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Biomedical subjects

R Ross

Publications and source records attributed to R Ross.

At least 19 recordsLinked to original sources
PubMed2000

Obesity reduction through lifestyle modification.

Obesity is a worldwide public health problem. One in three Canadians is overweight, a prevalence that is already high and increasing. Moreover, 54% of men and 37% of Canadian women are characterized as abdominally obese, the phenotype that is strongly associated with cardiovascular disease and type II diabetes. These observations underscore the importance of considering the efficacy of methods commonly used to reduce total and abdominal obesity. These strategies include a decrease in energy intake (diet), an increase in energy expenditure (exercise), or pharmacological intervention. The combination of diet and exercise is more commonly prescribed, with pharmacological intervention suggested only when lifestyle changes fail to achieve weight loss. The aim of this report is to review current knowledge regarding the influence of diet and exercise as treatment strategies for obesity reduction and provide recommendations for attaining and maintaining a healthy weight. The importance of diet composition in the treatment of obesity is also considered.

Abdomen↗
PubMed1999

Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin.

Active matrix metalloproteinases and degraded collagen are observed in disease states, such as atherosclerosis. To examine whether degraded collagen fragments have distinct effects on vascular smooth muscle cells (SMC), collagenase-digested type I collagen was added to cultured human arterial SMC. After addition of collagen fragments, adherent SMC lose their focal adhesion structures and round up. Analysis of components of the focal adhesion complex demonstrates rapid cleavage of the focal adhesion kinase (pp125(FAK)), paxillin, and talin. Cleavage is suppressed by inhibitors of the proteolytic enzyme, calpain I. In vitro translated pp125(FAK) is a substrate for both calpain I- and II-mediated processing. Mapping of the proteolytic cleavage fragments of pp125(FAK) predicts a dissociation of the focal adhesion targeting (FAT) sequence and second proline-rich domain from the tyrosine kinase domain and integrin-binding sequence. Coimmunoprecipitation studies confirm that the ability of pp125(FAK) to associate with paxillin, vinculin, and p130cas is significantly reduced in SMC treated with degraded collagen fragments. Further, there is a significant reduction in the association of intact pp125(FAK) with the cytoskeletal fraction, while pp125(FAK) cleavage fragments appear in the cytoplasm in SMC treated with degraded collagen fragments. Integrin-blocking studies indicate that integrin-mediated signals are involved in degraded collagen induction of pp125(FAK) cleavage. Thus, collagen fragments induce distinct integrin signals that lead to initiation of calpain-mediated cleavage of pp125(FAK), paxillin, and talin and dissolution of the focal adhesion complex.

Actinin↗
PubMed1999

NO synthase II in mouse skeletal muscle is associated with caveolin 3.

The inducible-type NO synthase (NOS II; iNOS) is constitutively expressed in slow-twitch skeletal muscle fibres of guinea-pigs [Gath, Closs, Gödtel-Armbrust, Schmitt, Nakane, Wessler and Förstermann (1996) FASEB J. 10, 1614-1620]. Here we studied the expression of NOS II in skeletal muscle of wild-type and NOS II-deficient mice and investigated the molecular basis for the membrane association of this NOS in muscle. A basal expression of NOS II mRNA and protein was detected in skeletal muscle from untreated wild-type mice; expression increased when mice were treated with bacterial lipopolysaccharide (LPS). No NOS II was found in any tissue of untreated or LPS-treated NOS II-deficient mice. Immunoprecipitation experiments were performed with homogenates of gastrocnemius muscle from untreated or LPS-treated wild-type mice. A NOS II-specific antibody precipitated caveolin 3 in all homogenates investigated, the effect being most pronounced in skeletal muscle from LPS-treated animals. Conversely, an antibody against caveolin 3 co-precipitated NOS II in muscle homogenates. Similarly, a weak co-precipitation of NOS II and caveolin 3 was seen in homogenates of untreated murine C2C12 myotubes; co-precipitation was markedly enhanced in cells stimulated with LPS/interferon gamma. The association of NOS II with caveolin 3 might have implications for the regulation of contraction of, and/or glucose uptake by, slow-twitch muscle fibres.

Animals↗
PubMed1999

Studies with a growth hormone antagonist and dual-fluorescent confocal microscopy demonstrate that the full-length human growth hormone receptor, but not the truncated isoform, is very rapidly internalized independent of Jak2-Stat5 signaling.

UNLABELLED: We have investigated trafficking of two negative regulators of growth hormone receptor (GHR) signaling: a human, truncated receptor, GHR1-279, and a GH antagonist, B2036. Fluorescent-labeled growth hormone (GH) was rapidly internalized by the full-length GHR, with >80% of the hormone internalized within 5 min of exposure to GH. In contrast, <5% of labeled GH was internalized by cells expressing truncated GHR1-279. Using another truncated receptor, GHR1-317 fused to enhanced green fluorescent protein (EGFP), we have exploited fluorescence energy transfer to monitor the trafficking of ligand-receptor complexes. The data confirmed that internalization of this truncated receptor is very inefficient. It was possible to visualize the truncated GHR1-317-EGFP packaged in the endoplasmic reticulum, its rapid movement in membrane bound vesicles to the Golgi apparatus, and subsequent transport to the cell membrane. The GH antagonist, B2036, blocked Jak2-Stat5-mediated GHR signaling but was internalized with a similar time course to native GH. THE RESULTS: 1) demonstrate the rapid internalization of GH when studied under physiological conditions; 2) confirm the hypothesis that internalization of cytoplasmic domain truncated human GHRs is very inefficient, which explains their dominant negative action; and 3) show that the antagonist action of B2036 is independent of receptor internalization.

Golgi Apparatus↗
PubMed1999

Long-term treatment of acromegaly with the somatostatin analogue SR-lanreotide.

OBJECTIVE: To assess the efficacy and tolerability of SR-lanreotide in the treatment of active acromegaly. PATIENTS AND DESIGN: 30 patients (17 men and 13 women) were treated in whom active acromegaly was confirmed by clinical features, a mean GH level of >5 mlU/l and failure to suppress GH to <2 mlU/l after a 75 g glucose load. Patients were treated for a median period of 60 weeks (range 12-168) with im injections of SR-lanreotide 30 mg given every 7-14 days. MEASUREMENTS: Mean GH and IGF-I levels were measured at baseline and every 12-weeks together with symptom score assessment. MRI of the pituitary gland was performed at baseline and if an adenoma was identified at yearly intervals. Gall bladder ultrasound scans were performed at baseline and then every 24-weeks. RESULTS: Twenty-three patients were treated for at least 48-weeks and, in these, GH levels fell from 10.5 mlU/l (7.6-17.6) (median and interquartile range) at baseline to 3.2 mlU/l (2.4-3.9) (p<0.0001) and IGF-I levels ftom 88.9 nmol/L (71.4-137.1) to 56.8 nmol/l (39.3-75.4) (p=0.0002). GH response to treatment was better in elderly patients (age> or =65 years) compared to younger patients but neither sex, pre-treatment GH levels, previous surgery nor previous radiotherapy influenced the response. Treatment resulted in a significant improvement in the symptoms of active acromegaly in the majority of patients. A significant reduction in the size of the pituitary adenoma was documented in 6 of 10 patients who had a repeat MRI scan after one year. Treatment was well-tolerated by the majority of patients; side effects were mainly transient gastrointestinal symptoms. These were severe in only 2 patients necessitating discontinuation of the drug. Two patients developed new gall stones and 4 female patients had temporal hair loss necessitating stopping treatment in one of them. There were minor effects on glucose tolerance which were not of clinical importance. CONCLUSION: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients.

Acromegaly↗
PubMed1999

Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop.

The transcription factor NF-kappa B is an important regulator of gene expression during immune and inflammatory responses, and can also protect against apoptosis. Here we show that endothelial cells undergo apoptosis when deprived of growth factors. Surviving viable cells exhibit increased activity of NF-kappa B, whereas apoptotic cells show caspase-mediated cleavage of the NF-kappa B p65/ReIA subunit. This cleavage leads to loss of carboxy-terminal transactivation domains and a transcriptionally inactive p65 molecule. The truncated p65 acts as a dominant-negative inhibitor of NF-kappa B, promoting apoptosis, whereas an uncleavable, caspase-resistant p65 protects the cells from apoptosis. The generation of a dominant-negative fragment of p65 during apoptosis may be an efficient pro-apoptotic feedback mechanism between caspase activation and NF-kappa B inactivation.

Amino Acid Sequence↗
PubMed1999

Effects of sex on the change in visceral, subcutaneous adipose tissue and skeletal muscle in response to weight loss.

OBJECTIVE: To examine the influence of sex on whole body and regional subcutaneous, visceral, total adipose tissue (AT), skeletal muscle (SM), and lean tissue in response to weight loss induced by diet alone (DO) or the combination of diet and aerobic (DA) or resistance exercise (DR). DESIGN: Sixty upper-body obese men and women were randomly assigned to one of three treatments: DO, DA, or DR. All tissues were measured using a whole body, magnetic resonance imaging protocol. RESULTS: Within each group reductions were observed for body weight ( approximately 11 kg), subcutaneous and visceral AT (P<0.01). After controlling for pretreatment differences in tissue size, reductions in total adiposity, total and regional subcutaneous and visceral adipose tissue were not different between sexes (P>0.1). Independent of sex, the reduction in visceral AT was greater than subcutaneous AT (P<0.05) in response to DO and DA. With the exception of DA women, the reduction in abdominal subcutaneous AT was greater (P<0.05) than lower-body subcutaneous AT in response to diet and exercise, but not diet alone, in both sexes (P>0.05). Independent of sex, skeletal muscle mass was preserved within the exercise groups (P>0.05) but not diet alone (P<0.05). Peak VO2 (l/min) improved in the DA groups as did muscular strength in the DR groups (P<0.01). CONCLUSIONS: These findings indicate that in response to diet or diet and exercise-induced weight loss, reductions in total adiposity, subcutaneous and visceral adipose tissue distribution are not different in obese men and women. Independent of sex, the combination of diet and exercise results in a preservation of skeletal muscle mass, a preferential reduction of abdominal subcutaneous AT, and improved functional capacity by comparison to diet alone.

Adipose Tissue↗
PubMed1999

Mouse langerhans cells differentially express an activated T cell-attracting CC chemokine.

Epidermal Langerhans cells represent an immature population of dendritic cells, not yet able to prime naïve T cells. Following in vitro culture Langerhans cells mature into potent immunostimulatory cells. We constructed a representative cDNA library of in vitro matured murine Langerhans cells. Applying a differential screening procedure 112 differentially expressed cDNA clones were isolated. Thirty-six clones represented cDNA fragments of the same gene, identifying it to be the most actively expressed gene induced in maturing Langerhans cells. A full-length cDNA was sequenced completely. The open reading frame codes for a protein of 92 amino acids containing a leader peptide of 24 amino acids, yielding a mature protein of 7.8 kDa molecular weight. Database searches revealed 99.4% sequence identity on the nucleotide level to the recently described mouse CC chemokine ABCD-1, as well as 74% sequence identity to the human CC chemokine, the macrophage-derived chemokine/stimulated T cell chemotactic protein. Expression was analyzed by reverse transcriptase-polymerase chain reaction on a large panel of cell types. Unlike the macrophage-derived chemokine, expression was not detected in macrophages stimulated by various cytokines. Expression is restricted to cultured Langerhans cells, in vitro cultured dendritic cells, and lipopolysaccharide-activated B cells. Recombinant protein was expressed in the yeast Pichia pastoris and purified to homogeneity. Whereas no chemotactic activity was observed in chemotaxis assays for naïve T cells, B cells, cultured dendritic cells, and Langerhans cells, a strong chemoattractant activity was exerted on activated T cells. Thus, production of this chemokine by dendritic cells may be essential for the establishment and amplification of T cell responses.

Amino Acid Sequence↗
PubMed1999

Is abdominal fat preferentially reduced in response to exercise-induced weight loss?

PURPOSE: It is known that a preferential deposition of fat in the abdominal region is the obesity phenotype that conveys the greatest health risk. Although physical activity is commonly prescribed to reduce obesity, the influence of exercise-induced weight loss on abdominal fat is unclear. This review was undertaken to clarify whether abdominal fat is preferentially reduced consequent to weight loss induced by regular exercise. METHODS: A literature search (Medline, 1966-1998) was performed using appropriate keywords to identify studies reporting changes in both whole body and abdominal fat in response to exercise. RESULTS: At present there are no randomized controlled trails (RCT) wherein it was clear that exercise alone induced weight loss. For the four RCT within which regular exercise was not associated with weight loss, abdominal fat measured by waist circumference was unchanged. A similar trend is observed for the nonrandomized studies. Abdominal obesity as measured by waist circumference is unchanged for those studies reporting no loss in weight or fat; however, a modest reduction (approximately 3 cm) is observed in response to exercise-induced weight loss of about 3 kg. Without exception, these studies were not designed to determine whether abdominal obesity was preferentially reduced. Absent from the literature are RCT that employ imaging techniques (e.g., computerized tomography or magnetic resonance imaging) to determine whether exercise-induced weight loss is associated with reductions in either visceral or abdominal subcutaneous fat. However, the findings from four nonrandomized or controlled studies report that exercise with or without weight loss is associated with reductions in both visceral and subcutaneous fat. CONCLUSION: There is insufficient evidence to determine whether exercise-induced weight loss is associated with reductions in abdominal fat. Clearly there is a need for carefully controlled studies wherein the primary aim is to determine the influence of regular exercise on total and abdominal adiposity.

Abdomen↗
PubMed1999

Maturation of epidermal Langerhans cells: increased expression of beta- and gamma-actin isoforms as a basis of specialized cell functions.

Epidermal Langerhans cells (LC) represent immature dendritic cells. During in vitro culture in the presence of keratinocytes they mature into potent immunostimulatory cells for naive T cells. This process is thought to simulate in vivo maturation of LC following activation by antigen contact. Maturation of LC is accompanied by morphological alterations. Applying a differential screening procedure we isolated differentially expressed cDNAs involved in the maturation events including cDNAs of the cytoskeletal actin isoforms beta- and gamma-actin. Stronger signals with hybridization probes derived from cultured LC compared with probes derived from freshly isolated LC indicate upregulation of actin expression. Upregulated expression of actin was confirmed by RT-PCR, Western blot and immunofluorescence analysis. Staining with fluorescence-labelled phalloidin that selectively binds to polymerized F-actin, indicates an increase in F-actin levels in cultured LC. Thus our data show that maturation of LC, which involves formation of dendritic structures and movement of formerly immobile cells, is accompanied by augmented expression of actin and formation of additional actin filaments. Furthermore, actin mRNA, often used as reference to assess mRNA amounts for Northern blotting or competitive RT-PCR because of its high and ubiquitous expression, is an inappropriate standard for the analysis of LC and DC.

Actins↗
PubMed1999

Nonradioactive detection of differentially expressed genes using complex RNA or DNA hybridization probes.

The analysis of differential gene expression has become increasingly important in recent years. Typically, differentially expressed genes are identified in a primary screening procedure, yielding candidate genes whose differential expression has to be verified. We provide a highly sensitive, efficient and nonradioactive differential screening procedure to analyze numerous candidate genes in a single step. This comprises labeling of poly(A)+ RNA of the cell types analyzed with DIG Chem-Link and differential hybridization to the candidate genes fixed on dot blots. DIG Chem-Link allows, to our knowledge, for the first time efficient and direct nonradioactive labeling of RNA in vitro. Advantages of this method include extremely short exposure times and the feasibility to re-use the probes after prolonged storage. Using this procedure, we isolated several genes that are differentially expressed in maturing Langerhans cells.

Animals↗
PubMed1999

Effects of aerobic or resistance exercise and/or diet on glucose tolerance and plasma insulin levels in obese men.

OBJECTIVE: This study had two objectives. First, we examined whether the influence of diet combined with either aerobic (DA) (n = 10) or resistance (DR) (n = 10) exercise has effects on insulin and glucose levels that are different in obese men. Second, we tried to determine whether the combination of diet and exercise is associated with improvements in insulin and glucose levels that are greater than those associated with diet alone (DO) (n = 9). RESEARCH DESIGN AND METHODS: Insulin and glucose levels were measured after an overnight fast and a 75-g oral glucose challenge (OGTT). Visceral adipose tissue (AT), subcutaneous AT, and skeletal muscle were measured by magnetic resonance imaging (MRI) before and after treatment (16 weeks). RESULTS: Reductions in weight (12.4 +/- 3.8 kg) and in visceral (37 +/- 15.1%) and subcutaneous AT (24.3 +/- 8.6%) were not different between treatments (P > 0.05). Skeletal muscle was maintained in the DA and DR groups but was reduced (7.3 +/- 2.8%) in the DO group (P < 0.05). Independent of treatment, fasting glucose and OGTT glucose did not change (P > 0.05). However, fasting insulin, OGTT insulin, and the insulin-to-glucose ratio decreased within all treatments (P < 0.05). Reductions in the OGTT insulin area under the curve were greater (P < 0.05) within the DA (52 +/- 12%) and DR (42 +/- 17%) treatments than in the DO (20 +/- 15%) treatment. Collapsed across group, reductions in visceral AT were related to reductions in fasting and OGTT glucose (P < 0.05), whereas reductions in abdominal subcutaneous AT correlated with reductions in fasting insulin (P < 0.05). CONCLUSIONS: Weight loss induced by diet and aerobic or resistance exercise has similar positive effects on lowering fasting and OGTT insulin values that are greater than those with diet alone. Because changes in glucose and insulin were related to reductions in visceral and abdominal subcutaneous AT, we conclude that reduction in abdominal obesity consequent to diet and exercise-induced weight loss is important for attaining improvements in plasma insulin levels, observations that strengthen the concept that abdominal obesity has an important role in mediating insulin resistance.

Adipose Tissue↗
PubMed1998

Interactions between synthetic vanilloids and the endogenous cannabinoid system.

The chemical similarity between some synthetic agonists of vanilloid receptors, such as olvanil (N-vanillyl-cis-9-octadecenoamide), and the 'endocannabinoid' anandamide (arachidonoyl-ethanolamide, AEA), suggests possible interactions between the cannabinoid and vanilloid signalling systems. Here we report that olvanil is a stable and potent inhibitor of AEA facilitated transport into rat basophilic leukemia (RBL-2H3) cells. Olvanil blocked both the uptake and the hydrolysis of [14C]AEA by intact RBL-2H3 cells (IC50 = 9 microM), while capsaicin and pseudocapsaicin (N-vanillyl-nonanamide) were much less active. Olvanil was more potent than previously reported inhibitors of AEA facilitated transport, i.e. phloretin (IC50 = 80 microM), AM404 (12.9% inhibition at 10 microM) or oleoylethanolamide (27.5% inhibition at 10 microM). Olvanil was a poor inhibitor of [14C]AEA hydrolysis by RBL-2H3 and N18TG2 cell membranes, suggesting that the inhibitory effect on [14C]AEA breakdown observed in intact cells was due to inhibition of [14C]AEA uptake. Olvanil was stable to enzymatic hydrolysis, and (i) displaced the binding of high affinity cannabinoid receptor ligands to membrane preparations from N18TG2 cells and guinea pig forebrain (Ki = 1.64-7.08 microM), but not from cells expressing the CB2 cannabinoid receptor subtype; (ii) inhibited forskolin-induced cAMP formation in intact N18TG2 cells (IC50 = 1.60 microM), this effect being reversed by the selective CB1 antagonist SR141716A. Pseudocapsaicin, but not capsaicin, also selectively bound to CB1 receptor-containing membranes. These data suggest that some of the analgesic actions of olvanil may be due to its interactions with the endogenous cannabinoid system, and may lead to the design of a novel class of cannabimimetics with potential therapeutic applications as analgesics.

Animals↗