Cyclometalation of aryl-substituted phosphinines through C-H-bond activation: a mechanistic investigation.

A series of 2,4,6-triarylphosphinines were prepared and investigated in the base-assisted cyclometalation reaction using [Cp*IrCl2]2 (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl) as the metal precursor. Insight in the mechanism of the C-H bond activation of phosphinines as well as in the regioselectivity of the reaction was obtained by time-dependent (31)P{(1)H} NMR spectroscopy. At room temperature, 2,4,6-triarylphosphinines instantaneously open the Ir-dimer and coordinate in an η(1)-fashion to the metal center. Upon heating, a dissociation step towards free ligand and an Ir-acetate species is observed and proven to be a first-order reaction with an activation energy of ΔEA = 56.6 kJ mol(-1) found for 2,4,6-triphenylphosphinine. Electron-donating substituents on the ortho-phenyl groups of the phosphorus heterocycle facilitate the subsequent cyclometalation reaction, indicating an electrophilic C-H activation mechanism. The cyclometalation reaction turned out to be very sensitive to steric effects as even small substituents can have a large effect on the regioselectivity of the reaction. The cyclometalated products were characterized by means of NMR spectroscopy and in several cases by single-crystal X-ray diffraction. Based on the observed trends during the mechanistic investigation, a concerted base-assisted metalation-deprotonation (CMD) mechanism, which is electrophilic in nature, is proposed.

Coronary Artery Calcification as a Marker for Coronary Artery Stenosis: Comparing Kidney Failure to the General Population.

RATIONALE & OBJECTIVE: The presence of calcified plaques in the coronary arteries is associated with cardiovascular mortality and is a hallmark of chronic kidney failure, but it is unclear whether this is associated with the same degree of coronary artery stenosis as in patients without kidney disease. We compared the relationship of coronary artery calcification (CAC) and stenosis between dialysis patients and patients without chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 127 dialysis patients and 447 patients without CKD with cardiovascular risk factors underwent cardiac computed tomography (CT), consisting of non-contrast-enhanced CT and CT angiography. CAC score and degree of coronary artery stenosis were assessed by independent readers. PREDICTOR: Dialysis treatment. OUTCOME: Association between calcification and stenosis. ANALYTICAL APPROACH: Logistic regression to determine the association between CAC score and the presence of stenosis in a matched cohort and, in the full cohort, testing for the interaction of dialysis status with this relationship. RESULTS: 112 patients were matched from each cohort, totaling 224 patients, using propensity scores for dialysis, balancing numerous cardiovascular risk factors. Median CAC score was 210 (IQR, 19-859) in dialysis patients and 58 (IQR, 0-254) in patients without CKD; 35% of dialysis patients and 36% of patients without CKD had coronary artery stenosis ≥ 50%. Per each 100-unit higher CAC score, the matched dialysis cohort had significantly lower ORs for stenosis than the non-CKD cohort, 0.67 (95% CI, 0.52-0.83) for stenosis ≥ 50% and 0.75 (95% CI, 0.62-0.90) for stenosis ≥ 70%. LIMITATIONS: No comparison with the gold standard fractional flow reserve. CONCLUSIONS: Dialysis patients have higher risk for coronary artery stenosis with higher CAC scores, but this risk is comparatively lower than in patients without CKD with similar CAC scores. In dialysis patients, a high CAC score can easily be found without significant stenosis. Our data enable "translation" of degree of calcification to the probability of coronary stenosis in dialysis patients.

Xerocomellus (Boletaceae) in western North America.

Understanding diversity in the genus Xerocomellus in western North America has been obscured by morphological variability, widespread use of species epithets typified by specimens from Europe and eastern North America, misunderstood phylogenetic relationships, and species complexes. We collected extensively and used genetic and morphological data to establish the occurrence of ten Xerocomellus species in western North America. We generated ITS sequences from five type collections and from vouchered representative collections to clarify our understanding of existing species concepts. We describe three new species (Xerocomellus atropurpureus, X. diffractus, and X. salicicola) and propose two new combinations (X. amylosporus and X. mendocinensis), transfer Boletus coccyginus to Hortiboletus, and provide a dichotomous key to species of Xerocomellus in western North America.

Facile synthesis of supported Ru-Triphos catalysts for continuous flow application in selective nitrile reduction.

The selective catalytic hydrogenation of nitriles represents an important but challenging transformation for many homogeneous and heterogeneous catalysts. Herein, we report the efficient and modular solid-phase synthesis of immobilized Triphos-type ligands in very high yields, involving only minimal work-up procedures. The corresponding supported ruthenium-Triphos catalysts are tested in the hydrogenation of various nitriles. Under mild conditions and without the requirement of additives, the tunable supported catalyst library provides selective access to both primary amines and secondary imines. Moreover, the first application of a Triphos-type catalyst in a continuous flow process is presented demonstrating high catalyst life-time over at least 195 hours without significant activity loss.

Balsamia (Sequestrate Helvellaceae, Ascomycota) in western North America.

Balsamia, a hypogeous, sequestrate genus in the Helvellaceae, has been characterized variously as having three to eight species in North America, and these have been considered either different from or conspecific with European species. No available modern systematic treatment of Balsamia exists to allow for accurate identification at the species level. We sequenced DNA from recent western North American Balsamia collections, assessed relationships by sequence similarity, and identified molecular taxonomic units. From these data, we determined which matched descriptions and types of named species. ITS sequences supported 12 Balsamia species in western North America, five originally described by Harkness and Fischer and seven new species that we describe here. No sequences from Balsamia collections in western North America were nested among those of European species. We found no clear evidence for separation of Balsamia into multiple genera.

The effect of switching protease inhibitors to raltegravir on endothelial function, in HIV-infected patients.

Objective Lipid management is one of the cornerstones of cardiovascular risk reduction. Treatment of HIV infection with protease inhibitors (PIs) may cause dyslipidaemia, whilst the integrase inhibitor raltegravir (RAL) has a relatively favorable effect on plasma lipids. We examined the effect of switching from PIs to RAL on endothelial function, and its effect on immunological and inflammatory parameters. Methods We performed a 16-week open-label prospective crossover study: 8 weeks intervention (switch PIs to RAL) and 8 weeks control (unchanged cART regimen). Flow-mediated dilatation (FMD), inflammatory plasma, and cellular markers of immune activation were measured at weeks 0, 8, and 16. Results Study participants (n = 22) with a median age of 50 years (IQR 42-60) and known HIV infection of 6.5 years (IQR 5.0-17.3) were on stable cART with undetectable HIV viral loads. After 8 weeks of RAL therapy, a reduction in FMD of -0.81% was seen, compared to +0.54% control (pairwise, p = 0.051), while fasting total cholesterol (-17% versus +10%; p < 0.001), LDL cholesterol (-21% versus -3%; p = 0.026), and triglycerides (-41% versus +18%; p = 0.001) significantly decreased during RAL therapy compared to the control. Furthermore, a relation between the change in percentage of B-1 cells and the change in FMD was found (ß 0.40, 95%CI 0.16; 0.64, p = 0.005) during treatment with RAL. Finally, during RAL therapy, 27% of the patients experienced an increased ALT rise. Conclusions We present an overall negative study, where switching from PIs to RAL slightly reduced the endothelial function while decreasing plasma lipids, thus possibly decreasing the CVD risk in the long term. A transient elevation of ALT was seen upon switch to RAL.

Modular solid-phase synthesis, catalytic application and efficient recycling of supported phosphine-phosphite ligand libraries.

In spite of decades of research in the field of homogeneous asymmetric catalysis the discovery of new high performance catalysts still relies heavily on trial-and-error. There is still a lack of efficient combinatorial methods which enable the synthesis and screening of vast ligand libraries, especially for bidentate phosphorus ligands. Here we present a highly modular solid-phase synthetic approach which provides facile access to libraries of phosphine-phosphite ligands in quantitative yield requiring only minimal work-up. The obtained library of supported phosphine-phosphites was successfully applied in rhodium catalyzed asymmetric hydrogenation obtaining high enantioselectivities up to 98%. Also, these polymer supported ligands could be successfully recycled under batch conditions exhibiting only a small decline of activity and no loss of selectivity.

Phosphinines versus mesoionic carbenes: a comparison of structurally related ligands in Au(i)-catalysis.

Gold(i) complexes based on a 2,4,6-triarylphosphinine and a mesoionic carbene derivative have been prepared and characterized crystallographically. Although structurally related, both heterocycles differ significantly in their donor/acceptor properties. These opposed electronic characteristics have been exploited in Au(i)-catalyzed cycloisomerization reactions. For the conversion of the standard substrate dimethyl 2-(3-methylbut-2-enyl)-2-(prop-2-ynyl)malonate the results obtained for both Au-catalysts were found to be very similar and comparable to the ones reported in the literature for other carbene- or phosphorus(iii)-based Au(i)-complexes. In contrast, a clear difference between the catalytic systems was found for the cycloisomerization of the more challenging substrate N-2-propyn-1-ylbenzamide. A combination of the phosphinine-based complex and [AgSbF6] or [Cu(OTf)2] leads to a catalytic species, which is more active than the mesoionic carbene-based coordination compound. We attribute these differences to the stronger π-accepting ability of phosphinines in comparison to mesoionic carbenes. The here presented results show for the first time that phosphinines can be used efficiently as π-accepting ligands in Au(i)-catalyzed cycloisomerization reactions.

Maraviroc Intensification Improves Endothelial Function in Abacavir-Treated Patients, an Open-Label Randomized Cross-Over Pilot Study.

BACKGROUND: The increased risk of abacavir in cardiovascular disease (CVD) in HIV-infected patients is still being debated. Maraviroc, a CCR5 blocker, has been shown to decrease immune activation and monocyte infiltration in atherosclerotic plaques in murine experiments. Therefore, we examined the effect of maraviroc intensification on flow-mediated dilatation (FMD) in abacavir-treated HIV-infected patients and its effect on immunological and inflammatory parameters. METHODS: A open-label prospective crossover study with a duration of 16 weeks: 8 weeks of intervention (maraviroc intensification) and 8 weeks of control (unchanged cART regimen). FMD, HIV-specific variables, expression of HIV co-receptors, markers of inflammation and coagulation and cellular markers of immune activation were measured at weeks 0, 8 and 16. The changes (Δ) in these variables were compared between intervention and control periods using non-parametric tests. To evaluate the relation with the change in FMD, linear regression modeling was used. RESULTS: Twenty-one male patients with suppressed plasma HIV-RNA, on cART, had a known HIV infection for 9.2 years (IQR 6.9-13.5) with abacavir use for 6.5 years (2.8-9.3). A significantly increased FMD of 0.73% (IQR -0.25 to 1.70) was seen after maraviroc intensification compared to a decrease of -0.42% (IQR -1.89 to 0.25; p = 0.049) in the control period. There was a negative relation between ΔFMD with ΔD-dimer (ß -22.70, 95% CI -39.27; -6.13, p = 0.011) and ΔCD95+ CD4+ T cells (ß -0.16, 95% CI -0.28; -0.04, p = 0.013), adjusted for age and duration of HIV. CONCLUSION: Maraviroc intensification modestly improves endothelial function in HIV-infected patients on an abacavir-containing regimen. TRIAL REGISTRATION: NCT01389063.

Routine chest roentgenography is unnecessary in the work-up of stage I and II breast cancer.

PURPOSE: Clinical practice guidelines of many professional societies call for routine staging chest x-rays (SCXR) for all patients with invasive cancer. Given the estimated 157,000 patients annually for whom this recommendation pertains, this screening examination represents a considerable health care expenditure. If it were shown that SCXR rarely changed the management of low-risk subsets of this population, it might be possible to selectively omit this practice from the care of these patients with substantial resultant cost savings. PATIENTS AND METHODS: All patients with clinical stage I and II breast cancer presenting to the Baystate Medical Center from 1989 through 1997 were identified through the Tumor Registry. Their hospital records were reviewed for clinical presentation and documentation of SCXR. RESULTS: One thousand four hundred ninety-four patients were identified with clinical stage I and II disease. SCXR were available for review on 1,003 patients. Only one asymptomatic patient was upstaged to stage IV based on a SCXR. Two patients with primary lung tumors were also identified. These data demonstrate an asymptomatic pulmonary metastasis detection rate of 0. 099% (95% confidence interval, 0.0% to 0.6%). The total charges of SCXR for this group approached $180,000. CONCLUSION: These data demonstrate the low diagnostic yield and high cost of routine SCXR in the management of asymptomatic patients with clinical stage I and stage II breast cancer. Because other studies have shown that SCXR changes neither quality of life nor overall survival, SCXR should be limited to symptomatic patients in whom metastatic disease is suspected.

Bryostatin 1 activates T cells that have antitumor activity.

Several strategies have been used to stimulate the growth of tumor-specific T cells in place of tumor antigen. One approach is to use pharmacologic agents to activate the second messenger pathways of T-cell activation. In the present study, we examined the ability of the protein kinase C activator bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to stimulate the growth of lymphocytes obtained from the axillary lymph nodes (DLN) draining a progressively growing intradermal plasmacytoma tumor. Draining lymph node cells were initially cultured with autologous tumor cells and 20 U/ml of interleukin-2 (IL-2) for 7 days. The lymphocytes were then incubated with various concentrations of bryostatin 1 plus 1 microM ionomycin and cultured for an additional 14 days in IL-2. DLN cells initially cultured with autologous tumor and then restimulated with 5 nM bryostatin 1 and 1 microM ionomycin exhibited marked in vitro proliferation and 15-fold expansion of cell numbers over 2 weeks. The cells expanded with B/I were predominantly CD8+ T cells and retained specific in vitro cytotoxicity against autologous tumor. When adoptively transferred to mice with established liver metastases, DLN cells restimulated with B/I-mediated specific tumor regression.

A double-blind, randomized, group-comparative study of the tolerability and efficacy of 6 weeks' treatment with mirtazapine or fluoxetine in depressed Chinese patients.

AIM: To compare the efficacy and tolerability of mirtazapine and fluoxetine treatment in a sample population consisting of Chinese patients suffering moderate-to-severe depression. METHOD: 133 patients with a diagnosis of major depressive episode (DSM-IV) and scoring 15 or more on the 17-item Hamilton Rating Scale for Depression (HAM-D) were randomly assigned to receive 6 weeks of treatment with either mirtazapine (15-45 mg/day) or fluoxetine (20-40 mg/day). Efficacy was assessed using the HAM-D and Clinical Global Impressions scale, with analyses performed on the intent-to-treat sample using the last-observation-carried-forward method. Safety analysis was based on the all-subjects-treated group. RESULTS: Mean daily doses were 34.1 mg for mirtazapine (N = 66) and 30.7 mg for fluoxetine (N = 66). Thirty patients in the mirtazapine group and 22 in the fluoxetine group dropped out. Both drugs proved equally effective for reduction of the overall symptoms of depression throughout the treatment period. At day 42, the mean reductions in HAM-D total score (compared with baseline) were 11.8 and 10.6 for the mirtazapine and fluoxetine groups, respectively; however, the changes were not statistically significant. Both treatments were well tolerated, with more nausea and influenza-like symptoms observed for the fluoxetine group, and greater weight increase and somnolence for the mirtazapine analog. CONCLUSION: Both mirtazapine and fluoxetine were indistinguishable in effectiveness for treatment of depressive symptoms, and both were well tolerated by our population of depressed Chinese patients. In line with analogous Western reports, the safety of mirtazapine and fluoxetine was comparable for our depressed Chinese patients; however, slightly different side effect profiles were noted for the 2 drugs in our study.

Ionic implantation of silicone chronic venous access devices does not alter thrombotic complications: a double-blinded, randomized clinical trial.

BACKGROUND: Ion implantation of silicone vascular catheters has been shown in preclinical and pilot studies to alter the thrombogenicity of silicone surfaces through the reduced adherence of thrombin. This prospective, randomized double-blinded study was designed to detect differences in function related to thrombotic events between ion-implanted and standard silicone chronic venous access devices (CVAD) placed in patients with cancer who are receiving chemotherapy. METHODS: Patients with nonleukemic malignancies who required venous access for chemotherapy and who were not receiving anticoagulants were randomized to receive standard or ion-implanted CVAD. Postoperative functional assessments of the ease of infusion or aspiration were performed by oncology nurses caring for the patients. RESULTS: Follow-up, available for 100 of 106 randomized patients, showed more episodes of occlusion to aspiration in the ion implantation group (47%) than in the control group (39%) but this difference was not significant. There were no significant differences between the 2 groups in the number of occasions when anticoagulation or local thrombolytic therapy was required nor were there differences in the numbers of infection or deep venous thromboses. CONCLUSIONS: Ion implantation of silicone catheter material does not alter the incidence of local thrombotic complications of CVAD. Although there were no serious complications resulting from this treatment, the use of ion-implanted catheters cannot be recommended on the basis of this trial.

A cytotoxic T-lymphocyte clone derived from mice with progressively growing tumors.

Tumor-specific T-cell clones were derived from spleen cells of mice bearing a syngeneic PHS-5 tumor (a P815 mastocytoma mutant). Cells were expanded in vitro and characterized and assayed for activity against the relevant tumor in vivo. Clone cells were CD4-, CD8+ T lymphocytes, as determined by fluorescence activated cell sorting analysis and were specifically cytotoxic against P815 tumor cells in vitro, as shown in chromium 51 release assays. These cells require both antigen and interleukin 2 to proliferate; neither alone is sufficient, even with the addition of interleukin 1. In an experimental P815 liver metastasis model, the adoptive transfer of GD11 or GD11.17 clone cells and injection of recombinant interleukin 2 (7500 U intraperitoneally) 3 days after infusion of tumor cells reduced the number of tumor nodules, while the adoptive transfer of lymphokine-activated killer cells was ineffective.

Psychoanalytic treatment of children and adolescents.

Psychoanalytic psychotherapy has had extensive application to a wide range of disorders in adolescents and children of different ages over the past 50 years. Psychoanalytic theory places particular emphasis on the meaning and function of symptomatic behavior in establishing internal equilibrium and adaptation to the environment. Children of different ages bring to treatment a variety of developmental issues and conflicts consistent with their stage of development. Case reports of psychoanalytic treatment serve as pieces of clinical research for preschoolers, latency age children, and adolescents. In children with physical/metabolic disorders, the child's physical disability becomes a ready foci for neurotic symptom formation requiring special therapeutic management. The special processes and tools of transference, resistance, interpretation, defense analysis, and working-through give the psychotherapist the necessary means to resolve deeply entrenched neurotic patterns.

Expansion and tumour specific cytokine secretion of bryostatin-activated T-cells from cryopreserved axillary lymph nodes of breast cancer patients.

Current adoptive immunotherapy strategies in cancer patients require large numbers of activated T-cells and are limited by the availability of autologous tumour. We describe a novel method of T-cell activation that produced relatively rapid, high-fold expansion of stored, frozen lymphocytes obtained from the lymph nodes of 20 breast cancer patients during axillary dissection but does not require autologous tumour. In vitro exposure of thawed cells to bryostatin-1 (B), a non-tumour promoting protein kinase C activator and ionomycin (I), a calcium ionophore, at day 0 followed by culture in low dose interleukin-2 (IL-2 20 units ml-1) and restimulation again on day 10 results in 269-28,206 fold (geometric mean = 2254) expansion in cell numbers counted 17 days after initial stimulation. Analysis of cell surface markers revealed that B/I expanded human cells were predominantly T-cells (83-97%) and consisted of a mixture of CD8+ (46-74%) and CD4+ (4-30%) cells. B/I expanded cells did not lyse autologous tumour cells when tested in a 4-h 51Cr release assay, but murine studies reported previously have demonstrated specific and curative in vivo efficacy in MCA-105 tumour-bearing mice despite an inability to lyse autologous tumour in vitro. B/I expanded T-cells from five of six patients secreted the cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in response to co-culture with autologous tumour cells but not with irrelevant tumour. These results are analogous to findings in a murine model, in which non-cytolytic B/I expanded T-cells mediated specific, curative anti-tumour effects in vivo, and lay the groundwork for a clinical trial of this novel strategy for the adoptive immunotherapy of breast cancer patients.

Epidermal growth factor receptor expression in squamous cell carcinoma of the hypopharynx.

Expression of the epidermal growth factor receptor (EGFR) has been demonstrated in normal and malignant squamous epithelia. Its presence has been suggested to be important in the pathophysiology and prognosis of epithelial cancers. Archival tumour specimens from 57 patients with squamous cell carcinoma of the hypopharynx were studied using OM-11-951, a new murine anti-EGFR monoclonal antibody which recognizes the receptor on deparaffinized tissue. By visual inspection, 28 (49%) tumours were EGFR negative; 29 (51%) tumours were EGFR positive. While patients whose tumours were EGFR positive were younger, there was no significant correlation with other clinical or pathological variables (including grade and stage). Patients whose tumours were EGFR negative had a median survival of 21 (95% CI 4.3-37.7) months compared with a median survival of 17 (95% CI 11.4-22) months for patients whose tumours were EGFR positive. The difference was not statistically significant. A multiple regression analysis did not demonstrate EGFR status to be important in predicting survival. These data cast doubt on the prognostic significance of EGFR expression in this neoplasm.

Usual and unusual radiologic manifestations of acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) infection in children.

AIDS is being recognized with ever-increasing frequency in children. This article includes a discussion of the common radiographic manifestations of AIDS as well as some rarely encountered problems. It is hoped that with heightened awareness of this spectrum of radiographic findings, radiologists may contribute to a prompt diagnosis of AIDS so that appropriate short-term therapy and counseling may be instituted.

Monocyte 5-HT1A receptors mediate pindobind suppression of natural killer cell activity: modulation by catalase.

Serotonin (5-hydroxytryptamine; 5-HT) modulates constituents of the immune system. 5-HT1A receptor antagonists potently suppress lymphocyte function. NK cell activity (NKCA) was measured after exposure of mononuclear cells to the 5-HT1A receptor antagonist pindobind and the 5-HT(1C/2) receptor antagonist ketanserin. Elutriated monocytes were exposed to pindobind, incubated with peripheral blood lymphocytes (PBL) in the presence or absence of an H2O2 scavenger catalase, and NKCA measured. Pindobind, but not ketanserin, suppressed NKCA in vitro. Pindobind-treated monocytes suppressed NKCA, whereas pindobind treatment of PBL did not affect NKCA. Catalase inhibited pindobind-induced suppression of NKCA. These data are consistent with previous results that 5-HT modulates NKCA via 5-HT1A receptors on monocytes and suggest that 5-HT may abrogate monocyte suppression of NKCA by inhibiting monocyte signals such as H2O2.

Magnetic resonance imaging of spinal arteriovenous malformations.

Magnetic resonance imaging (MRI) was performed on 12 patients with spinal arteriovenous malformations (AVM's). Six lesions were intramedullary, five were dural, and one was in a posterior extramedullary location. Serpentine filling defects similar to the classic myelographic findings were demonstrated within the high-signal cerebrospinal fluid on T2-weighted coronal scans. The intramedullary nidus was identified by MRI as an area of low-signal intensity within the cord in all six intramedullary AVM's. Neither the dural nor the posterior extramedullary lesions showed intramedullary components. It is concluded that MRI may noninvasively provide the initial diagnosis of a spinal AVM and distinguish intramedullary from dural and extramedullary lesions.