Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy

OBJECTIVE: We sought to determine whether type and location of thromboembolic disease in the pulmonary vascular tree predicts the hemodynamic result and clinical outcome in patients undergoing pulmonary endarterectomy. METHODS: From 1998 to 2000, 202 patients with pulmonary hypertension and pulmonary vascular resistance ranging from 194 to 2950 dynes-s-cm(-5) underwent pulmonary endarterectomy. Preoperative and postoperative tricuspid valve function, pulmonary artery pressure, and pulmonary vascular resistance were determined by means of transthoracic echocardiography and measurements with a Swan-Ganz catheter (Edwards Lifesciences, Irvine, Calif), respectively. Patients underwent intraoperative classification of thromboembolism as follows: type 1 (76 patients), fresh thrombus in the main-lobar pulmonary arteries; type 2 (81 patients), intimal thickening and fibrosis proximal to the segmental arteries; type 3 (38 patients), disease within distal segmental arteries only; and type 4 (7 patients), distal arteriolar vasculopathy without visible thromboembolic disease. RESULTS: Overall perioperative mortality was 4.5% (9/202 patients). By means of univariate analysis, patients with type 3 or 4 disease (distal pulmonary vasculopathy) had more residual postoperative tricuspid regurgitation (P <.0001), higher postoperative pulmonary artery systolic pressure (P <.0001), and greater postoperative pulmonary vascular resistance (P <.0001) compared with that seen in patients with type 1 or 2 disease, in whom thromboembolic disease was more surgically accessible. Factors such as severity of preoperative tricuspid regurgitation, patient age, and circulatory arrest time had no correlation with postoperative hemodynamic improvement. Patients with distal thromboembolic disease (type 3-4) had higher perioperative mortality, required longer inotropic support, and had longer hospital stays compared with patients with type 1 or 2 thromboembolic disease. CONCLUSION: The degree of improvement in pulmonary hypertension and tricuspid regurgitation after pulmonary endarterectomy is determined by the type and location of pulmonary thromboembolic disease. Classification of thromboembolism is useful for predicting patient outcome after pulmonary endarterectomy.     

Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.     

An analysis of men with clinically localized prostate cancer who deferred definitive therapy

PURPOSE: We evaluated expectant management of prostate cancer with definitive treatment deferred until evidence of cancer progression in men with low risk, localized cancers. MATERIALS AND METHODS: We retrospectively reviewed prospectively entered data base records. Patients with low risk cancer who were eligible for definitive therapy but chose deferred management between 1984 and 2001 composed the cohort. Followup included regular evaluations to detect progression by prostate specific antigen (PSA), digital rectal examination, transrectal ultrasound and prostate biopsy. Objective progression was defined by a point scale of changes in prognostic factors. Definitive treatment was recommended in patients with objective progression. RESULTS: The cohort comprised 88 patients with clinical stages T1-2, NX0, M0 prostate cancer, a mean age of 65.3 years and a mean initial PSA of 5.9 ng/ml. Systematic biopsy, which was repeated after the initial diagnostic biopsy, showed no cancer in 61% of cases. During a median followup of 44 months 22 patients had progression. Factors that predicted progression were repeat biopsy showing cancer (p = 0.004) and initial PSA (p = 0.014). Actuarial 5 and 10-year progression-free probabilities were 67% and 55%, respectively. Of the 31 patients treated 17 underwent radical prostatectomy, 13 received radiation therapy and 1 received androgen ablation. Seven men who did not show objective progression were treated because of anxiety. Only 1 patient, who was treated with radiation therapy, had biochemical recurrence. CONCLUSIONS: Deferred therapy may be a feasible alternative to curative treatment in select patients with favorable, localized prostate cancer. About half of these patients remain free of progression at 10 years and definitive treatment appeared effective in those with progression. Absent cancer on repeat needle biopsy identified cases highly unlikely to progress.     

Magnetometric evaluation of cadmium oxide-induced toxicity to pulmonary alveolar macrophages of Syrian golden hamsters

Since alveolar macrophages play an important role in the clearance of inhaled dust from air-ways, these cells have been used as a target for various toxic chemicals. Alveolar macrophages obtained from bronchoalveolar lavage of Syrian golden hamsters were concurrently exposed in vitro to Fe(3)O(4), as an indicator for magnetometry, and various concentrations of cadmium oxide (CdO) in this study. A rapid decrease of the remnant magnetic field, called relaxation, was observed after the cessation of an external magnetic field stimulus in macrophages concurrently exposed to phosphate-buffered saline or CdO at 0.1 microg/ml, while relaxation was delayed in those concurrently exposed to 1, 25, or 50 microg/ml CdO. Therefore, the concentration of CdO affecting relaxation in vitro was estimated at between 0.1 and 1 microg/ml. Release of LDH activity from CdO-exposed macrophages into the medium significantly increased at levels of 25 and 50 microg/ml CdO. Apoptosis was not detected in macrophages exposed to CdO by the DNA ladder detection method or morphological observations. Electron-microscopic examination revealed severe membrane damage and vacuolar changes in macrophages exposed to CdO. Since delayed relaxation is thought to occur by (1). disrupted cytoskeleton-driven random rotation of phagosomes containing iron oxide particles, (2). significant lactate dehydrogenase (LDH) activity release, and (3). detachment of cell membranes, CdO is considered to affect macrophage functions.     

Presence of simian virus 40 DNA sequences in human lymphoid and hematopoietic malignancies and their relationship to aberrant promoter methylation of multiple genes

The simian polyoma virus SV40 has been detected in specific human tumors including non-Hodgkin's lymphomas, although a causative role for the virus has not been convincingly demonstrated. Aberrant methylation of CpG islands in promoter regions is a frequent method of silencing tumor suppressor genes (TSGs) in cancers and may be induced by oncogenic viruses. We investigated the relationship between the presence of SV40 or EBV DNA sequences and the methylation profiles for 10 TSGs in 90 cases of non-Hodgkin's lymphomas/leukemias and 56 control tissues. SV40 sequences were present in 33/90 (37%) non-Hodgkin's lymphomas/leukemias, and EBV was present in 11/42 (26%) of non-Hodgkin's lymphomas. We found a highly significant correlation between the presence of SV40 and methylation of seven genes (P values, 0.006 to <0.0001). In lymphomas, there was no relationship between EBV and methylation. Oncogenic viruses and methylation were rarely present in control tissues. We investigated methylation of the same 10 TSGs in peripheral blood mononuclear cells (PBMC) from a healthy volunteer infected with EBV or EBV and SV40. Promoter methylation of CDH1 and CDH13 were noted in dual SV40- and EBV-infected PBMC, and these two genes were also highly significantly correlated to the presence of SV40 sequences in tumors. SV40 infection also resulted in appearance of the lymphoma/leukemia-specific marker, methylated SHP1. Methylation was completely absent in uninfected and EBV-infected PBMC. Our results demonstrate that the presence of SV40 in hematological malignancies is associated with promoter methylation of TSGs and that in all probability, the virus plays a role in tumor pathogenesis.     

Effects of reinforcement with the iliotibial tract flap in ACL reconstruction using bone-patellar tendon-bone

Introduction We attempted to reinforce the transplanted ligament by wrapping it with the iliotibial tract (ITT) flap to get more volume and to protect the graft from impingement in the intercondylar space postoperatively in reconstruction of the anterior cruciate ligament (ACL) using bone-patellar tendon-bone (BTB), and investigated the results in comparison with those of BTB alone.Materials and methods The study included 88 cases (88 knees). Group A comprised 43 knees with the reinforcement and group B 45 knees with BTB alone. Both groups were evaluated by second-look arthroscopy, magnetic resonance imaging (MRI), manual testing, International Knee Documentation Committee (IKDC) score, and histopathological evaluation more than 2 years after the reconstruction.Results In the second-look arthroscopic findings, 84% of the reconstructed ACL in group A had good appearance, and no fibrous split was observed. The ratio of fibrous disorder was significantly less in group A in comparison with group B (p=0.0037). Distinct reduction of the tension of the reconstructed ligament was observed in 9% of group A and 36% of group B (p=0.0088). Regarding the results of the Lachman test, the ratio of the negative group was higher in group A (p=0.0067). In the MRI findings fulfilled pictures to the inside of the reconstructed ligament were observed in 77% of the patients photographed in group A. In contrast, the fibrous split was observed in 55% in group B.Conclusions Reinforcement by wrapping with the ITT flap for the BTB autograft was effective in ACL reconstruction. The ratio of fibrous disorder and reduction of tension in the reconstructed ligament decreased.     

A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer

PURPOSE: We developed a preoperative nomogram for prediction of lymph node metastases in patients with clinically localized prostate cancer. MATERIALS AND METHODS: The study was a retrospective, nonrandomized analysis of 7,014 patients treated with radical prostatectomy at 6 institutions between 1985 and 2000. Exclusion criteria consisted of preoperative androgen ablation therapy, salvage radical prostatectomy and pretreatment prostate specific antigen (PSA) greater than 50 ng/ml. Preoperative predictors of lymph node metastases consisted of pretreatment PSA, clinical stage (1992 TNM) and biopsy Gleason sum. These predictors were used in logistic regression analysis based nomograms to predict the probability of lymph node metastases. RESULTS: Overall 5,510 patients with complete clinical and pathological information were included in the study. Lymph nodes metastases were present in 206 patients (3.7%). Pretreatment PSA, biopsy Gleason sum, clinical stage and institution represented predictors of lymph node status (p <0.001). Bootstrap corrected predictive accuracy of the 3-variable nomogram (clinical stage, Gleason sum and PSA) was 0.76. Inclusion of a fourth variable, which accounts for institutional differences in lymph node metastases, yielded an area under the receiver operating characteristics curve of 0.78. The negative predictive value of our nomograms was 0.99 when they predicted 3% or less chance of positive lymph nodes. CONCLUSIONS: Using clinical information, we produced 2 calibrated and validated nomograms, which accurately predict pathologically negative lymph nodes in men with localized prostate cancer who are candidates for radical prostatectomy.     

The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.     

Role of Tissue Kallikrein in Prevention and Recovery of Gentamicin-Induced Renal Injury

Gentamicin is an aminoglycoside antibiotic that induces severenephrotoxicity and acute renal failure. In the current project,we investigated the protective effects of tissue kallikrein(TK) protein administration (1 µg/h via osmotic minipumps)on kidney damage, apoptosis, and inflammation both during andafter a 10-day regimen of gentamicin (80 mg/kg body weight/daysc) in Sprague-Dawley rats. TK infusion during gentamicin treatmentsignificantly attenuated drug-induced renal dysfunction, corticaldamage, and apoptosis. Moreover, TK reduced inflammatory cellaccumulation in conjunction with diminished superoxide productionand decreased expression of tumor necrosis factor-, monocytechemoattractant protein-1, and intercellular adhesion molecule-1.The protective effects of TK were blocked by coinfusion of icatibant(1.3 µg/h), indicating a kinin B2 receptor–mediatedsignaling event. After cessation of gentamicin treatment, TKinfusion for 2 weeks completely restored kidney histology andmorphology comparable to that of saline-treated animals. Furthermore,TK reduced gentamicin-induced renal dysfunction and fibrosisas evidenced by decreased myofibroblast and collagen accumulationin the kidney. In vitro, gentamicin increased the number ofapoptotic cells and caspase-3 activity, but decreased phosphorylationof the prosurvival kinase Akt, in immortalized rat proximaltubular cells; addition of TK and bradykinin prevented theseeffects. In conclusion, our findings indicate that kallikrein/kininprevents and promotes recovery of gentamicin-induced renal injuryby inhibiting apoptosis, inflammatory cell recruitment, andfibrotic lesions through suppression of oxidative stress andproinflammatory mediator expression in animals during and aftergentamicin treatment.     

Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate

BACKGROUND: The growth and dissemination of tumors has been associated with angiogenesis, which is regulated by a group of polypeptide factors including vascular endothelial growth factor-C (VEGF-C). VEGF-C binds its receptor, vascular endothelial growth factor receptor-3 (VEGFR-3) to promote growth of tumor-associated lymphatic vessels. METHODS: In this study, microarray technology was used to build tissue arrays of normal prostate, benign prostate hyperplasia (BPH) and prostate carcinomas (PCa) using tissues from 640 patients. Slides were sectioned and stained with a polyclonal antibody to VEGFR-3 using a standard immunoperoxidase method and digitized. Immunoreactivity was scored using a 0-3+ semiquantitation scoring system for both intensity and percentage. The sum index was obtained by totaling the scores. RESULTS: VEGFR-3 is expressed in normal prostate, BPH, and PCa, but VEGFR-3 expression is up-regulated in PCa. We also found that VEGFR-3 is correlated with pre-operative prostate-specific antigen (Pre-PSA), Gleason score, and lymph node metastasis. The recurrence-free 5-year survival in cases with lower sum index (0-3) was significantly higher than that in cases with higher sum index (4-6) (77.3, 69.6%, respectively, P = 0.037) by Kaplan-Meier actuarial model. CONCLUSIONS: Our data suggest that VEGFR-3 expression is associated with tumor progression and may play an important role in facilitating lymphatic spread of PCa; high-level of VEGFR-3 expression in prostate cancer cells increases the risk of biochemical recurrence in prostate cancer patients treated by radical prostatectomy.