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PubMed2003

Non-invasive investigation of gastrointestinal functions with magnetic resonance imaging: towards an "ideal" investigation of gastrointestinal function.

Gastrointestinal (GI) function is complex and physiological measurements are subject to a variety of technical difficulties and practical limitations. The ideal technique would be non-invasive, widely available, convenient, and reliable and would not expose the subject to ionising radiation. It would permit direct assessment of GI function in the postprandial as well as the resting state, and be able to differentiate between food, secretion, and air in the lumen. GI structure and function are interdependent and the ideal technique would permit simultaneous assessment of these factors. Finally, the bowel operates as a functional whole and assessment of the GI tract proximal and distal to the area of interest is desirable. In this article the authors summarise the development and validation of magnetic resonance imaging techniques that overcome many of the deficiencies of existing methods, and have many characteristics of the "ideal" investigation of GI function.

Defecation↗

PubMed1993

Pre-employment lung function at age 16 years as a guide to lung function in adult life.

BACKGROUND: A study was conducted to find out if pre-employment lung function at age 16 improved the estimation of that between ages 25 to 27 compared with the use of reference values based on smoking history, stature, body mass index, and other concurrent anthropometric variables. METHODS: Apprentices attending a shipyard training school were assessed on six occasions from entry during their 17th year to age 25 to 27; results for 114 such men were analysed. The measurements were of stature, body mass, fat free mass and body fat, thoracic dimensions, forced expiratory volume and indices of forced expiratory flow, total lung capacity, and its subdivisions, transfer factor and KCO. RESULTS: At best about half the variance in the final lung function could be accounted for with the concurrent reference variables. For each lung function index the proportion of explained variance was substantially increased by also including in the prediction equation the pre-employment lung function expressed in standard deviation units. CONCLUSION: Estimation of the longitudinal decline in lung function during adult life should be based on initial and final measurements of which the first should ideally be at age 25 but those at age 16 can be used instead: such measurements have long term value and should be preserved.

Adolescent↗

PubMed2001

Divergent evolution of enzymatic function: mechanistically diverse superfamilies and functionally distinct suprafamilies.

The protein sequence and structure databases are now sufficiently representative that strategies nature uses to evolve new catalytic functions can be identified. Groups of divergently related enzymes whose members catalyze different reactions but share a common partial reaction, intermediate, or transition state (mechanistically diverse superfamilies) have been discovered, including the enolase, amidohydrolase, thiyl radical, crotonase, vicinal-oxygen-chelate, and Fe-dependent oxidase superfamilies. Other groups of divergently related enzymes whose members catalyze different overall reactions that do not share a common mechanistic strategy (functionally distinct suprafamilies) have also been identified: (a) functionally distinct suprafamilies whose members catalyze successive transformations in the tryptophan and histidine biosynthetic pathways and (b) functionally distinct suprafamilies whose members catalyze different reactions in different metabolic pathways. An understanding of the structural bases for the catalytic diversity observed in super- and suprafamilies may provide the basis for discovering the functions of proteins and enzymes in new genomes as well as provide guidance for in vitro evolution/engineering of new enzymes.

Amidohydrolases↗

PubMed2001

Renal effects of nabumetone, a COX-2 antagonist: impairment of function in isolated perfused rat kidneys contrasts with preserved renal function in vivo.

The constitutive cyclooxygenase (COX)-1 enzyme has been considered the physiologically important isoform for prostaglandin synthesis in the normal kidney. It has, therefore, been suggested that selective inhibitors of the 'inducible' isoform (COX-2) may be free from renal adverse effects. We studied the renal effects of the predominantly COX-2 antagonist nabumetone in isolated perfused kidneys. As compared with controls, kidneys removed after in vivo administration of oral nabumetone (15 mg/kg) disclosed altered renal function with reduced glomerular filtration rate, filtration fraction, and urine volume and enhanced hypoxic outer medullary tubular damage. By contrast, renal function and morphology were not affected in vivo by nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid. The latter agent (10-20 mg/kg i.v.) did not significantly alter renal microcirculation, as opposed to a selective substantial reduction in medullary blood flow noted with the nonselective COX inhibitor indomethacin (5 mg/kg i.v.). In a rat model of acute renal failure, induced by concomitant administration of radiocontrast, nitric oxide synthase, and COX inhibitors, the decline in kidney function and the extent of hypoxic medullary damage with oral nabumetone (80 mg/kg) were comparable to a control group, and significantly less than those induced by indomethacin. In rats subjected to daily oral nabumetone for 3 consecutive weeks, renal function and morphology were preserved as well. Both nabumetone and 6-methoxy-2-naphthylacetic acid reduced renal parenchymal prostaglandin E2 to the same extent as indomethacin. It is concluded that while nabumetone adversely affects renal function and may intensify hypoxic medullary damage ex vivo, rat kidneys are not affected by this agent in vivo, both in acute and chronic studies. COX selectivity may not explain the renal safety of nabumetone.

Acute Kidney Injury↗

PubMed2003

Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I Study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function).

BACKGROUND: Endothelial dysfunction is an important feature of atherosclerosis. Inhibition of the HMG-CoA pathway and of calcium channels improves endothelial function experimentally and in the forearm circulation. Thus, we investigated the effects of a statin and/or a calcium antagonist on coronary endothelial function in patients with coronary artery disease (CAD). METHODS AND RESULTS: In 343 patients undergoing percutaneous coronary intervention in 29 centers, acetylcholine (10(-6) to 10(-4) mol/L) was infused in a coronary segment without angiographically significant CAD. Changes in coronary diameter were measured by quantitative angiography. Endothelium-independent responses were assessed by intracoronary adenosine (1.2 mg/mL) and nitroglycerin (250 microg). Thereafter, patients were randomized in a double-blind manner to placebo, cerivastatin 0.4 mg/d, nifedipine 30 to 60 mg/d, or their combination. Studies were repeated at 6 months. In the most constricted segment, nifedipine but not cerivastatin reduced vasoconstriction to acetylcholine (18.8% versus placebo 10.0%; P<0.05). Patients not taking ACE inhibitors showed a smaller improvement in the placebo group (6.0%), but nifedipine still had an effect (17.0%; P<0.05 versus placebo). Analysis of all evaluable coronary segments revealed an 11% reduction of acetylcholine-induced vasoconstriction in patients receiving nifedipine and cerivastatin (P<0.05 versus placebo). Cerivastatin lowered LDL cholesterol by 35% (P<0.001). CONCLUSIONS: The ENCORE I trial demonstrates that multicenter studies on coronary endothelial function are feasible. After 6 months' treatment, nifedipine improved coronary endothelial function in the most constricted segment. The combination of nifedipine and cerivastatin tended to improve endothelial function; however, this only reached significance in an analysis of all coronary segments.

Acetylcholine↗

PubMed2001

Towards a new functional assessment of autistic dysfunction in children with developmental disorders: the Behaviour Function Inventory.

In order to assess particular disorders of psychological development and functioning in children with developmental disorders, we have developed a new tool, the Behaviour Function Inventory (BFI), based on 11 neurophysiological functions, disorders of which are considered to contribute to the core autistic syndrome. This article reports the reliability and validity study of this new scale. Factorial analysis computed on the 55 initial items identified six main dimensions which we characterized and labelled: interaction dysfunction, praxis dysfunction, auditory dysfunction, attention dysfunction, islet of ability and emotional dysfunction. Relationships between these six new variables and diagnostic subgroups, and chronological and developmental age, are discussed. The BFI offers precise information of the functional symptomatology of autism, showing clear evidence of some disordered areas of functioning. This new approach may provide valuable information in clinical research, especially for psychopathology and physiopathology studies.

Autistic Disorder↗

PubMed2003

Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli.

Dendritic cells (DCs) are a family of leukocytes that initiate T- and B-cell immunity against pathogens. Migration of antigen-loaded DCs from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. In humans, the major peripheral blood DC (PBDC) types, CD1c+ DCs and interleukin 3 receptor-positive (IL-3R+) plasmacytoid DCs, are significantly expanded in vivo with the use of Flt3 ligand (FL). DC-like cells can also be generated from monocyte precursors (MoDCs). A detailed comparison of the functional potential of these types of DCs (in an autologous setting) has yet to be reported. Here, we compared the functional capacity of FL-expanded CD1c+ PBDCs with autologous MoDCs in response to 3 different classes of stimuli: (1) proinflammatory mediators, (2) soluble CD40 ligand trimer (CD40L), and (3) intact bacteria (Escherichia coli). Significant differences in functional capacities were found with respect to changes in phenotype, migratory capacity, cytokine secretion, and T-cell stimulation. MoDCs required specific stimuli for the expression of functions. They responded vigorously to CD40L or E coli, expressing cytokines known to regulate interferon-gamma (IFN-gamma) in T cells (IL-12p70, IL-18, and IL-23), but required prostaglandin E2 (PGE2) during stimulation to migrate to chemokines. In contrast, PBDCs matured in response to minimal stimulation, rapidly acquired migratory function in the absence of PGE2-containing stimuli, and were low cytokine producers. Interestingly, both types of DCs were equivalent with respect to stimulation of allogeneic T-cell proliferation and presentation of peptides to cytotoxic T lymphocyte (CTL) lines. These distinct differences are of particular importance when considering the choice of DC types for clinical applications.

Antigens, CD1↗

PubMed2002

Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect.

Based on previous reports for impaired hematopoiesis in rheumatoid arthritis (RA), and in view of the current interest in exploring the role of autologous stem cell transplantation (ASCT) as an alternative treatment in patients with resistant disease, we have evaluated bone marrow (BM) progenitor cell reserve and function and stromal cell function in 26 patients with active RA. BM progenitor cells were assessed using flow cytometry and clonogenic assays in short-term and long-term BM cultures (LTBMCs). BM stroma function was assessed by evaluating the capacity of preformed irradiated LTBMC stromal layers to support the growth of normal CD34(+) cells. We found that RA patients exhibited low number and increased apoptosis of CD34(+) cells, defective clonogenic potential of BM mononuclear and purified CD34(+) cells, and low progenitor cell recovery in LTBMCs, compared with healthy controls (n = 37). Patient LTBMC stromal layers failed to support normal hematopoiesis and produced abnormally high amounts of tumor necrosis factor alpha (TNF alpha). TNF alpha levels in LTBMC supernatants inversely correlated with the proportion of CD34(+) cells and the number of colony-forming cells, and positively with the percentage of apoptotic CD34(+) cells. Significant restoration of the disturbed hematopoiesis was obtained following anti-TNF alpha treatment in 12 patients studied. We concluded that BM progenitor cell reserve and function and BM stromal cell function are defective in RA probably due, at least in part, to a TNF alpha-mediated effect. The role of these abnormalities on stem cell harvesting and engraftment in RA patients undergoing ASCT remains to be clarified.

Adult↗

PubMed2002

Isolation and structure-function studies of a glucagon-like peptide 1 receptor from goldfish Carassius auratus: identification of three charged residues in extracellular domains critical for receptor function.

A better understanding of the molecular mechanism of ligand-receptor interaction of glucagon-like peptide 1 (GLP-1) receptors (GLP-1Rs) is useful for the design of potent GLP-1 analogs that could potentially be used as a treatment for diabetic patients. Changes in the ligand and receptor sequences during evolution provide invaluable clues to evaluate the functional motifs of the receptor that are responsible for ligand interaction. For these reasons, in the present study, we have isolated and functionally characterized a GLP-1R from goldfish. Its amino acid sequence shows 50.8% and 52.3% identity with the human glucagon (hGLU) and GLP-1Rs, respectively, and 84.1% with the zebrafish GLP-1R (the only other GLP-1R isolated from teleost fish). Peptides that are structurally different from goldfish (gf)GLP-1, such as gfGLU and hGLU and human GLP-1 (7-36)amide, are also capable of stimulating this receptor, albeit with lower potencies than gfGLP-1. gfGLP-1 stimulates the formation of cAMP through the recombinant gfGLP-1R with EC(50) = 0.18 nM, whereas EC(50) values for gfGLU, human GLP-1 (7-36)amide, and hGLU are 0.53 nM, 0.9 nM, and 1.2 nM, respectively. These results indicate that the gfGLP-1R is structurally more flexible than its mammalian counterpart and that its binding pocket can accommodate a wider spectrum of peptide ligands. Previous studies demonstrated that the charged residues in the extracellular domains of mammalian GLP-1R, particularly those found in the N-terminal domain and the first exoloop, are important for ligand binding. We investigated the roles of the conserved charged residues in the function of the gfGLP-1R. Eleven mutant receptors were constructed, and the effects of mutations were determined by functional assays. Our results demonstrated that three charged residues (D(113), R(197), and D(205)) present in the extracellular domains are critical for receptor function.

Amino Acid Sequence↗

PubMed2001

Comparison of measured and estimated indices of insulin sensitivity and beta cell function: impact of ethnicity on insulin sensitivity and beta cell function in glucose-tolerant and normotensive subjects.

Type 2 diabetes mellitus is the result of an imbalance between insulin sensitivity and beta cell function. Although the assessment of these 2 parameters is critical for various studies, the current methods are time consuming and labor intensive. Recently, new estimated indices have been proposed. We examined the impact of ethnicity on the indices of insulin sensitivity and beta cell function measured from the hyperglycemic clamp and compared the results to the estimated indices, proposed by Matsuda and DeFronzo and Stumvoll et al., from a standard oral glucose tolerance test in 105 healthy, glucose-tolerant, and normotensive subjects from 4 ethnic groups. Among the ethnic groups, differences were noted in the measured insulin sensitivity (P = 0.0006) and beta cell function (P = 0.006 for the first phase insulin response, P = 0.0002 for the second phase insulin response). Although the estimated indices correlated with the measured indices (r(2) = 0.5184--0.3014), the estimated indices barely detected the differences among the ethnic groups. Multivariate analysis confirmed that ethnicity had an independent impact for the measured indices, but had only a modest impact on the estimated insulin sensitivity indices and had no impact on the estimated indices of beta cell function. We conclude that although the estimated indices of insulin sensitivity and beta cell function from the oral glucose tolerance test correlated with the measured ones in a wide spectrum of healthy, glucose-tolerant, and normotensive subjects, they were much less likely to detect the differences than measured ones among the ethnic groups.

Adolescent↗

PubMed1985

[Effects of Young's solution (YNG solution) on cardiac function and mitochondrial function during one hour ischemia at 30 degrees C and after reperfusion].

In a previous paper from this laboratory, protective effects of YNG solution on the myocardial mechanical function and metabolism of the heart arrested at 10 degrees C ascribable to the presence of Mg2+ were demonstrated. In order to further clarify the role played by Mg2+ in the protection, the present experiment was conducted using the isolated perfused guinea pig heart arrested at 30 degrees C. While the time to arrest of the contraction was equally short both with YNG (K+ + Mg2+) and K (K+) solutions, the time to resumption of contraction was significantly longer with K solution than with YNG solution, and the regular contraction was not resumed with the former solution. The recovery of the coronary flow, left ventricular pressure and dp/dt after reperfusion was around 100% with YNG solution, while the recovery was significantly poorer with K solution. Although the mitochondrial function was well maintained during the arrest both with YNG and K solution, the recovery of the mitochondrial function after reperfusion was observed only with YNG solution; severe damage was noted in mitochondria of the hearts arrested with K solution. There was a good correlation between the changes in mitochondrial function and those in cardiac function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

[Characterization of thyroglobulin in a patient with functioning and non-functioning benign thyroid tumors].

The chemical and immunological properties of thyroglobulin (Tg) in tissue obtained from a patient co-existed with two types of thyroid tumors, i.e., functioning and non-functioning, and were compared with the properties of Tg that was isolated from adjacent peripheral tissue. In the present observations, the Tg content was markedly increased in the non-functioning thyroid tumor. On the other hand, the Tg content in the functioning tumor was at the normal level. The iodine content of Tg was significantly lower in the non-functioning tumor than in peripheral tissues. Affinity with Lectins differed among Tg preparations, suggesting that the carbohydrate chain in the Tg was different in each nodule in a single individual.

Adenoma↗

PubMed2003

Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood.

Disorders of testicular function may have their origins in fetal or early life as a result of abnormal development or proliferation of Sertoli cells. Failure of Sertoli cells to mature, with consequent inability to express functions capable of supporting spermatogenesis, is a prime example. In a similar way, failure of Sertoli cells to proliferate normally at the appropriate period in life will result in reduced production of spermatozoa in adulthood. This review focuses on the control of proliferation of Sertoli cells and functional maturation, and is motivated by concerns about 'testicular dysgenesis syndrome' in humans, a collection of common disorders (testicular germ-cell cancer, cryptorchidism, hypospadias and low sperm counts) which are hypothesized to have a common origin in fetal life and to reflect abnormal function of Sertoli (and Leydig) cells. The timing of proliferation of Sertoli cells in different species is reviewed, and the factors that govern the conversion of an immature, proliferating Sertoli cell to a mature, non-proliferating cell are discussed. Protein markers of maturity and immaturity of Sertoli cells in various species are reviewed and their usefulness in studies of human testicular pathology are discussed. These markers include anti-Mullerian hormone, aromatase, cytokeratin-18, GATA-1, laminin alpha5, M2A antigen, p27(kip1), sulphated glycoprotein 2, androgen receptor and Wilms' tumour gene. A scheme is presented for characterization of Sertoli-cell only tubules in the adult testis according to whether or not there is inherent failure of maturation of Sertoli cells or in which the Sertoli cells have matured but there is absence, or acquired loss, of germ cells. Functional 'de-differentiation' of Sertoli cells is considered. It is concluded that there is considerable evidence to indicate that disorders of maturation of Sertoli cells may be a common underlying cause of human male reproductive disorders that manifest at various life stages. This recognition emphasizes the important role that animal models must play to enable identification of the mechanisms via which failure of proliferation and maturation of Sertoli cells can arise, as this failure probably occurs in fetal life.

Adult↗

PubMed1995

No effect of dietary fish oil on renal hemodynamics, tubular function, and renal functional reserve in long-term renal transplant recipients.

Dietary supplementation with fish oil rich in n-3 polyunsaturated fatty acids has been suggested to protect the kidney against cyclosporin A (CsA) toxicity. This study investigated the effects of a 10-wk dietary supplementation with fish oil on renal function and renal functional reserve in healthy volunteers (N = 9) and two groups of stable long-term kidney-transplanted patients treated with maintenance low-dose CsA (3.0 +/- 0.6 mg/kg; N = 9) or without CsA (N = 9). After an overnight fast, the subjects were water loaded, and clearance studies were performed, postponing morning medication. GFR and effective RPF were measured as the renal clearances of (99mTc)DTPA and (131I)hippuran, respectively. Renal tubular function was evaluated by use of the renal clearance of lithium and the urinary excretion of beta 2-microglobulin. Fish oil did not change baseline values of effective RPF, GFR, lithium clearance, and urinary excretion of beta 2-microglobulin in any of the groups. The infusion of amino acids induced a comparable increase in GFR, lithium clearance, and the urinary excretion rate of beta 2-microglobulin in all three groups with no additional effect of fish oil. Thus, long-term renal transplant recipients treated with a low maintenance dose of CsA had a well-preserved renal functional reserve, and dietary supplementation with fish oil in these patients did not improve renal function.

Adult↗

PubMed1998

Establishing discriminative control of responding using functional and alternative reinforcers during functional communication training.

Functional communication training (FCT) is a popular treatment for problem behaviors, but its effectiveness may be compromised when the client emits the target communication response and reinforcement is either delayed or denied. In the current investigation, we trained 2 individuals to emit different communication responses to request (a) the reinforcer for destructive behavior in a given situation (e.g., contingent attention in the attention condition of a functional analysis) and (b) an alternative reinforcer (e.g., toys in the attention condition of a functional analysis). Next, we taught the participants to request each reinforcer in the presence of a different discriminative stimulus (SD). Then, we evaluated the effects of differential reinforcement of communication (DRC) using the functional and alternative reinforcers and correlated SDs, with and without extinction of destructive behavior. During all applications, DRC (in combination with SDs that signaled available reinforcers) rapidly reduced destructive behavior to low levels regardless of whether the functional reinforcer or an alternative reinforcer was available or whether reinforcement for destructive behavior was discontinued (i.e., extinction).

Adolescent↗

PubMed2003

Immediate functional and non-functional loading of dental implants: a 2- to 60-month follow-up study of 646 titanium implants.

BACKGROUND: The aim of this study was the evaluation, from a clinical point of view, of implants subjected to immediate functional loading (IFL) and to immediate non-functional loading (INFL) in various anatomical configurations. METHODS: The study included 152 patients who had given their informed consent. A total of 646 implants were inserted. The implants were placed in 39 totally edentulous mandibles, 14 edentulous maxillae, 23 edentulous posterior mandibles, 16 edentulous anterior mandibles, 16 edentulous anterior maxillae, and 15 edentulous posterior maxillae. Fifty-eight implants were used to replace single missing teeth. In 65 cases, IFL was carried out for 422 implants. INFL was carried out in 116 cases, (224 implants). RESULTS: In the IFL group 6 of 422 implants failed (1.4%); in the INFL group 2 of 224 implants failed (0.9%). All the other implants appeared, from clinical and radiographic observations, to have successfully osseointegrated and have been functioning satisfactorily since insertion. All failures were observed in the first few months after implant loading. CONCLUSION: Immediate functional and non-functional loading seems to be a technique that gives satisfactory results in selected cases.

Adolescent↗

PubMed1993

Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function.

To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1981

Functional effectiveness of a myo-electric prosthesis compared with a functional split-hook prosthesis: a single subject experiment.

The functional effectiveness of a myo-electric prosthesis with sensory feedback compared with that of a split-hook is described. Thirty independent observations were made on a single subject with a right below-elbow amputation wearing the myo-electric prosthesis and the split-hook prosthesis. Using a first order autoregressive model for making inferences about the two sets of data, the split-hook was found to be functionally better (p less than 0.001) than the myo-electric prosthesis. Functional effectiveness was defined operationally as scores on the Minnesota Rate of Manipulation Placing Test and the Smith Test of Hand Function. No predictions are made regarding the use of either prosthesis for other amputees. However clinical evidence suggested suitability of the myo-electric prosthesis with sensory feedback for some other functional tasks.

Adult↗