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PubMed2001

Caries incidence following restoration of shortened lower dental arches in a randomized controlled trial.

CONTEXT: Removable partial dentures used to restore the shortened lower dental arch may adversely affect the remaining natural teeth and are associated with a low prevalence of use. OBJECTIVE: To report the findings for caries incidence 2 years after restoration of lower shortened arches with bilateral cantilever resin-bonded bridges (RBBs) and conventional partial dentures (RPDs). DESIGN: Randomised controlled trial. SETTING: Secondary care PATIENTS: 25 male and 35 female subjects of median age 67 years. were randomly allocated to 'bridge' and 'denture' treatment groups of 30 patients each matched for age and sex. Caries incidence was recorded during dental examinations 3 months, 1 and 2 years after insertion of new lower prostheses. INTERVENTIONS: Cantilever RBBs and conventional RPDs with cast metal frameworks. RESULTS: There was a highly significant difference in the frequency of new caries lesions, 11 and 51 in the bridge and denture groups respectively (P < 0.01). 20 out of 27 bridge patients and 9 of 23 denture patients had no caries experience. Multivariate modeling identified treatment group as the only significant predictor of caries occurrence. CONCLUSIONS: Two years after restoration of lower shortened arches for an elderly sample of patients, there was a significantly greater incidence of new and recurrent caries lesions in subjects restored with RPDs compared with cantilever RBBs.

Adult↗

PubMed2005

The pattern of polymorphism in Arabidopsis thaliana.

We resequenced 876 short fragments in a sample of 96 individuals of Arabidopsis thaliana that included stock center accessions as well as a hierarchical sample from natural populations. Although A. thaliana is a selfing weed, the pattern of polymorphism in general agrees with what is expected for a widely distributed, sexually reproducing species. Linkage disequilibrium decays rapidly, within 50 kb. Variation is shared worldwide, although population structure and isolation by distance are evident. The data fail to fit standard neutral models in several ways. There is a genome-wide excess of rare alleles, at least partially due to selection. There is too much variation between genomic regions in the level of polymorphism. The local level of polymorphism is negatively correlated with gene density and positively correlated with segmental duplications. Because the data do not fit theoretical null distributions, attempts to infer natural selection from polymorphism data will require genome-wide surveys of polymorphism in order to identify anomalous regions. Despite this, our data support the utility of A. thaliana as a model for evolutionary functional genomics.

Arabidopsis↗

PubMed2003

Lysozyme: a mediator of myocardial depression and adrenergic dysfunction in septic shock in dogs.

The objective of the present study was to identify the nature of a filterable cardiodepressant substance (FCS) that contributes to myocardial dysfunction in a canine model of Escherichia coli septic shock. In a previous study, it was found that FCS increased in plasma after 4 h of bacteremia (Am J Physiol 1993;264:H1402) in which FCS was identified by a bioassay that included a right ventricular trabecular (RVT) preparation. In that study, FCS was only partially identified by pore filtration techniques and was found to be a protein of molecular weight between 10 and 30 K. In the present study, FCS was further purified by size exclusion high-pressure liquid chromatography, until a single band was identified on one-dimensional gel electrophoresis. This band was then subjected to tandem mass spectrometry and protein-sequencing techniques and both techniques identified FCS as lysozyme c (Lzm-S), consistent with that originating from the canine spleen. Confirmatory tests showed that purified Lzm-S produced myocardial depression in the RVT preparation at concentrations achieved during sepsis in the in vivo preparation. In addition, Lzm-S inhibited the adrenergic response induced by field stimulation and the beta- agonist isoproterenol in in vitro preparations, these results suggesting that Lzm-S may inhibit the sympathetic response in sepsis. The present findings indicate that Lzm-S originating from disintegrating leukocytes from organs such as the spleen contributes to myocardial dysfunction in this model. The mechanism may relate to its binding or hydrolysis of a cardiac membrane glycoprotein thereby interfering with myocardial excitation-contraction coupling in sepsis.

Adrenergic Antagonists↗

PubMed2005

Economic evaluation of cardiac rehabilitation: a systematic review.

BACKGROUND: Economic evaluation is an important tool in the evaluation of competing healthcare interventions. Little is known about the economic benefits of different cardiac rehabilitation program delivery models. DESIGN: The goal of this study was to review and evaluate the methodological quality of published economic evaluations of cardiac rehabilitation services. METHODS: Electronic databases were searched for English language evaluations (trials, modeling studies) of the economic impact of cardiac rehabilitation. A review of study characteristics and methodological quality was completed using standardized tools. All costs are adjusted to 2004 US dollars. RESULTS: Fifteen economic evaluations were identified which met eligibility criteria but which displayed wide variation in the use of comparators, evaluation type, perspective and design. Evidence to support the cost-effectiveness of supervised cardiac rehabilitation in myocardial infarction and heart failure patients was identified. The range of cost per life year gained was estimated as from 2193 dollars to 28,193 dollars and from - 668 dollars to 16,118 dollars per quality adjusted life year gained. The level of evidence supporting the economic value of home-based cardiac rehabilitation interventions is limited to partial economic analyses. CONCLUSIONS: Evidence to support the cost-effectiveness of supervised cardiac rehabilitation compared with usual care in myocardial infarction and heart failure was identified. Further trials are required to support the cost-effectiveness of cardiac rehabilitation in cardiac patients who have under gone revascularization. The literature evaluating home-based and alternative delivery models of cardiac rehabilitation was insufficient to draw conclusions about their relative cost-effectiveness. The overall quality of published economic evaluations of cardiac rehabilitation is poor and further well-designed trials are required.

Cost-Benefit Analysis↗

PubMed2001

Heart transplantation changes the expression of distinct gene families.

We took advantage of the combination of a rat heart transplantation model with a modified differential display RT-PCR method to identify transcriptome changes in the right atria from transplanted compared with native hearts. Based on sequence homology search, the 37 cDNAs differentially displayed both 2 and 7 days posttransplantation were categorized into 7 unknown transcripts, 16 expressed sequence tags (ESTs), and 14 partially or completely characterized genes. The last group cDNAs, validated by relative RT-PCR, belonged to diverse gene families involved in specific metabolisms, protein synthesis, cell signaling, and transcription. Furthermore, we identified differential transcripts corresponding to denervation and fetal gene reexpression. We found coordinate downregulation of genes involved in energy metabolism and protein synthesis regulation, similar to that reported for senescent skeletal muscle. From these transcriptome changes, we propose that heart transplants and senescent muscles share common molecular mechanisms.

Animals↗

PubMed2002

Synthesis of macrocyclic, potential protease inhibitors using a generic scaffold.

A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range of proteinases, by using as a basis for the design the known structures of a series of enzyme-inhibitor complexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantage in the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature of the linking group was identified as a benzoxazole by molecular modeling, so as to preserve the recognized conformation of the peptide chain. The specificity of the potential inhibitor was tuned by variation of the P(1) group (by incorporating phenylalanine, aspartic acid, or lysine), to allow recognition by different enzyme classes. The targets were prepared from the bis-amino acid derivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with the iodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22-24 using HATU. None of the macrocylic compounds 25, 28-30, and 32 inhibited their target enzymes. NMR and MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound 29 was in fact a substrate of the enzyme. This result indicated that while the design had been partially successful in identifying a compound that bound, the reduction in entropic advantage due to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.

Catalysis↗

PubMed1999

Brain SPECT imaging and left hemispatial neglect covaried using partial least squares: the Sunnybrook Stroke study.

Hemispatial neglect, characterized as failure to attend to contralesional space, is hypothesized by current neuroanatomical models to result from damage to a network involving the frontal, parietal, and cingulate cortices, basal ganglia, and thalamus. This study investigated this model of neglect in 81 right hemisphere-damaged acute stroke patients using 99mTc-HMPAO single photon emission-computed tomography (SPECT). In order to exploit the inherent collinearity of SPECT regional brain ratios, a novel statistical technique, partial least squares (PLS), was utilized. It makes use of high correlations to identify biologically relevant patterns of brain activity. Averaged ipsilesional cerebellar ratios from 152 brain segments were covaried with performance on subtests of the Sunnybrook Neglect Battery. In this patient sample, the most influential region identified by PLS corresponded to the area surrounding the right temporal-parietal-occipital (TPO) junction that included the right lateral occipital, temporal, and inferior parietal lobes. Hypoperfusion in the medial frontal cortex, including the anterior cingulate, also emerged as significantly associated with more severe neglect. Thus, hypoperfusion in only two of the five hypothesized network regions emerged as significantly associated with hemispatial neglect on SPECT imaging. This work converges with structural imaging studies to suggest that damage to the TPO junction, not just the parietal lobe, may be the critical region for hemispatial neglect. Our study demonstrated the utility of PLS for analyzing functional imaging and behavioral data sets in a clinical population in relation to current neuroanatomical models of neglect.

Aged↗

PubMed2006

Variability patterns and positively selected sites at the gametophytic self-incompatibility pollen SFB gene in a wild self-incompatible Prunus spinosa (Rosaceae) population.

Current models for the generation of new gametophytic self-incompatibility specificities require that neutral variability segregates within specificity classes. Furthermore, one of the models predicts greater ratios of nonsynonymous to synonymous substitutions in pollen than in pistil specificity genes. All models assume that new specificities arise by mutation only. To test these models, 21 SFB (the pollen S-locus) alleles from a wild Prunus spinosa (Rosaceae) population were obtained. For seven of these, the corresponding S-haplotype was also characterized. The SFB data set was also used to identify positively selected sites. Those sites are likely to be the ones responsible for defining pollen specificities. Of the 23 sites identified as being positively selected, 21 are located in the variable (including a new region described here) and hypervariable regions. Little variability is found within specificity classes. There is no evidence for selective sweeps being more frequent in pollen than in pistil specificity genes. The S-RNase and the SFB genes have only partially correlated evolutionary histories. None of the models is compatible with the variability patterns found in the SFB and the S-haplotype data.

Alleles↗

PubMed2005

Development of the Qualeffo-31, an osteoporosis-specific quality-of-life questionnaire.

INTRODUCTION: Vertebral deformities are a common consequence of osteoporosis and are known to decrease quality of life. The Qualeffo-41 is a quality-of-life questionnaire especially developed for measuring quality of life in patients with vertebral deformities. It consists of 41 questions arranged in five domains: pain, physical function, social function, general health perception, and mental function. The objectives of this study were: (1) to develop a shorter version of the Qualeffo-41 by removing redundant questions; and (2) to investigate the scale characteristics, reliability, and validity of this shorter version. METHODS: The study was performed using data from the Qualeffo validation study and the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The analyses were performed in patients with vertebral deformities (n=579). Factor analysis on polychoric correlations and an item response theory (IRT) model, i.e., the generalized partial credit model (GPCM), were used to create a shorter version of Qualeffo-41. Using GPCM, scoring weights were computed for all items. RESULTS: Three items were removed from the data set because of too many missing values. Factor analysis identified three instead of five domains: (1) pain, (2) physical function, and (3) mental function. Five items had factor loadings <0.4 and were not included in the GPCM. After excluding several items, the domains pain (four items), physical function (18 items), and mental function (nine items) showed a good, reasonable, and excellent fit, respectively. This indicates that the mental function domain and the pain domain are more unidimensional than the physical function domain. All three domains showed a very high correlation (r > or =0.95) with the corresponding domains of the Qualeffo-41. CONCLUSIONS: Qualeffo-31 was developed, consisting of three domains with a reasonable to excellent fit to the GPCM. Although the fit to the GPCM supports the construct validity of the Qualeffo-31, validation in a new study should be performed before using it in practice.

Activities of Daily Living↗

PubMed2004

DNA microarray analysis of the correlation between gene expression patterns and acquired resistance to 5-FU/cisplatin in gastric cancer.

The mechanisms of intrinsic and/or acquired anti-cancer drug resistance have been described in in vitro resistance models, but the clinical relevance has remained undefined. We undertook a prospective study to identify correlations between gene expression and clinical resistance to 5-FU/cisplatin. We compared expression profiles from gastric cancer endoscopic biopsy specimens obtained at a chemosensitive state (partial remission after 5-FU/cisplatin) with those obtained at a refractory state (disease progression), using Affymetrix oligonucleotide microarray technology (U133A). Using 119 discriminating probes and a cross-validation approach, we were able to correctly identify the chemo-responsiveness of 7 pairs of training samples and 1 independent test pair. These exploratory data demonstrate that the gene expression profiles differ between chemosensitive and refractory state gastric cancer biopsy samples.

Adult↗

PubMed2006

External validation of the Mayo Clinic Stage, Size, Grade and Necrosis (SSIGN) score to predict cancer specific survival using a European series of conventional renal cell carcinoma.

PURPOSE: We validated the Mayo Clinic SSIGN score in an independent European sample of patients who were surgically treated for conventional RCC. MATERIALS AND METHODS: In our kidney cancer database we identified 388 patients who were treated with radical or partial nephrectomy for conventional RCC between 1986 and 2000. Associations of the pathological features studied with death from RCC were evaluated using the log rank test and Cox proportional hazards regression model. The predictive ability of competing models was evaluated using the c index. RESULTS: Median followup in the 290 patients who were alive at last followup was 5 years (range 5 months to 17 years). The estimated cancer specific survival rate 5 years following surgery was 81.3%. All features that comprise the SSIGN score except tumor size were significantly associated with death from RCC in a multivariate setting, resulting in a c index of 0.90. The median SSIGN score in the 388 patients studied was 3 (range 0 to 15). The c index in a model containing the clear cell SSIGN score was 0.88. Five-year cancer specific survival rates in patients with a score of 0 to 2, 3 to 4, 5 to 6, 7 to 9 and 10 or more were 100.0%, 90.5%, 63.6%, 46.8% and 0%, respectively. CONCLUSIONS: We provide the first external validation of the Mayo Clinic SSIGN score for conventional RCC. This simple algorithm resulted in a high degree of prognostic accuracy.

Adult↗

PubMed2005

Structural and mechanistic insights into the interaction between Rho and mammalian Dia.

Formins are involved in a variety of cellular processes that require the remodelling of the cytoskeleton. They contain formin homology domains FH1 and FH2, which initiate actin assembly. The Diaphanous-related formins form a subgroup that is characterized by an amino-terminal Rho GTPase-binding domain (GBD) and an FH3 domain, which bind somehow to the carboxy-terminal Diaphanous autoregulatory domain (DAD) to keep the protein in an inactive conformation. Upon binding of activated Rho proteins, the DAD is released and the ability of the formin to nucleate and elongate unbranched actin filaments is induced. Here we present the crystal structure of RhoC in complex with the regulatory N terminus of mammalian Diaphanous 1 (mDia1) containing the GBD/FH3 region, an all-helical structure with armadillo repeats. Rho uses its 'switch' regions for interacting with two subdomains of GBD/FH3. We show that the FH3 domain of mDia1 forms a stable dimer and we also identify the DAD-binding site. Although binding of Rho and DAD on the N-terminal fragment of mDia1 are mutually exclusive, their binding sites are only partially overlapping. On the basis of our results, we propose a structural model for the regulation of mDia1 by Rho and DAD.

Amino Acid Motifs↗

PubMed1998

Localization of a protein-DNA interface by random mutagenesis.

The type I restriction and modification enzymes do not possess obvious DNA-binding motifs within their target recognition domains (TRDs) of 150-180 amino acids. To identify residues involved in DNA recognition, changes were made in the amino-TRD of EcoKI by random mutagenesis. Most of the 101 substitutions affecting 79 residues had no effect on the phenotype. Changes at only seven positions caused the loss of restriction and modification activities. The seven residues identified by mutation are not randomly distributed throughout the primary sequence of the TRD: five are within the interval between residues 80 and 110. Sequence analyses have led to the suggestion that the TRDs of type I restriction enzymes include a tertiary structure similar to the TRD of the HhaI methyltransferase, and to a model for a DNA-protein interface in EcoKI. In this model, the residues within the interval identified by the five mutations are close to the protein-DNA interface. Three additional residues close to the DNA in the model were changed; each substitution impaired both activities. Proteins from twelve mutants were purified: six from mutants with partial or wild-type activity and six from mutants lacking activity. There is a strong correlation between phenotype and DNA-binding affinity, as determined by fluorescence anisotropy.

Amino Acid Sequence↗

PubMed2004

Significance of ovarian histology in the management of patients presenting a premature ovarian failure.

BACKGROUND: Premature ovarian failure (POF) is a heterogeneous syndrome, possibly due to mutations of genes involved in the normal development of the ovary and/or follicles. Based essentially on animal models, these mutations are associated with various ovarian phenotypes, from a complete absence of follicles to a partial follicular maturation. The aim of the present study was to determine whether ovarian histology, compared to pelvic ultrasonography, would be helpful in identifying which patients display an impaired follicular reserve and/or growth, and in orientating the search for POF aetiology. METHODS AND RESULTS: We studied a cohort of 61 patients suffering from POF with a normal karyotype. Their median age (range) at diagnosis was 26 years (15-39). The FSH plasma level was high, 67.0 IU/l (13-155). Estradiol and inhibin B plasma levels were low: 18.5 pmol/l (18.5-555) and 5 pg/ml (5-105) respectively. Both pelvic ultrasonography and ovarian biopsies were performed in each patient. The presence of follicles suggested at ultrasonography was confirmed at histology in 56% of the patients. Ovarian histology led to the distinction of two phenotypes: (i) small-sized ovaries, deprived of follicles; and (ii) normal-sized ovaries with partial follicular maturation. To confirm the value of ovarian biopsies, samples from 20 normal women were studied. These demonstrated that ovarian biopsy at random enables reliable assessment of follicular presence, especially when their size is <2 mm. CONCLUSION: Ovarian histology appears to be a reliable tool in evaluating the follicular reserve, and helpful and complementary to clinical and hormonal phenotyping in orienting the search for the various genetic causes of POF syndrome.

Adolescent↗

PubMed2006

Deletion of chromosome 21 disturbs human brain morphogenesis.

PURPOSE: Humans with small deletions of chromosome 21 provide important models for understanding the role of dosage-sensitive genes in brain morphogenesis. To identify chromosome 21 genes responsible for defects of the central nervous system, we determined the deleted regions and brain malformations in three unrelated individuals with overlapping partial deletions of chromosome 21. METHODS: Fluorescent in situ hybridization and magnetic resonance imaging were used to define the chromosomal structure and structural brain abnormalities present in these three individuals. RESULTS: The regions of chromosome 21 found to be deleted in these individuals were as follows: case 1: KCNJ6 to the telomere; case 2: ITSN1 to the telomere; and case 3: ITSN1 to PCNT2. The abnormalities of brain structure shared by all included microcephaly, pachygyria, polymicrogyria, colpocephaly, hypoplastic corpus callosum and white matter, hypoplastic cerebellum, and enlarged ventricular system. The clinical features in common included mental retardation, microcephaly, facial dysmorphism, and epilepsy (severe in one patient). CONCLUSION: From analyses of the molecular, cytogenetic, and neuroimaging data from these three individuals, combined with those from previously reported cases, we infer that deletion of an 8.4-Mb region in chromosome band 21q22.2-22.3 (KCNJ6-COL6A2) is associated with cortical dysplasia. We propose that one or more dosage-sensitive genes in this region contributes to cortical development and that deletion of 21q22.2-22.3 should be considered in the diagnosis of mentally retarded patients with facial dysmorphism and cerebral dysplasia.

Adolescent↗

PubMed1998

Nuclease overexpression mutants of Serratia marcescens.

A family of mutants overexpressing the Serratia marcescens extracellular nuclease has been known for decades. A number of these alleles are characterized here at the molecular level, and the mutant genes are identified, yielding a likely model for their phenotype. The known mutations exert their effect indirectly on nucA expression by elevating the basal SOS response of the cell. Mutations have been found in xerC and uvrD, both of which result in partial SOS induction. A classic nucsu allele, that of strain W1050, is also likely to be in xerC.

Adenosine Triphosphatases↗

PubMed2007

QSAR studies on chalcones and flavonoids as anti-tuberculosis agents using genetic function approximation (GFA) method.

Design of compounds having good anti-tubercular activity is gaining much importance in the field of tuberculosis research due to reemergence of antibiotic resistance strains. In this paper quantitative structure activity relationships (QSAR) were developed on chalcones, chalcone-like compounds, flavones and flavanones to understand the relationship between biological activity and structural features. Genetic function approximation (GFA) method was used to identify the descriptors that would lead to good regression equations. The best molecular descriptors identified were Jurs descriptors (Jurs charged partial surface area), hydrogen bond donor, principal moment of inertia, molecular energy, dipole magnetic, molecular area, absorption, distribution, metabolism and excretion (ADME) properties and Chi indices (Kier & Hall chi connectivity indices). Excellent statistically significant models were developed by this approach (r(2)=0.8-0.97) for the four groups of compounds. The cross validated r(2) (XV r(2)) which is an indication of the predictive capability of the model for all the cases was also very good (=0.79-0.94).

Antitubercular Agents↗

PubMed2001

[Therapeutic strategy for multiple sclerosis targeting NK and NKT cells].

Recent works from our laboratory have demonstrated that natural killer (NK) cells and CD1d-restricted NKT cells are functionally biased toward producing type 2 cytokine in the remission phase of multiple sclerosis, an autoimmune disease putatively mediated by Th1 T cells. Indirect evidence would indicate that the type 2 bias of NK and NKT cells is not the cause of MS but an adaptive change to protect against activation of pathogenic Th1 cells. In fact, NK cells biased for producing IL-5 (NK2 cells) would inhibit induction of Th1 cells in vitro. Here I propose that it is a reasonable strategy for the control of MS to maximize and/or optimize the regulatory potentials of the innate regulatory cells. We have already found that experimental autoimmune encephalomyelitis (EAE), an animal model for MS, can be inhibited when NKT cells are partially stimulated by glycolipid ligands for NKT cells. Experiments proved that the suppression of disease is mediated by IL-4 produced by NKT cells. Future studies should be directed for identifying useful ligands for inducing regulatory cytokines from NK and NKT cells.

Animals↗