Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study.
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Adult↗
Biomedical subjects
M Davies
Publications and source records attributed to M Davies.
Effect of lung-volume-reduction surgery in patients with severe emphysema.
BACKGROUND: Although many patients with severe emphysema have undergone lung-volume-reduction surgery, the benefits are uncertain. We conducted a randomized, controlled trial of the surgery in patients with emphysema. Patients with isolated bullae were excluded because such patients are known to improve after bullectomy. METHODS: Potentially eligible patients were given intensive medical treatment and completed a smoking-cessation program and a six-week outpatient rehabilitation program before random assignment to surgery or continued medical treatment. After 15 patients had been randomized, the entry criteria were modified to exclude patients with a carbon monoxide gas-transfer value less than 30 percent of the predicted value or a shuttle-walking distance of less than 150 m, because of the deaths of 5 such patients (3 treated surgically and 2 treated medically). RESULTS: Of the 174 subjects who were initially assessed, 24 were randomly assigned to continued medical treatment and 24 to surgery. At base line in both groups, the median forced expiratory volume in one second (FEV1) was 0.75 liter, and the median shuttle-walking distance was 215 m. Five patients in the surgical group (21 percent) and three patients in the medical group (12 percent) died (P=0.43). After six months, the median FEV1 had increased by 70 ml in the surgical group and decreased by 80 ml in the medical group (P=0.02). The median shuttle-walking distance increased by 50 m in the surgical group and decreased by 20 m in the medical group (P=0.02). There were similar changes on a quality-of-life scale and similar changes at 12 months of follow-up. Five of the 19 surviving patients in the surgical group had no benefit from the treatment. CONCLUSIONS: In selected patients with severe emphysema, lung-volume-reduction surgery can improve FEV1, walking distance, and quality of life. Whether it reduces mortality is uncertain.
Adrenergic beta-Agonists↗
Tyrosine 62 of the gamma-aminobutyric acid type A receptor beta 2 subunit is an important determinant of high affinity agonist binding.
The gamma-aminobutyric acid type A receptor (GABA(A)R) carries both high (K(D) = 10-30 nm) and low (K(D) = 0.1-1.0 microm) affinity binding sites for agonists. We have used site-directed mutagenesis to identify a specific residue in the rat beta2 subunit that is involved in high affinity agonist binding. Tyrosine residues at positions 62 and 74 were mutated to either phenylalanine or serine and the effects on ligand binding and ion channel activation were investigated after the expression of mutant subunits with wild-type alpha1 and gamma2 subunits in tsA201 cells or in Xenopus oocytes. None of the mutations affected [(3)H]Ro15-4513 binding or impaired allosteric interactions between the low affinity GABA and benzodiazepine sites. Although mutations at position 74 had little effect on [(3)H]muscimol binding, the Y62F mutation decreased the affinity of the high affinity [(3)H]muscimol binding sites by approximately 6-fold, and the Y62S mutation led to a loss of detectable high affinity binding sites. After expression in oocytes, the EC(50) values for both muscimol and GABA-induced activation of Y62F and Y62S receptors were increased by 2- and 6-fold compared with the wild-type. We conclude that Tyr-62 of the beta subunit is an important determinant for high affinity agonist binding to the GABA(A) receptor.
Amino Acid Sequence↗
Reactions of hypochlorous acid with tyrosine and peptidyl-tyrosyl residues give dichlorinated and aldehydic products in addition to 3-chlorotyrosine.
The toxicity of hypochlorous acid (HOCl) generated from activated neutrophils has been associated with several pathological processes such as atherosclerosis. Formation of 3-chlorotyrosine (Cl-Tyr) has been used as a marker for assessing the involvement of HOCl in such processes. In this study, we aimed to investigate the formation of Cl-Tyr from reaction of HOCl with tyrosine (both free and peptide-bound) and the fate of Cl-Tyr under such conditions. Tyrosine, N-acetyltyrosine, bovine serum albumin, and human low density lipoproteins were incubated with a range of reagent hypochlorite concentrations for varying periods in 10 mM phosphate buffer (pH 7.4) at 22 degrees C. The reaction products, and several biological samples, were hydrolyzed (in the case of proteins), isolated, and purified by high pressure liquid chromatography and characterized or quantitated by mass spectrometry and NMR. A significant amount of 3,5-dichlorotyrosine (diCl-Tyr) was obtained from the bovine serum albumin, low density lipoprotein, and some biological samples, in addition to Cl-Tyr, indicating that Cl-Tyr competes effectively for HOCl even when tyrosine is present in great excess. Cl-Tyr and diCl-Tyr were also formed from free tyrosine but then reacted further with HOCl. This finding differs from a claim in the literature that Cl-Tyr was not formed in such a system. The further reaction products of Cl-Tyr and diCl-Tyr with HOCl were elucidated as their corresponding mono- and dichlorinated 4-hydroxyphenylacetaldehydes. These results indicate the importance of assessing other products of HOCl action in addition to Cl-Tyr.
Animals↗
Do men and women fracture bones at similar bone densities?
When the World Health Organization (WHO) guidelines for the definition of osteoporosis in postmenopausal women were identified similar proposals were not developed for men as there was insufficient evidence about the relationship between bone density and fracture in men. We have therefore examined the relationship between bone density and vertebral fracture in men and women attending for assessment of possible osteoporosis. Two hundred and sixty-four women (age 64 [SD 10] years) and 37 men (age 55 [10] years) were studied. Bone density was measured in the lumbar spine and femoral neck by dual-energy X-ray absorptiometry and expressed both as bone mineral density (BMD; g/cm2) and as T-scores. In both sexes there was a sigmoid relationship between the cumulative frequency of vertebral fracture and bone density at both sites. There was a linear relationship between the log odds of fracture and bone mass for both sexes and both sites (r = 0.97-0.99; p < 0.0001). The slope of these lines was significantly steeper for men than women. The BMD at which there was 50% risk of fracture was higher in men than women (0.908 vs 0.844 g/cm2). The difference between the slopes was similar when the bone mass was expressed as a T-score. However, the T-score associated with 50% prevalence of fracture was similar in the two sexes (F: -2.77 vs M: -2.60). We conclude that although there is a different relationship between bone density and fracture in the two sexes the current WHO definition of osteoporosis in postmenopausal women can be appropriately applied to men.
Adult↗
Endogenous TGF-beta1 inhibits the growth and metastatic dissemination of rat oral carcinoma cell lines but enhances local bone resorption.
This study examined the effect of stable transfection of latent transforming growth factor-beta1 (TGF-beta1) cDNA into a predominantly polygonal, 4 nitroquinoline N-oxide (4NQO)-induced rat oral keratinocyte cell line. Seven polygonal and five spindle clonal populations were isolated that overexpressed TGF-beta1 protein by approximately two- to four-fold compared to vector-only transfected controls. Neutralisation experiments indicated that the majority of protein was in the latent form. There was no change in the proportion of polygonal and spindle cells in vitro after transfection with TGF-beta1 cDNA. Polygonal and spindle cells that overexpressed TGF-beta1 produced similar amounts of protein and grew more slowly in vitro than controls. The parent cell line and all transfected cells were growth inhibited (60-75%) by exogenous TGF-beta1. Orthotopic transplantation of the parent and the vector-only control cell lines resulted in primary tumours in the floor of the mouth in almost 100% (20/21) of athymic mice, with no evidence of bone resorption at the site of the primary tumour and pulmonary metastatic tumour deposits in some 40% (7/20) of these animals. The polygonal and spindle cells that overexpressed TGF-beta1 behaved similarly following orthotopic transplantation. A 96% (23/24) primary tumour take was evident following transplantation of cells that overexpressed TGF-beta1, with a significantly (P<0.02) higher number of animals showing bone resorption at the site of the primary tumour (35%; 8/23) compared to controls. By contrast, there was a significant (P<0.03) decrease in the number of animals with pulmonary metastases (4%; 1/23) following transplantation of TGF-beta1 overexpressing cells compared to controls. Overexpression of TGF-beta1 did not alter tumour cell differentiation in vivo. The results demonstrate that endogenous TGF-beta1 functions as a tumour suppressor in the rat-4NQO model of oral carcinogenesis without altering tumour cell morphology or differentiation but can also act to promote local bone resorption.
Animals↗
Management of disconnection between epidural filters and catheters: a dilemma for the anaesthetist.
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Anesthesia, Epidural↗
An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus.
Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)n (CTG)n, which is very long ( approximately 1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1. 25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile-onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.
Adult↗
Low-density lipoprotein stimulates mesangial cell proteoglycan and hyaluronan synthesis.
BACKGROUND: Hyperlipidaemia leads to glomerulosclerosis in small mammals and may contribute to progressive renal disease in man. One prominent feature of lipid-induced glomerular injury in animal models is the accumulation of mesangial matrix. These studies were designed to investigate whether low-density lipoprotein (LDL) enhanced mesangial cell (MC) matrix deposition by modulating the production of proteoglycans (PG) and hyaluronan (HA). METHODS: Growth arrested human MC were metabolically labelled with either 50 microCi/ml Na(2)[(35)S]sulphate or 25 microCi/ml [(3)H]glucosamine and stimulated with LDL (10-100 microg/ml). The radiolabelled PG and HA extracted from the cell layer and the culture medium were isolated, quantified and characterized. Comparison of the PG core proteins synthesized by MC was carried out using Western blot analysis. RESULTS: LDL stimulation led to a dose- and time-dependent increase in [(35)S]sulphate incorporation into PG in the culture medium and to a lesser extent in the cell layer. Analysis of the glycosaminoglycan (GAG) chains showed no difference in either their size or charge. Enzyme digestion studies demonstrated that the synthesis of both chondroitin sulphate PG (CSPG) and heparan sulphate PG (HSPG) was enhanced as was the production of the core proteins of versican (a large CSPG), perlecan (a basement membrane HSPG) and to a lesser extent decorin (a small dermatan sulphate PG (DSPG)). An increase in HA synthesis was also demonstrated in [(3)H]glucosamine labelled cells following LDL stimulation. CONCLUSION: LDL selectively enhances the synthesis of specific PG and HA by mesangial cells. Such effects may contribute to the expansion of the mesangial matrix and modify cell-matrix interactions in lipid-induced renal damage.
Blotting, Western↗
Risk behavior in a community sample of children and adolescents.
OBJECTIVES: First, to investigate whether there is covariation between risk behaviors, including suicidality, in a community probability sample of children and adolescents; and second, to investigate whether risk behavior is associated with selected potential correlates. METHOD: A sample of 9- to 17-year-old youths (N = 1,285) and their caretakers were interviewed in the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. The risk behaviors were marijuana smoking, alcohol use, intercourse, fighting, cigarette smoking, and suicidal ideation/attempts. Relationships between the risk behaviors were described using odds ratios. Linear regression analyses of an index of risk behavior on the selected potential correlates of risk behavior were conducted. RESULTS: There were significant relationships between all pairs of risk behaviors. The score on the index of risk behavior was associated with stressors, lack of resources, family psychiatric disorder, psychopathology, and functional impairment. CONCLUSIONS: Clinicians should be alerted to the possibility of risk behaviors, especially in children and adolescents engaging in other risk behaviors and those with inadequate resources, stressors, functional impairment, or psychopathology.
Adolescent↗
How specific is specific impairment?
OBJECTIVE: To describe the usefulness of impairment items placed at the end of each diagnostic section of a structured instrument (the Diagnostic Interview Schedule for Children Version 2.3) in an attempt to link impairment to specific diagnoses. METHOD: Data from 3 sites of the Methods for the Epidemiology of Child and Adolescent Mental Disorders Study were used to assess the reliability of the specific impairment measures by diagnosis, the extent to which global and specific measures of impairment impact on prevalence rates, the concordance between global and specific impairment, and the degree to which there may be a "halo effect" among specific impairment ratings. RESULTS: Test-retest reliability was better for parent than youth ratings. Fewer children were rated as impaired on well-validated global scales than on specific impairment ratings, suggesting that the threshold for specific ratings needs to be reevaluated. Agreement between specific and global ratings was poor. Most subjects with 2 or more diagnoses for which impairment was attributed to one diagnosis also had impairment attributed to other diagnoses for which they met symptom criteria, suggesting a halo effect in these ratings of specific impairment. CONCLUSIONS: Impairment measures are important in diagnostic assessments to distinguish those individuals whose psychopathology is of clinical significance. Specific impairment ratings used in structured instruments could be improved by including parameters of impairment that are diagnosis-specific.
Adolescent↗
Religiosity and substance use and abuse among adolescents in the National Comorbidity Survey.
OBJECTIVE: To replicate previous findings among adults of an inverse association between religiosity and substance use among a nationally representative sample of adolescents. METHOD: Subjects were 676 (328 female and 348 male) adolescents in the National Comorbidity Survey who were assessed for substance use and abuse with the Composite International Diagnostic Interview. Religiosity was assessed through affiliation with religious denomination and through response to 7 questions concerning belief and practice. RESULTS: Confirmatory factor analyses replicated in adolescents the 2 religiosity factors of personal devotion and personal conservatism previously identified by Kendler among adults, although the 2 factors were more highly correlated in adolescents than in adults. Personal devotion (a personal relationship with the Divine) and affiliation with more fundamentalist religious denominations were inversely associated with substance use and substance dependence or abuse across a range of substances (alcohol, marijuana, cocaine, or any contraband drug). Personal conservatism (a personal commitment to teaching and living according to creed) was inversely associated with use of alcohol only. CONCLUSION: Low levels of religiosity may be associated with adolescent onset of substance use and abuse.
Adolescent↗
Induction of hyaluronan metabolism after mechanical injury of human peritoneal mesothelial cells in vitro.
BACKGROUND: Hyaluronan (HA) is an important extracellular matrix component that is involved in cell movement and tissue repair. In vertebrates, HA synthase genes (HAS 1, HAS 2, and HAS 3) that control the synthesis of HA have been identified. In this article, we investigated HA synthesis in the response of human peritoneal mesothelial cells (HPMCs) to injury. METHODS: The expression of HAS 1, HAS 2, and HAS 3 mRNA and the synthesis of [(3)H]-labeled HA were examined in an in vitro model of peritoneal mesothelial cell damage. The staining for uridine diphosphoglucose dehydrogenase, a key enzyme in the synthesis of HA, and biotinylated HA-binding protein was used to determine the cellular location of HA synthesis and its site of deposition. RESULTS: Growth-arrested human HPMCs expressed low levels of mRNA for HAS 2 and HAS 3 but not HAS 1. Following injury to the monolayer, HAS 2 was up-regulated by 6 hours, reaching maximal expression between 12 and 24 hours. In contrast, the expression of HAS 3 was down-regulated. During the same time period, synthesis of HA was increased in the injured monolayer. This synthetic activity appeared to be restricted to cells at the edge of the wound and to cells entering the wound. In a separate series of experiments, the addition of HA to the injured monolayer at a concentration range found in peritoneal fluid (50 to 3300 ng/mL) increased the migration of cells into the wound in a dose-dependent manner. CONCLUSIONS: These studies provide evidence that HA is an important component of peritoneal mesothelial cell migration. The results also suggest that in this process, there is differential regulation of HAS gene expression and that the synthesis of HA is limited to cells located at the leading edge of the wound.
Cell Movement↗
Characterization of the interaction of zopiclone with gamma-aminobutyric acid type A receptors.
Zopiclone is a cyclopyrrolone that is used clinically as a hypnotic. Although this drug is known to interact with neuronal gamma-aminobutyric acid type A receptors, its binding site(s) within the receptor oligomer has been reported to be distinct from that of the classical benzodiazepines. After photoaffinity labeling with flunitrazepam, receptors in rat cerebellar membranes showed differentially reduced affinity for flunitrazepam and zopiclone by 50- and 3-fold, respectively. Because histidine 101 of the alpha-subunit is a major site of photolabeling, we have made specific substitutions of this residue and studied the consequences on the binding properties of zopiclone and diazepam using recombinant alpha1beta2gamma2-receptors transiently expressed in tsA201 cells. Both compounds showed similar binding profiles with receptors containing mutated alpha-subunits, suggesting a similar interaction with the residue at position 101. At alpha1beta2gamma3-receptors, flunitrazepam affinity was dramatically decreased by approximately 36-fold, whereas the affinity for zopiclone was decreased only 3-fold, suggesting a differential contribution of the gamma-subunit to the binding pocket. Additionally, we used electrophysiological techniques to examine the contribution of the gamma-subunit isoform in the receptor oligomer to ligand recognition using recombinant receptors expressed in Xenopus oocytes. Both compounds are agonists at alpha1beta2gamma2- and alpha1beta2gamma3-receptors, with flunitrazepam being more potent but less efficacious. In summary, these data suggest that histidine 101 of the alpha1-subunit plays a similar role in ligand recognition for zopiclone, diazepam, and flunitrazepam.
Amino Acid Substitution↗
Myotube formation is delayed but not prevented in MyoD-deficient skeletal muscle: studies in regenerating whole muscle grafts of adult mice.
We compared the time course of myogenic events in vivo in regenerating whole muscle grafts in MyoD(-/-) and control BALB/c adult mice using immunohistochemistry and electron microscopy. Immunohistochemistry with antibodies to desmin and myosin revealed a striking delay by about 3 days in the formation of myotubes in MyoD(-/-) autografts compared with BALB/c mice. However, myotube formation was not prevented, and autografts in both strains appeared similar by 8 days. Electron microscopy confirmed myotube formation in 8- but not 5-day MyoD(-/-) grafts. This pattern was not influenced by cross-transplantation experiments between strains examined at 5 days. Antibodies to proliferating cell nuclear antigen demonstrated an elevated level of replication by MyoD(-/-) myoblasts in autografts, and replication was sustained for about 3 days compared with controls. These data indicate that the delay in the onset of differentiation and hence fusion is related to extended proliferation of the MyoD(-/-) myoblasts. Overall, although muscle regeneration was delayed it was not impaired in MyoD(-/-) mice in this model.
Animals↗
The use of site-directed mutagenesis, transient transfection, and radioligand binding. A method for the characterization of receptor-ligand interactions.
Receptor-ligand interactions have traditionally been evaluated using a number of biochemical techniques including radioligand binding, photoaffinity labeling, crosslinking, and chemical modification. In modern biochemistry, these approaches have largely been superseded by site-directed mutagenesis in the study of protein function, owing in part to a better understanding of the chemical properties of oligonucleotides and to the ease with which mutant clones can now be generated. The Altered Sites II in vitro Mutagenesis System from the Promega Corporation employs oligonucleotides containing two mismatches to introduce specific nucleotide substitutions in the nucleic acid sequence of a target DNA. One of these mismatches will alter the primary sequence of a given protein, whereas the second will give rise to a silent restriction site that is used to screen for mutants. Transient transfection of tsA201 cells with mutant cDNA constructs using calcium phosphate as a carrier for plasmid DNA permits expression of recombinant receptors that can be characterized using radioligand binding assays. In this article, we focus on site-directed mutagenesis, heterologous expression in eukaryotic cells, and radioligand binding as a methodology to enable the characterization of receptor-ligand interactions.
Calcium Phosphates↗
Survey of raw egg use by home caterers.
Outbreaks of egg related salmonella infection continue to occur despite over ten years of national guidance on this subject. Fifty-four out of 70 registered home caterers in Cheshire responded to a telephone questionnaire, which revealed that a sixth prepared raw egg dishes containing shell eggs, none used pasteurised egg, and advice about storage of eggs and handwashing was not always followed. A postal questionnaire sent to 13 wholesalers and major supermarket chains showed that pasteurised egg was available in large packs from wholesalers but not from supermarkets. It is time to consider new approaches to reinforce advice about pasteurised egg use for raw egg dishes, storage, and measures to prevent cross contamination. These findings have implications for the training of home caterers and the general public.
Cooking↗