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Biomedical subjects

A S Klein

Publications and source records attributed to A S Klein.

At least 19 recordsLinked to original sources
PubMed2001

Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists.

A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).

Animals↗
PubMed2001

Human monocytic ehrlichiosis: an emerging pathogen in transplantation.

BACKGROUND: The spectrum of disease caused by Ehrlichia spp. ranges from asymptomatic to fatal. Awareness and early diagnosis of the infection is paramount because appropriate therapy leads to rapid defervescence and cure. If left untreated, particularly in immunosuppressed patients, ehrlichioses may result in multi-system organ failure and death. METHODS: We report the second case of human monocytic ehrlichiosis (HME) in a liver transplant recipient, and review the literature. RESULTS: The patient presented with fever and headache, had negative cultures, and despite broad-spectrum antimicrobial coverage appeared progressively septic. After eliciting a history of tick exposure we treated the patient empirically with doxycycline. The diagnosis of HME was confirmed by 1) polymerase chain reaction (PCR) for Ehrlichia chaffeensis, 2) acute and convalescent serum titers, and 3) in vitro cultivation of E chaffeensis from peripheral blood. CONCLUSION: Although human ehrlichioses are relatively uncommon, they are emerging as clinically significant arthropod-borne infections. Although epidemiological exposure is responsible for infection, immunosuppression makes patients more likely to succumb to disease. A high index of suspicion and early treatment results in a favorable outcome.

Animals↗
PubMed2001

Liver transplantation in patients with severe portopulmonary hypertension treated with preoperative chronic intravenous epoprostenol.

Portopulmonary hypertension (PPHTN) is no longer an absolute contraindication to orthotopic liver transplantation (OLT). The pre-OLT management of patients with PPHTN requires early diagnosis and chronic therapy with intravenous epoprostenol to decrease pulmonary vascular resistance (PVR). Close follow-up is necessary to reassess pulmonary artery pressures (PAPs) and evaluate right ventricular (RV) function. This assists in the optimal timing of OLT. Successful management also necessitates reassessment of pulmonary artery hemodynamics just before OLT, with clearly defined parameters used to determine whether to proceed. Even with the intraoperative and postoperative availability of potent pulmonary vasodilators, clinical management may be suboptimal in reducing PAP. Adequate reduction in PVR and improvement in RV function in response to chronic epoprostenol therapy may facilitate successful OLT. We present a case report and review the limited experience with this treatment.

Adult↗
PubMed2001

Budd-Chiari syndrome: current management options.

OBJECTIVE: To assess the outcomes of current treatment strategies for Budd-Chiari syndrome. SUMMARY BACKGROUND DATA: Budd-Chiari syndrome, occlusion or obstruction of hepatic venous outflow, is a disease traditionally managed by portal or mesenteric-systemic shunting. The development of other treatment options, such as catheter-directed thrombolysis, transjugular portosystemic shunting (TIPS), and liver transplantation, has expanded the therapeutic algorithm. METHODS: The authors reviewed the medical records of all patients diagnosed with Budd-Chiari syndrome at the Johns Hopkins Hospital during the past 20 years. RESULTS: A total of 54 patients were identified: 13 (24%) male patients and 41 (76%) female patients, ranging in age from 2 to 76 years (median 33 years). Twenty-one (39%) had polycythemia vera, 3 (5.6%) used estrogens, 11 (20%) had a myeloproliferative or coagulation disorder, and in 7 (13%) the cause remained unknown. Forty-three patients were treated with surgical shunting, 24 mesocaval and 19 mesoatrial. Actuarial survival rates at 1, 3, and 5 years after shunting were 83%, 78%, and 75%, respectively. Of 33 patients surviving more than 4 years, 28 (85%) had relief of clinical symptoms. Five patients required shunt revision and eight had radiologic procedures to maintain shunt patency. Primary and secondary shunt patency rates were 46% and 69% respectively for mesoatrial shunts and 70% and 85% respectively for mesocaval shunts. Clot lysis was successful as primary treatment in seven patients. TIPS was performed in three patients, one after a failed mesocaval shunt. During an average of 4 years of follow-up, these patients required multiple procedures to maintain TIPS patency. Six patients underwent liver transplantation. Of these, three had previous shunt procedures. Five of the transplant recipients are alive with follow-up of 2 to 9 years (median 6). CONCLUSIONS: Both shunting and transplantation can result in a 5-year survival rate of at least 75%, and other treatment modalities may be appropriate for highly selected patients. Optimal management requires that treatment be directed by the predominant clinical symptom (liver failure or portal hypertension) and anatomical considerations and be tempered by careful assessment of surgical risk.

Adult↗
PubMed2001

Features of recurrent primary sclerosing cholangitis in two consecutive liver allografts after liver transplantation.

Recurrence of primary sclerosing cholangitis (PSC) after liver transplantation is very uncommon. The true incidence of recurrence is unknown, mainly because of the difficulty in differentiating ischemic strictures from that of recurrent disease. Primary sclerosing cholangitis and ischemic strictures have identical histopathologic and cholangiographic features. We report a young man who had recurrence of PSC in two allografts and report our experience in 32 patients who had liver transplantation for PSC. Six patients (18%) had evidence of non-anastomotic strictures and, of these, only one patient (reported here) had unequivocal evidence of true recurrence. The strictures in other five patients happened because of ischemia. The recurrence of the disease in two allografts in an immunosuppressed patient, in the absence of ischemia, chronic rejection, or any known pathogen, raises the question of the role of an unidentified infectious agent in the etiopathogenesis of PSC.

Adult↗
PubMed2000

Plasmapheresis: an effective therapy for primary allograft nonfunction after liver transplantation.

BACKGROUND: The role of plasmapheresis in liver failure and hepatic coma remains controversial. Also, its use as a salvage strategy for patients with severe allograft dysfunction after liver transplantation has not been defined. This report reviews the use of plasmapheresis in primary hepatic allograft nonfunction (PNF). METHODS: From May of 1997 to October of 1998, five patients underwent plasmapheresis for PNF after other causes of immediate allograft dysfunction were excluded. These patients underwent two to five plasmapheresis procedures during which one plasma volume was removed and replaced with fresh frozen plasma (FFP) or with 50% FFP and 50% albumin. RESULTS: All recipients who underwent plasmapheresis had restoration of liver function. There was one death from pulmonary embolism, for an overall survival rate of 80%. The four surviving patients all had functioning allografts 1 year after liver transplantation. In contrast, during the same period, there were two patients in whom PNF was treated by retransplantation, and both died within 3 months after surgery with functioning allografts. CONCLUSIONS: Plasmapheresis provides an effective treatment option for PNF immediately after liver transplantation and may obviate the need for retransplantation.

Adolescent↗
PubMed2000

Successful liver transplantation in a patient with Budd-Chiari syndrome caused by homozygous factor V Leiden.

Budd-Chiari syndrome (BCS) is a rare form of portal hypertension characterized by hepatic venous outflow obstruction. Although hematologic disorders are the most common cause of this syndrome, to date, 30% of the cases have been classified as idiopathic. Resistance to activated protein C caused by factor V Leiden is the most common cause of thrombophilia; its role in the pathogenesis of BCS is now becoming apparent. We report successful liver transplantation in a patient with BCS caused by homozygous factor V Leiden. The patient was administered standard heparin anticoagulation until activated protein C resistance was normalized by the liver allograft. Liver transplantation corrected the thrombophilic state. The patient has excellent graft function, is not on anticoagulation therapy, and has had no recurrent venous thrombosis at 5 months posttransplantation. Activated protein C resistance caused by the factor V Leiden mutation may be responsible for idiopathic cases of BCS. To avoid unnecessary long-term anticoagulation after liver transplantation, factor V Leiden should be considered as a pathogenic factor in BCS. In addition, because of the high prevalence of factor V Leiden in the world population, cadaveric organ donors with a history of venous thrombosis should be screened for activated protein C resistance lest thrombophilia be transmitted to the recipient.

Adult↗
PubMed2000

Xanthine oxidase contributes to host defense against Burkholderia cepacia in the p47(phox-/-) mouse model of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide and downstream microbicidal reactive oxidants, leading to recurrent life-threatening bacterial and fungal infections. Xanthine oxidase (XO) is another enzyme known to produce superoxide in many tissues. Using the p47(phox-/-) mouse model of CGD, we evaluated the residual antibacterial activity of XO. Clearance of Burkholderia cepacia, a major pathogen in CGD, was reduced in p47(phox-/-) mice compared to that in wild-type mice and was further inhibited in p47(phox-/-) mice by pretreatment with the specific XO inhibitor allopurinol. Hepatic B. cepacia burden was similar in the two genotypes, but allopurinol significantly reduced net hepatic killing and killing efficiency only in p47(phox-/-) mice. Clearance and killing of intravenous Escherichia coli was intact in p47(phox-/-) mice and was unaffected by pretreatment with allopurinol. In CGD, XO may contribute to host defense against a subset of reactive oxidant-sensitive pathogens.

Allopurinol↗
PubMed2000

Endothelial cells potentiate phagocytic killing by macrophages via platelet-activating factor release.

The immunomodulatory function of endothelial cells (EC) includes the initiation of leukocyte margination, diapedesis, and activation through the upregulation of various cell surface-associated molecules. However, the effect that EC have on the phagocytic function of neighboring monocytes and macrophages is less well described. To address this issue, microvascular EC were cocultured with murine peritoneal macrophages, first in direct contact, then in a noncontact coculture system, and macrophage phagocytosis and phagocytic killing were assessed. The presence of increasing concentrations of EC resulted in a dose-dependent increase in macrophage phagocytic killing. This stimulatory effect was inhibited in a dose-dependent manner by the pretreatment of macrophage/EC cocultures with WEB-2086 or CV-6209, specific platelet-activating factor (PAF)-receptor antagonists, but not by anti-tumor necrosis factor-alpha, anti-interleukin (IL)-1alpha, or anti-IL-1beta. Furthermore, the effect was reproduced in the absence of EC by the exogenous administration of nanomolar concentrations of PAF. Microvascular EC potentiate macrophage phagocytic killing via the release of a soluble signal; PAF appears to be an important component of that signal.

Animals↗
PubMed1999

Autonomic and peripheral (sensorimotor) neuropathy in chronic liver disease: a clinical and electrophysiologic study.

Peripheral neuropathy has been reported in association with chronic liver disease. However, the precise incidence, severity and characteristics of neuropathy, and the relationship of neuropathy to different etiologies of liver disease have not been defined. In this study, 58 patients with advanced liver disease were evaluated in detail for the presence of neuropathy. Peripheral (sensorimotor) neuropathy was found in 71% and autonomic neuropathy was found in 48% of the patients. Although the majority of patients were asymptomatic, neurological examination showed distal sensory loss to pain, or vibration or distal loss of reflexes in 17 patients (29%). Sensory neuropathy was seen more commonly than motor axonal polyneuropathy on nerve conduction studies. Quantitative sensory testing was frequently abnormal (62%) and cooling thresholds were more affected than vibration thresholds. Overall, the pattern of neuropathy in patients with liver disease conformed to the pattern expected in "dying back" or length-dependent neuropathy. The neuropathy was most severe in patients with advanced hepatic decompensation. Comparison of causes of liver disease showed no significant differences in the severity of neuropathy among the different etiologies. In conclusion, axonal sensory-motor polyneuropathy and autonomic neuropathy are commonly seen in patients with end-stage liver disease of different causes.

Adult↗
PubMed1999

Phylogenetic relationships of the Hamamelidaceae inferred from sequences of internal transcribed spacers (ITS) of nuclear ribosomal DNA.

Intergeneric relationships in the Hamamelidaceae have long been controversial. In this study, sequences of the internal transcribed spacers of nuclear ribosomal DNA were used to reconstruct the phylogeny for the Hamamelidaceae. Three major clades were recognized in the ITS-based phylogenetic tree: (1) Mytilaria-Exbucklandia-Rhodoleia, (2) Disanthus, and (3) the Hamamelidoideae. Within the Hamamelidoideae there were three well-supported lineages: (1) Corylopsis-Loropetalum-Tetrathyrium-Maingaya-Matudaea, (2) Eustigmateae sensu Endress, plus Molinadendron-Dicoryphinae, and (3) Hamamelis-Fothergilleae sensu Endress, excluding Matudaea and Molinadendron. The Exbucklandioideae sensu Endress were not monophyletic, nor were the tribes in the Hamamelidoideae in their current circumscriptions except for the Corylopsideae. Strap-shaped petals, apetaly, and wind pollination have evolved three times independently in the Hamamelidaceae s.s. (Hamamelidaceae minus Altingioideae), suggesting that homoplasy should be considered in future classifications of the family.

Journal Article↗
PubMed1998

Endothelial cells potentiate oxidant-mediated Kupffer cell phagocytic killing.

Phagocytosis and killing of circulating organisms by Kupffer cells (KCs) are discrete, important components of host defense. However, the killing mechanism(s) are not fully understood, and the potential role of adjacent nonparenchymal cells such as hepatic endothelial cells has not been defined. Rat KCs -/+ an hepatic endothelial cell enriched cellular fraction (HECEF) were incubated with Candida parapsilosis and assayed for phagocytosis and phagocytic killing by validated fluorochromatic vital staining. The role of reactive oxygen metabolites in KC phagocytic functions was examined by inhibition with superoxide dismutase and/or catalase. Diphenyleneiodonium and allopurinol were used to examine the potential roles of NADPH oxidase and xanthine oxidase, respectively, in generating these toxic oxidants. Coculture with HECEF increased KC phagocytic activity (from 75% to 88%) and candidacidal activity (from 20% to 31%). Superoxide dismutase, catalase, diphenyleneiodonium, or allopurinol caused inhibition of candidacidal activity, but did not affect phagocytosis, and did not block the potentiation of phagocytosis or of killing caused by coculture with HECEF. Reactive oxygen intermediates generated by both NADPH oxidase and xanthine oxidase-dependent pathways are important in KC killing of Candida parapsilosis. In vitro, KC phagocytosis and killing are potentiated (via a non-oxidant-mediated mechanism) by coculture with a preparation of hepatic non-parenchymal cells composed primarily of endothelial cells.

Allopurinol↗
PubMed1998

Primary sclerosing cholangitis: resect, dilate, or transplant?

OBJECTIVE: The current study examines the results of extrahepatic biliary resection, nonoperative endoscopic biliary dilation with or without percutaneous stenting, and liver transplantation in the management of patients with primary sclerosing cholangitis (PSC). SUMMARY BACKGROUND DATA: Primary sclerosing cholangitis is a progressive inflammatory disease leading to secondary biliary cirrhosis. The most effective management of sclerosing cholangitis before the onset of cirrhosis remains unclear. METHODS: From 1980 to 1994, 146 patients with PSC were managed with either resection of the extrahepatic bile ducts and long-term transhepatic stenting (50 patients), nonoperative endoscopic biliary dilation with or without percutaneous stenting (54 patients), medical therapy (28 patients), and/or liver transplantation (21 patients). RESULTS: Procedure-related morbidity and mortality rates were similar between surgically resected and nonoperatively managed patients. In noncirrhotic patients, the serum bilirubin level was significantly (p < 0.05) reduced from preoperative levels (8.3+/-1.5 mg/dL) 1 (1.7+/-0.4 mg/dL) and 3 (2.7+/-0.9 mg/ dL) years after resection, but not after endoscopic or percutaneous management. For noncirrhotic PSC patients, overall 5-year survival (85% vs. 59%) and survival until death or transplantation (82% vs. 46%) were significantly longer (p < 0.05) after resection than after nonoperative dilation with or without stenting. For cirrhotic patients, survival after liver transplantation was longer than after resection or nonoperative dilation with or without stenting. Five patients developed cholangiocarcinoma, including three (6%) of the nonoperatively managed patients but none of the resected patients. CONCLUSIONS: In carefully selected noncirrhotic patients with PSC, resection and long-term stenting remains a good option. Patients with cirrhosis should undergo liver transplantation.

Adolescent↗
PubMed1998

Leptin regulates proinflammatory immune responses.

Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor alpha expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up-regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity.

Animals↗
PubMed1997

Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the U.S. Multicenter Liver Study Group.

BACKGROUND: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection. METHODS: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study. RESULTS: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients. CONCLUSIONS: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.

Adolescent↗
PubMed1996

Gamma delta-T cell-receptor-positive lymphocytes inhibit human hematopoietic progenitor cell growth in HIV type 1-infected patients.

In severe HIV infection, the majority of patients exhibit signs of hematopoietic deficiency including anemia, leukopenia, and thrombocytopenia. Besides other pathophysiological mechanisms, the disturbed helper/suppressor ratio of T-lymphocytes suggests that alterations within T cell subpopulations may have a suppressive effect on HIV-associated hematopoiesis. Since a delta TCS-1- and mostly CD-8-positive subpopulation of cytotoxic T-lymphocytes expressing the gamma delta-receptor is increased in peripheral blood and bone marrow of HIV-infected persons, it was the aim of this study to investigate the role of gamma delta-positive cells in HIV-associated bone marrow deficiency. The number of bone marrow-derived pluripotent colony-forming units (CFU-GEMM), burstforming units-erythrocyte (BFU-E), and colony-forming units-granulocyte-monocyte (CFU-GM) of HIV-1-positive patients was significantly (p < 0.05) increased after depletion of CD-8-positive, gamma delta-positive, and delta TCS-1-positive T-lymphocytes. In contrast, the depletion of these subpopulations had no stimulatory effect in healthy controls. Further experiments identified direct cellular contact between effector and hematopoietic progenitor cells and the production of interferon-gamma and tumor necrosis factor-alpha as the mechanisms mediating the suppressive effect of the delta TCS-1-positive cells in HIV-positive patients.

Adult↗
PubMed1996

Discriminant quantitation of posttransplant hepatic reticuloendothelial function. The impact of ischemic preservation.

This study focuses upon two discrete components of posttransplant hepatic reticuloendothelial system (RES) function-phagocytosis and killing of bacteria-under various conditions of ischemic preservation. We had previously reported that, following intravenous injection of rats with 51Cr and 125I double-labeled Escherichia coli, hepatic 51Cr levels can be used to reliably quantify hepatic phagocytic clearance of the bacteria from the blood (HPC), while the subsequent release of 125I from the liver accurately parallels hepatic bacterial killing. Here, Wistar rats were transplanted with syngeneic livers perfused with either normal saline (NS) or University of Wisconsin solution (UW) and stored at 4 degrees C for 1, 2, or 3 hr prior to implantation. Control rats underwent laparotomy and hepatic artery ligation. Using the double-labeled E coli assay, HPC was decreased in all transplanted animals when compared with controls, reaching a nadir on the third postoperative day (P < 0.05). In rats transplanted with livers preserved in NS, the fraction of phagocytosed organisms that were subsequently killed (hepatic killing efficiency=HKE) was increased to 142%, 129%, or 112% of normal following 1, 2, or 3 hr of cold ischemia, respectively; P < 0.05). Conversely, preservation of donor allografts in UW was associated with marked depression of HKE. Moreover, rats receiving NS- or UW-preserved livers tolerated an intravenous challenge with Streptococcus pneumoniae poorly (50% mortality) compared with hepatic artery ligated controls (12% mortality) at 7 days. Ischemic preservation of rat livers in NS resulted in a dose (of ischemia)-dependent reduction of hepatic phagocytosis coupled with a potentiation of HKE. Preservation in UW, however, produced a striking suppression of both components of hepatic RES function. Following a septic challenge survival was reduced in both groups of transplanted rats.

Adenosine↗