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.

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.

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.

alpha4 integrin in islet allograft rejection.

BACKGROUND: Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between alpha4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. METHODS: Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against alpha4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of alpha4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. RESULTS: Treatment with anti-alpha4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-alpha4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, alpha4 integrin+, cytotoxic T cells. CONCLUSIONS: These data show that alpha4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualitatively affecting either T cell activation or migration to the graft. Conversely, anti-alpha4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between alpha4 integrin and its ligands may provide novel forms of immunosuppression.

Internal levator advancement by Müller's muscle-conjunctival resection: technique and review.

BACKGROUND: Müller's muscle-conjunctival resection surgery presumably works by advancing the levator aponeurosis of the upper eyelid. The amount of blepharoptosis and the lid's response to the instillation of phenylephrine hydrochloride onto the superior ocular fornix are used to determine the extent of surgery needed. OBJECTIVES: To demonstrate the procedure developed and popularized by Allen M. Putterman, MD, performed by Michael Mercandetti, MD, MBA, and to describe the relationship between the amount of Müller's muscle-conjunctival resection performed and the amount of elevation achieved. METHODS: Data were retrospectively analyzed based on surgical cases done over a 5-year period by one surgeon (A.M.P.). RESULTS: A linear regression model was developed. From this regression a simple table correlating the amount of resection with the amount of elevation desired was derived. CONCLUSION: The surgeon will need to modify the table based on his or her clinical experience and postoperative results.

Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America.

The optimal treatment of patients with von Willebrand's disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety-nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF-containing FVIII product, type 3 patients with vWF-containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.

Save a child's heart: we can and we should.

BACKGROUND: Congenital heart disease (CHD) causes the death of thousands of children in developing countries. At the Wolfson Medical Center (WMC), a prototype program has been developed to address this issue. METHODS: Since 1996, indigent children have been referred to the program, with the cooperation of partners in developing countries. The project's aims are to (a) train their medical personnel at WMC, (b) travel to participating countries to teach, evaluate patients, operate, and promote the development of local centers, and (c) treat children with CHD, at WMC, who lack a local option for care either due to prohibitive costs or unavailability. The project's personnel are state employees who volunteer to treat additional patients within the framework of their salaries, and community volunteers. RESULTS: The program has seven partner sites in six countries, including two provinces in China (Hebei and Gansu), Ethiopia, Moldova, Nigeria, the Palestinian Authority, and Tanzania. Five physicians and 10 nurses have been trained from five participating countries. Over the past 4 years, 11 teaching trips have been made abroad, and operations have been performed at four partner sites. A total of 386 patients have been operated on-360 at WMC and 26 at other sites. There have been 17 (4.3%) acute deaths. Follow-up is 92% complete with 3 late deaths reported. CONCLUSIONS: Hospital-based regional centers can be created to promote the care of children with CHD in developing countries. Good results and follow-up care can be provided with appropriate planning.

Comparison of systemic vasodilators: effects on flow in internal mammary and radial arteries.

BACKGROUND: Spasm is a major concern with the use of arterial conduits in coronary artery bypass surgery (CABG). We evaluated the effect of systemic vasodilators on in vivo radial artery flow compared with internal mammary artery (IMA) flow. METHODS: Fifty patients undergoing primary CABG with a mean age of 69 +/- 5 years enrolled in this study and were randomized to 1 of 5 groups based on the vasodilating agent administered (nitroglycerin, nitroprusside, dobutamine, milrinone, and normal saline as control group). Radial artery and IMA flows, blood pressure, central venous pressure, and heart rate were measured before and 10 minutes after drug administration. RESULTS: Mean arterial pressure decreased significantly after drug administration in both the nitroglycerin (p = 0.007) and nitroprusside (p < 0.001) groups and increased in the dobutamine group (p < 0.001). There were no significant differences between IMA flow or radial flow among the groups before drug administration. A multivariate general linear model was created and revealed drug (specifically nitroglycerin) as the only predictor to increase flow in the IMA (p < 0.001) or the radial artery (p = 0.009). CONCLUSIONS: We conclude that intravenous nitroglycerin causes in vivo vasodilatation of both the IMA and radial artery and is a good systemic vasodilator to be given when harvesting these two conduits.

Morbid results of prolonged intubation after coronary artery bypass surgery.

OBJECTIVES: This study evaluated the morbid results of prolonged intubation after coronary artery bypass grafting (CABG). METHODS: Over 30 months, 66 of 1,112 patients undergoing CABG required prolonged intubation. They were matched with 66 patients who did not require prolonged intubation. Preoperative and operative variables were evaluated to determine which would predict prolonged intubation. The postoperative courses were then compared to evaluate the effect of prolonged intubation. The study population was divided into three groups: those who underwent early extubation, but required reintubation (n = 24); those who required initial prolonged intubation, but no reintubation (n = 22); and those who required initial prolonged intubation and reintubation (n = 20). RESULTS: Univariate analysis revealed unstable angina (p = 0.037), elevated creatinine (p = 0.001), reduced FEV(1) (p = 0.019), longer cardiopulmonary bypass time (p = 0.009), and a greater positive fluid balance at 24 h (p = 0.0001) as predictors of postoperative prolonged intubation. Multivariate regression analysis revealed elevated creatinine (p = 0.011), FEV(1) (p = 0.022), and fluid balance (p = 0.001) as predictors of prolonged intubation. The study population had longer ICU and hospital stays (p = 0.0001), with more infectious complications (p = 0.0001) and higher mortality (p = 0. 001). In the subgroups of the study population, patients not requiring reintubation had shorter ICU (p = 0.001) and hospital stays (p = 0.0001), fewer infectious complications (p = 0.0001), and reduced mortality (p = 0.0001). CONCLUSIONS: Patients undergoing CABG with reduced FEV(1), renal failure, and positive fluid balance 24 h postoperatively are at risk for prolonged intubation. Prolonged intubation results in significant acute and midterm morbidity and mortality. Early extubation followed by reintubation further increases morbidity and mortality rates in these patients.

Comparison of platelet activation in unstable and stable angina pectoris and correlation with coronary angiographic findings.

We sought to investigate the relation between platelet activation and the angiographic evidence of ruptured plaque in patients presenting with unstable and stable angina pectoris. We prospectively enrolled 25 consecutive patients (5 women and 20 men, mean age 62 +/- 3 years), 17 with unstable angina and 8 with stable angina. Systemic venous blood samples were collected within 4 to 6 hours of admission for flow cytometry analysis. Activation-dependent epitope CD63 and glycoprotein IIb/IIIa on the platelet membrane were assayed. Fibrinogen levels were also measured. All patients with unstable angina underwent cardiac catheterization and had angiographic evidence of ruptured plaque. Of the patients with stable angina, 5 underwent coronary angiography with smooth noncomplex lesions and 3 had negative technetium-99m sestamibi stress tests. Patients with unstable angina were characterized by 39% higher levels of fibrinogen than patients with stable angina (423 +/- 304 vs 304 +/- 51 mg/dl, p = 0.004). The percentage of platelets positive for the activation-dependent epitope CD63 was 5 times higher in patients with unstable than stable angina (14.6 +/- 5.6% vs 2.75 +/- 1.6%, p = 0.0026). They also had a 15% higher expression of their glycoprotein IIb/IIIa (517 +/- 79 vs 449 +/- 50 mean fluorescence intensity, p = 0.038). Thus, this study establishes a direct relation between the morphology of ruptured plaque and platelet activation in patients with unstable angina. This may allow for further risk stratification. Patients with unstable complex lesions had a fivefold higher expression of the platelet activation epitope CD63 than patients with stable angina. Furthermore, they had 15% more glycoprotein IIb/IIIa aggregation sites expressed on their platelet membrane, thus indicating an intense thrombogenic potential.

Outdoor air pollution and lung cancer.

In the 1950s evidence of an ongoing epidemic of lung cancer in the United States and Western Europe led researchers to examine the role of outdoor air pollution, which was considered by some to be a likely cause. Although epidemiologic research quickly identified the central role of cigarette smoking in this epidemic, and despite progress in reducing outdoor air pollution in Western industrialized countries, concerns that ambient air pollution is causing lung cancer have persisted to the present day. This concern is based on the fact that known carcinogens continue to be released into outdoor air from industrial sources, power plants, and motor vehicles, and on a body of epidemiologic research that provides some evidence for an association between outdoor air pollution and lung cancer. This article reviews the epidemiologic evidence for this association and discusses the limitations of current studies for estimating the lung cancer risk in the general population. It also identifies research needs and suggests possible approaches to addressing outstanding questions.

The effects of various organ preservation solutions on hepatocyte membrane potentials, intracellular calcium concentrations, and outcome following liver transplantation.

BACKGROUND: Hepatocyte membrane potential differences (PDs) may be altered by the preservation solutions used in liver transplantation. Such alterations could impact on the survival of the donor liver, extent of biochemical injury, and flux of important ionic compounds. The purpose of the present study was to document these outcomes in the presence of four different preservation solutions. METHODS: Livers of adult male Sprague-Dawley rats (N = 3 to 4 per group) were impaled with intracellular microelectrodes prior to and at various time periods for 6 hours following complete hepatic resection. Just prior to resection, each liver was perfused with preservation solutions associated with high (normal saline [NS]), moderate (Euro-Collins [EC]), and low (University of Wisconsin solution [UW]) risks of reperfusion injury. RESULTS: Baseline (in situ) PDs were similar in all groups (-37 +/- 4 mV, mean +/- SD). Ten minutes postresection, hepatic PDs were as follows: NS, -23.8 +/- 3.5 mV; EC, -11.4 +/- 0.4 mV; and UW, -8.7 +/- 0.3 mV (P <0.01 for all groups). Maximum depolarization occurred at 6 hours postresection (NS, -8.1 +/- 1.1 mV; EC, -7.7 +/- 1.3 mV; and UW, -8.6 +/- 1.0 mV). To determine whether these changes are of pathophysiologic importance, the NS solution was modified (addition of 0.1% ethanol) to achieve similar PD changes as those observed with UW. Liver transplants were then performed where the donor livers had been perfused and preserved for 6 hours with either NS or the modified NS (MNS) solution. Posttransplant (10 day) survival was 1 of 6 (17%) in the NS group and 4 of 6 (67%) in the MNS group (P <0.05). Regarding the effects of PD changes on ionic flux, intracellular calcium levels were documented for up to 4 hours by fluorescence video microscopy using Fura-2 in isolated hepatocytes exposed to NS, UW, and MNS solutions. Intracellular calcium levels were similar in all solutions at each time point studied. CONCLUSIONS: The results of this study indicate that hepatocytes undergo prompt and marked depolarization following hepatic resection, and the extent of the depolarization correlates with survival following transplantation.