlear blood flow similar to the one observed with ATP. These findings indicate that extracellular ATP and its metabolite adenosine have a modulatory role in cochlear blood flow possibly mediated by both P1 and P2 receptors.     

Quantification of cerebral blood flow with 99mTc-ECD SPECT by a single arterial or venous blood sample

The purpose of the study is to develop a simple and less invasive method for quantifying regional cerebral blood flow (rCBF) using 99mTc-ECD and SPECT. By employing a microsphere model, a new method to measure rCBF was developed, which required a single arterial or venous sample instead of continuous withdrawal of arterial blood. Using a regression line, the integral of input function of arterial blood from 0 to 30 min was inferred by activity of arterial blood sampled at time t; A(t), by activity multiplied by its octanol extraction rate; AN(t), by activity of venous blood at time t; V(t), and by activity multiplied by its octanol extraction rate; VN(t). The optimum sampling time of arterial or venous blood was examined when mean % error for inference became minimum. Consequently, minimum error of AN(6 min) was 5.5%, A(3 min) was 8.9%, VN(6 min) was 5.9%, and V(20 min) was 10.0%. Quantitative measurement of rCBF using the value of VN(6 min) was performed on other 6 subjects with dementia etc. To validate the method, 133Xe inhalation SPECT studies were also performed on the same subjects. We found a good agreement between them (r = 0.851). The presented one-point sampling methods were simple and less invasive for quantifying rCBF.     

Patients with diabetes-induced microangiopathy show a reduced frequency of carcinomas

Complete avulsion of the external ear, much less common than other minor ear trauma, presents a complex and difficult problem. The authors present a 35-year-old male cigarette smoker who suffered traumatic avulsion of the right ear, and describe the replantation procedure and the patient's postoperative course. Aesthetic positioning of the replanted ear, treating the external auditory meatus, protecting the ear against exposure to the sun, and counseling the patient about issues related to sensation are important factors in the care of patients who have undergone such a procedure.     

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

Substantial evidence exists that diabetes results in impaired endothelial dysfunction suggesting diminished nitric oxide production from diabetic endothelium. It is not known what factors contribute to the development of this defect. In this study, we tested whether chronic treatment in vivo with NOX-101, a water-soluble nitric oxide scavenger, prevents endothelial dysfunction in diabetes. Sprague-Dawley rats were made diabetic by an intravenous injection of streptozotocin. A subgroup of control or diabetic animals received twice daily subcutaneous injections of 80 mg/kg NOX-101 beginning at 48 h after streptozotocin was injected and throughout 8 weeks of diabetes. Body weights and glucose concentrations were monitored weekly. At the end of 8 weeks, blood glucose and glycosylated haemoglobin was raised in diabetic rats but serum insulin concentrations were reduced. Treatment with NOX-101 did not alter glucose or insulin concentrations in control or diabetic rats; however, total glycosylated haemoglobin was partially reduced compared with untreated rats. In a subgroup of 2-week diabetic and age-matched rats fasted for 24 h, NOX-101 abolished total urinary nitrate plus nitrite (an index of nitric oxide production in vivo). In isolated tissue baths, relaxation to the endothelium-dependent vasodilator, acetylcholine, was impaired in diabetic aortic rings and relaxation to nitroglycerin was unaltered. Treatment of control rats with NOX-101 did not alter maximum relaxation to acetylcholine but shifted the response curve slightly to the right. In contrast in diabetic rats, NOX-101 prevented the impairment in endothelium-dependent relaxation but had no effect on relaxation induced by nitroglycerin. These data suggest the possibility that diabetes-induced endothelial dysfunction in diabetes results, in part, from a paradoxical increase in nitric oxide production during the course of the disease. This suggests a novel pathway of vascular complications.     

Doppler ultrasound of blood flow velocities in ophthalmic and central retinal arteries during the early neonatal period

Dopamine has been implicated as a potential mediating factor in a variety of neurodegenerative disorders. Dopamine can be oxidized to form a reactive dopamine quinone that can covalently modify cellular macromolecules including protein and DNA. This oxidation can be enhanced through various enzymes including tyrosinase and/or prostaglandin H synthase. One of the potential targets in brain for dopamine quinone damage is tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. The present studies demonstrated that dopamine quinone, the formation of which was enhanced through the activity of the melanin biosynthetic enzyme, tyrosinase, covalently modified and inactivated tyrosine hydroxylase. Dihydroxyphenylalanine (DOPA; the catechol-containing precursor of dopamine) also inactivated tyrosine hydroxylase under these conditions. Catecholamine-mediated inactivation occurred with both purified tyrosine hydroxylase as well as enzyme present in crude pheochromocytoma homogenates. Inactivation was associated with covalent incorporation of radiolabelled dopamine into the enzyme as assessed by immunoprecipitation, size exclusion chromatography, and denaturing sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis. Furthermore, the covalent modification and inactivation of tyrosine hydroxylase was blocked by antioxidant compounds (dithiothreitol, reduced glutathione, or NADH). In addition to kinetic feedback inhibition and the formation of an inhibitory dopamine/Fe+3 complex, these findings suggest that a third mechanism exists by which dopamine (or DOPA) can inhibit tyrosine hydroxylase, adding further complexity to the regulation of catecholamine biosynthesis.     

Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha

BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interleukin-8. We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 49 patients with proven louse-borne relapsing fever. Immediately before the intramuscular injection of penicillin, the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P = 0.006). The controls had significantly greater mean maximal increases in temperature (1.5 vs. 0.8 degrees C, P < 0.001), pulse rate (31 vs. 13 per minute, P < 0.001), and systolic blood pressure (25 vs. 15 mm Hg, P < 0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50 vs. 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P < 0.001 for both comparisons). Levels of TNF-alpha were undetectable after treatment with anti-TNF-alpha Fab. CONCLUSIONS: Pretreatment with sheep anti-TNF-alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin treatment for louse-borne relapsing fever, reduces the associated increases in plasma concentrations of interleukin-6 and interleukin-8, and may be useful in other forms of sepsis.     

Effects of oral vanadyl treatment on diabetes-induced alterations in the heart GLUT-4 transporter

Vanadyl sulfate was administered orally during a 10-week trial period to streptozotocin-diabetic and control male rats to test the hypothesis that chronic vanadyl supplementation would prevent the decline in cardiac muscle cell glucose transporter protein (GLUT-4) that otherwise manifests in conjunction with insulin deficiency. Isolated cardiac myocytes and cardiac sarcolemmal vesicles were prepared from heart tissue of rats that had been maintained on the following regimens: untreated control, oral vanadyl-supplemented control (0.6 mg/ml), untreated diabetic (streptozotocin-induced; 60 mg/kg), and vanadyl-supplemented diabetic. Myocytes isolated from untreated diabetic rat hearts had decreased rates of glucose oxidation. Chronic, oral administration of vanadyl to diabetic rats maintained glucose oxidation rates of cardiac myocytes at control levels. Immunoblot analyses revealed that total cardiac myocyte and sarcolemmal GLUT-4 glucose transporter protein levels were significantly lower in the diabetic group relative to control. Vanadyl treatment of diabetic rats produced a normalization of both sarcolemmal GLUT-4 and total cardiac myocyte levels towards control levels. The reduction of GLUT-4 mRNA levels seen with untreated diabetes was also completely prevented with vanadyl treatment. These results demonstrate that chronic-oral vanadyl sulfate supplementation limits the decline in glucose oxidative capacity of cardiac myocytes that otherwise manifests in the untreated diabetic state. This action of vanadyl may occur via a mechanism that is linked to the preservation of sarcolemmal GLUT-4 protein levels.