A2 to B Blood Type Incompatible Deceased Donor Kidney Transplantation in a Recipient Infected with the Human Immunodeficiency Virus: A Case Report.

BACKGROUND: With the introduction of the Kidney Allocation System in the United States in December 2014, transplant centers can list eligible B blood type recipients for A2 organ offers. There have been no prior reports of ABO incompatible A2 to B deceased donor kidney transplantation in human immunodeficiency virus-positive (HIV+) recipients to guide clinicians on enrolling or performing A2 to B transplantations in HIV+ candidates. We are the first to report a case of A2 to B deceased donor kidney transplantation in an HIV+ recipient with good intermediate-term results. METHODS AND RESULTS: We describe an HIV+ 39-year-old African American man with end-stage renal disease who underwent A2 to B blood type incompatible deceased donor kidney transplantation. Prior to transplantation, he had an undetectable HIV viral load. The patient was unsensitized, with his most recent anti-A titer data being 1:2 IgG and 1:32 IgG/IgM. Induction therapy of basiliximab and methylprednisolone was followed by a postoperative regimen of plasma exchange, intravenous immunoglobulin, and rituximab with maintenance on tacrolimus, mycophenolate mofetil, and prednisone. He had delayed graft function without rejection on allograft biopsy. Nadir serum creatinine was 2.0 mg/dL. He continued to have an undetectable viral load on the same antiretroviral therapy adjusted for renal function. CONCLUSIONS: To our knowledge, this is the first report of A2 to B deceased donor kidney transplantation in an HIV+ recipient with good intermediate-term results, suggesting that A2 donor kidneys may be considered for transplantation into HIV+ B-blood type wait list candidates.

5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy.

BACKGROUND/AIMS: We previously reported that patients with chronic kidney disease (CKD) receiving warfarin therapy and whose international normalized ratio increases to >3.0 may develop acute kidney injury (AKI) as a result of glomerular hemorrhage and formation of obstructive red blood cell (RBC) casts. We named this condition warfarin-related nephropathy (WRN). We also previously reported that acute excessive anticoagulation with brodifacoum (superwarfarin) induces AKI in 5/6 nephrectomy (5/6NE) rats. Limitations of the brodifacoum model precluded a careful assessment of dose-response relationships. METHODS: Warfarin treatment was used in 5/6NE. RESULTS: Herein we report that warfarin treatment of 5/6NE rats resulted in a dose-dependent increase in serum creatinine (SC). The increase in SC following warfarin treatment was greater at 3 and 19 weeks after the ablative surgery, than that observed 8 weeks after the ablative surgery. The SC increase was correlated with the prothrombin time increase. Morphologically, 5/6NE, but not control rats, had acute tubular injury with RBC and RBC casts in the tubules. Treatment with vitamin K prevented SC increase and morphologic changes in the kidney associated with warfarin treatment. A single episode of WRN did not affect the progression of CKD in 5/6NE. CONCLUSION: (1) The 5/6NE model of CKD is an appropriate animal model to study the pathogenesis of WRN. (2) The pharmacokinetics of warfarin is better suited to the study of WRN than that of brodifacoum. (3) The more advanced stages of 5/6NE are more susceptible to WRN than the earlier stages. (4) Vitamin K treatment prevents WRN.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Time-resolved X-ray scattering using synchrotron radiation applied to the study of a polymorphic transition in carbamazepine.

The thermodynamic status of alpha-carbamazepine has been clarified using equilibrium solubility measurements, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), heated X-ray powder diffraction (XRPD), and temperature-controlled X-ray scattering techniques. alpha-Carbamazepine is the least stable of the three well-characterized anhydrous polymorphs of carbamazepine at 25 degrees C. In addition, it was confirmed that alpha-carbamazepine undergoes an exothermic transition to gamma-carbamazepine at 130 degrees C. The novel technique of time-resolved simultaneous small- and wide-angle X-ray scattering has been successfully applied to monitor this transition in situ. It was concluded that alpha-carbamazepine has a monotropic relationship with gamma-carbamazepine.

Elevated calcium in preneoplastic cells activates NF-kappa B and confers resistance to apoptosis.

Early preneoplastic cells (sup+) exhibit increased susceptibility to apoptosis, which is lost in late stage preneoplastic cells (sup-). Sup+ cells, which undergo apoptosis when cultured in low serum, show little or no DNA binding activity to nuclear factor (NF)-kappa B either in 10% or 0.2% serum. In contrast sup- cells, which are resistant to apoptosis in low serum, show a sustained constitutive activation of NF-kappa B. The constitutive activation of NF-kappa B observed in sup- cells is not due to loss of I kappa B alpha. We considered that the activation of NF-kappa B in sup- cells might be secondary to an increase in cytosolic Ca(2+), since sup- cells have a cytosolic Ca(2+) level that is double that in sup+ cells. In support of a role for Ca(2+), lowering cytosolic Ca(2+) in sup- cells by addition of the cell-permeable Ca(2+) chelator 1,2 bis(O-aminophenoxy)ethane-N, N, N', N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) reduced cytosolic Ca(2+) by approximately 31% relative to untreated sup- cells, concomitant with a 65% reduction in NF-kappa B DNA binding activity and a reduction in I kappa B kinase (IKK) activity. In sup- cells in low serum, addition of BAPTA-AM also resulted in a significant ( approximately 50%) increase in caspase-3 activity. Raising extracellular Ca(2+) in sup+ cells resulted in a slight activation of I kappa B kinase and in enhanced NF-kappa B DNA binding activity. Using proteasome and calpain inhibitors, we determined that the basal activity of NF-kappa B in sup- cells is largely proteasome-independent, but sensitive to calpain inhibitors. Taken together these data suggest that the elevated Ca(2+) in sup- cells causes a modest activation of IKK, which likely contributes to the enhanced basal activation of NF-kappa B in sup- cells; however, the predominant effect of Ca(2+) appears to be mediated by Ca(2+)-enhanced degradation by calpain.

Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism.

Diazoxide, a selective opener of the mitochondrial ATP-sensitive potassium channel, has been shown to elicit tolerance to ischemia in cardiac myocytes and in perfused heart. However, the mechanism of this cardioprotection is poorly understood. Because reactive oxygen species (ROS) are recognized as important intracellular signaling molecules and have been implicated in ischemic preconditioning, we examined diazoxide-induced ROS production in adult cardiomyocytes. Cells treated with 50 micromol/L diazoxide showed a 173% increase in ROS production relative to baseline. 5-Hydroxydecanoate was found to attenuate the diazoxide-induced increase in ROS generation. The diazoxide-induced increase in ROS also was abrogated by the addition of either the antioxidant N-acetylcysteine (NAC) or N-mercaptopropionylglycine. We also examined the ability of NAC to block the protective effects of diazoxide in the perfused rat heart. After 20 minutes of global ischemia and 20 minutes of reflow, hearts perfused with 100 micromol/L diazoxide before ischemia showed significantly improved postischemic contractile function relative to untreated hearts (84% versus 29% of initial left ventricular developed pressure, respectively). Hearts treated with diazoxide in the presence of 4 mmol/L NAC recovered 53% of initial left ventricular developed pressure, whereas hearts treated with NAC alone recovered 46% of preischemic function. Using (31)P NMR spectroscopy, we found that, similar to preconditioning, diazoxide significantly attenuated ischemia-induced intracellular acidification and enhanced post- ischemic recovery of phosphocreatine levels, both of which were blocked by cotreatment with NAC. These data suggest that the cardioprotective actions of diazoxide are mediated by generation of a pro-oxidant environment.

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Pulmonary injury in recipients of discordant hepatic and renal xenografts in the dog-to-pig model.

Work in our lab demonstrated that the early post-operative course of discordant hepatic and renal xenotransplantation is complicated by a pulmonary injury. The aim of this study was to characterize the nature of this injury, as well as to determine whether endothelin-1 (ET-1) and inducible-nitric oxide synthase (iNOS) are present in this form of pulmonary injury. Dog-to-pig orthotopic liver and kidney xenografts were performed. Pulmonary artery pressures were monitored throughout all procedures. The lungs were stained with monoclonal antibodies for ET-1, endothelin converting enzyme-1, and iNOS. The lungs from pig recipients of hepatic or renal xenografts were compared to lungs from untreated pigs. Pulmonary artery pressures were elevated in recipients of liver xenografts when the suprahepatic caval cross clamp was placed and continued to rise to systolic levels following unclamping. The mean pulmonary artery pressures in recipients of renal and hepatic xenografts rose significantly following revascularization. Pathology in lungs from kidney and liver recipients was similar, showing congestion with peribronchial and septal edema, with diffuse adhesion of PMN to alveolar endothelium. ET-1, endothelin converting enzyme-1 (ECE-1), and iNOS staining was widespread and intense in alveolar and pulmonary arterial endothelium. Discordant xenotransplantation of livers and kidneys is associated with a significant early pulmonary injury that is associated with early PMN infiltration and expression of ET-1 and iNOS.

Successful treatment of post-transplant lymphoproliferative disorder with interferon-alpha and intravenous immunoglobulin.

We report on the use of interferon-alpha (INF-a) and high-dose non-specific intravenous immunoglobulin (IVIg) in 2 patients (a 60-yr-old female and a 65-yr-old male) who developed post-transplant lymphoproliferative disorder (PTLD) 2 and 8 months after heart and liver transplantation, respectively. Both patients had received immunosuppression with ATG, CsA, azathioprine, and prednisone. The first patient did not receive additional immunosuppression with biological agents. The second patient developed 3 steroid-resistant acute rejection episodes requiring OKT3 (cumulative dose 100 mg) and ATG (cumulative dose 3450 mg). The first patient presented with nodules involving the liver, spleen, lungs and nasophar, ynx. The second patient presented with subcutaneous and liver nodules, as well as pert-portal and para-aortic lymphadenopathies. The histological diagnosis was diffuse B-cell PTLD in both patients. Despite reduction of immunosuppression, a progression of lesions was observed in both patients over 5 months and 2 months, respectively. The first patient received INF-alpha (2 x 10(6) IU, s.c. 3 times/wk) and IVIg (0.5 g/kg i.v. every 15 d) for.4 months, while the second patient received the same therapy for 12 and 7 months, respectively. Complete disappearance of all lesions was observed after 3 months of therapy in the first patient and after 7 months of therapy in the second patient, as assessed by CT scan. PTLD remains in remission 47 and 33 months after therapy, respectively. Our preliminary results suggest that the combination of INF-alpha and IVIg can be an effective therapy for PTLD which does not respond to reduction of immunosuppression.

Meningeal chondrosarcomas, a review of 31 patients.

We reviewed the literature to study the clinical features, the management and the outcome of meningeal chondrosarcomas. We included 31 patients in this review: 22 were mesenchymal and nine were non-mesenchymal. The mean age was 27 years and 64% arose from the cranial meninges. The treatment was mainly total surgical excision. Adjuvant therapy was given to 36% of patients. Spinal meningeal chondrosarcomas had a better prognosis (81% 1-year survival and 45% 3-year survival). There were no pathognomonic clinical or radiological features. We concluded that the best management of meningeal chondrosarcomas is total surgical excision whenever possible, followed by combined course of radiotherapy and chemotherapy as soon as possible.

Transfusion management in pediatric and adolescent scoliosis surgery. Efficacy of autologous blood.

STUDY DESIGN: A retrospective review of consecutive pediatric and adolescent patients who required posterior spinal fusion to correct scoliosis. OBJECTIVES: To 1) measure the participation of pediatric patients in predeposit programs for autologous and directed blood donation 2) to assess the success of autologous predonation in preventing allogeneic blood use, 3) to determine whether transfusion indications differed between patients who received allogeneic blood and those who received autologous blood, and 4) to assess factors that predict transfusion requirements during scoliosis surgery. SUMMARY OF BACKGROUND DATA: Authors of recent studies in adults have questioned whether transfusion of autologous blood is a cost-effective therapy when compared with the less-expensive alternative--transfusion of allogeneic blood. In children, the efficacy of autologous blood has not been assessed in a large population of surgical patients. In adults, the frequency of patient participation, the success of autologous donors in avoiding allogeneic transfusion, and the proportion of collected autologous units used during the perioperative period are measures used to establish the efficacy of autologous predonation programs. METHODS: Hospital and clinic records for each patient who underwent posterior spinal fusion from September 1, 1989 through September 1, 1994 were reviewed. Blood bank consultation, autologous donation records, anesthesia records, surgical reports, and hospital records were reviewed. Seventy percent of patients (164 of 243) participated in autologous donation. RESULTS: More than 90% of autologous donors successfully avoided receiving allogeneic blood. Patients with idiopathic scoliosis (n = 168) were more likely to participate in autologous donation (n = 144) and to avoid allogeneic blood (n = 135). Patients with neurologic causes of scoliosis more commonly used allogeneic or directed donation (56 of 75 patients). Nineteen patients with neuromuscular causes of scoliosis participated in autologous donation, but more than one half of this group (10 of 19 patients) required allogeneic blood in addition to autologous units. CONCLUSIONS: Using measures of efficacy similar to those reported in studies of adults, autologous blood was found to be more effective in meeting the transfusion needs of pediatric patients who required posterior spinal fusion than in meeting those needs in adult surgical patients in previous studies.

Initial management of the patient with newly diagnosed diabetes.

A family physician is often the one who makes an initial diagnosis of diabetes. The physician must consider the impact of this diagnosis on both the patient and the patient's family members. Outpatient management is less costly and less traumatic for the patient than inpatient care. Initial management goals are control of hyperglycemia, correction of fluid and electrolyte imbalances, and avoidance of hypoglycemia. For patients with type I (insulin-dependent) diabetes, the initial insulin dosage ranges from 0.25 to 1.0 U per kg per day. For patients with type II (non-insulin-dependent) diabetes, standard therapy begins with dietary modifications, exercise and an oral hypoglycemic agent, if needed. Insulin is indicated in patients with type II diabetes during times of acute stress, infection, surgery and pregnancy, and if the patient is allergic to sulfonylureas. Initially, patients only need to have a basic understanding of glucose monitoring, medications, diet and symptoms of hypoglycemia. Simple instructions can help the patient achieve glycemic control without being overwhelmed with information. As the patient learns more about diabetes and the treatment regimen, therapy can become more intensive.

Endothelin-1 immunoreactivity and mRNA in the transplanted human heart.

Endothelin-1 (ET-1) is a 21-residue peptide produced by endothelial cells and possesses a wide range of biological activities, including vasoconstriction, mitogenesis, and inotropic effects on the heart. The aim of the present study was to determine the cellular localization of ET-1 immunoreactivity and mRNA in routine endomyocardial biopsy specimens of transplanted human hearts, and to correlate the findings with the associated histological changes. Multiple-step paraffin sections of 72 biopsy samples were immunostained with antiserum to ET-1 and von Willebrand factor (factor VIII) using the avidin-biotin-peroxidase complex method. ET-1 immunoreactivity was localized to vascular and endocardial endothelial cells, as well as to cardiomyocytes. The pattern of endothelial cell immunostaining with the ET-1 antiserum was similar to that of factor VIII. Previous biopsy sites and areas of granulation tissue appeared to have greater ET-1 immunoreactivity, particularly in sections immunostained with the ET-1 antiserum. There was a significant correlation between the presence of ET-1 immunoreactivity and fibrosis or granulation tissue in the biopsy specimens (P < 0.03). There was no correlation between ET-1 immunoreactivity and the presence of cellular infiltrate, definitive rejection, or Quilty effect. In situ hybridization with radiolabeled RNA probes revealed expression of ET-1 mRNA in endothelial cells and myocytes, also in association with granulation tissue and fibrosis. No cellular reactivity was present in control sections stained with the ET-1 antiserum preadsorped with its synthetic peptide. The findings suggests a possible role for ET-1 in vascular regeneration and angiogenesis following myocardial injury.

Allergic rhinitis.

Allergic rhinitis commonly manifests for the first time in childhood or adolescence with seasonal or perennial sneezing, rhinorrhea, nasal congestion, and pruritus of the nose, eyes and throat. The nasal mucosa are pale blue and boggy, with a clear discharge. Patients should be instructed to avoid breathing tobacco smoke, to remove bedroom carpeting, to use foam pillows, to enclose mattresses and box springs in plastic covers, to keep house windows closed and to reduce indoor humidity by using air conditioning. If these avoidance procedures, together with oral and ocular antihistamines and/or decongestants, do not provide relief of symptoms, intranasal corticosteroids and cromolyn may be prescribed. Pharmacotherapy is more effective if it is used prophylactically. Second-generation antihistamines may reduce sedative and anticholinergic side effects. Intranasal decongestants should be used for only three to four days. Immunotherapy is appropriate for patients who remain unresponsive to therapy. Intranasal cromolyn should be the first drug considered in the treatment of pregnant women.

Expression of early and late activation markers on peripheral blood T lymphocytes does not reliably reflect immune events in transplanted hearts.

Monoclonal antibodies directed against early (receptors for interleukin-2 and transferrin [IL-2R, TfR]) and late (PTA1, alpha 1 integrin VLA-1) activation antigens were used as probes to monitor cardiac transplant patients for episodes of acute graft rejection. Age- and sex-matched patient control groups consisting of 11 patients awaiting cardiac transplantation and 13 kidney transplant recipients with long-term grafts, respectively, were used to define an upper limit for normal activation antigen expression (mean + 3 SD) in patients. Expression of all cell markers was significantly higher in both patient control groups than in healthy control individuals. Therefore, the level of activation marker expression in heart patients awaiting transplantation was used as comparison for the patient population under study. Sequential monitoring of 24 heart transplant recipients failed to demonstrate a significant correlation of increased activation marker expression with clinical events of immune activation. Subsequently 62 consecutive endomyocardial biopsy scores in 36 patients were compared with the expression of IL-2R, TfR and VLA-1 on peripheral blood T cells. Neither increased cellular infiltration of the endocardium, nor of the myocardium, was associated with increasing proportions of IL-2R, TfR, or VLA-1 positive T cells. Elevated T-cell expression of the three markers combined indicated acute graft rejection with a sensitivity, specificity, and overall accuracy of 38%, 52%, and 43%, respectively. Acute graft rejection in biopsies with associated myofiber damage (biopsy rejection scores 2 and 3A,B) was not associated with a change in the proportion of activated T cells in circulation within the first 6 months after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Melatonin secretion and puberty in female lambs exposed to environmental electric and magnetic fields.

This study determined whether chronic exposure of female lambs to the electric and magnetic fields (EMF) of a high voltage transmission line can alter pineal secretion of melatonin and the normal occurrence of puberty. Twenty female Suffolk lambs were assigned randomly in equal numbers to a control and a treatment group. Treatment from 2 to 10 mo of age consisted of continuous exposure within the electrical environment of a 500-kV transmission line (mean electric field 6 kV/m, mean magnetic field 40 mG). Treated lambs were penned directly beneath the transmission line; control lambs were maintained in a pen of similar construction 229 m from the line where EMF were at ambient levels (mean electric field < 10 V/m, mean magnetic field < 0.3 mG). Melatonin was analyzed by RIA in serum of blood samples collected at 0.5-3-h intervals over eight 48-h periods. To assess attainment of puberty, serum concentrations of progesterone were determined by RIA from blood samples collected twice weekly beginning at 19 wk of age. Concentrations of circulating melatonin in control and treated lambs were low during daylight hours and increased during nighttime hours. The characteristic pattern of melatonin secretion during nighttime (amplitude, phase, and duration) did not differ between control and treatment groups. Age at puberty and number of subsequent estrous cycles also did not differ between groups. These data suggest that chronic exposure of developing female sheep to 60-Hz environmental EMF does not affect the mechanisms underlying the generation of the circadian pattern of melatonin secretion or the mechanisms involved in the onset of reproductive activity.