Preparation and characterization of infection-resistant antibiotics-releasing hydrogels rods of poly[hydroxyethyl methacrylate-co-(poly(ethylene glycol)-methacrylate]: biomedical application in a novel rabbit penile prosthesis model. In this work, preparation and characterization of novel three different antibiotic loaded penile prosthesis in the rod form were investigated by copolymerization of 2-hydroxyethylmethacrylate (HEMA) with poly(ethylene glycol)-methacrylate, (PEG-MA). To achieve this goal, a series of novel copolymer hydrogels were prepared in rod form using HEMA and PEG-MA monomers via UV initiated photopolymerization. The thermal stability of the copolymer was found to be lowered by increase in the ratio of PEG-MA in the rod structure. Contact angle measurements on the surface of copolymer hydrogel demonstrated that the copolymer gave rise to a significant hydrophilic surface compared with pure poly(HEMA). The blood protein adsorption and platelet adhesion were significantly reduced on the surface of the copolymer hydrogels compared with control pure poly(HEMA). Poly(HEMA:PEG-MA;1:1)-1 formulation containing different antibiotics (20 mg antibiotic/g polymer) released about 90, 91, and 55% of the total loaded cephtriaxon, vancomycin, and gentamicin in 48 h at pH 7.4, respectively. Finally, antibiotics loaded biocompatible poly(HEMA:PEG-MA;1:1)-1 hydrogel compositions was used as a penile prosthesis in preventing cavernous tissue infections in a rabbit prosthesis model. The efficacy of the three different antibiotics loaded hydrogel system was evaluated in four different groups of rabbits, in which various infectious agents were inoculated. The animals were sacrificed after predetermined time periods, and clinical, histological and microbiological assessment on the implant side were carried out to detect infections. Eventually, we concluded that three different antibiotic loaded penile prostheses (i.e. poly(HEMA:PEG-MA;1:1)-1 hydrogel systems) were as effective as parenteral antibiotics applications.


Adhesion of Streptococcus mutans to various dental materials in a laminar flow chamber system. Newly developed dental materials have to be tested for their susceptibility to adhere bacteria causing caries and periodontitis. The objective of this study was to establish an in vitro laminar flow chamber assay for dental material evaluation with regard to the adhesion of oral bacteria. Test specimens of commonly used dental materials (ceramic (five brands of ceramics, n = 15/brand), composite (eight brands of composites, n = 15/brand), and alloy (two brands of alloys, n = 15/brand) specimens) were inserted in a laminar flow chamber system and rinsed with artificial saliva (2 h) and Streptococcus mutans NCTC 10,449 suspension (4 h) successively. The amount of adhered bacteria was quantified using a Resazurin reduction assay (Alamar Blue). Statistical analysis was performed using the Mann-Whitney U-test (alpha = 0.05). Regarding adhesion of Streptococcus mutans, significant differences between the various material classes were found. Highest fluorescence values (ranging from 973 to 3145), correlating with high bacterial adhesion, were found on composite samples, and lowest values (173-272) were found on the alloys. Ceramic specimens showed an intermediate adhesion of Streptococcus mutans (fluorescence values from 532 to 1326). Streptococcus mutans NCTC 10449 adhered differently to the various classes of dental materials. The established laminar flow chamber device provides a suitable method for evaluating the adhesion of oral bacteria to dental material surfaces.


An innovative method to obtain porous PLLA scaffolds with highly spherical and interconnected pores. Scaffolding is an essential issue in tissue engineering and scaffolds should answer certain essential criteria: biocompatibility, high porosity, and important pore interconnectivity to facilitate cell migration and fluid diffusion. In this work, a modified solvent casting-particulate leaching out method is presented to produce scaffolds with spherical and interconnected pores. Sugar particles (200-300 microm and 300-500 microm) were poured through a horizontal Meker burner flame and collected below the flame. While crossing the high temperature zone, the particles melted and adopted a spherical shape. Spherical particles were compressed in plastic mold. Then, poly-L-lactic acid solution was cast in the sugar assembly. After solvent evaporation, the sugar was removed by immersing the structure into distilled water for 3 days. The obtained scaffolds presented highly spherical interconnected pores, with interconnection pathways from 10 to 100 mum. Pore interconnection was obtained without any additional step. Compression tests were carried out to evaluate the scaffold mechanical performances. Moreover, rabbit bone marrow mesenchymal stem cells were found to adhere and to proliferate in vitro in the scaffold over 21 days. This technique produced scaffold with highly spherical and interconnected pores without the use of additional organic solvents to leach out the porogen.


Bend it like...Kawasaki.

Bend it like...Kawasaki.


Effect of the photoreaction solvent on surface and bulk properties of poly(lactic acid) and poly(hydroxyalkanoate) films. The major objective of this research was to modify the surface properties of poly(lactic acid) (PLA) and poly(hydroxyalkanoate) (PHA) films by using a sequential two-step photografting approach. In step 1, benzophenone was photografted on the film surface and in step 2, hydrophilic monomers acrylamide and acrylic acid were photopolymerized from the film surfaces. Another objective was to study the effect of the reaction solvent in step 2 on surface and bulk properties of these films. ATR-FTIR spectroscopy and water contact angle goniometry were used to characterize the resultant film surfaces. When ethanol was used as the solvent in step 2, there was significant penetration of the monomers into the films, and bulk properties such as toughness and percent elongation at break were drastically affected. The penetration of these monomers into the bulk was characterized using transmission FTIR microspectroscopy. Microtomed sections of the surface-modified films were placed in a diamond compression cell to perform the FTIR microspectroscopic analyses. The observed monomer penetration into the films was successfully reduced by using water instead of ethanol in step 2, and resultant films showed higher toughness and percent elongation at break than films surface-modified using ethanol as a solvent in step 2.


Approaches for prevention of restenosis. Coronary artery disease is characterized by a narrowing (stenosis) of the arteries that supply blood to the tissue of the heart. Continued restriction of blood flow manifests itself as angina and ultimately myocardial infarction (heart attack) for the patient. Heart bypass was once the only treatment for this condition, but over the years percutaneous coronary intervention (PCI) has become an increasingly attractive alternative to medical therapy and surgical revascularization for the treatment of coronary artery disease. A vascular stent is a medical device designed to serve as a temporary or permanent internal scaffold, to maintain or increase the lumen of a blood vessel. Metallic coronary stents were first introduced to prevent arterial dissections and to eliminate vessel recoil and intimal hyperplasia associated with PCI. Further advancement in the treatment of coronary artery disease is the development of drug-eluting stents that dramatically reduce the incidence of in-stent restenosis to less than 5%. Local drug delivery offers the advantages of allowing a relatively high local concentration of drug at the treatment site while minimizing systemic toxic effect. This review describes approaches for prevention of restenosis. It focuses on drugs for prevention of restenosis, bare metal stents, and drug-eluting stents. It also describes recent advances in bioresorbable stents. One of the chapters is dedicated to our novel composite bioresorbable drug-eluting fibers, designed to be used as basic elements in drug-eluting stents.


Comparative rheology of low- and iso-osmolarity contrast agents at different temperatures. Several contrast media (CM) are used for diagnostic angiography and coronary percutaneous interventions. Catheter miniaturization allows performance of most diagnostic studies using 4-5 F catheters and interventions using 5-6 F catheters. As a result of catheter lumen downsizing and viscosity of CM, the operators are sometimes required to forcefully inject to produce adequate images. The aim of the study is to perform a comparative rheology analysis between three different commonly used CM: iso-osmolar, nonionic iodixanol, Visipaque, (GE Healthcare); low-osmolar, nonionic ioversol, Optiray; and low-osmolar, ionic ioxaglate, Hexabrix, (Tyco Healthcare, US). The viscosity was experimentally assessed for temperature varying from 14 to 40 degrees C. To reproduce clinical use, an experimental set-up was used and the pressure developed to inject CM was evaluated at different temperatures and compared between the three CM. All three agents demonstrated a nonlinear inverse relationship between temperature and viscosity. At 14 degrees C iodixanol showed a twofold increase in viscosity compared with ioversol and ioxaglate. At 40 degrees C, the difference was reduced to 27%. At room temperature (20 degrees C), the difference in pressure needed to inject CM was 10% between iodixanol and ioxaglate and 6% between iodixanol and ioversol. As the temperatures increased, the differences in pressure became less important, becoming negligible (1%) at 37 degrees C. The viscosity of the iso-osmolar nonionic contrast agent iodixanol showed a stronger dependence on temperature compared with ioversol and ioxaglate. The impact of differences in viscosity and pressure to inject between CM were minimized at 37 degrees C. This emphasizes the importance of temperature control when using current low-osmolar CM and iso-osmolar CM with smaller sized catheters.


Antithrombogenicity of Hydromer's polymeric formula F202 immobilized on polyurethane and electropolished stainless steel. Hydromer's heparin-polymer complex (F202) was applied to polyurethane film and electropolished medical grade stainless steel. The presence of heparin on the surface was confirmed by FT-IR and immunofluorescent histochemistry. The F202 polymer was nonthrombogenic and the development of thrombi on these surfaces after exposure to recalcified human whole blood was minimal or absent. Platelet adhesion to these F202-coated surfaces, compared to control (uncoated) surfaces, was low or absent after exposure to platelet-rich plasma as determined by fluorescent staining and by immunohistochemistry. Our F202 polymer was not hemolytic after exposure to human erythrocytes and was not cytotoxic in a standard cytotoxic protocol. The F202 polymer could prove useful as an antithrombogenic coating for preventing thrombus formation on medical implants and catheters.


Freeze casting of porous hydroxyapatite scaffolds. I. Processing and general microstructure. Freeze casting of aqueous suspensions on a cold substrate was investigated as a method for preparing hydroxyapatite (HA) scaffolds with unidirectional porosity. In the present paper, we report on the ability to manipulate the microstructure of freeze-cast constructs by controlling the processing parameters. Constructs prepared from aqueous suspensions (5-20 volume percent particles) on a steel substrate at -20 degrees C had a lamellar-type microstructure, consisting of plate-like HA and unidirectional pores oriented in the direction of freezing. Sintering for 3 h at 1350 degrees C produced constructs with dense HA lamellas, porosity of approximately 50%, and inter-lamellar pore widths of 5-30 microm. The thickness of the HA lamellas decreased but the width of the pores increased with decreasing particle concentration. Decreasing the substrate temperature from -20 degrees C to -196 degrees C produced a finer lamellar microstructure. The use of water-glycerol mixtures (20 wt % glycerol) as the solvent in the suspension resulted in the production of finer pores (1-10 microm) and a larger number of dendritic growth connecting the HA lamellas. On the other hand, the use of water-dioxane mixtures (60 wt % dioxane) produced a cellular-type microstructure with larger pores (90-110 microm). The ability to produce a uniaxial microstructure and its manipulation by controlling the processing parameters indicate the potential of the present freeze casting route for the production of scaffolds for bone tissue engineering applications.


Histological evaluation and surface componential analysis of modified micro-arc oxidation-treated titanium implants. The objective of this study is to investigate soft tissue and bone tissue reaction to titanium implants treated by a modified micro arc oxidation (MAO) technique, and analyze the surface components and implant-bone contact ratio by animal experiments to evaluate the osseointegration condition of implants with this modified MAO surface. MAO titanium plates were installed subcutaneously in rabbits. Tissue reaction was evaluated by HE sections. MAO titanium implants designed for endosseous examination were installed in Beagles' femurs. Bone tissue surrounding implants was analyzed histologically. Surfaces of retrieved implants were observed and examined by SEM and EDX. All procedures were performed under the control of untreated pure titanium implants. Thin homogeneous fibrous envelope could be found without apparent inflammation cells infiltration around the subcutaneously imbedded MAO titanium plates, which was almost same as control group. Fast osteoid deposition comprising high content of calcium, phosphor, carbon, and nitrogen elements was found on the retrieved MAO implant surfaces, while comparatively less amount of carbon and nitrogen elements were found on the retrieved implants of control group. Matured bone tissue comprising bone trabeculae and Haversian canals appeared in 8 weeks, while it took 12 weeks needed to form matured bone tissue in control group. In conclusion, MAO titanium materials shows good biocompatibility and calcium phosphate inducement capability in vivo and could accelerate bone tissue growth and shorten the osseointegration time.


Wear of sequentially enhanced 9-Mrad polyethylene in 10 million cycle knee simulation study. Highly crosslinked polyethylene (HXPE) has been shown to be effective in reducing wear in total hip replacements. HXPE has not found widespread use in TKR, because the crosslinking inevitably leads to reductions in critical properties such as toughness and fatigue strength. Sequentially enhanced crosslinking (SXPE) have been suggested for improved wear resistance for tibial inserts with maintenance of mechanical properties and anticipated high oxidation resistance superior to conventional polyethylene (XLPE). We compared the wear of SXPE (9Mrad) to XLPE inserts (3Mrad) to 10 million cycles. Triathlon femoral condyles were identical in both. This is the first wear study of SXPE inserts. According to the power law relating irradiation dose to wear of XLPE inserts, wear of 9 Mrad inserts should be reduced by 70% compared to 3Mrad controls. The wear rates of the SXPE inserts were reduced by 86% at 10 million cycles duration, somewhat greater than predicted. The one prior investigation by the manufacturer reported a 79% wear reduction for SXPE compared to controls in a 5 million cycle simulator study in knee design and test parameters. There were important differences between the two studies. Nevertheless there clearly appeared to be a major benefit for sequentially enhanced polyethylene in tibial inserts. This combined wear reduction of 80-85% with improved oxidation resistance and retention of mechanical properties may prove beneficial for active patients who may otherwise risk high wear rates over many years of use.


Onium salt reduces the inhibitory polymerization effect from an organic solvent in a model dental adhesive resin. This study evaluated the effect of organic solvent concentration on the polymerization kinetics for a model dental adhesive resin containing a ternary photoinitiator system. A monomer blend based on the bis-GMA, TEGDMA, and HEMA was used as a model dental adhesive resin, which was polymerized using a binary system [camphorquinone (CQ) and ethyl 4-dimethylamine benzoate (EDAB)] and a ternary system [CQ, EDAB, and diphenyliodonium hexafluorphosphate (DPIHFP)]. Additionally, these blends had 0, 10, 20, 30, and 40 wt % ethanol added. Real-time Fourier transform infrared spectroscopy was used to investigate the polymerization reaction over photoactivation time. Data were plotted, and Hill's three-parameter nonlinear regression was performed for curve fitting. The addition of a solvent to the monomer blends decreased the polymerization kinetics, directly affecting the rate of polymerization, delaying vitrification, and attenuating the Trommsdorf effect. The introduction of DPIHFP displayed a strong increase in reaction kinetics, reducing the solvent inhibition effect. After 10 s of photoactivation, the binary system obtained in 0, 10, 20, 30, and 40% of ethanol, a degree of conversion of 44.6, 26.3, 13.4, 1.15, and 0.0%, respectively, whereas when a ternary system was used, the values were 54.6, 40.5, 27.4, 14.5, and 3.4%. An improvement was observed in the polymerization kinetics of a model dental adhesive resin when using a ternary photoinitiation system, making the material less sensitive to the residual presence of a solvent before photoactivation.


Comparison of ciprofloxacin hydrochloride-loaded protein, lipid, and chitosan nanoparticles for drug delivery. The aim of the present study was to develop single dose delivery systems based on nanotechnology for prolonged antibiotic release in a controlled manner. Five different drug-carrier ratios of ciprofloxacin hydrochloride-loaded nanoparticles of albumin, gelatin, chitosan (CS), and lipid [solid lipid nanoparticles (SLNs)] were prepared and characterized. Average particle size was found to be in the range of 73 +/- 2 to 98 +/- 44 nm for SLNs, 140 +/- 7 to 175 +/- 24 nm for albumin nanoparticles, 143 +/- 18 to 184 +/- 27 nm for gelatin nanoparticles, and 247 +/- 48 to 322 +/- 52 nm for CS nanoparticles. A drug-to-carrier ratio of 0.5:1 was preferred for CS nanoparticles having zeta potential of >20 mV and drug encapsulation of 35.01% +/- 2.66%. Similarly, 0.6:1 ratio was preferred for albumin nanoparticles with zeta potential >16 mV and drug encapsulation 48.20% +/- 3.01%. Zeta potentials of gelatin nanoparticles loaded with ciprofloxacin suggested that they were unstable and prone to flocculation. SLN with 0.25:1 drug carrier ratio showed 38.71% +/- 2.38% drug entrapment and -28 +/- 1 mV surface charge. All the nanoparticles showed sustained drug release avoiding "burst effect" of the free drugs for up to 120 h for albumin nanoparticles, 96 h for CS and gelatin nanoparticles, and 80 h for SLNs. The drug release profiles followed Higuchi model. Results suggest that CS nanoparticles and SLNs can act as promising carriers for sustained ciprofloxacin release in infective conditions.


Bioactive poly(2-hydroxyethylmethacrylate)/silica gel hybrid nanocomposites prepared by sol-gel process. A hybrid of poly(2-hydroxyethylmethacrylate) (pHEMA), a polymer widely employed for biomedical applications, and silica gel, exhibiting a well-known bioactivity, was produced by sol-gel. The amount of the inorganic precursor, tetraethoxysilane (TEOS), was mixed to the organic monomer, so as to have a final concentration of 30% (w/w) of silica gel to the mass of polymer. The nanocomposite was characterized for its composition by thermogravimetric (TG) analysis, swelling behavior, glass transition temperature using differential thermal analysis (DTA), morphology through scanning electron microscopy (SEM), and bioactivity using FT-IR spectroscopy, SEM, and energy dispersive system (EDS). The nanocomposite showed phase separation between the polymer and the silica gel, improved thermal stability and swelling properties and higher glass transition temperature than pHEMA. Moreover, bioactive SiO(2) gel nanoparticles promoted apatite formation on the surface of the modified hydrogel, when it was soaked in SBF. Therefore, the obtained bioactive nanocomposite can be used to make bioactive scaffold for bone engineering.


The local inflammatory environment and microorganisms in "aseptic" loosening of hip prostheses. Long term loosening of hip prostheses remains an important problem in orthopedics. Although various loosening mechanisms have been proposed, the exact process is still unclear. Particle disease and the pressure theory are widely known and generally accepted hypotheses to explain long term implant failure. Each proposed mechanism recognizes a local inflammatory response in which macrophages represent the main cell-type and several proinflammatory and antiinflammatory cytokines (IL-1beta, IL-6, TNFalpha, IL-10, TGFbeta), chemokines (IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, MIP-1alpha/CCL3) and other mediators (GM-CSF, M-CSF, MMP-1, PDGF-alpha, PGE(2), IL-11) are identified. The cytokines have different functions and some are capable of stimulating bone resorption in various ways; either directly or indirectly. Even though the implant loosening is thought to be "aseptic", several studies suggested a possible role for bacteria and a bacterial biofilm in implant failure. Biofilm-derived bacteria and bacterial products might have an underestimated and potential role in the loosening process. In this article we will discuss the possible role of a bacterial biofilm and the importance of the local surrounding environment in "aseptic" loosening of hip prostheses.


Bone healing response to an injectable calcium phosphate cement with enhanced radiopacity. The aim of this study was to determine the impact of barium sulfate on remodeling and regeneration in standard tibial defects in rabbits treated with the Norian skeletal repair system (SRS). Two formulations of SRS (with and without barium sulfate) were injected into the medullary canal of the tibia of New Zealand white rabbits. Animals were sacrificed at 6 weeks, 6 months, 1 year, and 2 years. Over the 2-year duration of the study, standard SRS and SRS with barium sulfate appeared to be biocompatible and osteoconductive with no evidence of either inflammation or fibrous tissue around the implant materials or at the bone-material interfaces. This outcome underscores the osteophilic property of the SRS. A difference we observed between the standard SRS and the SRS with barium sulfate was the appearance of acellular material contiguous to the SRS with barium sulfate. Energy dispersive X-ray spectroscopy (EDX) analysis was conducted and confirmed that the acellular material was barium sulfate. Pathological examination of additional tissues including regional lymph nodes revealed neither dissemination of calcium phosphate nor barium sulfate. We concluded that the residual barium sulfate detected by EDX was localized to the intramedullary canal of the tibia.


A facile method to construct hybrid multilayered films as a strong and multifunctional antibacterial coating. A multifunctional multilayered film containing TiO(2) nanoparticles as contact-active antibacterial agent and nanosilver as a release-active antibacterial agent was fabricated via layer-by-layer assembly. TiO(2) nanoparticles with the anatase crystalline dominant structure were synthesized via a sol-gel method. The QCM, AFM, and contact angle measurement results indicated that the TiO(2) nanoparticle-chitosan was successfully assembled with heparin via layer-by-layer assembly. The UV visible spectroscopy demonstrated that the silver ions could be loaded into the multilayers and in situ synthesize silver nanoparticles in the multilayers template. The short-term antibacterial assay showed the TiO(2)-chitosan/heparin multilayers loaded with nanosilver was bactericidal both in the low intensity UV light and in the dark. The long-term antibacterial assay indicated although the antibacterial in dark decreased with the PBS immersion time, the hybrid multilayered films sustained the long-term antibacterial in the low intensity UV light.


In vivo behavior of a novel injectable calcium phosphate cement compared with two other commercially available calcium phosphate cements. The aim of this study was to investigate the physicochemical and biological properties of a newly developed calcium phosphate cement (CPC). The novel cement was compared with two other commercially available CPCs. After mixing the powder and liquid phase, the CPCs were injected as a paste into a rabbit distal femoral defect model. The CPCs were evaluated after 24 h, 6 weeks, 26 weeks, and 52 weeks. The novel CPC was easy to handle and was fast setting. X-ray diffraction (XRD) and Fourier Transform Infrared Spectrometry (FTIR) at the different implantation periods showed that the cement had converted to carbonated hydroxyapatite and remained stable over time. Histological evaluation showed bone apposition on the cement surface without any inflammatory response or fibrous encapsulation. At later time points, all CPCs were completely covered by a thin layer of bone. Osteoclast-like cells present at the interface resorbed parts of the cement mass. Histological and histomorphometrical analyses did not show any significant differences between the three implanted CPCs. The results indicate that the investigated CPC is biocompatible, osteoconductive, as well as osteotransductive and seems to be both biologically safe and effective as a bone void filler.


Structural hierarchy of biomimetic materials for tissue engineered vascular and orthopedic grafts. Gelatine gels and gelatine/elastin gels have been prepared to be used in tissue engineered vascular grafts. Optical microscopy and atomic force microscopy (AFM) revealed that the gelatine formed nanofibrils as in soft collagen tissues. The gelatine/elastin gels were nanocomposites with flat elastin nanodomains embedded in the gelatine matrix mimicking the structure of the tunica media in arteries. Gelatine/"hydroxyapatite" (HA) nanocomposites were prepared with the in situ production of "HA" in solution. AFM revealed "HA" solid nanoparticles of about 20 nm size embedded in the gelatine matrix, which formed a hierarchical structure similar to that of the collagen matrix in bone. The application of amagnetic field of 9.4 T resulted in the elongation and orientation of gelatine particles and orientation of gelatine microfibrils in a direction perpendicular to that of the magnetic field. (c) 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2008.


Self-sterilization using silicone catheters coated with Ag and TiO2 nanocomposite thin film. Ag/titanium dioxide (TiO(2))-coated silicon catheters were easily fabricated with Ag nanoparticles deposition on both the inside wall and the outside wall of TiO(2)-coated catheters by TiO(2) photocatalysis. This is an application of the silicon catheters coated with TiO(2), which possess a self-sterilizing and self-cleaning property combining with UV light illumination (Ohko et al., J Biomed Mater Res: Appl Biomater 2001;58:97). Ag/TiO(2)-coated silicon catheters exhibited a strong bactericidal effect even in the dark. When the 2-5 x 10(5) of colony-forming units of Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus were respectively applied to the surface of the Ag/TiO(2) catheters, which were loaded with approximately 15 nmol cm(-2) of Ag, 99% effective sterilization occurred in a very short time: 20 min for E. coli, 60 min for P. aeruginosa, and 90 min for S. aureus. Additionally, the Ag/TiO(2)-coated catheters possessed a strong self-cleaning property. Using UV illumination, the photocatalytic decomposition rate of methylene blue dye representing the self-cleaning capability, on an Ag/TiO(2) catheter which was loaded with 2 nmol cm(-2) of Ag, was approximately 1.2 times higher (at maximum) than that on TiO(2) coating alone. Furthermore, the Ag nanoparticles can be pre-eminently and uniformly deposited onto the TiO(2) coating, and the amount of Ag was easily controllable from a few nanomoles per square centimeter to approximately 70 nmol cm(-2) by changing the UV illumination time for TiO(2) photocatalysis. This type of catheter shows a great promise in lowering the incidence of catheter-related bacterial infections.


The impact of prostate-specific antigen level at diagnosis on the relative survival of 28,531 men with localized carcinoma of the prostate. To evaluate the predictive value of prostate-specific antigen (PSA) in a population-based cohort, the authors analyzed relative survival in all men with localized prostate cancer who were registered in the Swedish National Prostate Cancer Register (NPCR) from 1996 to 2005. All men aged <75 years with localized tumors were identified in the NPCR. A Poisson regression analysis was performed using observed death as response and the expected death rate as offset. The expected and observed numbers of survivors were calculated with stratification for PSA level and 3 categories of tumor differentiation (Gleason score 2-6, 7, and 8-10). The regression model included PSA as linear splines with a breakpoint at a PSA level of 4 ng/mL and with tumor differentiation as a categoric variable. The Poisson regression analysis indicated a U-shaped curve for all 3 groups, with a negative correlation between PSA and relative survival in men with PSA levels <4 ng/mL and a positive correlation for men with PSA levels >4 ng/mL. The correlation was significant for all 3 groups, but the negative correlation between PSA and relative survival was significantly more pronounced in the group with Gleason scores from 8 to 10 than in the other 2 Gleason score groups. The demonstration of an inverse correlation between PSA level and relative survival in the group of men with PSA levels <4 ng/mL indicated the presence of a small but clinically important subgroup with undifferentiated tumors who have cells that have lost the ability to secrete PSA. This group should be taken into consideration when deciding on treatment and when choosing a cutoff level in PSA screening programs.


Utility of anti-L523S antibody in the diagnosis of benign and malignant serous effusions. Immunohistochemistry is helpful in distinguishing metastatic carcinoma from atypical mesothelial cells; however, it is not useful in differentiating atypical mesothelial cells from malignant mesothelial cells. K homolog domain containing protein overexpressed in cancer (KOC), a member of the insulin-like growth factor mRNA-binding protein (IMP) family, also known as L523S and IMP3, is expressed during embryogenesis and in various malignancies. Using a mouse monoclonal antibody (L523S) against KOC, KOC expression was investigated in malignant tumors and reactive mesothelial cells in serous effusions. Seventy-six cases with paraffin-embedded pleural, pericardial, and peritoneal serous effusion cell blocks including 60 malignant serous effusions (11 malignant pleural mesotheliomas and 49 metastatic carcinomas) and benign pleural effusions (14 cases with reactive mesothelial cells and 2 cases with atypical cells with uncertain significance) were selected for immunohistochemical analysis with L523S, calretinin, and CK5/6. Immunohistochemical studies showed that positive staining for KOC of variable degrees of intensity was observed in 47 of 60 cases in malignant serous effusions including 10 of 11 mesotheliomas and 36 of 49 metastatic carcinomas. The associated reactive mesothelial cells were negative for KOC but positive for calretinin and CK5/6. All 11 malignant mesotheliomas exhibited positivity for calretinin, and 9 of 11 cases had CK5/6 staining. In addition, 16 cases that were originally diagnosed either as pleural effusions with reactive mesothelial cells (14) or atypical cells with uncertain significance (2) were also tested for KOC expression. Interestingly, 3 of 16 cases exhibited various degrees of positivity for KOC, 2 of which were diagnosed as lung adenocarcinoma with a recurrence after tumor resection and 1 as malignant pleural mesothelioma. Anti-L523S antibody is a useful marker for the detection of malignant cells in serous effusions and it can have significant utility in differentiating reactive mesothelial cells from malignant mesothelioma and metastatic carcinoma in combination with calretinin and CK5/6 staining.


Use of multislice CT for the evaluation of emergency room patients with chest pain: the so-called "triple rule-out". Recent advances in computed tomography (CT) technology have made high resolution noninvasive coronary angiograms possible. Multiple studies involving over 2,000 patients have established that coronary CT angiography (CCTA) is highly accurate for delineation of the presence and severity of coronary atherosclerosis. The high negative predictive value (>95%) found in these studies suggests that CCTA is an attractive option for exclusion of coronary artery disease in properly selected emergency department patients with acute chest pain. CT is also a well established and accurate tool for the diagnosis of acute aortic dissection and pulmonary embolism. Recent technical developments now permit acquisition of well-opacified images of the coronary arteries, thoracic aorta and pulmonary arteries from a single CT scan. While this so called "triple-rule out" scan protocol can potentially exclude fatal causes of chest pain in all three vascular beds, the attendant higher radiation dose of this method precludes its routine use except when there is sufficient support for the diagnosis of either aortic dissection or pulmonary embolism. This article provides an overview of CCTA, and reviews the clinical evidence supporting the use of this technique for triage of patients with acute chest pain.


Structural and solvent effects on the 13C and 15N NMR chemical shifts of indoloquinoline alkaloids: experimental and DFT study. Indoloquinoline alkaloids represent an important class of antimalarial, antibacterial and antiviral compounds. They have been shown to bind to DNA via intercalation preferentially at GC-rich sequences containing nonalternating CC sites. The stability of complexes formed with biological macromolecules depends on noncovalent binding. In the present study, the ability of indoloquinolines to form intermolecular interactions with solvents was investigated by using NMR spectroscopy and density functional theory (DFT) (B3LYP/6-31G**) calculations. NMR data measured for indoloquinoline bases and the corresponding hydrochlorides are discussed in relation to the structure. DFT calculations of shielding constants in vacuo and in solution allowed the investigation of the influence of the environment on the NMR parameters. Calculations incorporating solvent effects indicated significant changes in the anisotropy of the electron distribution, reflected in the span of the chemical shielding tensor (Omega = sigma11 - sigma33). Solvent effects on the span of the 13C and 15N shielding tensor depended on the type of atom and the data indicated a significant influence of solute-solvent interactions.


Carboplatin hypersensitivity reaction in pediatric patients with low-grade glioma: a Canadian Pediatric Brain Tumor Consortium experience. Carboplatin-based regimens have demonstrated activity in pediatric patients with low-grade glioma (LGG). However, carboplatin hypersensitivity reaction (Cb HSR) represents a common and limiting factor for the continuation of therapy. The objectives of this study were to describe the prevalence, characteristics, and management of Cb HSR and to detail their impact on outcome. The authors conducted a comprehensive, national, retrospective review of children who were diagnosed with LGG between 1985 and 2004 and received treatment with carboplatin. One hundred five patients from 10 Canadian centers were included. The median patient age at diagnosis was 3.5 years (range, 0.3-16.8 years), and 33 patients (31.4%) had neurofibromatosis type 1. Carboplatin was administered monthly in 46 children and weekly in 59 children. Forty-four patients (41.9%) developed Cb HSR after a median of 10.5 infusions (range, 3-39 infusions). Cb HSR occurred significantly earlier among children on the weekly schedule (4.4 months vs 9.1 months; P = .02). The first allergic reaction was grade I or II in 36 patients (82%). The cumulative incidence of Cb HSR increased with the number of infusions, and there was no evidence of a plateau. The only predictive factor was being a girl rather than a boy (P = .02). Thirty-four of 44 patients with Cb HSR were re-exposed to carboplatin, and 24 of 34 patients (70.5%) had recurrent Cb HSR. A desensitization approach did not provide any advantage compared with premedication alone for altering Cb HSR. The median number of additional Cb infusions delivered was 4 (range, 0.5-34 infusions). The effect of Cb HSR on the 5-year progression-free survival rate was not statistically significant (P = .1). Forty-two percent of children with LGG who received carboplatin regimens experienced Cb HSR. Most rechallenged children had recurrent Cb HSR despite Cb HSR-altering regimens. Cb HSR did not have an impact on progression-free survival.


Infrapopliteal drug-eluting stents for chronic limb ischemia. We report our experience with the elective placement of below-knee, drug-eluting stents in patients with chronic limb ischemia. Infrapopliteal percutaneous transluminal angioplasty has been associated with a lower rate of procedural success and high rate of restenosis because of the small size of the tibial vessels and the prevalence of calcified and diffuse atherosclerotic disease. Prior published data reports 3-year patency rates below 25%. Bare metal stents have been reported in bailout situations. Drug-eluting stents have markedly reduced restenosis compared to bare metal stents in the coronary vasculature, but there is little data supporting the use of these devices below the knee. Elective placement of drug-eluting stents in infrapopliteal lesions was performed on 10 patients with severe (> or =Fontaine Stage IIb) claudication (n = 1) or limb-threatening ischemia (n = 9) (rest pain, nonhealing ulcers and gangrene). A total of 17 drug-eluting stents were electively placed in 12 below-knee arteries in 10 patients, resulting in an average of 1.7 +/- 0.7 stents per patient. The mean lesion length was 24.8 +/- 10.9 mm, the mean total stent length was 38.3 +/- 19.1 mm, and the mean nominal stent diameter was 2.8 +/- 0.3 mm. One patient required target vessel revascularization (TVR) at 3 weeks because of stent thrombosis. TVR was 10% at 12.4 +/- 6.5 months of follow-up. Clinically driven angiography in three different patients was performed at 4, 15, and 16 months and confirmed drug-eluting stent patency in each case. The use of below-knee drug-eluting stents is feasible and appears to be safe in our small series of complex infrapopliteal lesions causing chronic limb ischemia. The occurrence of a single case of stent thrombosis warrants continued observation in this cohort. Prospective clinical trials will be necessary to confirm the benefits and justify the costs of this strategy for treating patients with infrapopliteal culprit lesions and chronic limb ischemia.


Anecdotal vs. evidence-based, off label use of drug eluting stents for infrapopliteal disease: abusus non tollit usum (misuse does not nullify proper use).


Improvement of neurocognitive function after protected carotid artery stenting. To investigate the effect of protected carotid artery stenting on neurocognitive function with particular consideration of the angiographic filling of the ipsilateral anterior cerebral artery (ACA). An improved inflow to the supply area of the anterior cerebral artery after revascularisation of severe carotid artery stenosis may beneficially affect frontal lobe cognitive functions. We prospectively included 71 consecutive patients who underwent carotid artery stenting (CAS) due to high grade carotid artery stenosis. Intracranial angiograms and filling status of the ACA pre- and post-stenting were analyzed and a battery of 5 selected neuropsychological tests for frontal lobe function were applied prior to and 6 months after CAS. Patients with improvement in at least two tests were defined as having improved neurocognitive function. Compared to baseline, we found a significant improvement of the Trail-Making Test A (median 6% improved change-score; P = 0.01), the test of supermarket items showed a trend towards significant improvement (median 3.7% improved change-score; P = 0.09). In 32 patients (45%) an improvement of at least 2 neurocognitive tests was observed. Neuropsychological improvement was found more frequently in patients with a contrasted ipsilateral ACA after CAS (88%, 95% CI 77 to 99) compared to patients without angiographic filling of the ipsilateral ACA post CAS (13%, 95% CI 1 to 25), respectively (P < 0.01). Carotid artery stenting improves neurocognitive function in a considerable proportion of patients. A contrasted ipsilateral anterior cerebral artery after CAS is associated with improved neurocognitive function, presumably due to amelioration of frontal lobe perfusion.


Haematological toxicity of drugs used in psychiatry. Almost all classes of psychotropic agents have been reported to cause blood dyscrasias. Mechanisms include direct toxic effects upon the bone marrow, the formation of antibodies against haematopoietic precursors or involve peripheral destruction of cells. Agranulocytosis is probably the most important drug-related blood dyscrasia. The mortality from drug-induced agranulocytosis is 5-10% in Western countries. The manifestations of agranulocytosis are secondary to infection. Aggressive treatment with intravenous broad-spectrum antimicrobials and bone marrow stimulants may be required. Of drugs encountered in psychiatry, antipsychotics including clozapine (risk of agranulocytosis approximately 0.8%, predominantly in the first year of treatment) and phenothiazines (chlorpromazine agranulocytosis risk approximately 0.13%), and antiepileptics (notably carbamazepine, neutropenia risk approximately 0.5%) are the most common causes of drug-related neutropenia/agranulocytosis. Drugs known to cause neutropenia should not be used concomitantly with other drugs known to cause this problem. High temperature and other indicators of possible infection should be looked for routinely during treatment. Clozapine is well known as a drug that can cause blood dyscrasias, but olanzapine and other atypicals may also cause similar problems. In addition to genetic factors, there are likely to be dose-related and immunological components to these phenomena. Important lessons have been learnt from the haematological monitoring that is necessary with clozapine and the monitoring has been very successful in preventing deaths related to clozapine-induced agranulocytosis. Continuing research into the mechanisms of drug-induced neutropenia and agranulocytosis may serve to further enhance the safe use not only of clozapine, but also of other agents.


Early and mid-term results with the Growth Stent--a possible concept for transcatheter treatment of aortic coarctation from infancy to adulthood by stent implantation? Evaluation of the Growth Stent-a stent consisting of two stent halves connected by reabsorbable sutures-for the treatment of aortic coarctation in infants. Surveillance study of 13 Growth Stents implanted in 12 patients aged 1-15 months (median 5 months). Body weight ranged from 3.4-12.8 kg (median 5.4 kg). Eight patients suffered from aortic (re-)coarctation, four of them from stenosis of the aortic anastomosis after a Norwood I procedure. The follow-up period was 24 months (11-51 months). Pressure gradients immediately after stent implantation decreased from 30 mm Hg (range 20-50 mm Hg) to 8 mm Hg (range 0-15 mm Hg). Five patients had one (3 pts) or two (2 pts) balloon dilations 3-28 months (median 12 months) after Growth Stent implantation. The median pressure gradient decreased from 25 mm Hg (range 15-30 mm Hg) to 15 mm Hg (range 5-25 mm Hg). Six patients received a large stent after 19-34 months. Median body weight was 11.8 kg (9.4-15 kg). The Growth Stent is suitable for the acute treatment of aortic coarctation in infants and can be overstented later on--if necessary--with a larger stent without causing restriction.


Neurological complications of psychiatric drugs: clinical features and management. This paper reviews the main neurological complications of psychiatric drugs, in particular antipsychotics and antidepressants. Extrapyramidal syndromes include acute dystonia, parkinsonism, akathisia, tardive dyskinesia and tardive dystonia. Extrapyramidal symptoms (EPS) are less frequent with atypical than with conventional antipsychotics but remain common in clinical practice partly due to lack of screening by health professionals. Neuroleptic malignant syndrome (NMS) consists of severe muscle rigidity, pyrexia, change in conscious level and autonomic disturbance but partial forms also occur. NMS is particularly associated with the initiation and rapid increase in dose of high-potency antipsychotics but it has been reported with all the atypical antipsychotics and rarely with other drugs including antidepressants. Serotonin toxicity comprises altered mental state (agitation, excitement, confusion), neuromuscular hyperactivity (tremor, clonus, myoclonus, hyper-reflexia) and autonomic hyperactivity and occurs on a spectrum. Severe cases, termed serotonin syndrome, usually follow the co-prescription of drugs that increase serotonergic transmission by different pathways, for example a monoamine oxidase inhibitor (MAOI) and a selective serotonin reuptake inhibitor (SSRI). Most antipsychotics and antidepressants lower the seizure threshold and can cause seizures; the risk is greater with clozapine than with other atypical antipsychotics and greater with tricyclic antidepressants (TCAs) than with SSRIs. In randomised controlled trials in elderly patients with dementia atypical antipsychotics are associated with a higher risk of stroke and death than placebo. Cohort studies suggest that conventional drugs carry at least the same risk. Cessation of treatment with antipsychotics and antidepressants can lead to a wide range of discontinuation symptoms which include movement disorders and other neurological symptoms. Clinicians need to be familiar with strategies to reduce the risk of these adverse events and to manage them when they arise. Their occurrence needs to be balanced against the benefits of psychiatric drugs in terms of efficacy and improved quality of life in a range of disorders.


Cardiac side effects of psychiatric drugs. This review describes the common effects of psychotropic drugs on the cardiovascular system and offers guidance for practical management. Selected reports from the literature describing common side effects associated with psychotropic drugs are reviewed, and suggestions for further reading are given throughout the text. Orthostatic hypotension is the most common adverse autonomic side effect of antipsychotic drugs. Among the atypical antipsychotics the risk of orthostatic hypotension is highest with clozapine and among the conventional drugs the risk is highest with low potency agents. Rarely, orthostatic hypotension may result in neurocardiogenic syncope. QTc prolongation can occur with all antipsychotics but an increased risk is seen with pimozide, thioridazine, sertindole and zotepine. QTc prolongation is a marker of arrhythmic risk. Torsade de pointe, a specific arrhythmia, may lead to syncope, dizziness or ventricular fibrillation and sudden death. Heart muscle disease presents most commonly in the elderly as chronic heart failure, but myocarditis and cardiomyopathy, although relatively rare, are devastating, but potentially reversible complications of psychotropic drug therapy have been particularly linked to clozapine treatment. Patients with severe mental illness (SMI) are a 'high risk' population with regard to cardiovascular morbidity and mortality. It is probable that many patients accumulate an excess of 'traditional' risk factors for the development of cardiovascular disease, but other mechanisms including psychotropic drugs may also be influential in increasing risk in this vulnerable group. These risks need to be seen in the context of the undoubted therapeutic efficacy of the psychotropic armamentarium and the relief that these drugs bring to those suffering from mental disorder.


Improving drug safety and tolerability in psychiatric clinical practice.


External beam radiation treatment for rectal cancer is associated with a decrease in subsequent prostate cancer diagnosis. External beam radiation therapy (EBRT) for rectal cancer unavoidably delivers significant radiation dose to the prostate gland. The effect of this incidental exposure on subsequent prostate cancer diagnosis was investigated using the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Men diagnosed with localized or regional (L/R) rectal cancer from 1988-1997 and treated with EBRT and sphincter-sparing surgery (SSS) were identified. Men treated for L/R rectal cancer with SSS who did not receive EBRT, and men with L/R colon cancer who did not receive EBRT, were studied for comparison. Multiple Primary Standardized Incidence Ratios of observed to expected (O/E) cases of prostate cancer were calculated using SEER*Stat. In all, 1574 men with L/R rectal cancer treated with EBRT and SSS were identified. The median age at diagnosis was 64 and median survival was 76 months. Twenty were subsequently diagnosed with prostate cancer, a number significantly less than expected compared with the general population of similar age and race. The ratio of O/E cases was 0.28 (95% confidence interval [CI], 0.17, 0.43). In contrast, 3114 men diagnosed with rectal cancer undergoing SSS who were not treated with EBRT and 24,578 men diagnosed with colon cancer who were not treated with EBRT were subsequently diagnosed with prostate cancer at rates similar to the general population (O/E of 0.94 and 1.09). EBRT for L/R rectal cancer was associated with a 72% decrease in the frequency of subsequent prostate cancer diagnosis when compared with men of similar age and race. Possible mechanisms that may explain this observation are discussed.


Kaposi sarcoma: appraisal of therapeutic agents.


Pegylated liposomal doxorubicin as second-line therapy in the treatment of patients with advanced classic Kaposi sarcoma: a retrospective study. Classic Kaposi sarcoma (CKS) is a rare neoplasm that predominantly occurs in elderly subjects and has a variable clinical evolution. The clinical course is usually indolent, but occasionally the neoplasm progresses rapidly and spreads to internal organs, necessitating systemic chemotherapy. Because of the rarity of CKS, the best treatment has not been determined to date. To the authors' knowledge, few data exist regarding the use of pegylated liposomal doxorubicin (PLD) as first-line and second-line treatment in advanced CKS. The current retrospective study investigated the activity and toxicity of PLD in pretreated patients with aggressive, nonvisceral CKS. Patients were treated with PLD at a dose of 20 mg/m(2) intravenously every 3 weeks until disease progression or the occurrence of intolerable side effects. Objective responses were determined after 3 and 6 cycles; toxicity was assessed every cycle. Secondary endpoints were pain intensity, progression-free survival, and overall survival. Twenty men with pretreated CKS (median age, 67 years) were treated with PLD. All patients received at least 6 cycles of therapy. Complete and partial responses were observed in 2 patients (10%) and 14 patients (70%), respectively. Neutropenia was the most significant grade 3 hematologic toxicity observed (evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events [version 3.0]), occurring in 20% of patients. Only 1 patient (5%) demonstrated grade 4 neutropenia. Fourteen patients (70%) achieved remission of pain and/or edema after 6 cycles. The median progression-free survival was 9 months (95% confidence interval, 5-13 months). At a median follow-up of 36 months, 15 patients (75%) remained alive. PLD is associated with an improvement in objective response and pain intensity and is well tolerated as a second-line treatment for CKS.


Complete 1H and 13C NMR assignments and Z/E-stereoconfiguration determination of isomers of 1,4-diketone derivatives. Complete 1H and 13C NMR assignments and Z/E-stereoconfiguration determination for a series of new isomers of 1,4-diketone derivatives obtained via self-sorting tandem reaction were accomplished by means of one- and two-dimentional NMR experiments including 1H, 13C, gCOSY, gHSQC, gHMBC, and NOESY.


The use of MPA amide for the assignment of absolute configuration of a sterically hindered cyclic secondary amine by 'mix and shake' NMR method. We present here a new method using methoxyphenylacetic acid (MPA) as the chiral derivatizing agent (CDA) for the assignment of absolute configuration of cyclic secondary amines. The MPA amides were prepared using the purification-free 'mix and shake' method. A detailed conformational analysis for the two diastereomeric amides was conducted by 2D NMR experiments and molecular mechanics calculations. We have established that, in the most stable conformation of each syn rotamer of MPA amides, the H-alpha in the MPA moiety is oriented toward the bulky substituent group at the asymmetric carbon in the chiral amine, presumably to avoid steric and/or electrostatic interactions. The observed NMR data were correlated with the conformational model to allow unambiguous assignment of absolute configuration of secondary amines. The results demonstrate that the MPA can be used as a useful CDA in the case of sterically crowded cyclic secondary amines from which the MTPA amides are usually difficult to make.


Fatal toxicity of drugs used in psychiatry. Certified deaths from fatal poisoning (accidents, suicides and open verdicts) in England and Wales have declined steadily (from 3952 in 1979 to 2565 in 2004). There was also a small annual reduction in suicides in males and in females over this period. In 2004, self-poisoning accounted for 25% of suicides and open verdicts in males (n = 862) and 45% in females (n = 540). Poisoning death rates per million prescriptions were about 10 times higher for tricyclic antidepressants (TCAs) than for selective serotonin reuptake inhibitors (SSRIs), England and Wales, 1993-2004. However, despite the increased prescription of SSRIs and related compounds in recent years, there has been only a slight decrease (some 10%) in the annual number of antidepressant-related poisoning deaths, in line with the reduction in suicides (all methods) over this period. Citalopram appears to have higher overdose toxicity than other SSRIs. Of newer non-SSRI antidepressants, the overdose toxicity of venlafaxine, although lower than that of TCAs, appears to be higher than that of SSRIs, with seizures, serotonin syndrome, rhabdomyolysis, renal failure and hepatic failure having been reported. Poisoning deaths involving antipsychotics either alone, or with other drugs and/or alcohol are many fewer than those involving antidepressants (713 and 5602 deaths, respectively, England and Wales, 1993-2004). Following the restriction on thioridazine usage (2000), thioridazine-associated fatal poisoning fell to zero by 2002, but this was balanced by an increase in deaths associated with atypical antipsychotics, most notably clozapine, olanzapine and quetiapine. Antipsychotic-related poisoning deaths were higher in 2004 than at any time since 1993.


NMR spectral assignments of a new [C--O--C] isoflavone dimer from Andira surinamensis. The phytochemical investigation of extracts from the branch wood and branch barks of Andira surinamensis yielded a novel isoflavone dimer, 4'-methoxyisoflavone-(7-O-7'')-3''',4'''-methylenedioxyisoflavone (surinamensin), along with the triterpene lupeol and the known isoflavones 5,7-dihydroxy-4'-methoxyisoflavone (biochanin A), 5,4'-dihydroxy-7-methoxyisoflavone (prunetin), 7,3'-dihydroxy-4'-methoxyisoflavone (calycosin), and 5,7,3'-trihydroxy-4'-methoxyisoflavone (pratensein). The structure of the new isoflavone was elucidated by 1D and 2D homonuclear and heteronuclear NMR spectroscopy and by comparison with published data for closely related compounds.


Origin of 13C complexation shifts in the adduct formation of 2-butyl phenyl ethers with a dirhodium tetracarboxylate complex. Complexation of the oxygen atom in 2-butyl phenyl ethers to a rhodium atom of the dirhodium tetracarboxylate Rh(II) 2[(R)-(+)-MTPA]4(Rh*, MTPA-H = methoxytrifluoromethylphenylacetic acid identical with Mosher's acid) deshields an sp3-hybridized 13C nucleus directly bonded to the ether oxygen; apparently, the inductive effect of the oxygen is enhanced when it is complexed to the rhodium atom. On the other hand, deshielding complexation shifts of aromatic ipso-carbons (alpha-positioned) are minute but ortho- and para-carbon signals are influenced by the resonance effect of oxygen. This effect can be modulated by further substituents at the benzene ring. In turn, this modulation of the resonance correlates linearly ith the magnitude of the inductive effect exerted on the aliphatic alpha-carbon atoms. Diastereomeric dispersion effects at 13C signals can be observed for most compounds, indicating that enantiodifferentiation is possible in this class of ethers.


Inverse H-C ex situ HRMAS NMR experiments for solid-phase peptide synthesis. The growing importance of solid-phase peptide synthesis (SPPS) has necessitated the development of spectroscopic experiments that can be used to obtain structural and conformational information on resin-bound peptides. Despite the utility of two-dimensional high-resolution magic angle spinning (HRMAS) NMR experiments that provide homonuclear shift correlations, experiments that provide heteronuclear shift correlations are necessary for complex conformational and structural elucidatory problems. Here we report the optimization and implementation of non-gradient inverse NMR experiments for acquiring the 1H-13C shift correlations of resin-bound peptides. The use of non-gradient experiments is advantageous as many magic angle spinning (MAS) probes do not possess gradient coils. An HRMAS BIRD-HMQC experiment with a reduced 1JCH constant has proven very suitable for obtaining one-bond correlations. Long-range correlations can be interpolated by using a non-gradient HRMAS CT-HMBC-1 experiment where the resulting data is processed with forward linear prediction. It has been shown that removing the effects of 1H-1H J-modulation is crucial in order to view cross peaks that correspond to long-range correlations. Additionally, both experiments prove extremely useful over routine one-dimensional 13C HRMAS experiments for extracting carbon chemical shift data. The non-gradient HRMAS BIRD-HMQC and CT-HMBC-1 experiments can be used to assist in conformational analysis and to identify and deconvolute situations where accidental equivalence and seemingly correlated isochronous signals arise.


Comparison of triple-negative and estrogen receptor-positive/progesterone receptor-positive/HER2-negative breast carcinoma using quantitative fluorine-18 fluorodeoxyglucose/positron emission tomography imaging parameters: a potentially useful method for disease characterization. This study was designed to investigate the fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging characteristics of triple-negative (estrogen receptor-negative [ER-]/progesterone receptor-negative [PR-]/HER2-negative [HER2-]) breast carcinoma and compare the results with characteristics of ER+/PR+/HER2- breast carcinomas, which usually carry a favorable prognosis. Patients with newly diagnosed breast carcinoma who had undergone dual-time-point FDG-PET before any therapeutic intervention and were identified as either ER-/PR-/HER2- or ER+/PR+/HER2- (the control group) on histopathology of the surgical specimen, were considered candidates for inclusion in this analysis. These patients underwent FDG-PET as a component of a prospective study that evaluated the role of multimodality imaging for characterizing primary breast lesions and locoregional staging. Breast cancer lesions were imaged twice at approximately 63 minutes and 101 minutes after the administration of FDG. Maximum standardized uptake values (SUVmax) were measured at both time points (SUVmax1 and SUVmax2) to analyze the data generated. After FDG-PET imaging, the patients underwent either breast-conserving surgery or mastectomy, and histopathology reports were used to provide the definitive diagnosis against which the PET study results were compared. In total, 88 patients with breast cancer (29 patients with 'triple-negative' breast cancer and 59 patients with ER+/PR+/HER2- breast malignancies) were selected among 206 individuals who were enrolled in the study protocol. The 'triple-negative' group comprised 14.08% of the total study population. The age of the patients with this subtype of tumor ranged from 33 years to 75 years (mean age+/-standard deviation, 51.6 +/- 10.1 years), and tumors in this subgroup ranged in size from 0.9 cm to 6 cm (mean size, 1.99 cm). Among the histopathologic subtypes, 25 tumors were infiltrating ductal carcinoma (86%), and 1 tumor each (3.5% each subtype) was lobular, mixed ductal-lobular, medullary, and tubular. For the calculation of FDG-PET parameters in this group, only patients who had undergone FDG-PET studies before any intervention were considered, and 18 patients in the triple-negative group met this criterion. According to same criterion, a control group of 59 patients with ER+/PR+/HER2- cancer who had focal FDG uptake were selected for comparison with the triple-negative population. The breast cancer lesions were observed as areas with focally enhanced uptake of FDG in all patients (sensitivity, 100%) in the triple-negative group. The mean (+/-standard deviation) SUVmax1 of the primary lesion for the triple-negative group was 7.27 +/- 5.6, the mean SUVmax2 was 8.29 +/- 6.4, and the percentage change in SUVmax (%DeltaSUVmax) was 14.3 +/- 15.8%. In the control group of 59 patients with ER+/PR+/HER2- breast carcinoma, the mean values for SUVmax1, SUVmax2, and %DeltaSUVmax were 2.68 +/- 1.9, 2.84 +/- 2.2, and 3.7 +/- 13.0%, respectively. The mean values for SUVmax1, SUVmax2, and %Dgr;SUVmax in the triple-negative group were significantly higher compared with the values in the nontriple-negative control group (P = .0032, P = .002, and P = .017, respectively). When the 2 subgroups were compared according to tumor size, grade, and stage, the SUVmax1 was significantly higher in the triple-negative group for both size categories (5.4 vs 1.9, P = .006; and 9.2 vs 3.5, P = .04) and for grade 3 tumors (9.1 vs 3.9, P = .022). The %DeltaSUVmax values for patients in the triple-negative group who had tumors that measured < or =2 cm and > 2 cm were 14.8 and 13.8, respectively; and the corresponding values for patients in the control group were 0.6 and 6.7, respectively. Although the mean %DeltaSUVmax clearly was higher in the triple-negative group for both tumor size categories, comparison between the 2 groups demonstrated a statistically significant difference in tumors that measured < or =2 cm (P = .016). The authors also observed that, in the triple-negative group, tumor grades were correlated significantly with the magnitude of SUVmax1 and SUVmax2 (P = .012 and P = .01, respectively). Stage for stage, tumors from the triple-negative group appeared to have a higher mean SUVmax1 compared with tumors from nontriple-negative control group. However, the trend reached statistical significance in patients with stage II disease. Triple-negative breast tumors were associated with enhanced FDG uptake commensurate with their aggressive biology and were detected with very high sensitivity by using FDG-PET imaging.


Dielectric permittivity and temperature effects on spin-spin couplings studied on acetonitrile. Dielectric permittivity (epsilon) and temperature effects on indirect spin-spin coupling constants were studied using acetonitrile as a probe molecule. Experiments were accompanied by hybrid DFT (density functional theory) studies, where the solvent was modeled using the polarization continuum model. Owing to its numerous types of J-couplings, acetonitrile is a very convenient molecule against which various basis sets can be tested or the best basis set can be selected for a given study. The results show reasonable agreement between calculated and experimental values. According to our data, scalar spin-spin coupling constants undergo substantial shifts at lower values of the dielectric constant. Thus J-coupling values are not transferable between measurements made at differing epsilon-conditions, and the assumption of the epsilon-independence of the J-coupling can lead to crucial mistakes in experiments using low-epsilon media. Dielectric permittivity also causes small geometric fluctuations within the molecule, which themselves can affect J-coupling values. Examinations of the results computed with frozen and relaxed geometries show that geometry mediation mostly affects the spin-dipole term of the J-coupling; hence, for accurate evaluation of the latter, frozen geometries are not acceptable. Another interesting fact revealed is the connection between the solvent dielectric properties and the temperature-dependence slopes of J-couplings in corresponding media.


Conformational analysis of phorboxazole bis-oxazole oxane fragment analogs by NMR spectroscopy and molecular modeling simulations. We present a detailed conformational study of a simplified synthetic analog of the bis-oxazole oxane fragment found in the cytostatic agents phorboxazole A and B based on results from NMR spectroscopy and molecular modeling simulations. Complete 1H and 13C resonance assignments for the bis-oxazole oxane system were carried out through the use of COSY, HSQC, HMBC, TOCSY, and HSQC-TOCSY experiments, and its conformational preferences in solution were investigated by analysis of 3J(HH) coupling constants and NOE enhancements obtained from 1D and 2D NOESY experiments. In order to solve inconsistencies from our preliminary structural studies, simulated annealing studies were performed to thoroughly sample the phase space available to the molecule. Our results reveal that the six-membered oxane ring, which constitutes the most important moiety regarding the three-dimensional (3D) structure and flexibility of the analog, exists in rapid equilibrium between its two accessible chair conformers in an approximate ratio of 70:30. The information gathered from these studies will be of critical importance in our efforts to prepare novel compounds with phorboxazole-like structure and activity.


A multinuclear solid-state magnetic resonance study of the interactions between the inorganic and organic coatings of BaSO4 submicronic particles. Silica-coated BaSO4 submicronic particles, modified on the surface by treatment with stearic acid, have been characterized by means of 29Si, 13C, and 1H magic-angle-spinning (MAS) high-resolution techniques, and low-resolution 1H-FID analysis. Two types of adsorbed water were identified; adsorbed either inside or on the surface of BaSO4, most of the latter being removed by the silica coating. Evidences of silica-stearic acid interactions were found involving either carboxylic acid or carboxylate functional groups, and occurring by means of hydrogen and/or covalent bonds. Stearic acid was present as monolayer only, its chain being mostly rigid, even though a small fraction was subjected to fast inter-conformational motions.


Spectral analysis of 1H coupled 13C spectra of the amino acids: adaptive spectral library of amino acid 13C isotopomers and positional fractional 13C enrichments. The natural abundance 1H-coupled 13C NMR spectra of all proteogenic amino acids were measured in D2O at pH* 1. The accurate 1H,13C spin-spin coupling constants were analyzed using total-line-shape fitting. The obtained spectral parameters can be used to establish a spectral library of amino acid 13C isotopomers. The adaptive spectral library principle is introduced and discussed in this article. The simulated spectra can be applied to quantification of 13C isotopomer mixtures of amino acids and, thus, for exploring metabolic pathways. Also a protocol for amino acid 13C isotopomer metabolomic profiling in 13C labeled glucose feeding experiments is outlined. The approach is suggested to give invaluable information about positional fractional 13C enrichments, which are not easily available by any other method.


Synthesis of nearly enantiopure allylic amines by aza-Claisen rearrangement of Z-configured allylic trifluoroacetimidates catalyzed by highly active ferrocenylbispalladacycles. The development of the first highly active enantioselective catalyst for the aza-Claisen rearrangement of Z-configured allylic trifluoroacetimidates generating valuable almost enantiopure protected allylic amines is described. Usually Z-configured allylic imidates react significantly slower than their E-configured counterparts, but in the present study the opposite effect was observed. Z-Configured olefins have the principal practical advantage that a geometrically pure C=C double bond can be readily obtained, for example, by semihydrogenations of alkynes. Our catalyst, a C(2)-symmetric planar chiral bispalladacycle complex, is rapidly prepared from ferrocene in four simple steps. Key step of this protocol is an unprecedented highly diastereoselective biscyclopalladation providing dimeric macrocyclic complexes of fascinating structure. In the present study as little as 0.1 mol % of catalyst precursor were sufficient for most of the alkyl substituted substrates to give in general almost quantitative yields. NMR investigations revealed a monomeric structure for the active catalyst species. The bispalladacycle can also be used for the formation of almost enantiomerically pure allylic amines (ee > or =96 %) substituted with important functional groups such as ester, ketone, ether, silyl ether, acetal or protected amino moieties providing high-added-value allylic amine building blocks in excellent yield (> or =94 %). The preparative advantages should render this methodology highly appealing as a practical and valuable tool for the formation of allylic amines in target oriented synthesis.


Asymmetric organocatalysed [1,3]-sigmatropic rearrangements. The first organocatalysed enantioselective [1,3]-sigmatropic O- to N-rearrangement reactions are presented. The reactions take place under regio- and enantioselective control, and are catalysed by cinchona alkaloids. Two reactions have been developed the first one is the rearrangement of imidates to amides, while the other rearrangement occurs from carbamates to amines via a decarboxylation. Both transformations give nitrogen protected beta-amino acid derivatives as the product. These novel asymmetric organocatalysed [1,3]-sigmatropic O- to N-rearrangement reactions provide a reliable and efficient synthetic method for obtaining enantioenriched beta-amino acid derivates in good yield from racemic starting materials.


A versatile ditopic ligand system for sensitizing the luminescence of bimetallic lanthanide bio-imaging probes. The homoditopic ligand 6,6'-[methylenebis(1-methyl-1H-benzimidazole-5,2-diyl)]bis(4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}pyridine-2-carboxylic acid) (H(2)L(C2)) has been tailored to self-assemble with lanthanide ions (Ln(III)), which results in the formation of neutral bimetallic helicates with the overall composition [Ln(2)(L(C2))(3)] and also provides a versatile platform for further derivatization. The grafting of poly(oxyethylene) groups onto the pyridine units ensures water solubility, while maintaining sizeable thermodynamic stability and adequate antenna effects for the excitation of both visible- and NIR-emitting Ln(III) ions. The conditional stability constants (log beta(23)) are close to 25 at physiological pH and under stoichiometric conditions. The ligand triplet state features adequate energy (0-phonon transition at approximately 21 900 cm(-1)) to sensitize the luminescence of Eu(III) (Q=21 %) and Tb(III) (11 %) in aerated water at pH 7.4. The emission of several other VIS- and NIR-emitting ions, such as Sm(III) (Q=0.38 %) or Yb(III) (0.15 %), for which in cellulo luminescence is evidenced for the first time, is also sensitized. The Eu(III) emission spectrum arises from a main species with pseudo-D(3) symmetry and without coordinated water. The cell viability of several cancerous cell lines (MCF-7, HeLa, Jurkat and 5D10) is unaffected if incubated with up to 500 microM [Eu(2)(L(C2))(3)] during 24 h. Bright Eu(III) emission is seen for incubation concentrations above 10 microM and after a 15-minute loading time; similar images are obtained with Tb(III) and Sm(III). The helicates probably permeate into the cytoplasm of HeLa cells by endocytosis. The described luminescent helical stains are robust chemical species which remain undissociated in the cell medium and in presence of other complexing agents, such as edta, dtpa, citrate or L-ascorbate. Their derivatization, which would open the way to the sensing of targeted in cellulo phenomena, is currently under investigation.


Randomized, placebo-controlled, double-blind pilot trial of ramipril in McArdle's disease. McArdle's disease causes limitation in exercise capacity as well as disability, the severity of which has been associated with the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) haplotype-patients with the genotype associated with higher ACE activity show the most severe phenotype. Modulation of ACE activity through the use of inhibitors may thus positively affect disease expression. In a double-blind, randomized, placebo-controlled trial, we assessed the efficacy of an ACE inhibitor (2.5 mg ramipril) in 8 patients with McArdle's disease. End-points were changes in parameters of exercise physiology (cycloergometer and muscle 31P-magnetic resonance spectroscopy), quality of life (QoL) according to the Short Form 36 (SF-36), and disability according to the World Health Organization-Disability Assessment Scale II (WHO-DAS II). Patients had lower QoL and higher disability than controls. Measures of exercise physiology were not changed by ramipril in the whole group, but treatment induced higher peak VO2 (P = 0.017) in ACE D/D patients, yet not in I/D patients. Treatment significantly improved disability (P < 0.05). McArdle's disease is a disabling condition affecting patients' QoL. Treatment with ramipril improves disability and modifies exercise physiology only in D/D patients, raising the possibility of a differential haplotype-linked sensitivity to the treatment.


Self-assembly of unprecedented swollen multilamellar twisted ribbons from a racemic hydroxy fatty acid.


Probing the morphology and nanoscale mechanics of single poly(N-isopropylacrylamide) microgels across the lower-critical-solution temperature by atomic force microscopy. Submicrometer-sized particles of poly(N-isopropylacrylamide) (PNIPAM) are synthesized by surfactant-free radical polymerization. The morphology and nanomechanical properties of individual, isolated PNIPAM microgel particles at the silicon/air and silicon/water interfaces, below and above the PNIPAM volume-phase-transition temperature (VPTT), are probed by atomic force microscopy. In air, and in water below the VPTT, the PNIPAM spheres are flattened and adopt a pancakelike shape. Interestingly, above the VPTT the microgels adopt a more spherical form with increased height and decreased width, which is attributed to reduced interactions of the particles with the substrate. The elastic modulus calculated from force-indentation curves obtained for individual microgel spheres reveals that the stiffness of the particle's surface decreases by two orders of magnitude upon swelling in water. Additionally, the modulus of the PNIPAM spheres in water increases by one order of magnitude when crossing the VPTT from the swollen to the collapsed states, indicating a more compact chain packing at the particle surface.


Stretched cavity-assisted molding of micrometer and submicrometer photopolymerized hydrogel particles.


Capillarity-driven fluidic alignment of single-walled carbon nanotubes in reversibly bonded nanochannels.


Multipeak negative-differential-resistance molecular device.


Self-assembled-monolayer formation of long alkanedithiols in molecular junctions. The orientation of alkanedithiol molecules in self-assembled monolayers (SAMs) is of vital importance for their transport properties in molecular junctions. It is demonstrated that a too-low concentration of long alkanedithiols in ethanol leads to the formation of looped molecules, resulting in a 50-fold increase of the current through the SAM. X-ray photoelectron spectroscopy measurements show that high-concentration dithiol solutions result in a preferential standing-up phase. To obtain an almost full standing-up phase of 1,14-tetradecanedithiol (C14) a 30 mM concentration in ethanol is required, whereas a 0.3 mM concentration leads to a highly looped monolayer. The conduction through the full standing-up phase of C14 and C16 is in accordance with the exponential dependence on molecule length as obtained from shorter alkanedithiols.


Optical investigation of quantum confinement in PbSe nanocrystals at different points in the Brillouin zone. We present detailed investigations on the optical properties of PbSe nanocrystals. The absorption spectra of monodisperse, quasispherical nanocrystals exhibit sharp features as a result of distinct optical transitions. To study the size dependence, absorption spectra of nanocrystals ranging from 3.4 to 10.9 nm in diameter are analysed and a total of 11 distinct optical transitions are identified. The assignment of the various optical transitions is discussed and compared to theoretically calculated transition energies. By plotting all transitions as a function of nanocrystal size (D) we find that the energy (E) changes with the following relationship [Formula: see text] for the lowest energy transitions. The transition energy extrapolates to approximately 0.3 eV for infinite crystal size, in agreement with the bandgap of bulk PbSe at the L-point in the Brillouin zone. In addition, high-energy transitions are observed, which extrapolate to 1.6 eV for infinite crystal size, which is in good agreement with the bulk bandgap of PbSe at the Sigma-point in the Brillouin zone. Tight-binding calculations confirm that the high-energy transitions originate from the Sigma-point in the Brillouin zone. The Sigma-character of the high-energy transitions may be of importance to explain the mechanism behind multiple exciton generation in PbSe nanocrystals.


Molecular design of heteroprotein assemblies providing a bionanocup as a chemical reactor.


ChinaNANO 2007.

ChinaNANO 2007.


Ultrasound switch and thermal self-repair of morphology and surface wettability in a cholesterol-based self-assembly system.


Opposite signs of capacitive microsensor signals upon exposure to the enantiomers of methyl propionate compounds.


An entropically efficient supramolecular inhibition strategy for Shiga toxins.


Structural correlations and charge ordering in a room-temperature ionic liquid.


Octahedral coordination compounds of the Ni, Pd, Pt triad.


Active intramolecular conformational dynamics controlling the assembly of azobenzene derivatives at surfaces.


Isotope and surface temperature effects for hydrogen recombination on a graphite surface. We highlight the isotope and surface temperature effects for hydrogen atom recombination on a graphite surface. The reaction dynamics is studied using the semiclassical collisional method, according to which the mass and temperature effects are due to the coupling between the H/D dynamics and the dynamics of the phonon excitation/de-excitation mechanism of the substrate. All possible collisional schemes with H/D adsorbed on the surface and H/D impinging from the gas phase are considered. In particular, we focus on the recombination reaction between an H atom colliding with a D atom adsorbed on the surface and a D atom incident on an H adatom. For H(2) and D(2) formation, the surface temperature effect is investigated by comparing the results obtained for T(S)=800 K with those obtained at T(S)=500 K and T(S)=100 K. Despite the low masses involved in the dynamics, effective isotope and temperature effects were observed on the recombination probabilities, reaction energetics, and roto-vibrational states of formed molecules. The results show the need for correct treatment of the multiphonon excitation mechanism in molecule-surface interactions.


Random walks to synthetic riboswitches--a high-throughput selection based on cell motility.


A crossed molecular beam study on the reaction of boron atoms with methylacetylene and partially deuterated methylacetylene. The reactions of ground-state boron atoms, B((2)P(j)), with methylacetylene, CH3CCH(X(1)A(1)), and its [D3]-substituted isotopomer, CD3CCH(X(1)A(1)), are studied under single collision conditions using the crossed molecular beam technique at collision energies of 21.6 and 21.9 kJ mol(-1), respectively. Utilizing the CD3CCH reactant, detailed information on the dynamics is obtained. The reaction followed indirect scattering dynamics and proceeded through at least two reaction channels via atomic deuterium and hydrogen atom elimination pathways leading eventually to two isotopomers, that is, the C(2v) symmetric D2CCCBH(X(1)A(1)) and D2CCCBD(X(1)A(1)) structures via statistical and non-statistical reaction pathways, respectively.


An artificial aptazyme-based riboswitch and its cascading system in E. coli.


Affinity analyses on moldable optical polycarbonate.


Inorganic nanoparticles as carriers of nucleic acids into cells. The transfer of nucleic acids (DNA or RNA) into living cells, that is, transfection, is a major technique in current biochemistry and molecular biology. This process permits the selective introduction of genetic material for protein synthesis as well as the selective inhibition of protein synthesis (antisense or gene silencing). As nucleic acids alone are not able to penetrate the cell wall, efficient carriers are needed. Besides viral, polymeric, and liposomal agents, inorganic nanoparticles are especially suitable for this purpose because they can be prepared and surface-functionalized in many different ways. Herein, the current state of the art is discussed from a chemical viewpoint. Advantages and disadvantages of the available methods are compared.


Facile incorporation of platinum(IV) into polyoxometalate frameworks: preparation of [H2Pt(IV)V9O28]5- and characterization by 195Pt NMR spectroscopy.


Exploiting self-assembly for ligand-scaffold optimization: substrate-tailored ligands for efficient catalytic asymmetric hydroboration.


Enzymatic control of the size of DNA block copolymer nanoparticles.


Carboxylic Acid enriched nanospheres of semiconductor nanorods for cell imaging.


A self-catalyzing hydrogen-storage material.


Highly efficient catalyst systems using iron complexes with a tetradentate PNNP ligand for the asymmetric hydrogenation of polar bonds.


Processing of N-terminal unnatural amino acids in recombinant human interferon-beta in Escherichia coli. Incorporation of unnatural amino acids into recombinant proteins represents a powerful tool for protein engineering and protein therapeutic development. While the processing of the N-terminal methionine (Met) residues in proteins is well studied, the processing of unnatural amino acids used for replacing the N-terminal Met remains largely unknown. Here we report the effects of the penultimate residue (the residue after the initiator Met) on the processing of two unnatural amino acids, L-azidohomoalanine (AHA) and L-homopropargylglycine (HPG), at the N terminus of recombinant human interferon-beta in E. coli. We have identified specific amino acids at the penultimate position that can be used to efficiently retain or remove N-terminal AHA or HPG. Retention of N-terminal AHA or HPG can be achieved by choosing amino acids with large side chains (such as Gln, Glu, and His) at the penultimate position, while Ala can be selected for the removal of N-terminal AHA or HPG. Incomplete processing of N-terminal AHA and HPG (in terms of both deformylation and cleavage) was observed with Gly or Ser at the penultimate position.


Amphiphilic comb-like polymers based on poly(oxyethylene)s as drug-delivery carriers. Comb-like polymers with biocompatible oxyethylene backbones and amphiphilic side groups were synthesized via polymer-analogous reactions. Using these polymers, indomethacin-loaded polymeric micelles were fabricated with various drug-to-polymer weight ratios using the oil-in-water emulsion technique. In addition, the size, size distribution, CMC, drug-loading content, and entrapment efficiency of the polymeric micelles were analyzed. The volume-weighted diameters of polymeric micelles ranged from 10 to 140 nm and were narrowly distributed for passive targeting drug delivery. The CMCs were lower (approximately 10(-8) M) than for conventional surfactants and block copolymers.


Prohibition against competing cancer clinical trials: a counter argument.


Elderly breast cancer patients treated by conservative surgery alone plus adjuvant tamoxifen: fifteen-year results of a prospective study. In elderly patients with early breast cancer and a clinically clear axilla, axillary surgery, sentinel lymph node biopsy, and postoperative radiotherapy to the residual breast may not be necessary because of reduced life expectancy, effectiveness of hormone therapy in achieving long-term disease control, and generally favorable biologic behavior of breast cancer in elderly patients. The authors followed 354 prospectively recruited women aged > or =70 years who had primary, operable breast cancer and no palpable axillary lymph nodes. All 354 women were treated with conservative surgery and adjuvant tamoxifen and without axillary dissection or postoperative radiotherapy. Women who had resection margins in tumor tissue were excluded. Endpoints were cumulative incidence of axillary disease, cumulative incidence of ipsilateral breast tumor recurrence (IBTR), and breast cancer mortality. After a median follow-up of 15 years (interquartile range, 14-17 years), the crude cumulative incidence was 4.2% (4% in pathologic T1 [pT1] tumors) for axillary disease, 8.3% (7.3% in pT1 tumors) for IBTR, and 17% for breast cancer mortality. Of the 268 patients who died during follow-up, 222 patients (83%) died from causes unrelated to breast cancer. Elderly patients with early breast cancer and no palpable axillary lymph nodes may be safely treated safety by conservative surgery without axillary dissection and without postoperative radiotherapy, provided that surgical margins are in tumor-free tissue and that hormone therapy is administered. Sentinel lymph node biopsy is also unnecessary because of the low cumulative incidence of axillary disease, and axillary surgery can be reserved for the small proportion of patients who later develop overt axillary disease.


Neurocognitive function in patients with small cell lung cancer : effect of prophylactic cranial irradiation. The use of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) has been tempered by fears of detrimental effects on cognitive function. Neuropsychologic testing was prospectively conducted before and after PCI to evaluate its effects on cognitive function in patients with SCLC. Ninety-six patients who completely or partially responded to initial therapy underwent formal neurocognitive testing before PCI. Three patients who had central nervous system metastasis were excluded. Of the remaining patients, 69 received PCI (mean dose, 25 grays [Gy] in 10 fractions). Repeat testing was performed on 37 patients (median follow-up, 23 months; range, 6-120 months). Baseline impairment was defined as > or =1.5 standard deviations below the normative mean. Before undergoing PCI, 47% of patients had evidence of impaired cognitive function. After PCI, univariate analysis revealed significant transient declines in executive function (pre-PCI mean, 15.6 +/- 11.5; post-PCI, 27.1 +/- 17.6 [P = .008]) and language (pre-PCI mean, 33.8 +/- 9.9; post-PCI, 31.0 +/- 9.0 [P = .049]) at early timepoints. Controlling for noncentral nervous system disease progression the deficit in executive function was no longer significant. Moreover, these deficits were not sustained, and significant improvements in language and motor coordination were recorded. On multivariate analysis, no significant differences before and after PCI were found. Neurocognitive testing demonstrated that a substantial portion of patients with SCLC had impaired brain functioning at baseline. Persistent declines in cognitive function were not observed after cranial irradiation. These data do not favor the omission of PCI on the basis of fears of neurotoxic effects.


Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice. Glioblastoma, which is the most malignant brain tumor, remains incurable and almost always causes death. As a new treatment strategy, the combination of all-trans retinoic acid (ATRA) and paclitaxel was explored for controlling the growth of glioblastoma U87MG xenografts. Human glioblastoma U87MG xenografts were developed in athymic nude mice for treatments with ATRA, paclitaxel, and ATRA plus paclitaxel. The efficacy of treatments in controlling tumor growth was assessed by histologic examination, Western blot analysis, and immunofluorescent labelings. Astrocytic differentiation in U87MG xenografts was associated with increased GFAP expression and decreased telomerase expression. The combination of ATRA and paclitaxel was found to cause more apoptosis than paclitaxel alone. Apoptosis occurred with down-regulation of MEK-2 and overexpression of p-ERK, p-JNK, and p-p38 MAPK. Down-regulation of both Akt and p-Akt also favored the apoptotic process. Combination therapy activated the receptor-mediated pathway of apoptosis with induction of TNF-alpha, activation of caspase-8, and cleavage of Bid to tBid. Combination therapy also induced the mitochondria-mediated pathway of apoptosis with an increase in the Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and Smac/Diablo into the cytosol. In addition, combination therapy promoted phosphorylation of Bcl-2 for its inactivation and down-regulated NF-kappaB and BIRC proteins, indicating suppression of several cell survival factors. Western blot analysis demonstrated that activation of cysteine proteases such as calpain, caspase-12, caspase-9, and caspase-3 contributed to apoptosis. Immunofluorescent labelings confirmed overexpression of cysteine proteases in apoptosis. Treatment of U87MG xenografts with a combination of ATRA and paclitaxel induced differentiation and also multiple molecular mechanisms for apoptosis.


Cost-effectiveness of targeted and tailored interventions on colorectal cancer screening use. Colorectal cancer (CRC) screening is cost-effective but underused. The objective of this study was to determine the cost-effectiveness of targeted and tailored behavioral interventions to increase CRC screening use by conducting an economic analysis associated with a randomized trial among patients in a large, racially and ethnically diverse, urban family practice in Philadelphia. The incremental costs per unit increase were measured in individuals who were screened during the 24 months after intervention. Percent increase in screening was adjusted for baseline differences in the study groups. Each intervention arm received a targeted screening invitation letter, stool blood test (SBT) cards, informational booklet, and reminder letter. Tailored interventions incrementally added tailored messages and reminder telephone calls. Program costs of the targeted intervention were 42 dollars per participant. Additional costs of adding tailored print materials and of delivering a reminder telephone call were 150 dollars and 200 dollars per participant, respectively. The cost per additional individual screened was 319 dollars when comparing the no intervention group with the targeted intervention group. The targeted intervention was more effective and less costly than the tailored intervention. Although tailoring plus reminder telephone call was the most effective strategy, it was very costly per additional individual screened. Mailed SBT cards significantly boosted CRC screening use. However, going beyond the targeted intervention to include tailoring or tailoring plus reminder calls in the manner used in this study did not appear to be an economically attractive strategy.


GABA B receptor is a novel drug target for pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. Smoking, diabetes, and pancreatitis are risk factors. It has been shown that the growth of PDAC and pancreatic duct epithelial cells is regulated by beta-adrenoreceptors (beta-ARs). The activity of beta-ARs in the central nervous system is counteracted by gamma-aminobutyric acid (GABA) via GABA B receptor-mediated inhibition of adenylyl cyclase. The aim of the study was to investigate if GABA B R inhibits beta-AR signaling in PDAC and pancreatic duct epithelial cells, thus blocking driving forces of cancer progression, such as cell proliferation and cell migration. Intracellular cAMP was measured by immunoassays, DNA synthesis by BrdU incorporation assays, activation of ERK1/2 by ERK activation assays, and Western blots and metastatic potential by cell migration assays in the human PDAC cell lines PANC-1 and BXPC-3 and immortalized human pancreatic duct epithelial cells HPDE6-C7. The expression of norepinephrine, PKAR IIalpha, and GABA in PDAC microarrays was assessed by immunohistochemistry. RESULTS.: Stimulation of the GABA B R by GABA or baclofen inhibited isoproterenol-induced cAMP signaling below base levels. ERK1/2 activity in response to isoproterenol was blocked by GABA, an effect enhanced by transient overexpression of the GABA B R and abolished by GABA B R knockdown. DNA synthesis and cell migration were stimulated by isoproterenol, responses blocked by GABA and baclofen. Norepinephrine and PKAR IIalpha were overexpressed while GABA was underexpressed in human PDAC tissue arrays. The data suggest the stimulation of GABA B R signaling as a novel target for the treatment and prevention of pancreatic cancer.


Tremor dominant parkinsonism: Clinical description and LRRK2 mutation screening. Tremor dominant parkinsonism (TDP) is characterized by initial prominent resting and action tremor, mild parkinsonism, unpredictable response to medication, and a better prognosis than idiopathic Parkinson's disease (PD). We report on clinical features and longitudinal course of 26 patients suffering from TDP. Mean disease duration was 6.5 +/- 3 years, 61.5% of patients had a positive family history of tremor, 73% did not need drug treatment, performance of 123I-Ioflupane SPECT showed reduced striatal tracer uptake in 65.4% of patients, and odor identification testing was pathologic in all the patients tested (n = 22). Co-occurrence of action and resting tremor were the most annoying and disabling symptoms in all the patients, whereas rigidity and/or bradykinesia were clinically irrelevant in most of them. We also sequenced the full coding region of the Leucine-rich repeat kinase 2 gene (LRRK2) in all patients. We found a novel Val2390Met mutation that was not found in 864 chromosomes. Our results suggest a broader clinical heterogeneity related to LRRK2 mutations and points towards TDP as a subtype within the spectrum of PD, in which disabling tremor but otherwise mild parkinsonian signs and a better prognosis are the main characteristics.


Spastic paraplegia 15: linkage and clinical description of three Tunisian families. Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16-Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellin's syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity.


Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: Randomized, double-blind, noninferiority trial. The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT-A) and type B (BoNT-B) in toxin-naïve cervical dystonia (CD) subjects. BoNT-naïve CD subjects were randomized to BoNT-A or BoNT-B and evaluated in a double-blind trial at baseline and every 4-weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post-injection. Secondary measures included change in TWSTRS-subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT-B to BoNT-A. 111 subjects were randomized (55 BoNT-A; 56 BoNT-B). Improvement in TWSTRS-total scores 4 weeks after BoNT-B was noninferior to BoNT-A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per-protocol-population (PPP)). The median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs. 13.7 weeks, respectively; P-value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT-B but there were no differences for moderate/severe dry mouth. In this study, both BoNT-A and B were shown to be effective and safe for the treatment of toxin-naive CD subjects.


Corticobasal syndrome with Alzheimer's disease pathology.


Pathological crying in patients with Machado-Joseph disease.