Influence of technique of coronary artery implantation on long-term results in composite aortic root replacement.

BACKGROUND: Long-term results after composite graft aortic root replacement may depend on the insertion technique. The aim of this study is to assess the influence of the technique of coronary artery implantation on long-term results in composite aortic root replacement. METHODS: One hundred fifty consecutive patients (mean age, 55 years; 119 men) with different disorders of the ascending aorta who underwent aortic root replacement with a composite graft prosthesis between January 1985 and December 1999 were retrospectively studied. Thirteen patients had previously undergone cardiovascular surgery. The open button technique was performed in 65 patients (43.3%, group 1) and the inclusion technique in 85 patients (56.7%, group 2). Mean follow-up was 70.5 months. Surgery was elective in 110 procedures (73%). RESULTS: Global actuarial survival was 76.1% +/- 4.3% for group 1 and 73.7% +/- 3.9% for group 2 at 10 years (p = 0.22). Freedom from reoperation excluding early deaths was 81% +/- 3% for group 1 and 86% +/- 2.2% for group 2 at 10 years (p = 0.62). Group 2 demonstrated a statistically significantly higher occurrence of pseudoaneurysm formation versus group 1 (p = 0.04). CONCLUSIONS: Composite graft aortic root replacement is a safe and effective therapy for proximal aortic aneurysm and dissection, resulting in good early and long-term results irrespective of the anastomotic technique. However, the open button technique seems to avoid late false aneurysm formation at the anastomotic sites.     

Attenuated Salmonella targets prodrug activating enzyme carboxypeptidase G2 to mouse melanoma and human breast and colon carcinomas for effective suicide gene therapy

PURPOSE: We engineered the oncolytic Salmonella typhimurium-derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2 (CPG2) and to show enhanced antitumor efficacy on administration of different prodrugs. EXPERIMENTAL DESIGN: We characterized CPG2 expression in vectors by immunoblotting, immunofluorescence, and enzyme activity. We assessed prodrug activation by high-performance liquid chromatography. Target human tumor cell and bacterial vector cell cytotoxicity was measured by flow cytometry and colony-forming assays. Therapy was shown in two human tumor xenografts and one mouse allograft with postmortem analysis of bacterial and CPG2 concentration in the tumors. RESULTS: CPG2 is expressed within the bacterial periplasm. It activates prodrugs and induces cytotoxicity in human tumor cells but not in host bacteria. Following systemic administration, bacteria multiply within xenografts reaching 2 x 10(7)/g to 2 x 10(8)/g at 40 days postinoculation. The concentration of CPG2 in these tumors increases steadily to therapeutic levels of 1 to 6 units/g. The bacteria alone reduce the growth of the tumors. Subsequent administration of prodrugs further reduces significantly the growth of the xenografts. CONCLUSIONS: The bacteria multiply within tumors, resulting in a selective expression of CPG2. The CPG2-expressing bacteria alone reduce the growth of tumors. However, in the presence of prodrugs activated by CPG2, this oncolytic effect is greatly increased. We conclude that bacterial oncolytic therapy, combined with CPG2-mediated prodrug activation, has great potential in the treatment of a range of cancers.     

Development and validation of a patient-specific predictive instrument for the need for dose reduction in chemotherapy for breast cancer: a potential decision aid for the use of myeloid growth factors

A predictive instrument for chemotherapy dose reductions would help optimize delivery of planned chemotherapy and rationalize the use of myeloid growth factors. We analyzed data on 833 women with breast cancer treated with cyclophosphamide, doxorubicin, and fluorouracil, for six cycles in two phase III clinical trials. From the first study ( n=323), we generated a logistic regression model that predicts an individual patient's probability of receiving significantly reduced chemotherapy, defined as less than 85% of the planned dose over cycles 2-6, using data generated from cycle 1. The model was validated on data from the second study ( n=510). The predictive model's variables include nadir absolute neutrophil count (ANC) in cycle 1 (OR: 0.14, 95% CI: 0.06-0.30, P<0.001) and percent drop of platelets between day 1 and the nadir in cycle 1 (OR: 1.04, 95% CI: 1.02-1.05, P<0.001). Both variables are dose adjusted based on the chemotherapy cycle 1 dose. The model's discriminatory performance was good (ROC area=0.82), as was the calibration of predicted with actual frequencies of dose reductions. In the validation dataset, model variables remained significant, with an ROC area of 0.78 and good calibration. In summary, we devised and validated a predictive instrument that uses data from a patient's first cycle of chemotherapy to compute the probability of requiring a significant chemotherapy dose reduction on subsequent cycles. This instrument could help clinicians select patients who will benefit from early administration of myeloid growth factors.     

Risk of discontinuation of nevirapine due to toxicities in antiretroviral-naive and -experienced HIV-infected patients with high and low CD4+ T-cell counts

INTRODUCTION: It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cARTexperienced patients. PATIENTS AND METHODS: 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+ T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+ T-cell counts at initiation of NVPc (high [H], > 400/mm3 or > 250/mm3 for male or female, respectively, or low [L], < or = 400/mm3 or 5250/mm3 for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC). RESULTS: After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group (n = 588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n = 62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34-0.94; P = 0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23-0.87; P = 0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to < 3 months of NVPc exposure within the HE group (incidence: 0; per 1,000 person-years follow up; 95% CI: 0-6.9). After adjustment, there were no differences between the HE and HN groups in discontinuation due to TOXPC in patients starting efavirenz-based cART (RH: 0.91; 95% CI: 0.60-1.38; P = 0.66) or protease-inhibitor-based cART (RH: 1.13; 95% CI: 0.77-1.66; P = 0.52). CONCLUSIONS: Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretroviral-experienced than in antiretroviral-naive patients with high CD4+ T-cell counts.     

Astrocytes derived from fetal neural progenitor cells as a novel source for therapeutic adenosine delivery

PurposeIntracerebral delivery of anti-epileptic compounds represents a novel strategy for the treatment of refractory epilepsy. Adenosine is a possible candidate for local delivery based on its proven anti-epileptic effects. Neural stem cells constitute an ideal cell source for intracerebral transplantation and long-term drug delivery. In order to develop a cell-based system for the long-term delivery of adenosine, we isolated neural progenitor cells from adenosine kinase deficient mice (Adk^?/?) and compared their differentiation potential and adenosine release properties with corresponding wild-type cells.MethodsFetal neural progenitor cells were isolated from the brains of Adk^?/? and C57BL/6 mice fetuses and expanded in vitro. Before and after neural differentiation, supernatants were collected and assayed for adenosine release using liquid chromatography–tandem mass spectrometry (LC–MS/MS).ResultsAdk^?/? cells secreted significantly more adenosine compared to wild-type cells at any time point of differentiation. Undifferentiated Adk^?/? cells secreted 137 ± 5 ng adenosine per 10⁵ cells during 24 h in culture, compared to 11 ± 1 ng released from corresponding wild-type cells. Adenosine release was maintained after differentiation as differentiated Adk^?/? cells continued to release significantly more adenosine per 24 h (47 ± 1 ng per 10⁵ cells) compared to wild-type cells (3 ± 0.2 ng per 10⁵ cells).ConclusionsFetal neural progenitor cells isolated from Adk^?/? mice – but not those from C57BL/6 mice – release amounts of adenosine considered to be of therapeutic relevance.     

Left main coronary artery fistula to the right atrium and superior vena cava: case report and review of the literature

A unique arteriovenous fistula, originating from the left main coronary artery and branching to drain into the right atrium and superior vena cava is presented with review of the literature.     

Symptomatic lymphoceles after kidney transplantation – multivariate analysis of risk factors and outcome after laparoscopic fenestration

Ulrich F, Niedzwiecki S, Fikatas P, Nebrig M, Schmidt SC, Kohler S, Weiss S, Schumacher G, Pascher A, Reinke P, Tullius SG, Pratschke J. Symptomatic lymphoceles after kidney transplantation – multivariate analysis of risk factors and outcome after laparoscopic fenestration.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01073.x
© 2009 John Wiley & Sons A/S. Abstract: Lymphocele formation is a common complication after kidney transplantation, and laparoscopic surgery has become a widely accepted treatment option. The aim of this retrospective study was to analyze the risk factors of lymphocele development and to assess the treatment outcome after laparoscopic fenestration. We analyzed 426 renal allograft recipients operated between 2002 and 2006 receiving triple immunosuppression with calcineurin inhibitors. The incidence of lymphocele was 9.9%, while 24 (5.6%) patients with symptomatic lymphoceles required laparoscopic surgery. Serum creatinine at diagnosis was significantly higher in patients with lymphoceles treated surgically (3.2 ± 0.7 vs. 1.7 ± 0.6 mg/dL; p < 0.001). After successful laparoscopic intervention, creatinine concentrations recovered until discharge and were comparable to other patients (1.6 ± 0.5 vs. 1.5 ± 0.5 mg/dL; p = NS). While we observed a significant association of lymphocele formation with diabetes, tacrolimus therapy, and acute rejection in univariate testing, only diabetes remained a significant factor after multivariate analysis. Laparoscopic fenestration proved to be a safe and efficient method without any associated mortality and a low recurrence rate of 8.3% (n = 2). We conclude that diabetes is an independent risk factor for lymphocele development, and laparoscopic fenestration should be the treatment of choice for larger and symptomatic lymphoceles, as it is safe and offers a low recurrence rate.     

Astrocyte and Glutamate Markers in the Superficial,Deep, and White Matter Layers of the Anterior Cingulate Gyrus in Schizophrenia

Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. Recent evidence suggests that it is no longer tenable to consider neurons and their functions independently of the glia that interact with them. Although astrocytes have been viewed as harbingers of neuronal injury and CNS stress, their principal functions include maintenance of glutamate homeostasis and recycling, mediation of saltatory conduction, and even direct neurotransmission. Results of studies of astrocytes in schizophrenia have been variable, in part because of the assessment of single and not necessarily universal markers and/or assessment of non-discrete brain regions. We used laser capture microdissection to study three distinct partitions of the anterior cingulate gyrus (layers I–III, IV–VI, and the underlying white matter) in the brains of 18 well-characterized persons with schizophrenia and 21 unaffected comparison controls. We studied the mRNA expression of nine specific markers known to be localized to astrocytes. The expression of astrocyte markers was not altered in the superficial layers or the underlying white matter of the cingulate cortex of persons with schizophrenia. However, the expression of some astrocyte markers (diodinase type II, aquaporin-4, S100β, glutaminase, excitatory amino-acid transporter 2, and thrombospondin), but not of others (aldehyde dehydrogenase 1 family member L1, glial fibrillary acidic protein, and vimentin) was significantly reduced in the deep layers of the anterior cingulate gyrus. These findings suggest that a subset of astrocytes localized to specific cortical layers is adversely affected in schizophrenia and raise the possibility of glutamatergic dyshomeostasis in selected neuronal populations.