IL-24 intrinsically regulates Th17 cell pathogenicity in mice

In certain instances, Th17 responses are associated with severe immunopathology. T cell–intrinsic mechanisms that restrict pathogenic effector functions have been described for type 1 and 2 responses but are less well studied for Th17 cells. Here, we report a cell-intrinsic feedback mechanism that controls the pathogenicity of Th17 cells. Th17 cells produce IL-24, which prompts them to secrete IL-10. The IL-10–inducing function of IL-24 is independent of the cell surface receptor of IL-24 on Th17 cells. Rather, IL-24 is recruited to the inner mitochondrial membrane, where it interacts with the NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 13 (also known as Grim19), a constituent of complex I of the respiratory chain. Together, Grim19 and IL-24 promote the accumulation of STAT3 in the mitochondrial compartment. We propose that IL-24–guided mitochondrial STAT3 constitutes a rheostat to blunt extensive STAT3 deflections in the nucleus, which might then contribute to a robust IL-10 response in Th17 cells and a restriction of immunopathology in experimental autoimmune encephalomyelitis.     

GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis

We investigated glutathione S-transferase (GST) P1I le (105) Val, T1, and M1 polymorphisms in 45 patients with documented cryptogenic cirrhosis and 56 healthy control subjects. Polymerase chain reaction-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Ile/Val and Val/Val GSTP1 genotypes were more frequent in the patients with cirrhosis (n = 39, 87%) than in the control subjects (n = 10; 18%) (odds ratio [OR] 34.04; 95% confidence interval [CI] 10.70 to 108.31, P < 0.001). Among these patients with cirrhosis, 16 were heterozygous and 23 were homozygous, whereas only one person in the control group was homozygous. The GSTM1 null genotype was also more prevalent in cirrhotic patients than in healthy control subjects (OR 6.83, 95% CI 2.53 to 18.42, P < 0.001). The rate of GSTT1 deletion did not show a significant difference between the two groups (OR 2.35, 95% CI 0.76 to 7.28, P = 0.111). To our knowledge, this is the first evidence that GSTP1 and GSTM1 polymorphisms may be related to the development of cirrhosis by unknown mechanisms. The significant association of cryptogenic cirrhosis with Val/Val GSTP1 genotype encoding a low detoxification activity protein implicates this polymorphism as a risk factor for the occurrence of the disease. Presented as an abstract at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 19–22, 2003 (Poster of Distinction).     

Novel insights on the bottom–up rise strength transfer: investigating massed vs. distributed exercise training

Sport Sciences for Health - The purpose of this study is to investigate the Bottom–Up Rise Strength Transfer (BURST) induced by massed vs. distributed-rehabilitative exercise training....     

Limb lengthening in children with osteogenesis imperfecta]

The authors operated on 7 children (5 girls, 2 boys) suffering from osteogenesis imperfecta (oi) type I according to Sillence classification, with lower limbs discrepancy. We elongated 10 segments (7 femurs and 3 tibias). Mean age at operation time was 14.7 years (13-17 years). The mean leg length discrepancy was 9.3 cm (4-18 cm), and shortening of one bone was 6.5 cm (4-9 cm). We used Ilizarov technique twice in tibial lengthening. We used Wagner technique in one tibial elongation and in 7 femur elongation. Except for one tibia, in the remaining cases there was Rush rod inserted intramedullary in the bone being elongated. During tibial elongation we fixed lateral malleous by screw. The osteotomy was performed in proximal metaphysis of the 5 femurs and 3 tibias, and in distal femurs in two cases. The elongation was 1 mm for day, with frequency 4 x 1/4 mm. The mean bone lengthening achieved was 5.5 cm (2-9 cm); the mean lengthening of the limb was 7.9 cm (2-18 cm). The mean time of elongation was 2.8 months (2-5 months). Elongation index was 26 days for 1 cm of lengthening. The mean time of fixator removal was 9.2 months (4-13 months). Healing index was 58 day/1 cm (overall number of days for 1 cm lengthening). The complications occurred in all the patients. Although the risk of numerous complication is high, lower limbs lengthening in children with type I osteogeneis imperfecta is possible to perform and allows equalizing discrepant limbs or, at least reducing the difference.     

Free DIEP and SIEA breast reconstruction to internal mammary intercostal perforating vessels with arterial microanastomosis using a mechanical coupling device

Autologous breast reconstruction with microsurgical free tissue transfer has become routine, and perforator-based adipocutaneous flaps are recognized as an excellent option for many patients. Current efforts to optimize patient outcomes focus on minimizing operative morbidity both at the donor and recipient sites. The DIEAP flap avoids most of the abdominal wall morbidity associated with the TRAM. At the recipient site, however, partial rib resection, for access to the internal mammary (IM) artery and vein as recipient vessels, has a risk of chest wall pain, deformity, and pneumothorax. Perhaps more importantly, sacrifice of the IM vessels precludes their use for potential future coronary revascularization. To avoid this, the intercostal perforating branches from the internal mammary system may be used as recipient vessels for microanastomosis. This has been well described using suture technique, although the use of a mechanical coupling device for arterial anastomosis to the perforator has not been reported. We report nine cases whereby a mechanical coupling device was used to perform both the arterial and venous anastomoses of DIEAP and SIEA flap pedicles to IM intercostal perforating vessels. Flap ischemia time was shorter in all cases, allowed ease of anastomosis for vessel size mismatch, and is technically easier in deep wounds. This technique is a further refinement to free flap breast reconstruction and is a powerful application of the coupling device.     

Early Neurological Changes and Interpretation of Clinical Grades in Aneurysmal Subarachnoid Hemorrhage

ObjectivesHunt and Hess (HH) and World Federation of Neurological Surgeons (WFNS) grades are commonly used to report clinical severity of aneurysmal subarachnoid hemorrhage (aSAH). We sought to determine the impact of early neurological changes and the timing of clinical grade assignment on the prognostication accuracy.MethodsWe retrospectively reviewed a cohort of consecutive patients with aSAH who were admitted to an academic center. Patients with confirmed aneurysmal cause were included. Relevant clinical data including daily clinical grades, imaging data and functional outcome were analyzed. Favorable outcome was defined as mRS 0 to 3. Early neurological improvement (ENI) and early neurological deterioration (END) were respectively defined as any improvement or deterioration of HH grades from hospital day 1 to the earliest time from hospital day 2 to 5.ResultsOf 310 patients, 24% experienced early neurological changes from hospital day 1 to 3. For each point increase in HH grades from day 1 to day 3, the odds ratio for worse outcome was 2.57 (95% CI [1.74-3.79]) and for each point decrease in HH grades from day 1 to day 3, the odds ratio for worse outcome was 0.28 (95% CI [0.17-0.47]). Receiver Operating Characteristic curve analysis revealed that clinical grades on day 3 had higher accuracy in predicting worse outcome than clinical grades on day 1.ConclusionEarly changes in neurological status can alter trajectory of hospital course and functional outcome. The prognostic accuracy of the clinical grades from hospital day 3 is significantly greater than those on admission.