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.     

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.     

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.     

Mechanical complications of total shoulder inverted prosthesis

Our series of inverted prosthesis included 5 patients with a mean age of 73 +/- 6 years. In 4 cases, the implant was performed as a surgical revision. The follow up was 81 +/- 15 months. Three shoulders were pain free whereas two caused a dull pain after a free interval due to mechanical complications. The mean active elevation was 72 degrees while external rotation was - 2 degrees. The adjusted Constant score passed from 32 to 60. In case of complications, the score dropped to 32. Mechanical complications were important with in one case, an unscrening of the glenosphere and in two cases, a loosening of the glenoid prosthesis. This last and major complication occurred 6 years after surgery and was promoted by the occurrence of a progressive bone erosion in the scapula. This gap represented an attempt to accomodate the medial part of the humeral prosthesis under the scapula when the arm is at rest or in adduction. The concept of an inverted prosthesis is attractive and this implant remains one of the options in cuff-tear arthropathy. Our results were not as good as those reported by others but most of ours patients had been already operated before. The occurrence of an osseous gap on pilar of scapula may lead to failure of this prosthesis. This gap remains a threath as it can progress and as such warrants a design alteration of the prosthesis.     

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis

Background In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. Methods Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months–3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. Results When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for T1 but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. Conclusions This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM. Received: 3 April 2001, Received in revised form: 15 June 2001, Accepted: 18 June 2001     

Behavioural Development in Children of Divorce and Remarriage

We employed an autoregressive modelling technique with data from the Quebec Longitudinal Study to prospectively examine the developmental impact of family transition on behaviour while controlling for predivorce and preremarriage effects. Teachers rated children's anxious, hyperactive, physically aggressive, oppositional, and prosocial behaviour every 2 years from kindergarten through to the end of elementary school.Once individual and parental characteristics and antecedent family events were controlled, children who experienced parental divorce before age 6 exhibited comparatively more behavioural disturbance than their peers whose parents divorced later. With the exception of a protective effect on hyperactive behaviour, remarriage did not have a significant impact on children's behaviour when the legacy of divorce was controlled.Although the results suggest that children of divorced parents show difficulty in many areas of functioning, the effects of family transition on behavioural development were dependent on the child's age and the specific behavioural dimension assessed.Compared to other points in development, early childhood divorce was associated with long-term increases in anxious, hyperactive, and oppositional behaviour during later childhood.The effects of divorce on children's fighting were short-lived.Unlike previous prospective studies that suggest predivorce effects, we did not observe behavioural disturbance prior to divorce or remarriage.     

Secret drug tribulations and French legislation

From an official Montpellier prefecture paper of 18th century, we are interested in a secret drug from Provence origin: the Irro? powder. This purgative will pass from "secret" drug status to "patent" drug. It's notoriety will come from its arrival to Paris. The law of 21th germinal year XI, the decret of 25 prairial year XIII and this of 18th 1810 imposed to give the drug composition to an official status; that examined and permit it's sale. This secret will be produce for half century.     

Intrarenal detection of nitric oxide using electron spin resonance spectroscopy in hypertensive lipopolysaccharide-treated rats

The inhibition of nitric oxide (NO) synthesis by chronic administration of NG-nitro-l-arginine methyl ester (l-NAME) in rats is responsible for systemic hypertension. However, the mechanisms involved in this hypertension remain unclear. The effects of chronic l-NAME on kidney and blood NO production were studied in rats in a state of endotoxic shock due to lipopolysaccharide (LPS). A nitric oxide spin trapping technique using electron spin resonance (ESR) spectroscopy has been used to identify and measure the production of NO in the kidney. This method is based on the trapping of nitric oxide by a metal-chelator complex consisting of N-methyl-d-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) forming a water-soluble NO-FeMGD complex detected by ESR. After LPS injection (14 mg/kg, IV, 6 h before the sacrifice) to rats pretreated with l-NAME (10 mg/kg/d over 14 days), the NO-FeMGD complex was evaluated in the kidney (arbitrary units [AU]/g of kidney) and the density of polynuclear neutrophils was counted by light microscopy. Chronic inhibition of NO synthase by l-NAME, a nonspecific inhibitor, was responsible for a decrease of the NO-FeMGD complex levels in the kidney (24.9 +/- 1.6 AU versus 13.8 +/- 1.3 AU). LPS administration was responsible for a large increase in both NO-FeMGD complex and neutrophil levels in the kidney of normotensive rats (332.6 +/- 12.8 AU versus 24.9 +/- 1.6 AU for NO-FeMGD complex and 1.36 +/- 0.41 versus 0.11 +/- 0.03 for neutrophils). Conversely, LPS administration in hypertensive, l-NAME-pretreated rats was linked to a smaller increase in the NO-FeMGD complex (85.1 +/- 7.9 AU versus 332.6 +/- 12.8 AU) and a larger increase in glomerular neutrophils (2.48 +/- 0.36 versus 1.36 +/- 0.41) compared with normotensive rats. These results are in agreement with a direct implication of NO during LPS-and l-NAME-induced kidney injuries.     

Soft tissue sarcomas of the hand: report of a radiation-induced case

Soft tissue sarcoma surgery is based on techniques that are in the process of ongoing development. In this study, the case is reported of a female patient who was operated on at the age of 14 years for a primary synoviosarcoma of the dominant hand, which was treated by conservative surgery and 60 Gy adjuvant radiotherapy. Twenty-two years later, she presented with a clinical picture of recurrence, but with no detectable metastases. Amputation of the distal third of the forearm was performed. The anatomopathological examination showed the presence of a myxoid malignant fibrous histiocytoma. It was considered that this tumor had been radiation-induced. All the distinct diagnostic criteria were met, i.e., a latency of over two years, different diagnosis and the appearance of the tumor within (or next to) the irradiated field. Both the diagnostic methods (MRI, tumor biopsy, and CT scan of the chest to investigate possible tumor spread) and the surgical approach have been discussed. The latter has altered over the years from being systematically radical (amputation or compartimental resection) to systematically conservative (good local control via radiotherapy). The modern attitude reflects a return to a more balanced approach. The frequency of such tumors has probably been underestimated in reports in the literature, as the latency period can sometimes exceed 30 years, and an accurate determination of the etiology is not always possible. Two main factors should be taken into account in treatment strategy: i) distant metastases of high-grade soft tissue sarcomas often appear early in the course of the disease, and are not affected by surgery at the primary site; ii) local recurrence, which is associated with high morbidity, and is directly connected with incomplete resection. Technical progress and a multidisciplinary approach have resulted in more sophisticated treatment (allowing a larger surgical resection area, and better residual function). Surgical management remains the treatment of choice, as radiotherapy and chemotherapy have not demonstrated any positive effect on patient survival.