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Biomedical subjects

G Faulkner

Publications and source records attributed to G Faulkner.

At least 19 recordsLinked to original sources
PubMed2007

Intranuclear paracrystals observed in striated muscle specific LIM protein-deficient mouse cardiomyocytes.

A paracrystalline structure was observed within left ventricular cardiomyocyte nuclei of MLP(-/-) mice. The paracrystal possessed cross lines, approximately 8.0 micro m long and 0.3 micro m wide, with a slender spindle shape and a periodicity of 13 nm. Paracrystals were best observed along the longitudinal orientation of myofibrils and were detected in less than 10% of the nuclei observed. One dimension of the protein unit forming the paracrystal was 8.5 nm long. The electron density of the paracrystal appeared to be slightly higher than that of heterochromatin, suggesting that RNA-associated proteins are constituents of the paracrystal. This is the first report of intranuclear paracrystals in cardiomyocytes, which appear to be unique to MLP(-/-) mice.

Animals↗
PubMed2006

Simulation of impact test for determining "health" of percutaneous bone anchored implants.

There is an ongoing requirement for a clinically relevant, noninvasive technique to monitor the integrity of percutaneous implants used for dental restorations, bone-anchored hearing aids, and to retain extra-oral prostheses (ear, eye, nose, etc). Because of the limitations of conventional diagnostic techniques (CT, MRI), mechanical techniques that measure the dynamic response of the implant-abutment system are being developed. This paper documents a finite element analysis that simulates a transient response to mechanical impact testing using contact elements. The detailed model allows for a specific interface between the implant and bone and characterizes potential clinical situations including loss of bone margin height, loss of osseointegration, and development of a soft connective tissue layer at the bone-implant interface. The results also show that the expected difference in interface stiffness between soft connective tissue and osseointegrated bone will cause easily measurable changes in the response of the implant/abutment system. With respect to the loss of bone margin height, changes in the order of 0.2 mm should be detectable, suggesting that this technique is at least as sensitive as radiography. A partial loss of osseointegration, while not being as readily evident as a bone margin loss, would still be detectable for losses as small as 0.5 mm.

Computer Simulation↗
PubMed2005

The transcriptional landscape of the mammalian genome.

This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.

3' Untranslated Regions↗
PubMed2004

Physical activity and older adults: a review of health benefits and the effectiveness of interventions.

The purpose of this multidisciplinary review paper is to critically review evidence from descriptive, efficacy and effectiveness studies concerned with physical activity and older people. Both levels of fitness (aerobic power, strength, flexibility and functional capability) and measures of physical activity involvement decline with age, and the extent to which this is due to a biological ageing processes or disuse (physical inactivity) is critically examined. The review will consider the evidence for a causal relationship between sedentary behaviour/physical activity programmes and cardiovascular, musculoskeletal and psycho-social health, independent living and health-related quality of life into old age. The review also considers the effectiveness of different physical activity interventions for older people and issues relating to cost-effectiveness. The implications for future policy in terms of research, health care services, and education and training are briefly discussed.

Aged↗
PubMed2004

The strength duration test: a novel tool in the identification of occult neuropathy in women with pelvic floor dysfunction.

OBJECTIVE: The Strength-duration test (SDT) is a simple minimally invasive measure of muscle innervation, recently adapted for the assessment of the external anal sphincter (EAS). This test can discriminate women with faecal incontinence from controls. The purpose of this study was to determine if the SDT could detect denervation of the EAS in women with weak but anatomically intact EAS and normal pudendal nerve terminal motor latency (PNTML). PATIENTS AND METHODS: Thirteen women with weak but intact EAS on endoanal ultrasound (EAUS) with normal maximum resting pressure and PNTML were recruited to undergo the SDT. The results from this group were compared to control data for the SDT previously collected in our unit. RESULTS: Nine of 13 women were found to have SDT above a 95% confidence interval of the mean curve for controls and six had a SDT outside a 90% confidence interval for individuals derived from control data, suggesting denervation of the EAS. The mean area under the curve was significantly higher in our study group compared to controls (91.0 microsmA vs 72.2 microsmA, P = 0.047) as was the current intensity measured at the 1 ms pulse duration (18.2 mA vs 12.94 mA, P = 0.048), typical of denervation with this test. CONCLUSION: The SDT was abnormal in nine of the 13 study patients. This may partly explain reduced maximum voluntary contraction seen in this group of patients. SDT may be a more sensitive tool in detecting neuropathy than latency measurement.

Adult↗
PubMed2003

Schizophrenia and weight management: a systematic review of interventions to control weight.

OBJECTIVE: Weight gain is a frequent side effect of antipsychotic medication which has serious implications for a patient's health and well being. This study systematically reviews the literature on the effectiveness of interventions designed to control weight gain in schizophrenia. METHOD: A systematic search strategy was conducted of major databases in addition to citation searches. Study quality was rated. RESULTS: Sixteen studies met the inclusion criteria. Five of eight pharmacological intervention studies reported small reductions in weight (<5% baseline body weight). All behavioural (including diet and/or exercise) interventions reported small reductions in, or maintenance of, weight. CONCLUSION: Weight loss may be difficult but it is not impossible. Given the inconsistent results, the widespread use of pharmacological interventions cannot be recommended. Both dietary and exercise counselling set within a behavioural modification programme is necessary for sustained weight control.

Antipsychotic Agents↗
PubMed2002

Mental health nursing and the promotion of physical activity.

Evidence and recent policy initiatives support the promotion of physical activity and exercise within acute inpatient settings. Mental health nurses may perform an important role in encouraging physical activity and legitimizing its incorporation within care planning. This exploratory study aimed to investigate perceptions of the role of exercise and physical activity as a therapeutic strategy within inpatient settings. Given the exploratory nature of the study, a qualitative design using semistructured interviews was considered most appropriate. As part of a larger study regarding the promotion of physical activity within one United Kingdom (UK) Mental Health Trust, 12 mental health nurses were interviewed. All participants identified a need for increasing opportunities for physical activity on inpatient wards. Three interrelated themes emerged that related to how physical activity and exercise was conceptualized by the participants. First, exercise and physical activity was seen as a potentially beneficial distracting strategy rather than an adjunctive strategy in its own right. Secondly, exercise was considered as a lifestyle choice and an individual responsibility. Thirdly, a difficulty in articulating a possible relationship between the 'physical' and the 'mental' was predominant. The implications of these perceptions are discussed in relation to developing a greater profile for physical activity and exercise on acute wards.

Adult↗
PubMed2001

Characterization of human skeletal muscle Ankrd2.

Human Ankrd2 transcript encodes a 37-kDa protein that is similar to mouse Ankrd2 recently shown to be involved in hypertrophy of skeletal muscle. These novel ankyrin-rich proteins are related to C-193/CARP/MARP, a cardiac protein involved in the control of cardiac hypertrophy. A human genomic region of 14,300 bp was sequenced revealing a gene organization similar to mouse Ankrd2 with nine exons, four of which encode ankyrin repeats. The intracellular localization of Ankrd2 was unknown since no protein studies had been reported. In this paper we studied the intracellular localization of the protein and its expression on differentiation using polyclonal and monoclonal antibodies produced to human Ankrd2. In adult skeletal muscle Ankrd2 is found in slow fibers; however, not all of the slow fibers express Ankrd2 at the same level. This is particularly evident in dystrophic muscles, where the expression of Ankrd2 in slow fibers seems to be severely reduced.

Animals↗
PubMed2001

Stealth monensin immunoliposomes as potentiator of immunotoxins in vitro.

Stealth monensin liposomes (SML) were prepared using dipalmitoyl phosphatidylcholine, cholesterol, distearoyl glycerophosphoethanolamine coupled to polyethylene glycol, stearylamine, and N-succinimidyl pyridodithiopropionate linked to stearyl amine, in the molar ratio of 10:5:1.4:1.4:1.5. SML was conjugated to the anti-MY9 antibody by a disulfide linkage to form stealth monensin immunoliposomes (SMIL) by an already established procedure. The encapsulation concentrations of monensin in SML and SMIL were 10(-7) and 4.9x10(-8) M, respectively. More than 20% of monensin remained in circulation after 24 h in BALB/c mice. The ability of SML and SMIL to potentiate the effect of anti-MY9 immunotoxin (anti-MY9-IT) was tested against human leukemia HL-60 sensitive and resistant tumor cells in vitro. SML and SMIL potentiated the activity of anti-MY9-IT by 10-20 times against HL-60 sensitive tumor cell lines. However, greater potentiation of anti-MY9-IT was observed in combination with SML and SMIL against HL-60 resistant tumor cells, found to be 200 and 500 times, respectively. The potentiation of anti-MY9-IT by SMIL was more than two-fold compared with SML against both HL-60 sensitive and resistant tumor cells. Transmission electron microscopy studies conducted with HL-60 resistant cells incubated with anti-MY9-IT and monensin liposomes showed significant dilation of the golgi, which was reversible after re-incubation in fresh medium. Our studies show that SML and SMIL can be successfully used to potentiate the activity of ricin based anti-MY9-IT in vitro, and further in vivo studies will demonstrate the usefulness of this approach.

Animals↗
PubMed2001

Three-dimensional force systems from vertically activated orthodontic loops.

When both vertical alignment and first-order rotation of teeth are to occur simultaneously, a 3-dimensional force system is required. This numerical study evaluated several appliances (rectangular loops and L-loops) used to vertically align teeth. Consideration was given to how these designs might be modified to produce the appropriate force system to allow both movements to occur simultaneously. It was found that the rectangular loop was the most appropriate choice for first-order corrections. For the rectangular loops studied, the in-plane force system was shown to be essentially independent of the out-of-plane effects, which allowed the 2 corrections to be controlled separately.

Algorithms↗
PubMed2001

Exercise and mental health: it's just not psychology!

Exercise has been suggested as an effective adjunctive treatment for a range of mental health conditions. In this study, we explored the perceptions of exercise held by course directors of doctoral training programmes in clinical psychology in England. Given the exploratory nature of the study, we used a qualitative design incorporating semi-structured interviews. Although most participants held favourable attitudes regarding exercise, this was related more to exercise being seen as a positive lifestyle activity that is worth encouraging, rather than exercise being recommended as an adjunctive treatment for mental health problems. Inductive analysis identified four themes that underpinned such a response: inconsistent positions on the evidential criteria used to evaluate the role of exercise, which masked themes regarding the perceived 'simplicity' of exercise interventions, a practical adherence to a mind-body dichotomy, and the incompatibility of exercise with traditional models of understanding and treating clinical conditions. The barriers we have highlighted will continue to hinder the consideration of exercise as a common therapeutic adjunct at present. Although further research is required to examine the relationship between exercise and mental health, consideration must also be given to how such research should be disseminated to mental health professionals.

Attitude of Health Personnel↗
PubMed2001

Telethonin and other new proteins of the Z-disc of skeletal muscle.

This brief review outlines some of the most relevant proteins of the Z-disc and the complex network of interactions that link them together in a stable structure. Apart from the well-known Z-disc proteins such as actin, cap-Z, titin, nebulin, and alpha-actinin 2, several other Z-disc proteins have been recently discovered, including telethonin and myotilin that have been linked to limb girdle muscular dystrophies. Some proteins including ALP and ZASP have known interaction domains (PDZ and LIM motifs), whereas others like FATZ have no canonical interaction domains, although they are known to bind several proteins. Another new Z-disc protein is gamma-filamin that could provide a link between the plasma membrane and myofibrils because it binds directly to gamma- and delta-sarcoglycans and indirectly to alpha-actinin 2 via FATZ and myotilin. A greater knowledge of Z-disc proteins and their interactions is essential for understanding their role in the structure and function of muscle.

Animals↗
PubMed2001

Dysferlin protein analysis in limb-girdle muscular dystrophies.

Dysferlin is the protein product of the DYSF gene mapped at 2p31, which mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. To date, nine autosomal recessive forms (AR-LGMD) have been identified: four genes, which code for the sarcoglycan glycoproteins, are associated with both mild and severe forms, the sarcoglycanopathies (LGMD2C, 2D, 2E and 2F). The other five forms, usually causing a milder phenotype are LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2G (telethonin), LGMD2H (9q31-11), and LGMD21 (19q13.3). We studied dysferlin expression in a total of 176 patients, from 166 LGMD families: 12 LGMD2B patients, 70 with other known forms of muscular dystrophies (LGMD2A, sarcoglycanopathies, LGMD2G), in an attempt to assess the effect of the primary gene-product deficiency on dysferlin. In addition, 94 still unclassified LGMD families were screened for dysferlin deficiency. In eight LGMD2B patients from five families, no dysferlin was observed in muscle biopsies, both through immunofluorescence (IF) and Western blot methodologies, while in two families, a very faint band was detected. Both patterns, negative or very faint bands, were concordant in patients belonging to the same families, suggesting that dysferlin deficiency is specific to LGMD2B. Myoferlin, the newly identified homologue of dysferlin was studied for the first time in LGMD2B patients. Since no difference was observed between patients mildly and severely affected, this protein do not seem to modify the phenotype in the present dysferlin-deficient patients. Dystrophin, sarcoglycans, and telethonin were normal in all LGMD2B patients, while patients with sarcoglycanopathies (2C, 2D, and 2E), LGMD2A, LGMD2G, and DMD showed the presence of a normal dysferlin band by Western blot and a positive pattern on IF. These data suggest that there is no interaction between dysferlin and these proteins. However, calpain analysis showed a weaker band in four patients from two families with intra-familial concordance. Therefore, this secondary deficiency of calpain in LGMD2B families, may indicate an interaction between dysferlin and calpain in muscle. Dysferlin was also present in cultured myotubes, in chorionic villus, and in the skin. Dysferlin deficiency was found in 24 out of a total of 166 Brazilian AR-LGMD families screened for muscle proteins (approximately 14%), thus representing the second most frequent known LGMD form, after calpainopathy, in our population.

Adult↗
PubMed2000

FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle.

We report the identification and characterization of a novel 32-kDa protein expressed in skeletal muscle and located in the Z-disc of the sarcomere. We found that this protein binds to three other Z-disc proteins; therefore, we have named it FATZ, gamma-filamin/ABP-L, alpha-actinin and telethonin binding protein of the Z-disc. From yeast two-hybrid experiments we are able to show that the SR3-SR4 domains of alpha-actinin 2 are required to bind the COOH-terminal region of the FATZ as does gamma-filamin/ABP-L. Furthermore, by using a glutathione S-transferase overlay assay we find that FATZ also binds telethonin. The level of FATZ protein in muscle cells increases during differentiation, being clearly detectable before the onset of myosin. Although FATZ has no known interaction domains, it would appear to be involved in a complex network of interactions with other Z-band components. On the basis of the information known about its binding partners, we could envisage a central role for FATZ in the myofibrillogenesis. After screening our muscle expressed sequence tag data base and the public expressed sequence tag data bases, we were able to assemble two other muscle transcripts that show a high level of identity with FATZ in two different domains. Therefore, FATZ may be the first member of a small family of novel muscle proteins.

Actinin↗
PubMed2000

Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.

Amino Acid Sequence↗
PubMed2000

The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors.

Hematopoietic progenitor cells from Fanconi anemia (FA) group C (FA-C) patients display hypersensitivity to the apoptotic effects of gamma interferon (IFN-gamma) and constitutively express a variety of IFN-dependent genes. Paradoxically, however, STAT1 activation is suppressed in IFN-stimulated FA cells, an abnormality corrected by transduction of normal FANCC cDNA. We therefore sought to define the specific role of FANCC protein in signal transduction through receptors that activate STAT1. Expression and phosphorylation of IFN-gamma receptor alpha chain (IFN-gammaRalpha) and JAK1 and JAK2 tyrosine kinases were equivalent in both normal and FA-C cells. However, in coimmunoprecipitation experiments STAT1 did not dock at the IFN-gammaR of FA-C cells, an abnormality corrected by transduction of the FANCC gene. In addition, glutathione S-transferase fusion genes encoding normal FANCC but not a mutant FANCC bearing an inactivating point mutation (L554P) bound to STAT1 in lysates of IFN-gamma-stimulated B cells and IFN-, granulocyte-macrophage colony-stimulating factor- and stem cell factor-stimulated MO7e cells. Kinetic studies revealed that the initial binding of FANCC was to nonphosphorylated STAT1 but that subsequently the complex moved to the receptor docking site, at which point STAT1 became phosphorylated. The STAT1 phosphorylation defect in FA-C cells was functionally significant in that IFN induction of IFN response factor 1 was suppressed and STAT1-DNA complexes were not detected in nuclear extracts of FA-C cells. We also determined that the IFN-gamma hypersensitivity of FA-C hematopoietic progenitor cells does not derive from STAT1 activation defects because granulocyte-macrophage CFU and erythroid burst-forming units from STAT1(-/-) mice were resistant to IFN-gamma. However, BFU-E responses to SCF and erythropoietin were suppressed in STAT(-/-) mice. Consequently, because the FANCC protein is involved in the activation of STAT1 through receptors for at least three hematopoietic growth and survival factor molecules, we reason that FA-C hematopoietic cells are excessively apoptotic because of an imbalance between survival cues (owing to a failure of STAT1 activation in FA-C cells) and apoptotic and mitogenic inhibitory cues (constitutively activated in FA-C cells in a STAT1-independent fashion).

Animals↗
PubMed1999

ZASP: a new Z-band alternatively spliced PDZ-motif protein.

PDZ motifs are modular protein-protein interaction domains, consisting of 80-120 amino acid residues, whose function appears to be the direction of intracellular proteins to multiprotein complexes. In skeletal muscle, there are a few known PDZ-domain proteins, which include neuronal nitric oxide synthase and syntrophin, both of which are components of the dystrophin complex, and actinin-associated LIM protein, which binds to the spectrin-like repeats of alpha-actinin-2. Here, we report the identification and characterization of a new skeletal muscle protein containing a PDZ domain that binds to the COOH-terminal region of alpha-actinin-2. This novel 31-kD protein is specifically expressed in heart and skeletal muscle. Using antibodies produced to a fragment of the protein, we can show its location in the sarcomere at the level of the Z-band by immunoelectron microscopy. At least two proteins, 32 kD and 78 kD, can be detected by Western blot analysis of both heart and skeletal muscle, suggesting the existence of alternative forms of the protein. In fact, several forms were found that appear to be the result of alternative splicing. The transcript coding for this Z-band alternatively spliced PDZ motif (ZASP) protein maps on chromosome 10q22.3-10q23.2, near the locus for infantile-onset spinocerebellar ataxia.

Actinin↗