Anti-tumor immunotherapy via antigen delivery from a live attenuated genetically engineered Pseudomonas aeruginosa type III secretion system-based vector.

Immunotherapy requiring an efficient T lymphocyte response is initiated by antigen delivery to antigen-presenting cells. Several studies have assessed the efficiency of various antigen loading procedures, including microbial vectors. Here a live strain of Pseudomonas aeruginosa was engineered to translocate a recombinant antigenic protein into mammalian cells via the type III secretion system, a bacterial device translocating effector proteins into host cells. Optimization of the vector included virulence attenuation and determination of the N-terminal sequence allowing translocation of fused antigens into cells. In vitro delivery of an ovalbumin fragment by the bacterial vector into dendritic cells induced the activation of ovalbumin-specific CD8(+) T lymphocytes. Mice injected with the ovalbumin-delivering vector developed ovalbumin-specific CD8(+) T lymphocytes and were resistant to a subsequent challenge with an ovalbumin-expressing melanoma. Moreover, in a curative assay, injection of the vaccine vector 5 and 12 days after tumor implantation led to a complete cure in five of six animals. These results highlight the utility of type III secretion system-based vectors for anti-tumor immunotherapy.     

Skin cancers and precancerous lesions in Parkinson's disease patients.

Our objective was to evaluate the frequency of neoplastic and preneoplastic skin lesions in Parkinson's disease (PD) patients when compared with an aged-matched population. We performed a cross-sectional survey in PD patients and in an age-matched control group. Patients and controls were examined by a movement disorder specialist and a dermatologist. 150 PD patients and 146 controls were included. Thirty-five PD patients (23.3%) presented skin lesions that could be classified as neoplastic or preneoplastic vs. 20 subjects in the control group (13.7%) (OR 95%, CI 1.92 [1.05, 3.51]). However, this difference lost statistical significance when adjusted for gender (recruitment of controls was matched just for age with an over representation of males in the PD group). Twenty-nine PD patients (19%) presented actinic keratosis and basal cell carcinoma was diagnosed in 4 patients (3%). Although nonconclusive, our results are in agreement with previous studies suggesting an increased risk of skin cancer in PD patients. The frequency of actinic keratosis in PD patients and the associated risk to develop melanoma recommends its screening in future epidemiological studies.     

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.     

Factors affecting early and long-term outcomes after completion pneumonectomy

Objective: To identify factors that affect operative mortality and morbidity and long-term survival after completion pneumonectomy. Methods: We retrospectively reviewed the charts of consecutive patients who underwent completion pneumonectomy at our cardiothoracic surgery department from January 1996 to December 2005. Results: We identified 69 patients, who accounted for 17.8% of all pneumonectomies during the study period; 22 had benign disease and 47 malignant disease (second primary lung cancer, n = 19; local recurrence, n = 17; or metastasis, n = 11). There were 50 males and 19 females with a mean age of 60 years (range, 29–80 years). Postoperative mortality was 12% and postoperative morbidity 41%. Factors associated with postoperative mortality included obesity (p = 0.005), coronary artery disease (p = 0.03), removal of the right lung (p = 0.02), advanced age (p = 0.02), and renal failure (p < 0.0001). Preoperative renal failure was the only significant risk factor for mortality by multivariate analysis (p = 0.036). Bronchopleural fistula developed in seven patients (10%), with risk factors being removal of the right lung (p = 0.04) and mechanical stump closure (p = 0.03). Overall survival was 65% after 3 years and 46% after 5 years. Long-term survival was not affected by the reason for completion pneumonectomy. Conclusion: Although long-term survival was acceptable, postoperative mortality and morbidity rates remained high, confirming the reputation of completion pneumonectomy as a challenging procedure. Significant comorbidities and removal of the right lung were the main risk factors for postoperative mortality. Improved patient selection and better management of preoperative renal failure may improve the postoperative outcomes of this procedure, which offers a chance for prolonged survival.     

Atypical forms of isolated partial atrioventricular septal defect increase the risk of initial valve replacement and reoperation.

OBJECTIVE: We consider the short- and long-term outcomes of the repair of the isolated partial atrioventricular (AV) septal defect to determine the role played by the atypical forms on the initial AV valve replacement and on the risk of reoperation. METHODS: Two hundred and eight patients underwent an operation for this malformation between 1974 and 2001. Clinical and echocardiographic examinations were performed on all patients, the AV valve regurgitation was graded from 1 to 4 and a residual interatrial shunt was sought. Median age at the intervention was 5.8 years (3 months to 67 years). RESULTS: Median follow-up time was 7.5 years (range 0-22.6 years). The cumulative 30-day, 5- and 20-year survival rates were 96.5, 95.4 and 94.6%, respectively. AV valve replacement was associated with a high mortality (P<0.001). A reoperation was performed on 12 patients (5.7%) including six patients within less than a 30-day period, especially to repair residual AV valve regurgitation. We performed four AV valve repairs by annuloplasty and six AV valve replacements. Two patients who had initially undergone an AV valve replacement underwent a reoperation for valve thrombosis. The cumulative 30-day, 5- and 20-year rates of freedom from reoperation were 96.5, 93.6 and 83%, respectively. An atypical form was present in 24 patients (11.5%) and was a risk factor for initial AV valve replacement (P<0.001) and for reoperation (P<0.001). A complete AV block occurred in 13 patients (6.2%), all of them within a 30-day period. The AV valve replacement was a high risk factor for a complete AV block (P<0.001). At the end of our study 180 patients (96%) were in NYHA I and 8 in NYHA II. CONCLUSIONS: The morbi-mortality of the isolated partial AV septal defect is primarily perioperative and is linked with the presence of an atypical form of the lesion. This atypical form was the main reason for reoperation for AV valve regurgitation. The AV valve replacement was associated with a high mortality and with the occurrence of complete AV block. Using a standardized technique, the AV septal defect can be repaired with excellent long-term clinical and echographic results.     

Inversion of Melatonin Circadian Rhythm in Chronic Alcoholic Patients during Withdrawal: Preliminary Study on Seven Patients

Aims: The inversion of melatonin circadian rhythm secretionin some alcoholics during both intake and acute withdrawal hasbeen widely reported. In the same way, what happens to thisinversion when these patients are in long-term withdrawal isnot known. To document this abnormality in alcoholics afterwithdrawal we investigated melatonin secretion observed duringchronic alcoholization and after withdrawal. Methods: We measuredthe urinary 6-sulfatoxymelatonin (6SM) (6SM/creatinine ratio),main metabolite of the hormone, in two fractions, one diurnaland the other nocturnal, in seven alcohol-dependent patientspresenting with this abnormality during alcoholization at twotimes: in acute withdrawal phase (under benzodiazepines) and15 days after beginning of withdrawal (free of any psychotropictreatment). Results: Our results show that this reversed rhythmof melatonin secretion as seen by the diurnal excretion of 6SM(6SM/creatinine ratio) persists during acute withdrawal in morethan half of the patients and is still present 15 days afterwithdrawal in three patients. Conclusion: It is remarkable thatthe inversion of the melatonin rhythms gets corrected in fourout of seven patients after withdrawal. But, the circadian disorganizationof melatonin secretion in three patients could underline a desynchronizationin some alcoholic patients and may indicate more widespreadcircadian temporal structure disturbances in these patients.     

Ethylene oxide does not extinguish the osteoinductive capacity of demineralized bone: A reappraisal in rats

We examined the influence of ethylene oxide (EO) and gamma irradiation on the osteoinductive capacity of demineralized bone. Demineralized bone powder prepared from Wistar rats was exposed to EO (55 °C or 40 °C) or gamma irradiation (25 KGy) or was preserved in ethanol. Sterilely-prepared bones served as controls. The powder was packed in a gelatin capsule and implanted for 6 weeks in muscles of 6-week-old female rats. Exposure of demineralized bone particles to EO 55 °C resulted in an almost complete loss of osteoinductivity. Irradiated bones lost about 40% of their osteoinductive capacity, while sterilization with EO at 40 °C resulted in only a slight alteration of the osteoinductivity, as assessed by the recovered weight ratio, calcium content, alkaline phosphatase activity measurements and histo-morphometry. Ethanol treatment had no influence on the new bone yield when compared to controls.

As EO exposure at 40 °C is a true sterilization procedure, it can be recommended in a clinical setting for its small effect on osteoinductive capacity as assessed experimentally in rats.     

Das traumatisch bedingte Kompartmentsyndrom des Unterschenkels

Zusammenfassung Um den Stellenwert der Sonographie als Methode der Diagnostik von Sp?tsch?den der Muskulatur nach operativ behandeltem Kompartmentsyndrom zu prüfen, wurden 27 Patienten (sechs Frauen, 21 M?nner) der Abteilung für Unfallchirurgie des Universit?tsklinikums Essen am ventralen Unterschenkel nach durchschnittlich 98 Monaten (43 bis 154 Monate) nach dem Trauma standardisiert untersucht und ein Vergleich mit der gesunden Gegenseite durchgeführt. Bei 15 Patienten war die Dermatofasziotomie wegen eines drohenden und bei zw?lf Patienten wegen eines manifesten Kompartmentsyndroms erfolgt. Im Vergleich zur gesunden Gegenseite konnte eine qualitative Gradeinteilung (0 bis 3) der Ver?nderungen erstellt werden, die das Ausma? der Echogenit?tsvermehrung sowie des Verlustes der muskeltypischen Textur wiedergibt. Grauwerthistogramme konnten die qualitative Einteilung best?tigen. Die Gruppe mit manifestem Kompartmentsyndrom zeigte ausschlie?lich deutliche und massive Ver?nderungen (Grad 2 und 3). Bei drohendem Kompartmentsyndrome fand sich zweimal Grad 2 und 13mal Grad 0 oder 1. Die sonographischen Ver?nderungen sind erkl?rbar durch die bekannten pathomorphologischen Zust?nde nach Kompartmentsyndrom der Muskulatur (Denervierung, Vernarbung). Die Sonographie eignet sich zur Beurteilung der Weichteile nach Kompartmentsyndrom. Die Ergebnisse unterstützen die Forderung nach einer frühzeitigen Fasziotomie bei drohendem Kompartmentsyndrom zur Pr?vention vor Muskel- und Nervensch?digungen.

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Traumatic compartment syndrome of the lower limb: Significance of ultrasonography in evaluating long-term damage of muscle after dermatofasciotomy

To determine the significance of sonography in evaluating long-term damage of muscle surgically treated for compartment syndrome 27 patients of the Department for Trauma Surgery, University Clinic Essen, Germany, were examined on their anterior lower limb after an average of 98 (43 to 154) months after trauma. They had had a fasciotomy for imminent (n=15) or manifest (n=12) compartment syndrome. Comparing the healthy side a qualitative grading (0 to 3) of the changes could be introduced reflecting the extent of the increase in echogenicity and the loss of the typical muscle texture. Gray scale histograms confirmed the qualitative grading. Patients with manifest compartment syndrome showed severe changes (grade 2 and 3). In imminent compartment syndrome 2 patients with grade 2 and 13 patients with grade 0 or 1 were found. The sonographical changes can be explained by the known pathomorphological changes after compartment syndrome (denervation, scarification). Sonography is useful in the evaluation of soft tissue after compartment syndrome. The results underline the demands of early fasciotomy in imminent compartment syndrome for prevention of damage of muscle and nerve.