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PubMed1997

Ovulation defect and its restoration by bone marrow transplantation in osteopetrotic mutant mice of Mitf(mi)/Mitf(mi) genotype.

Mutation within the Mitf gene causes, in microphthalmic Mitf(mi)/Mitf(mi) (mi/mi) mice, multiple defects, including white coat color and functional defects in macrophages and osteoclasts. Our previous mating experiments have demonstrated that the mi mutation reduces the numbers of newborns and induces uterine inversion at delivery. The present study was designed to determine the causes of these pregnancy defects. The histology and number of F4/80-positive macrophages were not different between the ovaries of 23-day-old mi/mi and +/+ mice given eCG 48 h earlier. When ovulation was induced in these mice by hCG, the number of ovulated ova was significantly smaller in mi/mi mice than in wild-type (+/+) mice (p < 0.05). When bone marrow cells from +/+ mice were transplanted i.p. into 42 mi/mi female newborns, successful transplantation was observed in 16 of them at 20 days after birth. In one of these, the upper incisors had erupted. The mean number of tubal ova in mi/mi mice significantly increased after transplantation (p < 0.05) and was almost equal to that of +/+ mice. No uterine inversion occurred at 6 deliveries in 5 mi/mi females after bone marrow transplantation, while it occurred at 4 of 5 deliveries in mi/mi females during the same observation period (p < 0.05). These results indicate that bone marrow-derived cells, defective in mi/mi mice, are necessary for normal ovulation and delivery; the findings are consistent with the notion that macrophages play major roles in ovulation.

Animals↗

PubMed2005

Intra-class correlation estimates for assessment of vitamin A intake in children.

In many community-based surveys, multi-level sampling is inherent in the design. In the design of these studies, especially to calculate the appropriate sample size, investigators need good estimates of intra-class correlation coefficient (ICC), along with the cluster size, to adjust for variation inflation due to clustering at each level. The present study used data on the assessment of clinical vitamin A deficiency and intake of vitamin A-rich food in children in a district in India. For the survey, 16 households were sampled from 200 villages nested within eight randomly-selected blocks of the district. ICCs and components of variances were estimated from a three-level hierarchical random effects analysis of variance model. Estimates of ICCs and variance components were obtained at village and block levels. Between-cluster variation was evident at each level of clustering. In these estimates, ICCs were inversely related to cluster size, but the design effect could be substantial for large clusters. At the block level, most ICC estimates were below 0.07. At the village level, many ICC estimates ranged from 0.014 to 0.45. These estimates may provide useful information for the design of epidemiological studies in which the sampled (or allocated) units range in size from households to large administrative zones.

Analysis of Variance↗

PubMed2005

Supramolecular blueprint approach to metal-coordinated capsules.

An important problem in designing any large network is the assembly of systems that are resilient to change. From a chemical point of view, an analogy can be used where one requires supramolecular assemblies to maintain their dimensionality combined with limited structural perturbation in response to variation in its intermolecular framework. The identification of hydrogen-bonded framework patterns within experimentally known supramolecular assemblies that are structurally robust to disruption and selective hydrogen substitution are envisioned to act as a supramolecular blueprint or template for metal-ion retroinsertion. Here, we report the formation of a large neutral discrete pseudo-spherical coordination capsule assembled from 6 pyrogallol[4]arene ligands and 24 Cu(II) metal ions. Amazingly, this coordination capsule is structurally analogous to its hydrogen-bonded counterpart. This result shows a robust ability of pyrogallol[4]arene molecules to self-assemble into large hexameric cage structures from either the hydrogen-bonding or metal-ligand coordination process. The identification of robust supramolecular assemblies that conserve their structure in response to interchangeability between hydrogen-bonded networks for metal coordination, or inversely, represents an important advancement in supramolecular design.

Journal Article↗

PubMed2000

Attenuation of the bidirectional effects of chlordiazepoxide and FG 7142 on conditioned response suppression and associated cardiovascular reactivity by loss of cortical cholinergic inputs.

RATIONALE: Basal forebrain cortical cholinergic projections have been hypothesized to mediate the enhanced cardiovascular defensive response initiated by the putative anxiogenic benzodiazepine receptor (BZR) partial inverse agonist FG 7142 (FG). The present study was designed to test the broader hypothesis that the integrity of this cholinergic projection is required for the mediation of the bidirectional modulatory effects of BZR agonists and inverse agonists on anxiety and associated cardiovascular reactivity. OBJECTIVES: The interactions between the effects of 192 IgG-saporin-induced lesions of basal forebrain corticopetal cholinergic neurons and of the BZR agonist chlordiazepoxide (CDP) and FG on the performance of rats tested in a conditioned suppression paradigm and on associated cardiovascular reactivity were assessed. METHODS: Lesioned and control animals were equipped with a telemetric device to record heart rate, trained in an operant lever task, and then tested for suppression of responding during presentation of a conditioned stimulus (CS) and a general contextual cue that was previously associated with shock. FG, CDP (8 mg/kg) and vehicle were administered IP in separate extinction sessions. RESULTS: In control animals, operant responding was suppressed during presentation of the CS and contextual cue. Administration of FG enhanced this suppression, while CDP attenuated it. Lesions attenuated overall response suppression as well as the modulatory effects of BZR ligands on responding during presentation of the contextual stimulus. Likewise, lesions attenuated the cardioacceleratory response to the contextual stimulus and the ability of the BZR ligands to modulate this response. CONCLUSIONS: The behavioral and autonomic responses to anxiety-related stimuli, as well as the modulatory effects of BZR ligands, are mediated in part via cortical cholinergic inputs.

Animals↗

PubMed2004

The design and synthesis of a selective inhibitor of fucosyltransferase VI.

Inversion of configuration of the C-2[prime or minute] hydroxyl of methyl N-acetyllactosamine was accomplished by a two-step procedure involving oxidation to a ketone followed by reduction with NaBH(4). After deprotection, the resulting derivative was examined as a substrate for [small alpha]-(2,6)- and [small alpha]-(2,3)-sialyltransferase and fucosyltransferase III, IV, V and VI. It was found that none of these enzymes could glycosylate. However, it showed exquisite selectivity for inhibition of fucosyltransferase VI. The kinetic data support an unusual mechanism in which the inhibitor can bind to the GDP-fucose complex as well as another enzyme form.

Amino Sugars↗

PubMed1999

Charge optimization leads to favorable electrostatic binding free energy.

Variational optimization of molecular electrostatic charge distributions is a tool for the study of association reactions of molecules in solution. In principle, this method can be used in drug design and protein folding to analyze and improve molecular interactions and to provide electrostatic templates for molecular design. This optimization problem reduces to an inverse source problem in classical electrostatics, where the sources are determined by a combination of external and self-polarization potentials. In this paper, we show that the electrostatic portion of the free energy of association for electrostatically optimized molecules has an upper bound of zero in many situations of physical interest. That is, variational optimization provides a ligand-charge distribution that contributes favorably to the energetics of binding, even in a strongly polar medium. This stabilizing effect on association reactions is contrary to the usual role of electrostatics in aqueous complexes, in which desolvation effects generally dominate. We also show the existence and nonuniqueness of the variational solution and make a connection to the electrostatic image charge problem.

Biophysical Phenomena↗

PubMed2004

Minimum energy pulse synthesis via the inverse scattering transform.

This paper considers a variety of problems in the design of selective RF-pulses. We apply a formula of Zakharov and Manakov to directly relate the energy of an RF-envelope to the magnetization profile and certain auxiliary parameters used in the inverse scattering transform (IST) approach to RF-pulse synthesis. This allows a determination of the minimum possible energy for a given magnetization profile. We give an algorithm to construct both the minimum energy RF-envelope as well as any other envelope that produces a given magnetization profile. This includes an algorithm for solving the Gel'fand-Levitan-Marchenko equations with bound states. The SLR method is analyzed in terms of traditional scattering data, and shown to be a special (singular) case of the IST approach. RF-envelopes are computed for a variety of examples.

Journal Article↗

PubMed1990

Intramolecular transposition by a synthetic IS50 (Tn5) derivative.

We report the formation of deletions and inversions by intramolecular transposition of Tn5-derived mobile elements. The synthetic transposons used contained the IS50 O and I end segments and the transposase gene, a contraselectable gene encoding sucrose sensitivity (sacB), antibiotic resistance genes, and a plasmid replication origin. Both deletions and inversions were associated with loss of a 300-bp segment that is designated the vector because it is outside of the transposon. Deletions were severalfold more frequent than inversions, perhaps reflecting constraints on DNA twisting or abortive transposition. Restriction and DNA sequence analyses showed that both types of rearrangements extended from one transposon end to many different sites in target DNA. In the case of inversions, transposition generated 9-bp direct repeats of target sequences.

Base Sequence↗

PubMed1997

On the immunogenic properties of retro-inverso peptides. Total retro-inversion of T-cell epitopes causes a loss of binding to MHC II molecules.

Retro-inversion is considered an attractive approach for drug and vaccine design since it provides the modified peptides with higher resistance to proteolytic degradation. We therefore investigated in detail the effect of retro-inversion on the immunological properties of synthetic peptides. We have synthesized retro-inverso analogues of MHC II restricted peptides that thus contained the correct orientation of the side chains but an inverse main chain. Retro-inversion made the peptides unable to compete in I E(d) or I A(d) binding tests, demonstrating a very low, if any, capacity to bind to MHC II molecules. These results confirm previous structural data that hydrogen bonds between residues of MHC II molecules and the main chain of antigenic peptides play a major interacting role. In vito experiments further showed that retro-inversion of a T-cell epitope causes its inability to either sustain in vitro T-cell stimulation or to prime specific T cells. Moreover, the retro-inverso peptide was not recognized by antibodies raised against the native peptide and did not elicit antibodies when injected into BALB/c mice. Retro-inverso peptides appear to be poor immunogens as a result of their weak capacity to bind to MHC II molecules. As an advantage, they are not expected to trigger undesirable humoral responses such as hypersensitivity or allergic disease. These results also provide a molecular explanation regarding the weak immunogenicity of D-amino acids containing polypeptides.

Amino Acid Sequence↗

PubMed2002

Feasibility study of patient-specific surgical templates for the fixation of pedicle screws.

Surgery for scoliosis, as well as other posterior spinal surgeries, frequently uses pedicle screws to fix an instrumentation on the spine. Misplacement of a screw can lead to intra- and post-operative complications. The objective of this study is to design patient-specific surgical templates to guide the drilling operation. From the CT-scan of a vertebra, the optimal drilling direction and limit angles are computed from an inverse projection of the pedicle limits. The first template design uses a surface-to-surface registration method and was constructed in a CAD system by subtracting the vertebra from a rectangular prism and a cylinder with the optimal orientation. This template and the vertebra were built using rapid prototyping. The second design uses a point-to-surface registration method and has 6 adjustable screws to adjust the orientation and length of the drilling support device. A mechanism was designed to hold it in place on the spinal process. A virtual prototype was build with CATIA software. During the operation, the surgeon places either template on patient's vertebra until a perfect match is obtained before drilling. The second design seems better than the first one because it can be reused on different vertebra and is less sensible to registration errors. The next step is to build the second design and make experimental and simulations tests to evaluate the benefits of this template during a scoliosis operation.

Bone Screws↗

PubMed1980

Effects of a 1% chlorhexidine gel during the healing phase after inverse bevel mucogingival flap surgery.

A split-mouth double-blind trial was designed to compare the effects of chlorhexidine and placebo gels during the healing phase following mucogingival flap surgery. Fifteen patients were treated with 30 inverse bevel flap procedures, one on each side of the maxilla, with an interval of 4 weeks between each procedure. Gel was applied to the gums using a toothbrush once daily. Comparison of results revealed no significant differences in Plaque Index, Gingival Index, crevicular fluid or depth of pockets. More pain and swelling were recorded on the side treated with placebo gel, and more patients indicated that they preferred the chlorhexidine gel. The results were comparable to previous investigations using penicillin and suggest that, because of the reduced pain and swelling, chlorhexidine gel may be a suitable alternative to penicillin after periodontal flap surgery.

Chlorhexidine↗

PubMed2005

Conventional chest physiotherapy compared to other airway clearance techniques for cystic fibrosis.

BACKGROUND: Cystic fibrosis is an inherited life-limiting disorder, characterised by pulmonary infections and thick airway secretions. Chest physiotherapy has been integral to clinical management in facilitating removal of airway secretions. Conventional chest physiotherapy techniques (CCPT) have depended upon assistance during treatments, while more contemporary airway clearance techniques are self-administered, facilitating independence and flexibility. OBJECTIVES: To compare CCPT with other airway clearance techniques in terms of their effects on respiratory function, individual preference, adherence, quality of life and other outcomes. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched CINAHL from 1982 to 2002 and AMED from 1985 to 2002. Date of most recent search: January 2004. SELECTION CRITERIA: Randomised or quasi-randomised clinical trials including those with a cross-over design where CCPT was compared with other airway clearance techniques. Studies of less than seven days duration were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers allocated quality scores to relevant studies and independently extracted data. If we were unable to extract data, we invited authors to submit their data. We excluded studies from meta-analysis when data were lost or study design precluded comparison. For some continuous outcomes, we used the generic inverse variance method for meta-analysis of data from cross-over trials and data from parallel-designed trials were incorporated for comparison. We also examined efficacy of specific techniques and effects of treatment duration. MAIN RESULTS: Seventy-eight publications were identified by the searches. Twenty-nine of these were included, representing 15 data sets with 475 participants. There was no difference between CCPT and other airway clearance techniques in terms of respiratory function measured by standard lung function tests. Studies undertaken during acute exacerbations demonstrated relatively large gains in respiratory function irrespective of airway clearance technique. Longer-term studies demonstrated smaller improvements or deterioration over time. Ten studies reported individual preferences for technique, with participants tending to favour self-administered techniques. Heterogeneity in the measurement of preference precluded these data from meta-analysis. AUTHORS' CONCLUSIONS: This review demonstrated no advantage of CCPT over other airway clearance techniques in terms of respiratory function. There was a trend for participants to prefer self-administered airway clearance techniques. Limitations of this review included a paucity of well-designed, adequately-powered, long-term trials.

Cystic Fibrosis↗

PubMed2002

Mechanisms of inverse agonism at G-protein-coupled receptors.

Many drugs with important therapeutic actions that had been assumed to be antagonists at G-protein-coupled receptors (GPCRs) have been shown to be inverse agonists. For both basic pharmacology and drug design it is important to understand the mechanisms whereby these drugs achieve their effects. It had been assumed that these drugs achieved their effects by stabilizing an inactive state of the receptor (R) at the expense of a partially activated state (R*). In this article, I consider this and other mechanisms that could explain inverse agonist actions, and conclude that more than one mechanism can apply to inverse agonism at GPCRs.

Animals↗

PubMed1985

Restorative proctocolectomy with ileal reservoir for ulcerative colitis and familial adenomatous polyposis: a comparison of three reservoir designs.

One hundred and four patients were treated by restorative proctocolectomy with ileal reservoir for ulcerative colitis and familial polyposis. Three different designs of reservoir were used (triple loop 68, double loop 13, quadruple loop 23). There were no postoperative deaths but six (5.8 per cent) had the reservoir removed. Rates for pelvic sepsis were 25, 15 and 13 per cent, and for intestinal obstruction requiring laparotomy 14.7,0 and 8.6 per cent. Function was assessed in 88 patients (58, 12 and 18) after mean intervals from closure of the ileostomy of 23.7, 12.7 and 4.5 months. Frequency of defaecation per 24 h was 3.7 +/- 1.6, 5.5 +/- 1.6 and 4.1 +/- 1.3, being significantly greater for double loop reservoirs; night evacuation was more prevalent in the same group (26, 58 and 22 per cent). Significantly fewer patients with triple than with double loop reservoirs required antidiarrhoeal medication (19 and 58 per cent). Normal continence occurred in 67, 75 and 89 per cent of patients in the three groups. All patients with double or quadruple loop reservoirs defaecated spontaneously while only 41 per cent with triple loop reservoirs did so. Mean intra-operative reservoir volumes were 177 +/- 64, 172 +/- 58 and 325 +/- 37 ml and volumes after closure of the ileostomy were 416 +/- 176, 197 +/- 69 and 322 +/- 33 ml respectively. Double loop reservoirs were significantly smaller than the other two designs after ileostomy closure. There was an inverse relationship between reservoir volumes and frequency. A quadruple loop reservoir directly connected to the anal sphincter preserved spontaneous evacuation and resulted in function similar to that obtained with the triple loop reservoir.

Colectomy↗

PubMed1993

Metabolic control design.

The response of metabolic variables to small parameter changes is quantitatively described by the control coefficients. Their values (the control profile) depend on the rate equations of the enzymes which compose the metabolic system. A procedure, called Metabolic Control Design (MCD), is developed which achieves the "inverse", namely to calculate the kinetic properties of the enzymes which would produce a preconceived control profile when they are embedded in the network. It is shown that the lack of interaction between some variable metabolites and enzymes (i.e. some epsilon-elasticity coefficients are zero), together with the well-known conservation and summation relationships, reduce the number of control coefficients to which arbitrary values can be assigned. A choice of the values of these coefficients constitutes the pre-established control profile. The same procedure can also be used as an in situ method to detect unknown interactions between enzymes and metabolites. Finally, we discuss some implications of the results to the evolution of living organisms.

Animals↗

PubMed2005

Isolation and characterization of a fructosyl-amine oxidase from an Arthrobacter sp.

An Arthrobacter sp. was isolated that, when induced by fructosyl-valine, expressed a fructosyl-amine oxidase (FAOD) that was specific for alpha-glycated amino acids. The N-terminal amino acid sequence of the purified oxidase was determined and used to design oligonucleotides to amplify the gene by inverse PCR. Expression of the gene in Escherichia coli produced 0.23 units FAOD per mg protein, over 30-fold greater than native expression levels, with properties almost indistinguishable from the native enzyme. The presence of FAOD was confirmed in other Arthrobacter ssp.

Amino Acid Oxidoreductases↗

PubMed2006

Comparison of inverse-planned three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for non-small-cell lung cancer.

PURPOSE: Lungs are the major dose-limiting organ during radiotherapy (RT) for non-small-cell lung cancer owing to the development of pneumonitis. This study compared intensity-modulated RT (IMRT) with three-dimensional conformal RT (3D-CRT) in reducing the dose to the lungs. METHODS: Ten patients with localized non-small-cell lung cancer underwent computed tomography (CT). The planning target volume (PTV) was defined and the organs at risk were outlined. An inverse-planning program, AutoPlan, was used to design the beam angle-optimized six-field noncoplanar 3D-CRT plans. Each 3D-CRT plan was compared with a series of five IMRT plans per patient. The IMRT plans were created using a commercial algorithm and consisted of a series of three, five, seven, and nine equidistant coplanar field arrangements and one six-field noncoplanar plan. The planning objectives were to minimize the lung dose while maintaining the dose to the PTV. The percentage of lung volume receiving >20 Gy (V20) and the percentage of the PTV covered by the 90% isodose (PTV90) were the primary endpoints. The PTV90/V20 ratio was used as the parameter accounting for both the reduction in lung volume treated and the PTV coverage. RESULTS: All IMRT plans, except for the three-field coplanar plans, improved the PTV90/V20 ratio significantly compared with the optimized 3D-CRT plan. Nine coplanar IMRT beams were significantly better than five or seven coplanar IMRT beams, with an improved PTV90/V20 ratio. CONCLUSION: The results of our study have shown that IMRT can reduce the dose to the lungs compared with 3D-CRT by improving the conformity of the plan.

Carcinoma, Non-Small-Cell Lung↗

PubMed2001

Inverse association between sense of humor and coronary heart disease.

Prospective studies have suggested that antisocial Type A personality traits may be associated with an increased incidence of coronary heart disease (CHD). However, few data have addressed whether more favorable personality characteristics may be inversely correlated with CHD. Therefore, two standardized questionnaires designed to either assess anger and hostility or to measure the propensity to laugh under a variety of situations encountered in everyday life, were administered to 300 consecutive subjects. Compared to controls, CHD subjects were significantly less likely to experience laughter during daily activities, surprise situations or social interactions (P<0.005). Logistic regression analysis revealed an inverse correlation between humor and CHD, even after adjustment for other covariates, including hypercholesterolemia, hypertension and diabetes mellitus (P=0.03). A significant inverse association was also observed between humor production and antisocial Type A personality traits (P=0.0001). These data extend previous observations linking antisocial Type A personality traits to CHD and raise the possibility that the propensity to laugh may contribute to cardioprotection.

Analysis of Variance↗