Low-profile stent system for treatment of atherosclerotic renal artery stenosis: the GREAT trial

PURPOSE: The Palmaz Genesis Peripheral Stainless Steel Balloon Expandable Stent in Renal Artery Treatment (GREAT) Trial was designed to assess the safety and performance of a low-profile stent for the treatment of obstructive renal artery disease by looking at 6-month renal artery patency uniformly analyzed by a Core Lab. MATERIALS AND METHODS: Fifty-two consecutive patients (mean age, 63.7 years) were successfully treated with the Palmaz Genesis Peripheral Stent (Cordis, Miami, FL) on the Slalom 0.018-inch Delivery System (Cordis Europe N.V., Oosteinde 8, NLO-9301 LJ Roden, The Netherlands) at 11 investigational centers. Patients with severe renal failure and > 8-mm renal artery were excluded. Primary endpoint was angiographic determination of in-stent percent diameter stenosis at 6 months. Fifty-one patients were treated with one stent, one patient was treated with two stents to cover the complete lesion. RESULTS: Mean percentage diameter stenosis before renal angioplasty was 68.2% +/- 12.0%. No stent implantation failure, displacement, need for additional stent implantation, or procedural complication was observed. Six-month angiography was performed in 41 of 52 patients (79%) resulting in a mean in-stent percent diameter stenosis or Quantitative Vessel analysis (QVA) at 6 months of 23.9%. The in-stent binary (percent diameter stenosis > 50%) restenosis rate at 6 months was 14.3%. No fatal events occurred up to 6 months after implantation. Major adverse events occurred in five patients: four patients (7.7%) required a revascularization and one patient (1.9%) experienced a cerebrovascular event, which regressed spontaneously. CONCLUSIONS: The Palmaz Genesis stent (Cordis) provides good results for renal artery stent placement, with an in-stent binary restenosis rate (percent diameter stenosis > 50%) at 6 months of 14.3% as determined with angiography.     

Electron Transport in Naphthalene Diimide Derivatives

Two naphthalene diimides derivatives containing two different (alkyl and alkoxyphenyl) N-substituents were studied, namely, N,N′-bis(sec-butyl)-1,4,5,8-naphthalenetetracarboxylic acid diimide (NDI-s-Bu) and N,N′-bis(4-n-hexyloxyphenyl)-1,4,5,8-naphthalenetetracarboxylic acid diimide (NDI-4-n-OHePh). These compounds are known to exhibit electron transport due to their electron-deficient character evidenced by high electron affinity (EA) values, determined by electrochemical methods and a low-lying lowest unoccupied molecular orbital (LUMO) level, predicted by density functional theory (DFT) calculations. These parameters make the studied organic semiconductors stable in operating conditions and resistant to electron trapping, facilitating, in this manner, electron transport in thin solid layers. Current–voltage characteristics, obtained for the manufactured electron-only devices operating in the low voltage range, yielded mobilities of 4.3 × 10⁻⁴ cm²V⁻¹s⁻¹ and 4.6 × 10⁻⁶ cm²V⁻¹s⁻¹ for (NDI-s-Bu) and (NDI-4-n-OHePh), respectively. Their electron transport characteristics were described using the drift–diffusion model. The studied organic semiconductors can be considered as excellent candidates for the electron transporting layers in organic photovoltaic cells and light-emitting diodes     

Parthenolide reduces the frequency of ABCB5-positive cells and clonogenic capacity of melanoma cells from anchorage independent melanospheres

Growing evidence suggests that the cancer stem cell phenotype in melanoma is dynamically regulated. Therefore, effective therapies have to target simultaneously bulk tumor cells and melanoma stem-like cells. The aim of the present study was to investigate the effects of parthenolide on heterogeneous cancer cell populations from anchorage-independent melanospheres. Cells derived from nodular melanoma specimens were grown under serum-free sphere-forming conditions. The effects of parthenolide on cellular viability, immunophenotype and self-renewing capacity were assessed with cells from dissociated melanospheres. Its penetration capacity was evaluated with intact melanospheres. In melanoma cells that survived treatment with parthenolide, a different immunophenotype than that in untreated control was found. The frequency of cells expressing the ABCB5 transporter was markedly reduced. Most importantly, melanoma cells that survived parthenolide treatment lost their self-renewing capacity. Significantly lower influence of drug on cellular viability and frequency of ABCB5-positive cells was observed in intact melanospheres. The potential clinical significance of our findings is based on the ability of parthenolide to affect both bulk and melanoma stem-like cells with clonogenic capacity and high expression of the ABCB5 transporter. Its low penetration capacity, however, may limit its action to easily accessible melanoma cells, either circulating in the blood or those in the vicinity to blood vessels within the tumor. Because of limited penetration capacity of parthenolide, this drug should be further explored as a part of multimodal therapies rather than as a stand-alone therapeutic agent.     

Evaluation of DNA Primase DnaG as a Potential Target for Antibiotics

Mycobacteria contain genes for several DNA-dependent RNA primases, including dnaG, which encodes an essential replication enzyme that has been proposed as a target for antituberculosis compounds. An in silico analysis revealed that mycobacteria also possess archaeo-eukaryotic superfamily primases (AEPs) of unknown function. Using a homologous recombination system, we obtained direct evidence that wild-type dnaG cannot be deleted from the chromosome of Mycobacterium smegmatis without disrupting viability, even in backgrounds in which mycobacterial AEPs are overexpressed. In contrast, single-deletion AEP mutants or mutants defective for all four identified M. smegmatis AEP genes did not exhibit growth defects under standard laboratory conditions. Deletion of native dnaG in M. smegmatis was tolerated only after the integration of an extra intact copy of the M. smegmatis or Mycobacterium tuberculosisdnaG gene, under the control of chemically inducible promoters, into the attB site of the chromosome. M. tuberculosis and M. smegmatis DnaG proteins were overproduced and purified, and their primase activities were confirmed using radioactive RNA synthesis assays. The enzymes appeared to be sensitive to known inhibitors (suramin and doxorubicin) of DnaG. Notably, M. smegmatis bacilli appeared to be sensitive to doxorubicin and resistant to suramin. The growth and survival of conditional mutant mycobacterial strains in which DnaG was significantly depleted were only slightly affected under standard laboratory conditions. Thus, although DnaG is essential for mycobacterial viability, only low levels of protein are required for growth. This suggests that very efficient inhibition of enzyme activity would be required for mycobacterial DnaG to be useful as an antibiotic target.     

Neutrophils are active in total joint implant loosening

Background?Polymorphonuclear neutrophils (PMN) are the first cells to take part in the local foreign body reaction in aseptic loosening of endoprostheses. The aim of this study was to evaluate the systemic host reaction to total joint replacement by measuring the production of nitric oxide by neutrophils before and after total joint replacement.Patients and method?Blood samples were collected from 33 patients (27 hips and 6 knees) before surgery, and 2 weeks, 2 months and 2.5–3 years after surgery. The levels of nitric oxide produced by PMN were measured by the method described by Markert et al. (1994).Results?Patients reporting pain in the region of the implant 3 years after surgery, and also patients with radiographic signs of loosening, had higher production of NO in the early period and 3 years after the implantation than those with good clinical results.Interpretation?We propose that elevated levels of nitric oxide production by PMNs may serve as a marker of total joint prosthesis loosening.     

Prospective evaluation of pain control and quality of life in patients with chronic pancreatitis following bilateral thoracoscopic splanchnicectomy

Background

Abdominal pain in chronic pancreatitis (CP) is the most common symptom with a highly unfavorable impact on the quality of life. It has been shown that bilateral thoracoscopic splanchnicectomy (BTS) may produce marked pain relief for the majority of patients. The aim of this study was to evaluate the effectiveness of BTS in pain control and quality-of-life improvement in patients with a severe form of CP.

Methods

Between April 2000 and April 2009, a total of 30 patients qualified for BTS due to CP-related pain. Their age ranged from 28 to 60 years. A 12-month follow-up period was planned for all the patients enrolled. To evaluate effectiveness of BTS, an 11-point Numeric Rating Scale (NRS) and the Quality of Life Questionnaire C-30 (QLQ-C30) in its basic form, developed by European Organization for Research and Treatment of Cancer, were used. An NRS value between 0 and 3 was considered a positive postoperative pain control result.

Results

The bilateral splanchnicectomy procedure was performed successfully in 27 of 30 qualified patients. A positive effect based on decreased pain (p < 0.05) at 12 months was achieved in 24 patients (80 %). The initial change in quality of life was not significant but it gradually improved with time (preop vs. 12 months QLQ-C30 score, p < 0.001).

Conclusions

This study showed that BTS is safe and efficacious for pain alleviation in patients with severe CP. It may significantly increase the chances of a long-lasting, life-changing improvement in the quality of life.     

Distribution of CFTR mutations in the Czech population: Positive impact of integrated clinical and laboratory expertise,detection of novel/de novo alleles and relevance for related/derived populations

BackgroundThis two decade long study presents a comprehensive overview of the CFTR mutation distribution in a representative cohort of 600 Czech CF patients derived from all regions of the Czech Republic.MethodsWe examined the most common CF-causing mutations using the Elucigene CF-EU2v1? assay, followed by MLPA, mutation scanning and/or sequencing of the entire CFTR coding region and splice site junctions.ResultsWe identified 99.5% of all mutations (1194/1200 CFTR alleles) in the Czech CF population. Altogether 91 different CFTR mutations, of which 20 were novel, were detected. One case of de novo mutation and a novel polymorphism was revealed.ConclusionThe commercial assay achieved 90.7%, the MLPA added 1.0% and sequencing increased the detection rate by 7.8%. These comprehensive data provide a basis for the improvement of CF DNA diagnostics and/or newborn screening in our country. In addition, they are relevant to related Central European populations with lower mutation detection rates, as well as to the sizeable North American “Bohemian diaspora”.     

Adequacy Indices for Dialysis in Acute Renal Failure: Kinetic Modeling

Many aspects of the management of renal replacement therapy in acute renal failure (ARF), including the appropriate assessment of dialysis adequacy, remain unresolved, because ARF patients often are not in a metabolic steady state. The aim of this study was to evaluate a system of adequacy indices for dialysis in ARF patients using urea and creatinine kinetic modeling. Kinetic modeling was performed for two different fictitious patients (A and B) with characteristics described by the average parameters for two patient groups and for two blood purification treatments: sustained low efficiency daily dialysis (SLEDD) in Patient A and continuous venovenous hemofiltration (CVVH) in Patient B, based on data from a clinical report. Urea and creatinine generation rates were estimated according to the clinical data on the solute concentrations in blood. Then, using estimated generation rates, two hypothetical treatments were simulated, CVVH in Patient A and SLEDD in Patient B. KT/V, fractional solute removal (FSR) and equivalent renal clearance (EKR) were calculated according to the definitions developed for metabolically unstable patients. CVVH appeared as being more effective than SLEDD because KT/V, FSR, and EKR were higher for CVVH than SLEDD in Patients A and B. Creatinine KT/V, FSR, and EKR were lower and well correlated to the respective indices for urea. Urea and creatinine generation rates were overestimated more than twice in Patient A and by 30–40% in Patient B if calculated assuming the metabolically stable state than if estimated by kinetic modeling. Adequacy indices and solute generation rates for ARF patients should be estimated using the definition for unsteady metabolic state. EKR and FSR were higher for urea and creatinine with CVVH than with SLEDD, because of higher K·T and minimized compartmental effects for CVVH.