Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.

Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy.

Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.

CT and radiographic appearance of extracranial Onyx(®) embolization.

Onyx(®) (ev3, Irvine, CA, USA) is a liquid embolic agent composed of ethylene vinyl alcohol copolymer dissolved in dimethyl sulphoxide used for the treatment of intracranial arteriovenous malformations. Onyx is a preferred embolizing agent due to its unique properties, non-adhesive nature, and durability. In addition to its approved intracranial application, Onyx is also being used successfully in extracranial embolization in areas including extracranial aneurisms and vascular malformations, trauma, gastrointestinal bleeding, and neoplasms. Because of its increasing utilization, it is important for reporting radiologists to be able to recognize its extracranial appearance across different imaging techniques and to be familiar with its uses. The goal of this review is to describe the extracranial uses of Onyx and its appearance in various extracranial locations at radiography and CT, while providing didactic examples. Onyx appears radiodense at CT and plain radiography and has a curvilinear pattern following the expected path of the vessel embolized. At CT, Onyx creates streak artefact that may obstruct the view of surrounding tissues consistent with descriptions of other tantalum devices.

Robust T cell responses to aspergillosis in chronic granulomatous disease: implications for immunotherapy.

Chronic granulomatous disease (CGD) patients are highly susceptible to invasive aspergillosis and might benefit from aspergillus-specific T cell immunotherapy, which has shown promise in treating those with known T cell defects such as haematopoietic stem cell transplant (HSCT) recipients. But whether such T cell defects contribute to increased risks for aspergillus infection in CGD is unclear. Hence, we set out to characterize the aspergillus-specific T cell response in CGD. In murine CGD models and in patients with CGD we showed that the CD4(+) T cell responses to aspergillus were unimpaired: aspergillus-specific T cell frequencies were even elevated in CGD mice (P < 0·01) and humans (P = 0·02), compared to their healthy counterparts. CD4-depleted murine models suggested that the role of T cells might be redundant because resistance to aspergillus infection was conserved in CD4(+) T cell-depleted mice, similar to wild-type animals. In contrast, mice depleted of neutrophils alone or neutrophils and CD4(+) T cells developed clinical and pathological evidence of pulmonary aspergillosis and increased mortality (P < 0·05 compared to non-depleted animals). Our findings that T cells in CGD have a robust aspergillus CD4(+) T cell response suggest that CD4(+) T cell-based immunotherapy for this disease is unlikely to be beneficial.

Pathophysiology, assessment and management of the child with growth hormone resistance.

Defects in the growth hormone (GH)-insulin-like growth factor (IGF)I axis may cause GH resistance characterized by IGFI deficiency and growth failure. The range of defects causing GH resistance is broad as are their biochemical and phenotypical characteristics. We propose that GH-IGFI axis defects form a continuum of clinical and biochemical effects ranging from GH deficiency to GH resistance. The pathophysiology of GH resistance is described followed by a scheme for investigation of the child with severe short stature and normal GH secretion. We critically discuss GH therapy for such patients and define acceptable growth responsiveness. Finally we discuss therapy with IGF-I within the limits of the USA Food and Drug Administration and European Medicines Agency labels for GH resistance.

In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study.

BACKGROUND: Twenty-five percent of new anti-factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non-severe disease, its strength of association and the influence of other factors have remained undefined. OBJECTIVE: To evaluate risk factors for inhibitor development in patients with non-severe hemophilia A. METHODS: Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor. RESULTS: Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those ≥30years of age compared with those <30years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76-57.81 vs. OR 2.54; 95% CI, 0.61-10.68]. Having previously received <50days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis. CONCLUSIONS: These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A.

Evaluation of coupled perturbed and density functional methods of computing the parity-violating energy difference between enantiomers.

We present new coupled-perturbed Hartree-Fock (CPHF) and density functional theory (DFT) computations of the parity-violating energy difference (PVED) between enantiomers for H(2)O(2) and H(2)S(2). Our DFT PVED computations are the first for H(2)S(2) and the first with the new HCTH and OLYP functionals. Like other "second generation" PVED computations, our results are an order of magnitude larger than the original "first generation" uncoupled-perturbed Hartree-Fock computations of Mason and Tranter. We offer an explanation for the dramatically larger size in terms of cancellation of contributions of opposing signs, which also explains the basis set sensitivity of the PVED, and its conformational hypersensitivity (addressed in the following paper). This paper also serves as a review of the different types of "second generation" PVED computations: we set our work in context, comparing our results with those of four other groups, and noting the good agreement between results obtained by very different methods. DFT PVEDs tend to be somewhat inflated compared to the CPHF values, but this is not a problem when only sign and order of magnitude are required. Our results with the new OLYP functional are less inflated than those with other functionals, and OLYP is also more efficient computationally. We therefore conclude that DFT computation offers a promising approach for low-cost extension to larger biosystems, especially polymers. The following two papers extend to terrestrial and extra-terrestrial amino acids respectively, and later work will extend to polymers.

Experience with epidural anaesthesia in pregnant women with von Willebrand disease.

The use of epidural anaesthesia (EA) in women with von Willebrand disease (vWD) is limited secondary to fears of complications. Currently, there are no standard recommendations for the use of EA in women with vWD. A retrospective chart review was performed of women with vWD who received EA at the time of term pregnancy. EA was administered to 15 women at the time of 17 deliveries, four by caesarian section and 13 by normal spontaneous vaginal delivery. Ninety-three per cent of these women had type 1 vWD. None of the women received DDAVP or clotting factor concentrates prior to the administration of EA. There were no complications directly related to EA. Postpartum haemorrhage did occur in 47% of the deliveries, with three women requiring blood transfusion. In this small series, EA appears to be safely administered to pregnant type 1 vWD patients at the time of term delivery.

Viral hepatitis and the surgeon.

BACKGROUND: Viral hepatitis is an infection of the liver caused by one or more of six known (HAV-HGV) hepatotropic viruses. It is a common problem among health care workers and their patients. Surgeons are at particular risk of both acquiring and transmitting some of these viruses from and to their patients. Unfortunately, specific immunoprophylaxis for viral hepatitis is presently limited to protecting against the spread of hepatitis A and B viral infections, leaving a high degree of vigilance and careful surgical technique as the only means available to prevent the transmission of other viruses relative to the surgeon. The purpose of this paper is to review the various forms of viral hepatitis including the nature of the virus, serologic testing, clinical features, epidemiology (with specific reference to those issues that arise in surgical practice), treatment and prevention.

Malignant thymoma invading pulmonary artery. Changing treatment options.

BACKGROUND: Curative treatment of malignant thymoma is resection; however, this may be precluded by invasion of vital organs. PATIENTS AND METHODS: Two patients with extensive intrathoracic spread of thymoma (Stages III and IV A) are presented. Treatment involved a combination of resection, radiotherapy and chemotherapy. RESULTS: One patient survived 9 years, 4 months, but eventually died of metastatic spread; the other one is well and without evidence of disease 30 months after treatment. CONCLUSIONS: Thymoma is a slow-growing tumor. Successful surgical treatment in advanced cases is possible, if aided by radiotherapy and chemotherapy. The adjuvant therapy converts a non-resectable tumor to a resectable one.

99mTc-MDP bone SPECT for the evaluation of sternal ischaemia following internal mammary artery dissection.

Coronary artery bypass grafting (CABG) is one of the most frequently performed operations in the United States. The use of internal mammary artery (IMA) grafting has been identified as increasing the risk of sternal wound infections and mediastinitis. The purpose of our study was to prospectively evaluate the effect of different techniques of left internal mammary artery (LIMA) harvesting on sternal vascularity. Thirty-three patients undergoing primary coronary artery bypass grafting were studied. The patients were divided into groups that received a skeletonized IMA (group I, n=11), a pedicled IMA (group II, n=12), or a semiskeletonized IMA (group III, n=10) graft. Each patient underwent a preoperative 99mTc-methylene diphosphonate bone scan using single photon emission computed tomography (SPECT). The ratio of the mean counts/pixel for each side of the sternum was obtained. Post-operatively, all patients had a repeat bone SPECT. Ratios of unilateral sternal uptakes were compared to the preoperative study. A univariable analysis of post-operative to pre-operative ratios revealed statistically significant reduction in vascularity to the left side of the sternum post-operatively in group II compared with groups I and III (0.68 0.12 vs 0.99 0.24 and 0.93 0.09; P<0.01). There was no difference between groups I and III (P=1). Multivariable analysis revealed only the type of harvesting to be associated with post-operative reduction in left to right sternal activity ratio (P<0.02). Pairwise comparisons revealed that differences are due to pedicled type of harvesting (group II vs group I, P=0.03; II vs III, P=0.001; and I vs III, P=0.115). A pedicled IMA graft causes acute post-operative sternal ischaemia. This does not occur when the IMA is skeletonized or semiskeletonized. Hence, it may be prudent to minimize dissection during mobilization of the IMA to decrease the likelihood of post-operative sternal complications.

Thymoglobulin induction decreases rejection in solitary pancreas transplantation.

BACKGROUND: Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS: Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS: The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS: Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Hiatal hernia in pediatric gastroesophageal reflux.

BACKGROUND: This study compares esophageal pH-monitoring parameters of children with gastroesophageal reflux (GER) with or without hiatal hernia (HH) and determines the outcome of those with GER and HH. METHODS: Among 718 children with GER, 45 children (6%) with associated HH were retrospectively studied. They were divided into those with neurologically normal development (NN, n = 35) and those with neurologic disorders (ND, n = 10). The pH-monitoring parameters of 27 of these (60%) were compared with pH-monitoring parameters of 27 control children who had GER without HH. RESULTS: Esophageal clearance was longer in patients with HH compared with those without HH (P < 0.05). All 35 NN patients underwent a trial of conservative treatment, which failed in 9 patients (25.7%). Surgery was the initial treatment in 8 ND patients. Follow-up was available in 20 NN and 10 ND patients. Nine of 11 conservatively treated NN patients improved. All NN (n = 9) and ND (n = 8) patients who underwent surgery improved. Conservative treatment failed in 2 NN and in 2 ND patients. CONCLUSIONS: Presence of HH in children with GER is associated with prolonged exposure of the esophagus to acid and a high failure rate of nonoperative treatment. However, medical treatment should be tried in NN children despite the significant failure rate.

Delayed postoperative paraplegia complicating repair of type A dissection.

We describe the very rare event of delayed transient paraplegia after repair of type A dissection of the aorta and discuss therapeutic options. We also suggest insertion of a spinal catheter as soon as there are signs or symptoms of spinal cord injury to drain spinal fluid and maximize the effect of elevated spinal cord perfusion pressure.

Comparison of the effects of ketoprofen on platelet function in the presence and absence of aspirin.

PURPOSE: Although aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) exert inhibitory effects on platelets in vitro and in vivo, there are insufficient data to substantiate the use of NSAIDs alone as antiplatelet drugs in patients already taking aspirin. We therefore sought to determine whether aspirin, added to NSAID therapy, further suppresses platelet function. SUBJECTS AND METHODS: We enrolled 25 healthy adult volunteers who were administered ketoprofen (extended-release capsules, 200 mg daily) for 1 week, followed by ketoprofen (200 mg daily) and aspirin (325 mg daily) or ketoprofen (200 mg daily) alone during the second week. Platelet aggregation, stimulated by epinephrine and arachidonic acid, and cyclooxygenase activity, measured by thromboxane B(2), were measured at baseline, on day 8, and on day 15. RESULTS: On day 8, all subjects demonstrated abnormal platelet aggregation (>50% inhibition), which persisted at day 15 in both the aspirin and no aspirin groups. One week of ketoprofen treatment reduced thromboxane B(2) levels by 84% in the aspirin group and by 85% in the no aspirin group (P = 0.8), without any further inhibition measured on day 15. CONCLUSION: Extended-release ketoprofen significantly inhibited platelet aggregation and thromboxane B(2) production in healthy volunteers. Addition of aspirin had no additional effect. Trials are warranted to determine whether these in vitro effects result in clinical antiplatelet activity in patients who require chronic treatment with NSAIDs, thereby avoiding the toxicity of NSAID/aspirin combination therapy.