Short-term and long-term cardiovascular actions of different doses of perindopril in the rabbit

Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demonstrate if short-term results can predict chronic outcomes. In short-term treatment, five doses of perindopril were examined in random order separated by a one week recovery period in each of six rabbits. Two doses of perindopril which resulted in a moderate hypotensive effect (-14 mmHg) and no hypotensive effect, respectively, were then selected for long-term treatment. Each rabbit in the short-term study received perindopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg(-1) day(-1) for a week at a time. Rabbits on long-term treatment received either 0.3 or 0.01 mg kg(-1) day(-1) perindopril for six weeks. All rabbits had their mean arterial blood pressure (MAP) and heart rate recorded throughout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotensin converting enzyme (ACE) inhibition were also assayed. Perindopril treatment for one week produced a dose-dependent hypotensive effect with the threshold dose, 0.06 mg kg(-1) day(-1), producing a 6.5+/-1.8 mmHg fall in MAP. The highest dose (10.0 mg kg(-1) day(-1)) produced a large fall in blood pressure of -29.6+/-4.2 mmHg. The 0.01 and 0.06 mg kg(-1) day(-1) doses of perindopril produced an average 2.65 fold increase in plasma AngI levels compared to the initial control. The three higher doses (0.32-10.0 mg kg(-1) day(-1)) of perindopril produced an equivalent 5.7 fold increase in plasma AngI levels compared to the initial controls. However, over six weeks 0.01 mg kg(-1) day(-1) perindopril induced a similar decrease in MAP as the 30 fold higher dose (-9.3 mmHg compared to -11.7 mmHg,). This was in spite of a 3 fold difference in plasma perindoprilat concentrations between the high and low dose perindopril groups. Plasma ACE inhibition was >80% with both doses of perindopril. The results indicate that while perindopril decreases MAP in a dose-dependent manner in short-term (one week) periods, over longer treatment times (six weeks) low concentrations of perindopril, non-hypotensive with shortterm treatment, may be as anti-hypertensive as considerably higher doses. (C) 1996 The Italian Pharmacological Society.

Use of an Inflatable Silicone Balloon Improves the Success Rate of Bladder Autoaugmentation at Long-Term Followup

Purpose: Most groups have reported disappointing results with autoaugmentation or detrusor myectomy for low capacity/compliance neuropathic bladders. Failure may be due to an ischemic diverticulum or mucosal shrinkage. We investigated whether a Silimed (R) silicone balloon placed in the bladder after autoaugmentation could prevent these problems, improving surgical results. Materials and Methods: We compared the results of standard bladder autoaugmentation in 12 children (group 1) with those in 10 (group 2) who underwent the same surgery using a bladder conformer. The conformer was a silicone balloon filled with saline that remained in the bladder for 2 weeks. All patients had a neuropathic bladder with poor capacity and compliance, resulting in urinary leakage between catheterizations. Preoperative and postoperative evaluation included a voiding diary, ultrasound, voiding cystourethrogram and urodynamics. Results: In group 1 only 1 patient became dry, 4 had little improvement in continence, 4 remained unchanged and 3 became worse. In group 2, 6 patients (60%) become continent without medication, 2 (20%) become continent with oxybutynin and 2 remained unchanged. Bladder capacity and compliance did not change significantly in group 1. However, in group 2 capacity changed from a mean of 140 to 240 ml and mean +/- SD compliance increased from 15.6 +/- 16.8 to 34.3 +/- 22.8 ml/cm H(2)O (p = 0.02). Conclusions: The inflatable balloon improved our long-term results of bladder auto-augmentation. A larger series may be necessary to confirm procedure efficacy and safety.

On the structure, electrochemistry, and spectroscopy of the (N,N'-bis(2'-(dimethylamino)ethyl)-N,N'-dimethylpropane-1,3-diamine)copper(II) ion

The synthesis, spectroscopy, and electrochemistry of the acyclic tertiary tetraamine copper(II) complex [CuL(1)](ClO4)(2) (L(1) = N,N-bis(2'-(dimethylamino)ethyl)-N,N'-dimethylpropane-1,3-diamine) is reported. The X-ray crystal structure of [CuL(1)(OClO3)(2)] reveals a tetragonally elongated CuN4O2 coordination sphere, exhibiting relatively long Cu-N bond lengths for a Cu-II tetraamine, and a small tetrahedral distortion of the CuN4 plane. The [CuL(1)](2+) ion displays a single, reversible, one-electron reduction at -0.06 V vs Ag/AgCl. The results presented herein illustrate the inherent difficulties associated with the separation and characterization of Cu-II complexes of tertiary tetraamines, and some previously incorrect assertions and unexplained observations of other workers are discussed.

Long-Term Effect of Early Postoperative Pelvic Floor Biofeedback on Continence in Men Undergoing Radical Prostatectomy: A Prospective, Randomized, Controlled Trial

Purpose: The impact of pelvic floor muscle training on the recovery of urinary continence after radical prostatectomy is still controversial. We tested the effectiveness of biofeedback-pelvic floor muscle training in improving urinary incontinence in the 12 months following radical prostatectomy. Materials and Methods: A total of 73 patients who underwent radical prostatectomy were randomized to a treatment group (36) receiving biofeedback-pelvic floor muscle training once a week for 3 months as well as home exercises or a control group (37). Patients were evaluated 1, 3, 6 and 12 months postoperatively. Continence was defined as the use of 1 pad or less daily and incontinence severity was measured by the 24-hour pad test. Incontinence symptoms and quality of life were assessed with the International Continence Society male Short Form questionnaire and the Incontinence Impact Questionnaire. Pelvic floor muscle strength was evaluated with the Oxford score. Results: A total of 54 patients (26 pelvic floor muscle training and 28 controls) completed the trial. Duration of incontinence was shorter in the treatment group. At postoperative month 12, 25 (96.15%) patients in the treatment group and 21 (75.0%) in the control group were continent (p = 0.028). The absolute risk reduction was 21.2% (95% CI 3.45-38.81) and the relative risk of recovering continence was 1.28 (95% CI 1.02-1.69). The number needed to treat was 5 (95% CI 2.6-28.6). Overall there were significant changes in both groups in terms of incontinence symptoms, lower urinary tract symptoms, quality of life and pelvic floor muscle strength (p <0.0001). Conclusions: Early biofeedback-pelvic floor muscle training not only hastens the recovery of urinary continence after radical prostatectomy but allows for significant improvements in the severity of incontinence, voiding symptoms and pelvic floor muscle strength 12 months postoperatively.

Crystal structure of Escherichia coli xanthine phosphoribosyltransferase

Xanthine phosphoribosyltransferase (XPRT; EC 2.4.2.22) from Escherichia coil is a tetrameric enzyme having 152 residues per subunit. XPRT catalyzes the transfer of the phosphoribosyl group from 5-phospho-alpha-D-ribosyl l-pyrophosphate (PRib-PP) to the 6-oxopurine bases guanine, xanthine, and hypoxanthine to form GMP, XMP, and IMP, respectively. Crystals grown in the absence of substrate or product were used to determine the structure of XPRT at a resolution of 1.8 Angstrom by multiple isomorphous replacement. The core structure of XPRT includes a five-stranded parallel B-sheet surrounded by three or-helices, which is similar to that observed in other known phosphoribosyltransferase (PRTase) structures. The XPRT structure also has several interesting features. A glutamine residue in the purine binding site may be responsible for the altered 6-oxopurine base specificity seen in this enzyme compared to other 6-oxopurine PRTases. Also, we observe both a magnesium ion and a sulfate ion bound at the PRib-PP binding site of XPRT. The sulfate ion interacts with Arg-37 which has a cis-peptide conformation, and the magnesium ion interacts with Asp-89, a highly conserved acidic residue in the PRib-PP binding site motif. The XPRT structure also incorporates a feature which has not been observed in other PRTase structures. The C-terminal 12 residues of XPRT adopt an unusual extended conformation and make interactions with a neighboring subunit. The very last residue, Arg-152, could form part of the active site of a symmetry-related subunit in the XPRT tetramer.

Pore structure characterisation of pillared clays using a modified MP method

The data of nitrogen adsorption on pillared clays (PILC) are converted to comparison plots (t-plots) to derive their pore size distribution (PSD). As in the MP method, the surface area of a group of pores having similar pore sizes is calculated from the slopes of tangent lines at two succeeding points on a comparison plot. By the modified MP method in this work, the tangent line is extrapolated to the adsorption axis on the t-plot, and the difference between intercepts is used to obtain the volume of the group of pores. From the information of surface area and pore volume, the average width of the pore group can be calculated and hence the PSDs of PILCs are obtained by carrying out such calculation procedures from high to low t. With this method, PSDs of several pillared clays are calculated over a wide pore size range, from micropores to mesopores. It is found that the modified MP method could result in the underestimation of the width of ultramicropores due to the enhancement in adsorption energy in these pores. Nevertheless, the method can be very useful in calculating the surface area and pore volume, as well as a mean width of these pores. For super-micropores and mesopores, pore size can also be underestimated, due to deviation of the pore shape from a slit. The principles of the improved MP method, as well as problems associated with it are thoroughly discussed in this paper. In general, this modified method provides practically meaningful results which are consistent with the pore dimension obtained from powder X-ray diffraction measurements, but involves no complicated theoretical treatment or assumptions.

Long-term administration of IgG2a anti-NK1.1 monoclonal antibody ameliorates lupus-like disease in NZB/W mice in spite of an early worsening induced by an IgG2a-dependent BAFF/BLyS production

The role of natural killer (NK) T cells in the development of lupus-like disease in mice is still controversial. We treated NZB/W mice with anti-NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti-NK1.1 mAb increased the production of anti-dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti-NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus-like disease. Augmented titres of anti-dsDNA in NZB/W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti-NK1.1 mAb reduced the levels of interleukin-16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti-dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B-cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B-cell activity for the production of anti-dsDNA. We concluded that NK T cells are involved in the progression of lupus-like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology.

Anti-Group A Streptococcal Vaccine Epitope STRUCTURE, STABILITY, AND ITS ABILITY TO INTERACT WITH HLA CLASS II MOLECULES

Streptococcus pyogenes infections remain a health problem in several countries due to poststreptococcal sequelae. We developed a vaccine epitope (StreptInCor) composed of 55 amino acids residues of the C-terminal portion of the M protein that encompasses both T and B cell protective epitopes. The nuclear magnetic resonance (NMR) structure of the StreptInCor peptide showed that the structure was composed of two microdomains linked by an 18-residue alpha-helix. A chemical stability study of the StreptInCor folding/unfolding process using far-UV circular dichroism showed that the structure was chemically stable with respect to pH and the concentration of urea. The T cell epitope is located in the first microdomain and encompasses 11 out of the 18 alpha-helix residues, whereas the B cell epitope is in the second microdomain and showed no alpha-helical structure. The prediction of StreptInCor epitope binding to different HLA class II molecules was evaluated based on an analysis of the 55 residues and the theoretical possibilities for the processed peptides to fit into the P1, P4, P6, and P9 pockets in the groove of several HLA class II molecules. We observed 7 potential sites along the amino acid sequence of StreptInCor that were capable of recognizing HLA class II molecules (DRB1*, DRB3*, DRB4*, and DRB5*). StreptInCoroverlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules and could be considered as a universal vaccine epitope.

A long-term prospective randomized controlled study of non-specific interstitial pneumonia (NSIP) treatment in scleroderma

The association of cyclophosphamide (CYC) and prednisone (PRED) for the treatment of lung fibrosis in systemic sclerosis (SSc) was only evaluated in uncontrolled studies, although in idiopathic interstitial lung disease (ILD) this association seems to be beneficial in patients with non-specific interstitial pneumonia (NSIP). Objectives: To treat SSc-ILD in a prospective open-label controlled study based on lung pattern during 12 months of treatment. Methods: A 3-year analysis was also performed. Twenty-four consecutive patients with SSc and ILD were submitted to an open lung biopsy. Eighteen patients (NSIP) were randomized in two groups: CYC versus CYC + PRED during 12 months. Lung function tests (diffusion lung capacity of monoxide carbone corrected for hemoglobin concentration (DLCO-Hb), forced vital capacity (FVC), total lung capacity) and Modified Rodnan Skin Score (MRSS) were performed before, after one of treatment and after 3 years from the end of the treatment. Results: Pulmonary function tests were similar in both groups on baseline. After 1 year of treatment, FVC% was comparable between CYC groups (p = 0.72) and in CYC + PRED (p = 0.40). Three years after the end of treatment, FVC% values (p = 0.39 in group CYC and p = 0.61 in CYC + PRED and p = 0.22 in CYC + PRED) and DLCO-Hb (p = 0.54 in CYC and p = 0.28 in CYC + PRED) were similar compared to 1 year of treatment. We observed a reduction of the MRSS in the CYC + PRED group after 1 year of treatment (p = 0.02); although after 3 years, MRSS values remained stable in both groups. Conclusions: CYC was effective to stabilize lung function parameters in NSIP lung pattern of SSc disease for 3 years after the end of a 1-year therapy.

Structure of TcpG, the DsbA protein folding catalyst from Vibrio cholerae

The efficient and correct folding of bacterial disulfide bonded proteins in vivo is dependent upon a class of periplasmic oxidoreductase proteins called DsbA, after the Escherichia coli enzyme. In the pathogenic bacterium Vibrio cholerae, the DsbA homolog (TcpG) is responsible for the folding, maturation and secretion of virulence factors. Mutants in which the tcpg gene has been inactivated are avirulent; they no longer produce functional colonisation pill and they no longer secrete cholera toxin. TcpG is thus a suitable target for inhibitors that could counteract the virulence of this organism, thereby preventing the symptoms of cholera. The crystal structure of oxidized TcpG (refined at a resolution of 2.1 Angstrom) serves as a starting point for the rational design of such inhibitors. As expected, TcpG has the same fold as E. coli DsbA, with which it shares similar to 40% sequence identity. Ln addition, the characteristic surface features of DsbA are present in TcpG, supporting the notion that these features play a functional role. While the overall architecture of TcpG and DsbA is similar and the surface features are retained in TcpG, there are significant differences. For example, the kinked active site helix results from a three-residue loop in DsbA, but is caused by a proline in TcpG (making TcpG more similar to thioredoxin in this respect). Furthermore, the proposed peptide binding groove of TcpG is substantially shortened compared with that of DsbA due to a six-residue deletion. Also, the hydrophobic pocket of TcpG is more shallow and the acidic patch is much less extensive than that of E. coli DsbA. The identification of the structural and surface features that are retained or are divergent in TcpG provides a useful assessment of their functional importance in these protein folding catalysts and is an important prerequisite for the design of TcpG inhibitors. (C) 1997 Academic Press Limited.

Genetic population structure of the catadromous perciform: Macquaria novemaculeata (Percichthyidae)

Genetic population structure in the catadromous Australian bass Macquaria novemaculeata was investigated using samples from four locations spanning 600 km along the eastern Australian coastline. Both allozymes and mtDNA control region sequences were examined. Population subdivision estimates based on allozymes revealed low levels of population structuring (G(st)=0.043, P<0.05). However, mtDNA indicated moderate levels of geographic population structure (G(st)=0.146, P<0.01). Phylogenetic analysis of mtDNA control region sequences (mean sequence divergence 1.9%) indicated little phylogeographic structuring. Results suggested that genotypic variation within each river population, while bring affected primarily by genetic drift, was also prevented from more significant divergence by homogenizing levels of gene flow-synonymous with a one-dimensional stepping-stone model of population structure. The catadromous life history of Macquaria novemaculeata was considered to br influential on the pattern of population structure displayed. Results were compared to the few population genetic studies involving catadromous fishes, indicating that catadromy alone is unlikely to be a good predictor of population structure. A more comprehensive suite of biological characteristics than simple life-history traits must be considered fully to allow reliable predictive models of population structure to be formulated. (C) 1997 The Fisheries Society of the British Isles.

Solution structure of the sodium channel antagonist conotoxin GS: A new molecular caliper for probing sodium channel geometry

Background: The venoms of Conus snails contain small, disulfide-rich inhibitors of voltage-dependent sodium channels. Conotoxin GS is a 34-residue polypeptide isolated from Conus geographus that interacts with the extracellular entrance of skeletal muscle sodium channels to prevent sodium ion conduction. Although conotoxin GS binds competitively with mu conotoxin GIIIA to the sodium channel surface, the two toxin types have little sequence identity with one another, and conotoxin GS has a four-loop structural framework rather than the characteristic three-loop mu-conotoxin framework. The structural study of conotoxin GS will form the basis for establishing a structure-activity relationship and understanding its interaction with the pore region of sodium channels. Results: The three-dimensional structure of conotoxin GS was determined using two-dimensional NMR spectroscopy. The protein exhibits a compact fold incorporating a beta hairpin and several turns. An unusual feature of conotoxin GS is the exceptionally high proportion (100%) of cis-imide bond geometry for the three proline or hydroxyproline residues. The structure of conotoxin GS bears little resemblance to the three-loop mu conotoxins, consistent with the low sequence identity between the two toxin types and their different structural framework. However, the tertiary structure and cystine-knot motif formed by the three disulfide bonds is similar to that present in several other polypeptide ion channel inhibitors. Conclusions: This is the first three-dimensional structure of a 'four-loop' sodium channel inhibitor, and it represents a valuable new structural probe for the pore region of voltage-dependent sodium channels. The distribution of amino acid sidechains in the structure creates several polar and charged patches, and comparison with the mu conotoxins provides a basis for determining the binding surface of the conotoxin GS polypeptide.

The effect of internal thoracic artery grafts on long-term clinical outcomes after coronary bypass surgery

Objectives: We sought to compare long-term outcomes after coronary bypass surgery with and without an internal thoracic artery graft. Methods: We analyzed clinical outcomes over a median follow-up of 6.7 years among 3,087 patients who received coronary bypass surgery as participants in one of 8 clinical trials comparing surgical intervention with angioplasty. We used 2 statistical methods (covariate adjustment and propensity score matching) to adjust for the nonrandomized selection of internal thoracic artery grafts. Results: Internal thoracic artery grafting was associated with lower mortality, with hazard ratios of 0.77 (confidence interval, 0.62-0.97; P = .02) for covariate adjustment and 0.77 (confidence interval, 0.57-1.05; P = .10) for propensity score matching. The composite end point of death or myocardial infarction was reduced to a similar extent, with hazard ratios of 0.83 (confidence interval, 0.69-1.00; P = .05) for covariate adjustment to 0.78 (confidence interval, 0.61-1.00; P = .05) for propensity score matching. There was a trend toward less angina at 1 year, with odds ratios of 0.81 (confidence interval, 0.61-1.09; P = .16) in the covariate-adjusted model and 0.81 (confidence interval, 0.55-1.19; P = .28) in the propensity score-adjusted model. Conclusions: Use of an internal thoracic artery graft during coronary bypass surgery seems to improve long-term clinical outcomes. (J Thorac Cardiovasc Surg 2011; 142: 829-35)

Lung Diffusing Capacity Relates Better to Short-Term Progression on HRCT Abnormalities Than Spirometry in Mild Asbestosis

Background Pulmonary function tests (PFT), particularly spirometry and lung diffusing capacity for carbon monoxide (DL(CO)), have been considered useful methods for the detection of the progression of interstitial asbestos abnormalities as indicated by high-resolution computed tomography (HRCT). However, it is currently unknown which of these two tests correlates best with anatomical changes over time. Methods In this study, we contrasted longitudinal changes (3-9 years follow-up) in PFTs at rest and during exercise with interstitial abnormalities evaluated by HRCT in 63 ex-workers with mild-to-moderate asbestosis. Results At baseline, patients presented with low-grade asbestosis (Huuskonen classes I-II), and most PFT results were within the limits of normality. In the follow-up, most subjects had normal spirometry, static lung volumes and arterial blood gases. In contrast, frequency of DL(CO) abnormalities almost doubled (P < 0.05). Twenty-three (36.5%) subjects increased the interstitial marks on HRCT. These had significantly larger declines in DL(CO) compared to patients who remained stable (0.88 vs. 0.31 ml/min/mm Hg/year and 3.5 vs. 1.2%/year, respectively; P < 0.05). In contrast, no between-group differences were found for the other functional tests, including spirometry (P > 0.05). Conclusions These data demonstrate that the functional consequences of progression of HRCT abnormalities in mild-to-moderate asbestosis are better reflected by decrements in DL(CO) than by spirometric changes. These results might have important practical implications for medico-legal evaluation of this patient population. Am. J. Ind. Med. 54:185-193, 2011. (c) 2010 Wiley-Liss, Inc.