High-dimensional profiling reveals Tc17 cell enrichment in active Crohn's disease and identifies a potentially targetable signature.

The immune-pathology in Crohn's disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn's disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn's disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions.

[COVID-19: treatment strategies of German-speaking pediatric rheumatologists : Results of an online survey]. / COVID-19: Behandlungsstrategien der deutschsprachigen Kinderrheumatologen : Ergebnisse einer Online-Umfrage.

BACKGROUND: Reliable data on the course and treatment of pediatric COVID-19 ("corona virus disease 2019") in immunosuppressed patients with rheumatic diseases are missing. AIM: Delineation of individual strategies of the members of the Society for Pediatric Rheumatology (GKJR) in cases of COVID-19. METHODS: In May 2020 all GKJR members were invited to take part in an online survey. Opinion data regarding an approach using disease-modifying anti-rheumatic drugs (DMARD) in cases of COVID-19 as well as the readiness to use new therapeutic agents in patients in different stages of the disease were collected. RESULTS: A total of 71 respondents (27.3% of all contacted pediatric rheumatologists) took part in the survey. Of these 28.2% had treated patients with COVID-19. Over 95% of the respondents did not support a preventive adaptation of the anti-rheumatic treatment during the SARS-CoV­2 pandemic. In the case of outpatients under immunosuppression with proven COVID-19 more than 50% of the respondents would refrain from administering intravenous high-dose steroids, cyclophosphamide, anti-CD20 antibodies as well as BAFF, CTLA­4 and TNF-alpha blockades. Conversely, >70% of the respondents would continue the treatment with nonsteroidal anti-inflammatory drugs, hydroxychloroquine (HCQ), oral steroids, mycophenolate, IL­1 blockade and immunoglobulins (Ig). In the case of inpatients 74.6% of respondents would consider targeted COVID-19 treatment. In stable patients with oxygen treatment (stage I) HCQ (18.3%), azithromycin (16.9%) and Ig (9.9%) were most frequently used. In cases of early signs (stage II) or a manifest cytokine storm (stage III) anakinra (40.8% for stage II and 46.5% for stage III), tocilizumab (26.8% and 40.8%, respectively), steroids (25.4% and 33.8%, respectively) and remdesivir (29.6% and 38.0%, respectively) were most frequently used. The need for a personalized approach based on the current clinical situation was emphasized by many respondents. CONCLUSION: The currently low prevalence of COVID-19 in Germany limits the general clinical experience. Therefore, the presented results have to be interpreted with caution and mostly as hypothetical treatment considerations. It is to be expected that there will always be a limited amount of evidence on pediatric COVID-19; therefore, a continuous and critical exchange of expert opinions on the treatment strategies is important.

Improvement of renal graft function after conversion from a calcineurin inhibitor including immunosuppression to a mycophenolate sodium including regimen: a 4-year follow-up.

BACKGROUND: The most common immunosuppressive regimens after renal transplantation include calcineurin inhibitors (CNI). However, due to renal toxicity long-term graft survival does not seem to be positively affected by CNIs. METHODS: In the present study, we investigated 17 patients, in which the CNI immunosuppression was converted to a CNI-free, mycophenolate sodium (MPS) regimen. Conversion was performed due to progressive impairment of the graft function from suspected CNI toxicity. We retrospectively analyzed graft function as well as toxicity and surrogate markers for 4 years before and 4 years after conversion using a repeated-measures mixed model data analysis and/or a paired sample t-test. RESULTS: The mean time point of therapy conversion was 11.2 ± 4.6 years after transplantation. Within 1 month of CNI discontinuation, allograft function improved significantly, remaining at a significant level for 2 years. The estimated glomerular filtration rate increased from 43.4 ± 14.8 to a maximum of 55.7 ± 21.7 mL/min at 1 year after conversion (P = .0027). After 4 years, the end of the observation period, renal function was similar to the baseline. There were no significant side effects. CONCLUSION: These data suggested that, when chronic CNI-toxicity is suspected, renal allograft recipients may benefit from CNI withdrawal in favor of a MPS-including immunosuppressive regimen.

Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins.

The hepatitis C virus (HCV)-specific CD4+ T-cell response against nonstructural proteins is strongly associated with successful viral clearance during acute hepatitis C. To further develop these observations into peptide-based vaccines and clinical immunomonitoring tools like HLA class II tetramers, a detailed characterization of immunodominant CD4+ T-cell epitopes is required. We studied peripheral blood mononuclear cells from 20 patients with acute hepatitis C using 83 overlapping 20-mer peptides covering the NS3 helicase and NS4. Eight peptides were recognized by > or = 40% of patients, and specific CD4+ T-cell clones were obtained for seven of these and three additional, subdominant epitopes. Mapping of minimal stimulatory sequences defined epitopes of 8 to 13 amino acids in length, but optimal T-cell stimulation was observed with 10- to 15-mers. While some epitopes were presented by different HLA molecules, others were presented by only a single HLA class II molecule, which has implications for patient selection in clinical trials of peptide-based immunotherapies. In conclusion, using two different approaches we identified and characterized a set of CD4+ T-cell epitopes in the HCV NS3-NS4 region which are immunodominant in patients achieving transient or persistent viral control. This information allows the construction of a valuable panel of HCV-specific HLA class II tetramers for further study of CD4+ T-cell responses in chronic hepatitis C. The finding of immunodominant epitopes with very constrained HLA restriction has implications for patient selection in clinical trials of peptide-based immunotherapies.

[Three patients with hereditary multiple exostoses and malignant degeneration of an osteochondroma located in the pelvis]. / Drie patiënten met hereditaire multipele exostosen en maligne ontaarding van een bekkenosteochondroom.

In three male patients with hereditary multiple exostoses (HME), aged 50, 29 and 31 years, peripheral low-grade chondrosarcoma in the pelvic region led to swelling or pain. In the first patient, curative resection was not feasible because of the size and extension of the tumour. However, rapid tumour growth and unbearable pain necessitated a debulking procedure 16 months later. Histopathologic examination revealed a highly malignant dedifferentiated chondrosarcoma. The patient died two years after initial presentation as a result of local tumour growth. In the second patient, treatment consisted of wide resection of the tumour. Five years after the surgery the patient was free of disease. The third patient was initially treated by intralesional resection, followed by partial hemipelvectomy because of residual tumour. Thirteen months later, a local recurrence occurred that was treated by wide excision. Four years after the partial hemipelvectomy the patient was both pain-free and disease-free. Patients with HME are at increased risk for malignant degeneration of pelvic osteochondroma to chondrosarcoma. Periodic control of patients with pelvic osteochondromas is advised, preferably once every two years.

Monomeric and dimeric amidinate complexes of magnesium.

Treatment of anhydrous magnesium bromide with 2 equiv of (1,3-di-tert-butylacetamidinato)lithium, (1,3-di-tert-butylbenzamidinato)lithium, (1,3-diisopropylacetamidinato)lithium, or (1-tert-butyl-3-ethylacetamidinato)lithium (prepared in situ from the corresponding carbodiimide and alkyllithium) in diethyl ether at ambient temperature afforded bis(N,N'-di-tert-butylacetamidinato)magnesium (81%), bis(N,N'-di-tert-butylbenzamidinato)magnesium (82%), bis[bis(N,N'-diisopropylacetamidinato)magnesium] (70%), or bis[bis(1-tert-butyl-3-ethylacetamidinato)magnesium] (93%), respectively, as colorless crystalline solids. These complexes were characterized by spectral and analytical data and by single-crystal X-ray crystallography for bis(N,N'-di-tert-butylbenzamidinato)magnesium, bis[bis(N,N'-diisopropylacetamidinato)magnesium], and bis[bis(1-tert-butyl-3-ethylacetamidinato)magnesium]. In the solid-state structure, bis[bis(1-tert-butyl-3-ethylacetamidinato)magnesium] was found to contain mu,eta(2):eta(1)-amidinato ligands. Bis[bis(N,N'-diisopropylacetamidinato)magnesium] exists in a monomer-dimer equilibrium in toluene-d(8) between -20 and +60 degrees C. A van't Hoff analysis of this equilibrium afforded DeltaH degrees = -14.7 +/- 0.2 kcal/mol, DeltaS degrees = -44.9 +/- 0.2 cal/(mol.K), and DeltaG degrees (298 K) = -1.32 +/- 0.2 kcal/mol. The potential application of the new compounds in the chemical vapor deposition of magnesium-doped group 13 compound semiconductor films is discussed.

Early transition metal complexes containing 1,2,4-triazolato and tetrazolato ligands: synthesis, structure, and molecular orbital studies.

Several early transition metal complexes bearing 1,2,4-triazolato and tetrazolato ligands have been prepared by reaction of the pyrazolato complexes Ti(tBu(2)pz)(4-x)Cl(x) (tBu(2)pz = 3,5-di-tert-butylpyrazolato; x = 1, 2) and M(tBu(2)pz)(5-x)Cl(x) (M = Nb, Ta: x = 2, 3) with the sodium or potassium salts derived from 1,2,4-triazoles and tetrazoles. The X-ray structure analysis of Ti(tBu(2)pz)(2)(Me(2)C(2)N(3))(2) shows eta(2)-coordination of the 1,2,4-triazolato ligands, while in Ti(tBu(2)pz)(3)(C(2)H(2)N(3)) and Nb(tBu(2)pz)(3)(Me(2)C(2)N(3))(2) the analogous groups are joined in a eta(1)-fashion in the solid-state structure. Solution NMR studies at different temperatures suggest transition states involving eta(2)-1,2,4-triazolato ligands for the complexes containing eta(1)-1,2,4-triazolato ligands in the solid state. X-ray crystal structures of analogous tetrazolato complexes Ti(tBu(2)pz)(3)(PhCN(4)) and Nb(tBu(2)pz)(3)(PhCN(4))(2) show eta(1)-coordination of the 2-nitrogen atoms of the tetrazolato ligands. Molecular orbital calculations have been carried out on several model titanium complexes and provide detailed insight into the bonding between early transition metal centers and 1,2,4-triazolato and tetrazolato ligands. The eta(2)-coordination mode of 1,2,4-triazolato and tetrazolato ligands is predicted to be more stable than the eta(1)-coordination mode by 13.8-5.2 kcal/mol.

A randomized trial of the long-term effects of digital ocular compression in the late postoperative period.

PURPOSE: To determine whether digital ocular compression is a viable technique to lower intraocular pressure in patients at least 3 months after trabeculectomy. PATIENTS AND METHODS: A 6-month prospective, randomized, controlled, single-masked trial of 29 patients who underwent a trabeculectomy at the Glaucoma Service of Wills Eye Hospital. Patients were assigned to two groups: ocular compression or cheekbone compression (control group). The ocular compression group performed compression to the operated eye three times a day in the pattern of 10 seconds of pressure, 5 seconds of rest, and 10 seconds of pressure. Pressure was applied with the index finger through the closed lid to the center of the cornea. Pressure was steady and firm, but not painful. No massaging was performed. The cheekbone compression group applied pressure to the zygomatic arch with an identical style and frequency. RESULTS: At 6 months, the change in mean intraocular pressure for the ocular compression group was 0.25 mm Hg compared with -0.44 mm Hg for the control group (P = 0.7). A few patients in both groups experienced large swings in intraocular pressure and mild to moderate discomfort. CONCLUSION: Ocular compression had little to no success in the long-term management of increased intraocular pressure in the late postoperative period in this study.

Cortical fibroblast culture from human biopsies.

BACKGROUND: Tubulointerstitial fibrosis is an integral part of progressive renal disease. Human cortical fibroblasts are believed to be key effector cells in fibrogenesis. Thus, a reliable culture of these cells is necessary for studies of their pathophysiology. METHODS: Cortical fibroblast culture from routine kidney biopsies were analyzed and the cells were characterized. Indirect immunofluorescence staining was done after the first passage for cytokeratin, vimentin, alpha-smooth muscle actin, CD 44, CD 54, CD 68, collagen types I, III, and HLA-DR. We then assessed the utility of the putative fibroblast markers CD 90, prolyl-4-hydroxylase (P4H) and F1b in simultaneous stainings of tubular epithelial cells. RESULTS: During the study period, 49 biopsy cores were cultured and cortical fibroblasts could be successfully established in 21 cases (42.9%). There was no relation between the success rate of culture and the degree of interstitial fibrosis, but an association was seen with the time of completion of the first passage. There was a negative correlation between the extent of scarring and the percentage of cytokeratin positive cells (r = -0.66, p < 0.001). All primary fibroblasts were negative for factor VIII, HLA-DR, CD 68, and cytokeratin. They expressed alpha-smooth muscle actin and collagen types I and III to variable degrees. There was a robust correlation between the percentage of alpha-smooth muscle actin positive cells and interstitial scarring but no such association with collagen type I or type III positive cells. The three putative fibroblast markers did not prove useful in differentiating between tubular epithelial cells and fibroblasts. However, since only fibroblasts stained positive for CD 90 and negative for cytokeratin, these two markers may suffice to distinguish fibroblasts from other renal cellular elements. CONCLUSIONS: Cortical renal fibroblasts can be easily cultured from kidney biopsy cores, though the success rate of pure cultures is below 50%. Staining for CD 90 and cytokeratin may suffice for initial characterization of these cells.

Direct evidence for a geometrically constrained "entatic state" effect on copper(II/I) electron-transfer kinetics as manifested in metastable intermediates.

The absolute magnitude of an "entatic" (constrained) state effect has never been quantitatively demonstrated. In the current study, we have examined the electron-transfer kinetics for five closely related copper(II/I) complexes formed with all possible diastereomers of [14]aneS(4) (1,4,8,11-tetrathiacyclotetradecane) in which both ethylene bridges have been replaced by cis- or trans-1,2-cyclohexane. The crystal structures of all five Cu(II) complexes and a representative Cu(I) complex have been established by X-ray diffraction. For each complex, the cross-reaction rate constants have been determined with six different oxidants and reductants in aqueous solution at 25 degrees C, mu = 0.10 M. The value of the electron self-exchange rate constant (k(11)) has then been calculated from each cross reaction rate constant using the Marcus cross relation. All five Cu(II/I) systems show evidence of a dual-pathway square scheme mechanism for which the two individual k(11) values have been evaluated. In combination with similar values previously determined for the parent complex, Cu(II/I)([14]aneS(4)), and corresponding complexes with the two related monocyclohexanediyl derivatives, we now have evaluated a total of 16 self-exchange rate constants which span nearly 6 orders of magnitude for these 8 closely related Cu(II/I) systems. Application of the stability constants for the formation of the corresponding 16 metastable intermediates--as previously determined by rapid-scan cyclic voltammetry--makes it possible to calculate the specific electron self-exchange rate constants representing the reaction of each of the strained intermediate species exchanging electrons with their stable redox partners--the first time that calculations of this type have been possible. All but three of these 16 specific self-exchange rate constants fall within--or very close to--the range of 10(5)-10(6) M(-1) s(-1), values which are characteristic of the most labile Cu(II/I) systems previously reported, including the blue copper proteins. The results of the current investigation provide the first unequivocal demonstration of the efficacy of the entatic state concept as applied to Cu(II/I) systems.

Electron/atom transfer in halo-bridged homobimetallic complexes. structure and donor-acceptor properties of face-to-face dicopper complexes with teraazamacrocyclic ligands.

The syntheses and donor-acceptor properties of some novel, halo-bridged dicopper(II) complexes of alpha,alpha'-bis(5,7-dimethyl-1,4,8,11-tetraazacyclotetradecane-6-yl)-o-xylene are reported. These complexes were characterized by their magnetic and electrochemical behavior, X-ray structure analysis, FAB mass spectroscopy, and electronic spectra. The bromo-bridged complex crystallized in the tetragonal system, space group P4(3)2(1)2, with a = 12.6584(5) A, c = 28.6483 (14) A, Z = 4, R = 0.071, and Rw = 0.147. The chloro-bridged complex crystallized in the monoclinic system, space group C2/c, with a = 32.749(2) A, b = 18.8915(9) A, c = 26.022(2) A, beta =114.831 degrees, Z = 12, R = 0.080, and Rw = 0.132. Both molecules have C2 symmetry. The two copper(II) ions are axially bridged by a bromine or a chlorine, and the two macrocycles are bridged by an o-xylene group. Each complex displays a cofacial ring arrangement. The Cu-X distance (where X = Cl, Br) is shorter than the sum of van der Waals radii of Cu and X. The phenyl ring is approximately orthogonal to the Cu-X-Cu axis. The nonhalo-bridged complex has a significant affinity for halides (Kf approximately 10(4) M(-1)). The chloride-bridged complex had barely resolved differential pulse polarographic waves (DeltaE1/2 approximately 28 mV), while the bromide-bridged complex exhibited two CV waves in the 1.0-1.5 V range (DeltaE1/2 = 0.24 V). All the Cu(II)/Cu(I) couples were irreversible with a cathodic peak at about - 0.9 V. The magnetic susceptibility results below 20 K follow Curie-Weiss behavior, indicating that the magnetic interaction between the two Cu centers is weakly antiferromagnetic with J < or = -1 cm(-1) for all three complexes. A bridging-ligand-mediated superexchange model is used to treat the magnetic and electron-transfer coupling in the Cu(II)(X-)Cu(II) complexes. A single set of perturbation theory parameters is consistent with the magnetic and electrochemical observations on the chloride-bridged complex and the magnetic properties of the bromide-bridged complex. The electrochemical behavior of the latter suggests a relatively low-energy, high-spin configuration for the Cu(III)(Br-)Cu(II) complex. The analysis attributes the weak Cu(II)/Cu(II) coupling to the orthogonality of the donor and acceptor orbitals to the bridging axis. It is inferred that bridging halide-mediated metal-metal dsigma/psigma coupling significantly alters the chemical properties of the bimetallic complexes only when the donor and acceptor orbitals are coaxial with the bridging ligand. In such a limit, the coupling takes the form of a three-center bonding contribution.

Effects of pentoxifylline, pentifylline and gamma-interferon on proliferation, differentiation, and matrix synthesis of human renal fibroblasts.

BACKGROUND: Kidneys that progress to end-stage renal failure are almost invariably characterized by the presence of tubulointerstitial fibrosis. Therapeutic interventions to halt the progressive deterioration of renal function are still limited. Pentoxifylline, pentifylline, and gamma-interferon have shown a potential benefit in the treatment of fibrotic processes in the skin and lung. Thus, the aim of the present study was the analysis of potential anti-fibrotic effects of these substances on human kidney fibroblasts in vitro. METHODS: Primary renal fibroblasts were established from human kidney biopsies and were studied in addition to two renal fibroblast cell lines. Cells were first growth arrested by withdrawal of fetal calf serum (FCS) and subsequently stimulated with 10% FCS in the presence of different concentrations of pentoxifylline (PTX), pentifylline (PTF), or gamma-interferon (IFN-gamma). Fibroblast proliferation was determined by bromodeoxyuridine incorporation and cell counts. Northern and western blot hybridizations for basic fibroblast growth factor (FGF)-2 and transforming growth factor (TGF)-beta1 were performed to analyse inhibitory effects. The effects of all three substances on matrix synthesis were evaluated by immunoblot analyses and ELISA for collagen type I and fibronectin after stimulation with TGF-beta1. Finally, differentiation into myofibroblasts was examined by double immunofluorescence staining for alpha-smooth-muscle actin and Hoechst dye H33258. RESULTS: PTX and PTF resulted in a dose- and time-dependent inhibition of proliferation in all fibroblast lines (maximum 78.9+/-6.2% at 500 microg/ml PTX). Conversely, IFN-gamma had only modest effects on fibroblast proliferation, resulting in a maximum of 36.0+/-6.1% inhibition at 500 U/ml. Northern blot hybridizations determined that FGF-2 mRNA levels in fibroblasts were decreased up to 73.7 and 91.5% by PTX (1000 microg/ml) and PTF (100 microg/ml), whereas IFN-gamma led to a reduction of 46.2% at 1000 U/ml, indicating that the inhibitory effects of all three substances may be mediated through inhibition of FGF-2 synthesis. These findings were corroborated by immunoblot analyses where again PTX and PTF had the strongest inhibitory effects. No change in TGF-beta1 mRNA levels was noted. Synthesis of cellular and secreted collagen type I was robustly inhibited by PTX and PTF, whereas IFN-gamma exerted the strongest inhibitory effect on fibronectin synthesis and secretion. In addition, IFN-gamma down-regulated the expression of alpha-smooth-muscle actin up to 73.3% (at 1000 U/ml) whereas PTX and PTF resulted in a down-regulation of up to 49.7+/-1.8 and 80.0+/-4.4% (at 1000 and 100 microg/ml) respectively. PTF was in all experiments about 10 times more potent than equimolar concentrations of PTX. CONCLUSIONS: PTX and PTF exerted robust inhibitory effects on fibroblast proliferation, extracellular matrix synthesis, and myofibroblastic differentiation. Conversely, IFN-gamma caused strong inhibition of fibronectin synthesis and alpha-smooth-muscle cell actin expression but had only weak inhibitory influences on fibroblast proliferation and collagen type I synthesis. Inhibitory effects of all three substances on proliferation may be mediated through inhibition of FGF-2 synthesis.

Acetabular fractures in children and adolescents.

A retrospective study of 29 acetabular fractures in children 2 to 16 years of age with an average followup of 14 years is presented. Nineteen patients had an additional dislocation of the femoral head and 14 patients had an associated neurologic injury. Surgical treatment was performed in 16 patients and consisted of open reduction and internal fixation in 14 patients and a simple arthrotomy in two patients. Thirteen patients were treated nonoperatively with traction or bedrest. The outcome was satisfactory in all patients with undisplaced fractures and fractures with disruption of a small fragment. Eight patients with linear fractures with instability all were treated surgically. All but one of the patients had a satisfactory functional outcome; one patient had early degenerative changes develop after an open pelvic and acetabular fracture. Patients with central fractures and dislocations had a relatively poor outcome, and congruency was achieved in only one of the four patients who were treated surgically. Results may deteriorate with time, as was seen when the results of the current study were compared with those published 10 years previously.

Neonatal infectious spondylitis of the cervical spine presenting with quadriplegia: a case report.

STUDY DESIGN: A case report.- OBJECTIVE: To highlight the evaluation and treatment of neonatal infectious spondylitis of the cervical spine. SUMMARY OF BACKGROUND DATA: Most authors advise intravenous antibiotics as first-choice treatment. The place of aspiration or operative drainage is debated, as is the position and duration of immobilization. METHODS: A 3-week-old neonate was presented with intermittent quadriplegia. RESULTS: Additional investigation demonstrated an osteolytic process in the body of C3 with a large epidural abscess compressing the spinal cord. Because an infectious spondylitis of C3 was suspected, aspiration of the abscess was performed, and antibiotic therapy was started. The patient improved to neurologically normal within 3 weeks and remains asymptomatic throughout a follow-up period of 7 years. CONCLUSIONS: Neonatal infectious spondylitis should be diagnosed early and treated promptly; otherwise, it may have devastating consequences.

Effect of conformational constraints on gated electron-transfer kinetics. 3. Copper(II/I) complexes with cis- and trans-cyclopentanediyl-1,4,8,11-tetrathiacyclotetradecane.

Previous kinetic and electrochemical studies of copper complexes with macrocyclic tetrathiaethers-such as 1,4,8,11-tetrathiacyclotetradecane ([14]aneS4)-have indicated that electron transfer and the accompanying conformational change occur sequentially to give rise to a dual-pathway mechanism. Under appropriate conditions, the conformational change itself may become rate-limiting, a condition known as "gated" electron transfer. We have recently hypothesized that the controlling conformational change involves inversion of two donor atoms, which suggests that "gated" behavior should be affected by appropriate steric constraints. In the current work, two derivatives of [14]aneS4 have been synthesized in which one of the ethylene bridges has been replaced by either cis- or trans-1,2-cyclopentane. The resulting copper systems have been characterized in terms of their Cu(II/I)L potentials, the stabilities of their oxidized and reduced complexes, and their crystal structures. The electron self-exchange rate constants have been determined both by NMR line-broadening and by kinetic measurements of their rates of reduction and oxidation with six or seven counter reagents. All studies have been carried out at 25 degrees C, mu = 0.10 M (NaClO4 and/or Cu(ClO4)2), in aqueous solution. Both Cu(II/I) systems show evidence of a dual-pathway mechanism, and the electron self-exchange rate constants representative of both mechanistic pathways have been determined. The first-order rate constant for gated behavior has also been resolved for the Cu(I)(trans-cyclopentane-[14]aneS4) complex, but only a limiting value can be established for the corresponding cis-cyclopentane system. The rate constants for both systems investigated in this work are compared to values previously determined for the Cu(II/I) systems with the parent [14]aneS4 macrocycle and its derivatives involving phenylene and cis- or trans-cyclohexane substituents. The results are discussed in terms of the influence of the fused rings on the probable conformational changes accompanying the electron-transfer process.

Formation and dissociation kinetics and crystal structures of nickel(II)-macrocyclic tetrathiaether complexes in acetonitrile. Comparison to nickel(II)-macrocyclic tetramines.

Complex formation and dissociation rate constants have been independently determined for solvated nickel(II) ion reacting with eight macrocyclic tetrathiaether ligands and one acyclic analogue in acetonitrile at 25 degrees C, mu = 0.15 M. The macrocyclic ligands include 1,4,8,11-tetrathiacyclotetradecane ([14]aneS4) and seven derivatives in which one or both ethylene bridges have been substituted by cis- or trans-1,2-cyclohexane, while the acyclic ligand is 2,5,9,12-tetrathiatridecane (Me2-2,3,2-S4). In contrast to similar complex formation kinetic studies on Ni(II) reacting with corresponding macrocyclic tetramines in acetonitrile and N,N-dimethylformamide (DMF), the kinetics of complex formation with the macrocyclic tetrathiaethers show no evidence of slow conformational changes following the initial coordination process. The differing behavior is ascribed to the fact that such conformational changes require donor atom inversion, which is readily accommodated by thiaether sulfurs but requires abstraction of a hydrogen from a nitrogen (to form a temporary amide). The latter process is not facilitated in solvents of low protophilicity. The rate-determining step in the formation reactions appears to be at the point of first-bond formation for the acyclic tetrathiaether but shifts to the point of chelate ring closure (i.e., second-bond formation) for the macrocyclic tetrathiaether complexes. The formation rate constants for Ni(II) with the macrocyclic tetrathiaethers parallel those previously obtained for Cu(II) reacting with the same ligands in 80% methanol-20% water (w/w). By contrast, the Ni(II) dissociation rate constants show significant variations from the trends in the Cu(II) behavior. Crystal structures are reported for the Ni(II) complexes formed with all five dicyclohexanediyl-substituted macrocyclic tetrathiaethers. All but one are low-spin species.

Synthesis and characterization of calcium complexes containing eta 2-pyrazolato ligands.

Treatment of calcium bromide with 3,5-di-tert-butylpyrazolatopotassium (2 equiv) in tetrahydrofuran afforded Ca(tBu2pz)2(THF)2 (69%). The reaction of this compound with pyridine (3 equiv), tetramethylethylenediamine (TMEDA, 1 equiv), N,N,N',N',N"-pentamethyldiethylenetriamine (PMDETA, 1 equiv), triglyme (1 equiv), and tetraglyme (1 equiv) yielded Ca(tBu2pz)2(py)3 (51%), Ca(tBu2pz)2(TMEDA) (74%), Ca(tBu2pz)2(PMDETA) (50%), Ca(tBu2pz)2(triglyme) (73%), and Ca(tBu2pz)2(tetraglyme) (57%), respectively. Treatment of the tetrahydrofuran adduct of Ca(Me2pz)2, generated in situ, with PMDETA (1 equiv), triglyme (1 equiv), and tetraglyme (1 equiv) afforded Ca(Me2pz)2(PMDETA) (65%), Ca(Me2pz)2(triglyme) (54%), and Ca(Me2pz)2(tetraglyme) (40%), respectively. The X-ray crystal structures of Ca(tBu2pz)2(py)3, Ca(tBu2pz)2(TMEDA), Ca(tBu2pz)2(PMDETA), Ca(tBu2pz)2(triglyme), and Ca(Me2pz)2(PMDETA) revealed six-, seven-, or eight-coordinate calcium centers with eta 2-pyrazolato ligands. Ca(tBu2pz)2(triglyme) sublimes at 160 degrees C (0.1 mmHg). The potential utility of these complexes as source compounds for chemical vapor deposition processes is discussed.

99mTc(L-L)3+ complexes containing ether analogs of DMPE.

Novel 99mTc(L-L)3+ complexes have been investigated for potential use in myocardial perfusion imaging. Bidentate chelators have been prepared that are based on substituent analogs of 1,2-bis(dimethylphosphino)ethane, onto which alkyl ether groups have been incorporated. The new ligands are: (1) MMPE, 1,2-bis(methyl methoxyethyl phosphino)ethane, (2) MIBPE, 1,2-bis(methyl methoxyisobutyl phosphino)ethane, (3) FURPE, 1,2-bis(methyl tetrahydrofuran phosphino)ethane, and (4) PYRPE, 1,2-bis(methyl tetrahydropyran phosphino)ethane. These ligands have been reacted with 99mTc and the resulting complexes evaluated for myocardial imaging properties. 99mTc(MMPE)3+ exhibited the most favorable myocardial imaging characteristics in animal models. Results indicate that pendent ether moieties can improve the myocardial imaging properties of cationic technetium complexes.

A novel chromium(0)-promoted four-component cycloaddition reaction.

[formula: see text] Reaction of (eta 6-thiepin-1,1-dioxide)tricarbonylchromium(0) with excess terminal alkynes under photoactivation conditions affords novel pentacyclic adducts formally derived from a sequential [6 pi + 2 pi]/[6 pi + 2 pi]/[2 sigma + 2 pi] cycloaddition process.

Rotationplasty of the lower limb for childhood osteosarcoma of the femur.

BACKGROUND: Surgical management of osteosarcoma of the limb in childhood often involves extensive surgery. Intervention ranges from local resection to amputation depending on the level and the extent of the disease process. However, where the disease is extensive the level of amputation may preclude effective prosthetic use. In these circumstances resection of the diseased segment of the limb, i.e. an intercalary amputation and reconstruction with rotation of the tibial component of the limb can provide function equivalent to a below-knee amputee. METHODS: To examine the role of rotationplasty of the lower limb for childhood osteosarcoma of the femur, a retrospective study was carried out which examined the function of five patients who had been treated by a tibial rotationplasty. The records of two patients who had died from metastatic disease 2 and 4 years after surgery were examined. The three surviving patients were examined clinically and their clinical records and radiographs were reviewed. RESULTS: Of the two patients who died from metastatic disease, neither had local recurrence of the tumour, neurovascular complications, late derotations or psychological problems. In the three patients who survived, there had been no local recurrence of tumour or other complication and each has an excellent level of activity with below-knee function using a rotationplasty prosthesis. CONCLUSIONS: For children with osteosarcoma of the femur and with extensive disease that precludes complete limb preservation, resection and tibial rotationplasty provides function far superior to a high above-knee amputation or a hip disarticulation without the risk of local recurrence.