Renal ischemia-reperfusion injury in the rat is prevented by a novel immune modulation therapy

BACKGROUND: Vasogen Inc.'s (Mississauga, Ontario, Canada) immune modulation therapy (IMT) is a therapy in which cells from the patient's own blood are modified by ex vivo exposure to specific physicochemical stressors, including oxidation, ultraviolet (UV) light, and an elevated temperature. The therapy has been shown to have a beneficial effect in models of inflammation and vascular diseases. This study tested the hypothesis that IMT can prevent renal ischemia-reperfusion (I/R) injury in rats. METHODS: Whole blood was collected from syngeneic age-matched donors by cardiac puncture. It was treated with a combination of controlled physiochemical stressors consisting of elevated temperature, a gas mixture of medical oxygen containing ozone, and UV light. The treated blood (150 microL) was injected in the gluteal muscle. Control animals received the same volume of untreated blood or physiological saline. Transient (45 or 60 minutes) left-renal ischemia was produced with simultaneous contralateral nephrectomy in treated and control spontaneously hypertensive rats (SHR). Young and old male and female rats were studied. Plasma creatinine, diuresis, and the survival rates of each group were compared. Renal apoptosis-necrosis was estimated by DNA laddering, histology, and in situ terminal deoxynucleotidyl transferase assay. mRNA levels of several regulators of apoptosis-regeneration were determined in control and postischemic kidneys by Northern blotting. RESULTS: IMT pretreatment of SHR significantly reduced renal I/R injury compared with equivalent placebo treatments consisting of untreated blood- or saline-injected SHR, as evidenced by a significant increase of the survival rate curves in young and old male SHR, which correlated with 24-hour postischemic diuresis. The increases in plasma creatinine following renal I/R were significantly lower in IMT-treated young male and old female SHR compared with saline or untreated blood-injected controls. Dilution analysis showed that the protective effect of treated blood was lost by dilution. Loss of epithelial cells was reduced in IMT-treated rats, with a significant decline in the peak of apoptosis 12 hours after acute ischemic renal injury. IMT did not modify the pattern of mRNA levels of several genes involved in the inflammation and regeneration processes. CONCLUSION: Our data demonstrate that IMT prevents the destruction of kidney tissue and the resulting animal death caused by renal I/R injury.     

Treatment with anti-CD154 antibody and donor-specific transfusion prevents acute rejection of myoblast transplantation

BACKGROUND: Achieving immunological tolerance to transplanted myoblasts would reduce the adverse effects associated with the sustained immunosuppression required for this experimental therapeutic approach in Duchenne muscular dystrophic patients. METHODS: Mdx mice were transplanted with fully allogeneic BALB/c myoblasts in the tibialis anterior muscles. Seven days before transplantation (-7), host mice received 107 total donor spleen cells i.v. (donor-specific transfusion, DST) with 500 microg of anti-CD154 mAb i.p. on days -7, -4, 0, +4. RESULTS: Results showed a high level of dystrophin expression in 83, 60, and 20% of the mice 1, 3, and 6 months, respectively, after transplantation of myoblasts. No antibodies against the donor cells were produced up to 3 months after transplantation. However, abundant activated cytotoxic cells were present in muscles still expressing high percentage of dystrophin positive fibers. CONCLUSIONS: In conclusion, the DST + anti-CD154 mAb treatments effectively prolonged myoblast survival, but this treatment could not develop tolerance to complete allogeneic myoblast transplantation.     

Assessment of initial base deficit as a predictor of outcome: mechanism of injury does make a difference

Initial base deficit in injured patients has been shown to predict the adequacy of resuscitation and outcome. The usefulness of base deficit as a predictor of outcome, however, may be dependent on the mechanism of injury. We conducted a retrospective review of the trauma registry, supplemented by chart review, of all trauma patients treated at a Level I trauma center from January 1995 through July 2001. Data collected included mechanism of injury, base deficit, Injury Severity Score, and outcome. From 1995 through 2001 a total of 3275 patients (23% of trauma admissions) at a mean age of 34 +/- 15 years had a base deficit recorded at the time of admission. The patients were 78 per cent male, and the mechanism of injury was blunt trauma in 58.2 per cent. Mortality increased with successive increases in base deficit but was markedly lower for a given base deficit in those patients having sustained stab wounds and/or severe lacerations as compared with those with gunshot wounds or blunt trauma. The value of the base deficit as a predictor of outcome depends upon the mechanism of injury and appears most useful for patients sustaining gunshot wounds or blunt trauma. Future studies in patients with penetrating trauma using base deficit as a predictor of outcome should separate patients with gunshot wounds from those with stab wounds or lacerations.     

Comparability of total score performance on the Rey-Osterrieth Complex Figure and a modified Taylor Complex Figure

One of the most commonly used neuropsychological measures of visuo-spatial abilities is the Rey-Osterrieth Complex Figure (ROCF) Test. Previous research has reliably shown that its companion figure, the Taylor Complex Figure, is not a comparable measure of visuo-spatial memory. The aims of the three studies presented here are to (a) introduce a modified version of the Taylor Figure (MTCF), and (b) examine the comparability of the ROCF and the MTCF using two different administration procedures. The first two studies used a between-subjects design in which half of the study participants received the ROCF and half received the MTCF. In Study 1, an incidental procedure was used in which participants were asked to first copy a figure and then reproduce it from memory without prior warning. In Study 2, an intentional procedure was used in which participants were first asked to observe the figures for the express purpose of reproducing them from memory followed by delay and copy trials. In Study 3, a within-subjects design using counterbalancing and an intentional procedure was used to examine the comparability of the two figures when administered to the same participants as in a true test-retest situation. Overall, the studies demonstrated that learning, memory, and copy score performance on the MTCF was comparable to that on the ROCF.     

Central neural mechanisms contributing to the perception of tactile roughness

This paper summarizes recent work showing that tactile roughness appreciation increases in a nearly linear fashion as tactile element spacing or spatial period (SP, distance centre-to-centre between raised dots in these experiments) is increased from 1.5 to 8.5 mm. Although a previous study had reported a U-shaped psychophysical function peaking at a nominal SP of 3.2 mm, differences in the surfaces (including changing SP in only one dimension as compared with two and higher dot heights that minimized contact with the smooth floor) likely contributed to the difference in the results. Roughness estimates were also unaffected by a 2-fold change in scanning speed (50 vs. 95 mm/s). Parallel recordings from neurones in primary somatosensory cortex (SI) during a texture discrimination task indicate that the discharge frequency of many SI cells shows a monotonic relation with SP (up to 5 mm tested). For some cells, the texture signals were ambiguous because discharge frequency co-varied with both texture and the scanning speed, as has also been reported for the peripheral mechanoreceptors that are activated by textured surfaces. Yet other SI cells showed a speed-invariant response to surface texture, consistent with perceptual constancy for roughness over a range of scanning speeds. We suggest that such a discharge pattern could be based on a simple intensive, or mean rate, code: an invariant central representation of surface texture could be obtained by subtracting a speed-varying signal from the ambiguous signals that co-vary with roughness and speed.     

Reward processing in primate orbitofrontal cortex and basal ganglia

This article reviews and interprets neuronal activities related to the expectation and delivery of reward in the primate orbitofrontal cortex, in comparison with slowly discharging neurons in the striatum (caudate, putamen and ventral striatum, including nucleus accumbens) and midbrain dopamine neurons. Orbitofrontal neurons showed three principal forms of reward-related activity during the performance of delayed response tasks, namely responses to reward-predicting instructions, activations during the expectation period immediately preceding reward and responses following reward. These activations discriminated between different rewards, often on the basis of the animals' preferences. Neurons in the striatum were also activated in relation to the expectation and detection of reward but in addition showed activities related to the preparation, initiation and execution of movements which reflected the expected reward. Dopamine neurons responded to rewards and reward-predicting stimuli, and coded an error in the prediction of reward. Thus, the investigated cortical and basal ganglia structures showed multiple, heterogeneous, partly simultaneous activations which were related to specific aspects of rewards. These activations may represent the neuronal substrates of rewards during learning and established behavioral performance. The processing of reward expectations suggests an access to central representations of rewards which may be used for the neuronal control of goaldirected behavior.     

Expression of hsp70 gene in lymphocytes from normotensive and hypertensive humans.

The impact of environmental factors on hypertension depends to a certain extent on the individual's genetic background. Environmental temperature is one of the known modulators of blood pressure. We have previously demonstrated abnormal expression of a major environmentally-controlled gene, hsp70, in hypertensive mice and rats. We have developed a simple ex vivo method for the evaluation of hsp genes expression in humans. In the present study, we investigated the accumulation of hsp70 mRNA in lymphocytes from normotensive and hypertensive humans. The data showed a higher accumulation of hsp70 mRNA in lymphocytes from hypertensives vs normotensives (2.04 +/- 0.35 vs 1.48 +/- 0.29 OD mm2, P < 0.05) submitted to heat stress (15 min at 42 degrees C). Basal levels were the same in both groups (0.11 +/- 0.01 vs 0.10 +/- 0.01 OD mm2, respectively). These results support our hypothesis that alterations in the expression of a major environmentally-controlled gene, hsp70, may be involved in enhanced environmental responses even in human hypertension.     

Congenital angiodysplasia of the parotid area--report of two cases

Two cases of angiodysplasia of the parotid area are reported. Both appeared to consist of an anomalous mature venous mass. Both patients complained of a swelling which grew hard and bulged when the internal jugular vein pressure was elevated. Venography demonstrated venous enlargement while arteriography failed to demonstrate small arterial communications such as were present in one case. Radical surgical resection was successfully performed. Pathogenesis, classification, and treatment of these lesions are discussed.     

Non monotonic morphometric changes produced at mouse neuromuscular junctions following in vivo stimulation at various frequencies

Summary Morphometric changes have been studied at the mouse neuromuscular junction (NMJ) as a function of the frequency of stimulation. In vivo stimulation was made at either 10, 25, 50 or 100 Hz. No significant change in the area of NMJ profiles is observed after stimulation. This indicates that stimulation does not change the volume of the nerve terminal. There is also no change of the volume density of mitochondria. However, there are significant reductions of the numerical density on area (N_A, number/m²) of the clear vesicles following stimulation at 25, 50 or 100 Hz. The N_A of clear vesicles is not further reduced following stimulation at 50 or 100 Hz than after the stimulation at 25 Hz. The numerical density on area of the coated vesicles was significantly increased following the stimulation at 25 Hz and 100 Hz. It is not increased more following stimulation at 50 Hz or 100 Hz than following stimulation at 25 Hz. One possible interpretation of the clear vesicle and the coated vesicle results is that less vesicles are liberated per sec by the NMJ with stimulation at 50 and 100 Hz than at 25 Hz because the action potential may fail to invade some terminal arborizations. The total surface density (i.e. surface of membrane in m² per m³ of nerve terminal) of the clear vesicles, the coated vesicles, the vacuoles and the presynaptic plasma membrane is not changed significantly following stimulation at any frequency. This indicates that there is no net loss of membrane at any of the frequencies investigated.This work is supported by grant from the Muscular Dystrophy Association of Canada