Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

Amoxicillin-current use in swine medicine.

Amoxicillin has become a major antimicrobial substance in pig medicine for the treatment and control of severe, systemic infections such as Streptococcus suis. The minimum inhibitory concentration 90% (MIC 90) is 0.06 µg amoxicillin/ml, and the proposed epidemiological cut-off value (ECOFF) is 0.5 µg/ml, giving only 0.7% of isolates above the ECOFF or of reduced susceptibility. Clinical breakpoints have not been set for amoxicillin against porcine pathogens yet, hence the use of ECOFFs. It has also been successfully used for bacterial respiratory infections caused by Actinobacillus pleuropneumoniae and Pasteurella multocida. The ECOFF for amoxicillin against A. pleuropneumoniae is also 0.5 µg/ml demonstrating only a reduced susceptibility in 11.3% of isolates. Similarly, P. multocida had an ECOFF of 1.0 µg/ml and a reduced susceptibility in only 2.6% of isolates. This reduced susceptibility disappears when combined with the beta-lactamase inhibitor, clavulanic acid, demonstrating that it is primarily associated with beta-lactamase production. In contrast, amoxicillin is active against Escherichia coli and Salmonella species but using ECOFFs of 8.0 and 4.0 µg/ml, respectively, reduced susceptibility can be seen in 70.9% and 67.7% of isolates. These high levels of reduced susceptibility are primarily due to beta-lactamase production also, and most of this resistance can be overcome by the combination of amoxicillin with clavulanic acid. Currently, amoxicillin alone is considered an extremely valuable antimicrobial in both human and animal medicine and remains in the critically important category of antibiotics alongside the fluoroquinolones and macrolides by the World Health Organization as well as the third- and fourth-generation cephalosporins, but these cephalosporins show marked resistance to basic beta-lactamase production and are only destroyed by the extended-spectrum beta-lactamases. Amoxicillin alone and in combination with clavulanic acid are currently classed together in Category 2 in the European Union. By reviewing the pharmacodynamic data and comparing this with pharmacokinetic data from healthy and infected animals and clinical trial data, it can be seen that the product has a good efficacy against S. suis and A. pleuropneumoniae, in spite of usage over many years. However, it may be much less efficacious on its own against E. coli, due to reduced susceptibility and resistance associated with beta-lactamase production, which is largely overcome by the use of clavulanic acid. It is felt that this differentiation may be useful in future classification of amoxicillin alone, in comparison with its combined use with clavulanic acid and thereby preserve the use of the more critically important antibiotics in veterinary medicine and reducing the risk of their resistance being transmitted to human.

Renal Transplant Arterial Stenosis Treated With Bare-Metal Versus Drug-Eluting Stents: Comparison of Treatment Outcomes.

INTRODUCTION: This study aims to evaluate outcomes of bare-metal stents (BMS) versus drug-eluting stents (DES) in patients who undergo stenting for transplant renal arterial stenosis. MATERIALS AND METHODS: We retrospectively reviewed records of renal transplantation patients who underwent transplant renal arterial stenting from September 2009 to September 2013. All stents greater than 5 mm were excluded to allow for equivalent comparison between the DES and BMS groups. Statistical comparisons were performed using a two-tailed Fischer exact test, and analysis of continuous variables was analyzed using a one-way analysis of variance. RESULTS: The final study population included a total of 18 patients who received either BMS or DES (11 and 7 patients, respectively) for transplant renal arterial stenosis. The most common indications for stenting were increasing creatinine level and abnormal Doppler velocities. There were more re-interventions with BMS (n = 4/11) than DES (n = 0/7), but the trend was not statistically significant (P = .12). Three patients who received BMS had a clinically significant decrease in blood pressure versus 4 in the DES group (P = .33). Six patients who received BMS had a clinically significant decrease in creatinine level versus 3 in the DES group (P = 1.0). CONCLUSION: There is an absolute but not statistically significant difference in the incidence of restenosis requiring repeat intervention between the BMS and DES groups. No difference was detected in clinical success as measured by decreases in blood pressure or creatinine. Future larger studies are needed to corroborate these findings.

An assessment of electric vehicles: technology, infrastructure requirements, greenhouse-gas emissions, petroleum use, material use, lifetime cost, consumer acceptance and policy initiatives.

Concerns about climate change, urban air pollution and dependence on unstable and expensive supplies of foreign oil have led policy-makers and researchers to investigate alternatives to conventional petroleum-fuelled internal-combustion-engine vehicles in transportation. Because vehicles that get some or all of their power from an electric drivetrain can have low or even zero emissions of greenhouse gases (GHGs) and urban air pollutants, and can consume little or no petroleum, there is considerable interest in developing and evaluating advanced electric vehicles (EVs), including pure battery-electric vehicles, plug-in hybrid electric vehicles and hydrogen fuel-cell electric vehicles. To help researchers and policy-makers assess the potential of EVs to mitigate climate change and reduce petroleum use, this paper discusses the technology of EVs, the infrastructure needed for their development, impacts on emissions of GHGs, petroleum use, materials use, lifetime costs, consumer acceptance and policy considerations.

Characterisation of multiresistant Brachyspira hyodysenteriae isolates from Czech pig farms.

The aim of the present study was to evaluate the importance of clonal spread of Brachyspira hyodysenteriae resistant to pleuromutilins (tiamulin, valnemulin) on farms in the Czech Republic. Agar dilution method and macrorestriction fragment profile analysis by pulsed field gel electrophoresis were used to characterise 35 B hyodysenteriae isolates that were obtained from clinical cases of swine dysentery on 32 farms between 2000 and 2005. Most isolates showed multiple resistances to tiamulin, valnemulin, tylosin and lincomycin. A total of six pulsotypes were detected in these multiresistant isolates. An analysis of epidemiological data showed that multiresistant B hyodysenteriae isolates were more often detected on fattening farms (59 per cent), compared with farms with other types of production. Furthermore, it was found that multiresistant B hyodysenteriae clones were most frequently selected on farms with endemic incidence of swine dysentery. This finding was confirmed by the characterisation of 21 B hyodysenteriae isolates obtained from three large-scale operations in seven consecutive years.

Alcohol and suicidal behavior in adolescents.

This review describes epidemiology, pathophysiology, risk factors, treatment and prevention of suicidal behavior in adolescents. As one of the leading causes of death of young adults, adolescent suicide has become a public health problem and an increase in the adolescent suicide rate has been observed over the past several decades. One important risk factor thought to contribute to the recent rise in suicidal behavior among young adults is increasing alcohol abuse among adolescents. The link between alcohol and suicide in adolescents is complicated and multiple risk factors are important in explaining and understanding suicidal behavior among adolescents. Comorbid psychopathology, which is common among adolescent alcohol abusers, substantially increases the risk for suicide behavior. Availability of alcohol and guns at home may also contribute to suicide risk in adolescents. Studies of stress hormones, brain neurotransmitters, hereditary factors, behavioral measures and gender differences shed light in understanding this complex phenomenon. Ideally, treatment of adolescents who receive a diagnosis of an alcohol use disorder and co-occurring suicidality should follow an integrated protocol that addresses both conditions. Future studies of psychological and neurobiological mechanisms of suicidality in adolescents with alcohol and/or substance abuse are merited.

Minocycline-induced black thyroid gland: Medical curiosity or a marker for papillary cancer?

PURPOSE: Black pigmentation of the thyroid gland is a rare side effect of minocycline. METHODS: Only 26 cases, in addition to the 2 we present, have been reported in the literature. Eleven cases of thyroid carcinoma associated with black thyroid syndrome have been reported. CONCLUSIONS: The incidence of papillary cancer may be increased in thyroid glands stained by the minocycline pigment, which warrants an increased index of suspicion in patients who develop thyroid nodules and have previously been treated with minocycline.

Computational explorations of vinylcyclopropane-cyclopentene rearrangements and competing diradical stereoisomerizations

The rearrangements and stereoisomerizations of four systems, vinylcyclopropane, 4-tert-butylvinylcyclopropane, 5-methylvinylcyclopropane, and 2,5-dimethylvinylcyclopropane, as well as a variety of deuterated derivatives and 1- and 2-methyl-, methoxy-, difluoro-, and amino-substituted species, were studied by density functional theory calculations using the B3LYP functional and the 6-31G basis set. Energies were evaluated with CASSCF(4, 4)/6-31G single point calculations. The major product is obtained by the si pathway. Structures on this path are essentially pure diradical in character. Higher energy diradical species and intermediates are responsible for the scrambling of the stereochemistry. The stereoselectivity of the reaction is increased by substituents which increase the relative energy of the species involved in competing stereoselectivities. The computed secondary kinetic isotope effects reproduce the experimental values reported in the literature.

Paclitaxel esters of malic acid as prodrugs with improved water solubility.

The synthesis of paclitaxel esters of malic acid is described. These compounds were found to have improved water solubility and are stable in solution at neutral pH. The C2' modified compounds behave as prodrugs, that is, paclitaxel is generated upon exposure to human plasma, whereas the C7 modified derivatives do not. 2'-Malyl paclitaxel sodium salt demonstrated enhanced antitumour activity and less toxicity in a P388 murine leukaemia in vivo model when compared to paclitaxel.

Novel 23-base-pair duplication mutation in TSC1 exon 15 in an infant presenting with cardiac rhabdomyomas.

Tuberous sclerosis (TSC) is a dominantly inherited disorder due to mutations at two gene loci, the TSC1 locus on chromosome 9q34 and the TSC2 locus on chromosome 16p13.3. The TSC2 and the TSC1 genes have now been cloned, enabling mutation analysis. We report results of mutation analysis in a sporadic case of TSC first identified in intra-uterine life on the basis of the presence of cardiac rhabdomyomas. Postnatally this infant was also found to have subependymal nodules on brain computed tomographic scan. Hypomelanotic macules were not detected neonatally or at 12 months of age. The specific TSC1 exon 15 mutation found in our patient has not previously been reported in cases of TSC. This mutation involves duplication of a 23-bp segment of DNA between two 9-bp repeated sequence elements within exon 15. These repeat elements are located between nucleotides 1892-1900 and between nucleotides 1915-1923 within the TSC1 gene sequence. It is likely that the presence of these two repeated elements predisposes to misalignment of DNA strands and unequal crossing over. The mechanism of origin of rhabdomyomas in TSC is reviewed. Loss of heterozygosity in the TSC gene regions has been reported in cardiac rhabdomyomas; however, these lesions are self-limiting in their growth. The basis for this self limiting proliferation is not clear. One interesting postulation is that cardiac rhabdomyomas may be due to delay or failure of apoptosis which occurs as part of the normal remodeling process in the heart.

Validation of lucigenin as a chemiluminescent probe to monitor vascular superoxide as well as basal vascular nitric oxide production.

Lucigenin has been widely used as a chemiluminescent substrate to monitor vascular superoxide (O*-2) formation. The validity of lucigenin for detection of O*-2 has been questioned because O*-2 is generated by lucigenin itself. It has been shown that the concentration of lucigenin is a critical parameter affecting the validity of this assay. In the present studies we evaluated a reduced concentration of lucigenin (5 microM) as a tool to quantify O*-2 production in vascular tissue. Lucigenin-induced effects on endothelial function were assessed by isometric tension recording of isolated aortic rings suspended in organ baths. The effects of lucigenin on O*-2 production were studied using spin trapping and electron spin resonance spectroscopy. Lucigenin at 250 microM but not at 5 microM caused a significant attenuation of endothelium-dependent relaxations to acetylcholine, which was prevented by pretreatment with superoxide dismutase. Spin-trapping studies revealed that lucigenin at 250 microM increased vascular O*-2 production several fold while 5 microM lucigenin did not stimulate O*-2 production. Inhibition of NO synthase by NG-momomethyl-l-arginine as well as the removal of the endothelium almost doubled lucigenin-derived chemiluminescence (LDCL), indicating that basal production of endothelium-derived NO depresses the baseline chemiluminescence signal. Thus, lucigenin at a concentration of 5 microM seems to be a sensitive and valid probe for assessing O*-2 in vascular tissue. It can also be used as an indirect probe to estimate basal vascular NO release.

In vitro simulation of contact fatigue damage found in ultra-high molecular weight polyethylene components of knee prostheses.

An in vitro simulation of fatigue loading of ultra-high molecular weight polyethylene (UHMWPE) knee components was carried out on a knee simulator and on a rolling and sliding wear tester. Tibial components for the knee simulator were gamma-sterilized, implantable components taken from manufacturing inventory. The rolling/sliding UHMWPE discs were machined from bar stock and either gamma sterilized in air and accelerated aged, or left as non-sterilized (controls). Cracking and delamination of samples that had been gamma sterilized in air and aged were observed in both types of tests. Contact fatigue damage was visible in as few as 150,000 cycles using the knee simulator at loads of 122 N (275 1b). The rolling/sliding samples showed signs of damage in as few as 130,000 cycles with an estimated stress of 15 MPa and 25 per cent sliding. However, cracking and delamination were not generated in the never-sterilized or recently sterilized controls. UHMWPE that has been gamma sterilized in air and aged is shown to be susceptible to contact fatigue damage. These results are important to the interpretation of in vitro total knee replacement simulations used to assess the performance of tibial bearings.

Deep pelvic abscesses: transperineal US-guided drainage.

PURPOSE: To examine the efficacy of transperineal sonographically guided drainage of deep pelvic abscesses. MATERIALS AND METHODS: Twelve drainage procedures were performed in 11 adults with symptoms of infection and cross-sectional images demonstrating a deep pelvic abscess. Eight patients had recently undergone abdominoperineal resection, seven of whom underwent preoperative radiation therapy. Two had chronic osteomyelitis with adjacent fluid collections, and one developed an infected hematoma after trauma. With ultrasound (US) guidance for initial access, catheters were placed for drainage in 11 procedures. One patient was treated with aspiration alone. Patients underwent clinical follow-up and subsequent imaging as necessary. RESULTS: Transperineal needle placement was successful in 12 of 12 patients (100%). In procedures that required catheter placement, 10 of 11 placements (91%) were achieved with the transperineal approach. One patient required fluoroscopic transvaginal catheter placement after opacification of the collection transperineally. Catheter drainage was maintained for 2-146 days (mean, 40 days; median, 21 days). Clinical success was achieved in nine of 10 patients (90%) by means of transperineal drainage. There were no complications, although premature catheter removal occurred in two patients. CONCLUSION: US-guided transperineal abscess drainage may be successfully performed in patients who cannot undergo conventional transabdominal, transvaginal, or transrectal catheter drainage.

Quantification of superoxide radical formation in intact vascular tissue using a Cypridina luciferin analog as an alternative to lucigenin.

Lucigenin has been frequently used for the chemiluminescent detection of superoxide (*O-2) in intact tissue. More recent studies, however, revealed that lucigenin per se causes formation of *O-2 raising doubt about this probe to detect reliably *O-2. We therefore tested a more recently described chemiluminescence probe (2-methyl-6-phenyl-3,7-dihydroimidazol[1,2-alpha]pyrazine-3-one (CLA)) to estimate the ability of vascular tissue to generate *O-2 as an alternative to lucigenin. In a cell free system as well as in vascular tissue, CLA-enhanced chemiluminescence was dose dependently inhibited by superoxide dismutase (SOD), vitamin C and sodium nitroprusside (SNP). Electron spin resonance studies revealed that lucigenin (250 microM) but not CLA (1 microM) caused extra *O-2 production in vascular tissue. Stimulation of vessels with NADH (200 microM) increased CLA enhanced chemiluminescence, which was inhibited by low concentrations of superoxide dismutase (20U/ml). Endothelial removal as well as the nitric oxidase-synthase inhibitor increased CLA chemiluminescence in vessels. We conclude that CLA is a sensitive and specific chemiluminescence probe to detect *O-2 production in intact vascular tissue.

Dissimilatory ATP sulfurylase from the hyperthermophilic sulfate reducer Archaeoglobus fulgidus belongs to the group of homo-oligomeric ATP sulfurylases.

In the hyperthermophilic sulfate reducer Archaeoglobus fulgidus DSM 4304T, two open reading frames (sat and ORF2) are located upstream of the aprBA genes encoding adenosine-5'-phosphosulfate (APS) reductase. sat-ORF2-aprBA probably form a transcriptional unit, since sat is preceded by putative promoter sequences and termination signals are found downstream of aprA. While the 117-residue ORF2 product does not show significant similarity to known proteins, the 456-residue, 52.78-kDa, sat-encoded polypeptide exhibits similarity to the homo-oligomeric adenosine triphosphate (ATP) sulfurylases from sulfur-oxidizing bacteria and from sulfate-assimilating bacteria and eukaryotes. Functional overexpression of sat in Escherichia coli proved that the encoded protein acts as an ATP sulfurylase. The recombinant protein was purified to homogeneity and found to be a homo-dimer. Comparison of sulfate and thiosulfate grown A. fulgidus revealed that ATP sulfurylase and APS reductase are constitutive enzymes. Distance matrix analyses allowed insights into the evolution of prokaryotic ATP sulfurylases.

Impact of gamma sterilization on clinical performance of polyethylene in the knee.

Damage and rapid wear of the ultrahigh-molecular-weight polyethylene bearings of knee components continue to be major sources of failure of knee prostheses. Despite considerable research into the roles of design, polyethylene thickness and quality, and component alignment, the source of the rapid wear failures has remained a mystery. This study documents elevated oxidation resulting from the use of gamma sterilization in air, the most common sterilization technique used by the orthopaedic implant industry. This oxidation reduces static strength and elongation properties and significantly decreases the resistance of polyethylene bearings to fatigue, a frequent source of early damage of many of these devices.

The Otto Aufranc Award. Impact of gamma sterilization on clinical performance of polyethylene in the hip.

Despite studies to determine their causes, significant variations in polyethylene acetabular component wear rates, radial cracking of component rims, and occasional delamination cannot be explained. A subsurface white band frequently occurs in such damaged components. These damaged components often are gamma sterilized. To date, the origin of the band and its effect on polyethylene chemical and mechanical properties, and hence, clinical performance, have not been confirmed, and correlations between radiation sterilization and clinical wear have not been made. By developing techniques for polyethylene retrieval testing and rating, chemical analysis, and mechanical analysis, this research has determined that gamma sterilization in air alters the chemical and mechanical properties of polyethylene over time, resulting in high subsurface oxidation, reduced ductility, and reduced strength. Gamma sterilization-induced oxidation is found to be most severe in the subsurface region of components, and coincides with zones of significantly reduced strength and ductility. This chemical and mechanical property degradation is time dependent and is not typically visible until after 3 years' postirradiation. The presence of the subsurface white band significantly correlates with clinical cracking and delamination observed in retrieved components. Wear of the retrieved components often is observed to have progressed into this heavily oxidized, weakened, and embrittled zone. A method for accelerated aging shows that irradiating in air causes oxidation damage in polyethylene components that is not seen with other sterilization methods. Modifications of gamma sterilization techniques to minimize this damage are discussed.