Oxidative C-H/C-H Coupling of Dipyrromethanes with Azines by TiO2-Based Photocatalytic System. Synthesis of New BODIPY Dyes and Their Photophysical and Electrochemical Properties.

Oxidative C-H/C-H coupling reactions of dipyrromethanes with azines in the presence of a heterophase oxidative photocatalytic system (O2/TiO2/visible light irradiation) were carried out. As a result of cyclization of obtained compounds with boron trifluoride etherate, new hetaryl-containing derivatives of 4,4-difluoro-4-boron-3a,4a-diaza-s-indacene were synthesized. For the obtained compounds, absorption and luminescence spectra, quantum yields of luminescence as well as cyclic volt-amperograms were measured.

Use of Methyl Tert-Butyl Ether for the Treatment of Refractory Intrahepatic Biliary Strictures and Bile Casts: A Modern Perspective.

Cholelithiasis is a prevalent problem in the United States with 14% or more adults affected. Definitive treatment of cholelithiasis is cholecystectomy. When cholecystectomy yields minimal resolution treatment options include expectant management of asymptomatic gallstones or endoscopic retrograde cholangiopancreatogram. We present a case of intrahepatic biliary casts where surgical option was not possible, interventional radiology was unsuccessful, and methyl tert-butyl ether was used to dissolve the biliary obstruction. Dissolution therapy of gallstones was first reported in 1722 when Vollisnieri used turpentine in vitro. While diethyl ether has excellent solubilizing capacity, its low boiling point limited its use surgically as it vaporizes immediately. Diethyl ether can expand 120-fold during warming to body temperature after injection into the biliary system making it impractical for routine use. The use of dissolution is out of favor due to the success of laparoscopic cholecystectomy. Epidemiological studies have shown the general population should have minimal concerns from passive exposure. Dissolution using MTBE remains a viable option if surgical or endoscopic options are not available. However, because of risks involved to both the patient and the staff, careful multidisciplinary team approach must be undertaken to minimize the risks and provide the best possible care to the patient.

Morphology of the proximal femur differs widely with age and sex: relevance to design and selection of femoral prostheses.

The ability of uncemented femoral stems to osseointegrate properly depends largely on their fit in the proximal femur. We evaluated the topography of the proximal femur and determined differences based on age and sex. Retrospectively, anteroposterior radiographs from 312 (168 male, 144 female) pre-operative total hip arthroplasty (THA) patients (age of 21-85 years) were collected. Radiographic measurements were taken at 10 mm intervals along the length of the femur. Variables including canal flare index (CFI) and cortical index (CI) were calculated. Data were binned into three age groups and separated by sex for comparison. Measurements showed that CFI decreased with age for both sexes; however, females demonstrated a greater decrease. Decrease in flare occurred primarily on the lateral side. CI also decreased with age, the most pronounced drop occurring in older females. A clear difference exists between male and female proximal femoral geometry. This decrease is most likely attributed to the loss of cortical bone. The medial component likely demonstrates less loss of flare due to strong compressive forces that are transmitted through this portion of the femur. These results demonstrate the necessity of considering age and sex when selecting a proper prosthesis.

Revision for stiffness following TKA: a predictable procedure?

BACKGROUND: Stiffness is a known complication following total knee arthroplasty. Multiple options are available to address this problem but revision TKA has been reported to be an effective treatment especially in the presence of technical issues such as oversized or loose components. However, it is not clearly known what factors may affect the outcome of revision TKA for stiffness. The purpose of this study was to evaluate the results of TKA revision for stiffness and to determine which potential factors may predict the outcome. MATERIALS AND METHODS: Between 1999 and 2006, 39 patients (24 females and 15 males) were revised for stiffness following their primary TKA. The average age was 60.8 years with an average BMI of 30.7. The mean follow up was 74.4 months. RESULTS: Following revision TKA, the overall range of motion and flexion contracture improved significantly from 68 to 90 (p=0.001) and from 14 to 5 (p<0.0001), respectively. Although the KSS were significantly improved from 45.72 to 77.10 (p<0.0001), the functional score did not improve significantly. Of the 39 knees which had stiffness, 10 (25.6%) required a second revision. We could not find any demographic or operative characteristics as a predictor failure. CONCLUSION: Our study shows that TKA revision is a viable option, still unpredictable, to improve the ROM in patients with prolonged stiffness after TKA. Although revision for stiffness is not always successful in terms of achieving functional range of motion, it could improve pain in presence of less than functional range of motion. LEVEL OF EVIDENCE: Prognostic Level II.

Primary total hip arthroplasty with an uncemented femoral component five- to nine-year results.

This study reports the outcome of total hip arthroplasty with use of an uncemented, tapered stem with a 5- to 9-year follow-up. The first 200 consecutive patients (214 hips) undergoing total hip arthroplasty with the Accolade TMZF stem (Stryker Orthopaedics, Mahwah, NJ) were enrolled prospectively. Follow-up for these patients averaged 7.6 years and encompassed review of clinical records as well as review of serial anteroposterior and lateral radiographs. There were 5 revision surgeries for aseptic loosening, 2 cases of infection, instability, and polyethylene wear. Our failure rate, defined as hips needing revision, was 2.6%, and the failure rate due to aseptic loosening of the femoral component was 0.6%. These results demonstrate the high success rate of this implant providing support for its continued use.

Identification and validation of novel human pregnane X receptor activators among prescribed drugs via ligand-based virtual screening.

Human pregnane X receptor (hPXR) plays a key role in regulating metabolism and clearance of endogenous and exogenous substances. Identification of novel hPXR activators among commercial drugs may aid in avoiding drug-drug interactions during coadministration. We applied ligand-based computational approaches for virtual screening of a commonly prescribed drug database (SCUT). Bayesian classification models were generated with a training set comprising 177 compounds using Fingerprints and 117 structural descriptors. A cell-based luciferase reporter assay was used for evaluation of chemical-mediated hPXR activation in HepG2 cells. All compounds were tested at 10 µM concentration with rifampicin and dimethyl sulfoxide as positive and negative controls, respectively. The Bayesian models showed specificity and overall prediction accuracy up to 0.92 and 0.69 for test set compounds. Screening the SCUT database with this model retrieved 105 hits and 17 compounds from the top 25 hits were chosen for in vitro testing. The reporter assay confirmed that nine drugs, i.e., fluticasone, nimodipine, nisoldipine, beclomethasone, finasteride, flunisolide, megestrol, secobarbital, and aminoglutethimide, were previously unidentified hPXR activators. Thus, the present study demonstrates that novel hPXR activators can be efficiently identified among U.S. Food and Drug Administration-approved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.

Stiffness after revision total knee arthroplasty.

Stiffness after a revision total knee arthroplasty (TKA) is a disabling complication that has largely been overlooked in the literature. This study attempts to define the prevalence of stiffness after revision TKA and to determine the risk factors that may lead to its development. Thirty-two knees (4.0%) presented with stiffness that we defined as a range of motion less than 90 degrees . Risk factors were found to be poor preoperative range of motion, stiffness as primary indication for revision, younger age, shorter interval between index primary and revision TKA, presence of well-fixed components at the time of revision, postoperative wound drainage, and lower Charlson index. Because of the challenges of treating stiffness, efforts should be invested in preventing this complication.

A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3.

The constitutive androstane receptor (CAR) is constitutively activated in immortalized cell lines independent of xenobiotic stimuli. This feature of CAR has limited its use as a sensor for xenobiotic-induced expression of drug-metabolizing enzymes. Recent reports, however, reveal that a splicing variant of human CAR (hCAR3), which contains an insertion of five amino acids (APYLT), exhibits low basal but xenobiotic-inducible activities in cell-based reporter assays. Nonetheless, the underlying mechanisms of this functional shift are not well understood. We have now generated chimeric constructs containing various residues of the five amino acids of hCAR3 and examined their response to typical hCAR activators. Our results showed that the retention of alanine (hCAR1+A) alone is sufficient to confer the constitutively activated hCAR1 to the xenobiotic-sensitive hCAR3. It is noteworthy that hCAR1+A was significantly activated by a series of known hCAR activators, and displayed activation superior to that of hCAR3. Moreover, intracellular localization assays revealed that hCAR1+A exhibits nuclear accumulation upon 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) treatment in COS1 cells, which differs from the spontaneous nuclear distribution of hCAR1 and the nontranslocatable hCAR3. Mammalian two-hybrid and glutathione S-transferase pull-down assays further demonstrated that hCAR1+A interacts with the coactivator SRC-1 and GRIP-1 at low level before activation, while at significantly enhanced level in the presence of CITCO. Thus, the alanine residue in the insertion of hCAR3 seems in charge of the xenobiotic response of hCAR3 through direct and indirect mechanisms. Activation of hCAR1+A may represent a sensitive avenue for the identification of hCAR activators.

TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL.

The adapter protein TRAF6 is critical for mediating signal transduction from members of the IL-1R/TLR and TNFR superfamilies. The TRAF6 RING finger domain functions as an ubiquitin E3 ligase capable of generating non-degradative K63-linked ubiquitin chains. It is believed that these chains serve as docking sites for formation of signaling complexes, and that K63-linked autoubiquitination of TRAF6 is essential for formation and activation of a complex involving the kinase TAK1 and its adapters, TAB1 and TAB2. In order to assess independently the E3 ligase and ubiquitin substrate functions of TRAF6, we generated, respectively, RING domain and complete lysine-deficient TRAF6 mutants. We found that while the TRAF6 RING domain is required for activation of TAK1, it is dispensable for interaction between TRAF6 and the TAK1-TAB1-TAB2 complex. Likewise, lysine-deficient TRAF6 was found to interact with the TAK1-TAB1-TAB2 complex, but surprisingly was also found to be fully competent to activate TAK1, as well as NFkappaB and AP-1 reporters. Furthermore, lysine-deficient TRAF6 rescued IL-1-mediated NFkappaB and MAPK activation, as well as IL-6 elaboration in retrovirally-rescued TRAF6-deficient fibroblasts. Lysine-deficient TRAF6 also rescued RANKL-mediated NFkappaB and MAPK activation, and osteoclastogenesis in retrovirally-rescued TRAF6-deficient bone marrow macrophages. While incapable of being ubiquitinated itself, we demonstrate that lysine-deficient TRAF6 remains competent to induce ubiquitination of IKKgamma/NEMO. Further, this NEMO modification contributes to TRAF6-mediated activation of NFkappaB. Collectively, our results suggest that while TRAF6 autoubiquitination may serve as a marker of activation, it is unlikely to underpin RING finger-dependent TRAF6 function.

Cutting edge: requirement for TRAF6 in the induction of T cell anergy.

TRAF6, TNFR-associated factor 6, is a key adaptor downstream from the TNF receptor and TLR superfamily members. T cell-specific deletion of TRAF6 (TRAF6-DeltaT) was recently shown to result in the development of multiorgan inflammatory disease and the resistance of responder T cells to suppression by CD4+CD25+ regulatory T cells. In this study we examined the role of TRAF6 in an additional mechanism of peripheral tolerance, anergy. We have determined that the loss of TRAF6 restores the ability of CD28-/- T cells to proliferate and produce IL-2. Consistent with this, TRAF6-DeltaT T cells were resistant to anergizing signals both in vitro and in vivo. Resistance to anergy was correlated with decreased expression of Cbl-b. These findings reveal that in addition to its role in rendering T cells susceptible to control by CD4+CD25+ regulatory T cells, TRAF6 is essential for the induction of T cell anergy, implicating TRAF6 as a critical mediator of peripheral tolerance.

TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis.

TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.

'Working at the margins' or 'leading from behind'? A Canadian study of hospital-community collaboration.

Collaboration between hospitals and community organisations has been promoted over the past 20 years by various levels of government, hospital associations, health promotion advocates, and others at the state/province, national and international levels as a way to improve the 'efficiency of the system', reduce duplication, enhance effectiveness and service coordination, improve continuity of care, and enhance community capacity to address complex issues. Nevertheless, and despite a growing literature on interagency collaboration, systematic documentation and empirical analysis of hospital-community collaboration (HCC) is almost completely lacking in the literature, particularly as regards collaborations that address the determinants of health beyond the hospital walls. In this paper, we describe the methodology and key findings from a research study of HCC. The Hospital Involvement in Community Action (HICA) study undertook detailed qualitative case studies (in four urban, suburban, rural and northern locations) and a telephone survey (of 139 community organisations in a large urban centre) in order to learn about the range of collaborations and working relationships that exist between hospitals and community agencies in the province of Ontario (Canada), and the factors that influenced (enabled and/or hindered) HCC. Particular attention was paid to barriers and enablers at three nested levels of context (policy, hospital and community) and, drawing primarily on the qualitative case studies, it is this aspect that is the focus of this paper. That such collaborations continue to be widespread despite a generally unfavourable policy environment and hospital institutional culture that poses significant barriers, suggests that the extent to which HCC flourishes (or exists at all) crucially depends on the presence and ongoing enthusiasm/commitment of one or more 'champions' within the hospital, and the commitment of both parties to overcome the marked cultural differences between hospital and community. We conclude with a discussion of implications for policy and practice.

Eyes wide shut?--A conceptual and empirical critique of methadone maintenance treatment.

BACKGROUND: Methadone maintenance treatment (MMT) has been the 'gold standard' pharmacotherapy treatment for illicit opioid dependence for over 30 years. It has been widely evaluated, and is generally claimed to be 'effective'. METHODS: The objective of this paper is to review the rationale of MMT as an intervention for a biomedical disorder with primary social objectives as well as the methodological quality and evidence of MMT outcome research. Data sources included opioid dependence treatment practice, review and outcome research literature (1965-2001) in the form of peer-reviewed articles, books, monographs and reports that are preeminently cited and reviewed international studies on MMT. RESULTS/DATA SYNTHESIS: Rigorous and appropriate evaluation (i.e., RCTs, intent-to-treat, patient-centered) methods in MMT evaluations are rare. Evidence of MMT's effectiveness on primary treatment objectives is mixed and appears to be largely partial and short-term. Positive outcomes may be the result of selection effects of compliant patients and loss in proportion when more rigorous standards of analysis are applied. CONCLUSIONS: The quality of existing MMT research, and evidence for its general effectiveness are limited. Key concepts of self-medication and psychiatric comorbidity are largely ignored in MMT treatment and research frameworks, although they may serve to explain MMT's limited treatment success. Emerging new opioid pharmacotherapies require the fundamental review of the existing MMT paradigm as well as the application of rigorous and appropriate evaluation methods for future treatment.

Screening for antisocial personality disorder in drug users--a qualitative exploratory study on feasibility.

Knowledge about co-occurring personality disorders in drug users is important for planning therapy and prevention. The objective of this study was to assess whether the SCID-II (Structured Clinical Interview for DSM-III-R) Screen for antisocial personality disorder was feasible and acceptable in a population of opioid users. A qualitative study on veridicality and emotional quality in responses to SCID-II Screen was carried out by personal interview in a multifunctional addiction centre. The subjects were 10 outpatient participants (six female, four male) in methadone substitution treatment. The SCID-II Screen triggered a high level of emotions. Some questions were mainly interpreted from a victim's perspective, even though the intention was the perpetrator's view. Questions were seen as sex-biased. Provision of support to deal with potential emotional problems should be supplied. Potential revision should be considered to include the female perspective in the screen.