Muscle activity during lifting: examining the effect of core conditioning of multifidus and transversus abdominis.

BACKGROUND: It is well accepted that both multifidus and transversus abdominis muscles have a vital role in maintaining spinal stability. OBJECTIVE: To determine if multifidus and transversus abdominis could be strengthened by a six-week conditioning program and to establish if the amount of electromyographic (EMG) activity in external oblique differed in a lifting and holding task after the conditioning program. METHODS: EMG activity of external oblique during a lifting and holding task was obtained. Multifidus cross-sectional area and transversus abdominis width were measured using real time ultrasound in six males and five females, with no back pain (mean age of 26.3 (± 5.4) years). The participants then performed a six-week muscle-conditioning program for multifidus and transversus abdominis, after which the EMG activity of external oblique and dimensions of multifidus and transversus abdominis were re-measured. RESULTS: Both multifidus and transversus abdominis significantly increased in size. There was significantly less activity in external oblique during a lifting task after the conditioning program, with no change in external oblique activity during a holding task. CONCLUSIONS: this study may indicate a link between the dimensional increase of multifidus and transversus abdominis, and the decrease in EMG activity in external oblique during lifting.

Faecal calprotectin in the assessment of Crohn's disease activity.

BACKGROUND: Clinical and laboratory assessment of activity in Crohn's disease (CD) correlate poorly with endoscopic findings. Calprotectin is a calcium-binding protein abundant in neutrophil cytosol, and extremely stable in faeces. Faecal calprotectin (FC) is an excellent surrogate marker of neutrophil influx into the bowel lumen. AIM: To assess whether FC concentration from a spot stool sample reliably detects active inflammation in patients with CD. DESIGN: Cross-sectional comparative study. METHODS: Subjects had a previously confirmed diagnosis of CD and were suspected on clinical grounds to be in the midst of a relapse. Thirty-five entered the study; they underwent radiolabelled white cell scanning (WCS) and had a stool sample collected for calprotectin measurement on the same day. A Crohn's disease activity index (CDAI) was also calculated for each. The WCS scans were scored at six standard sites to give a mean total, 'extent', 'severity' and 'combined extent and severity' scores. RESULTS: FC was significantly and positively correlated with mean total (r = 0.73, p < 0.001), 'extent' (r = 0.71, p < 0.001), 'severity' (r = 0.64, p < 0.001) and combined 'extent and severity' WCS scores (r = 0.71, p < 0.001). A cut-off of faecal calprotectin > 100 microg/g gave a sensitivity of 80%, specificity of 67%, positive predictive value of 87% and a negative predictive value of 64% in identifying those with and without any inflammation on WCS. There was, however, no significant correlation between CDAI and mean total WCS score (r = 0.21, p = 0.24), nor between CDAI and FC (r = 0.33, p = 0.06). DISCUSSION: While the CDAI does not accurately reflect inflammatory activity in CD, a one-off FC reliably detects the presence or absence of intestinal inflammation in adult patients with CD, compared to WCS.

Helicobacter pylori eradication for peptic ulceration: an observational study in a Scottish primary care setting.

Despite being established for the treatment of peptic ulcer (PU) disease, few studies have assessed the long-term effectiveness and economic benefits of Helicobacter pylori (Hp) eradication in primary care. Our aim was to investigate the effect of community based Hp eradication for patients with chronic peptic ulcer disease requiring maintenance acid suppression. The endpoints used were the patients dyspeptic symptoms and the requirement for the prescription of maintenance acid suppression therapy. The study area covered seven general practices in the Glasgow area. Patients with previously diagnosed peptic ulcer disease receiving prescribed acid suppression therapy were invited to a dyspepsia clinic. Hp status was assessed by Helisal rapid blood test (HRBT). Positive patients received Hp eradication therapy and were reviewed six weeks later. At six months a review of practice records was carried out, and two years after eradication a postal questionnaire was sent to participating patients. A total of 243 patients attended the initial clinic of which 81.9% were HRBT positive. 156 of 196 patients offered Hp eradication re-attended at six weeks. The per protocol eradication rate was 91.7%. After six months patients who had received eradication therapy were less likely to require maintenance acid suppression therapy compared with those to whom eradication was not given. Two years after treatment 76.5% of patients felt their symptoms were improved, but 42.2% were still receiving maintenance therapy. The estimated cost of treatment per month per patient had fallen from 20.23 Pounds to 9.39 Pounds after eradication. In conclusion we felt that community based Hp eradication for patients with chronic PU disease is effective, however it does not completely alleviate dyspepsia. Predictors of symptomatic response or of no longer requiring acid suppression therapy after two years were younger age of onset of PU disease and absence of pre-documented gastro-oesophageal reflux disease or hiatus hernia. Hp eradication improves patients symptoms, reduces the requirement for maintenance acid suppression and is cost-effective after two years follow-up in this targeted group.

Asthma leaflets for patients: what do asthma nurses use?

This study investigated patient information leaflets used by trained asthma nurses, and nurses' satisfaction with these. Main outcome measures were frequency of use, sources of material, and rating of reliability and readability. A total of 775 practice nurses with a diploma in asthma working in the general practice setting were surveyed using a postal questionnaire. Forty two percent of questionnaires (326) were returned. The provision of asthma information is an integral part of patient care by the trained asthma nurse. Most nurses (260, 83%) gave out between one and ten leaflets per week. An abundance of diverse information is available from a variety of sources, main sources used were Glaxo-Wellcome (cited by 47% of respondents), National Asthma Campaign (NAC) (19% of respondents) and Astra (19%). Pharmaceutical company material was considered more easily available, free of charge and more attractively presented. NAC material was viewed as more accurate. Assessment of NAC, Glaxo-Wellcome and Astra booklets revealed that they conformed to British Thoracic Society Guidelines for acute asthma. Thus, nurses stated a preference for charity information but in practice used a predominance of pharmaceutical company information. This appears to be because pharmaceutical company information was more readily available and free of charge. Nurses felt unease with self-perceived over-reliance on pharmaceutical company information.

Quantitative imaging in live human cells reveals intracellular alpha(1)-adrenoceptor ligand-binding sites.

Cellular distribution and binding characteristics of native alpha(1)-adrenoceptors (ARs) were determined in a live, single, human smooth muscle cell (SMC) with confocal laser scanning microscopy and a fluorescent ligand, BODIPY-FL prazosin (QAPB). This allowed single-cell competitive ligand binding and showed that 40% of alpha(1)-AR-binding sites in native cells are intracellular. QAPB had high affinity and acted as a nonselective, competitive antagonist versus [(3)H]prazosin at cloned human alpha(1a)-, alpha(1b)-, and alpha(1d)-AR subtypes on membrane preparations and whole cells. RS100329 had 70-fold selectivity for alpha(1a)-ARs versus alpha(1b)- and alpha(1d)-ARs, validating its use to identify this subtype. In similar cells QAPB-associated fluorescence provided quantitative data analogous and comparable to [(3)H]prazosin binding in whole cells. In human, dissociated, prostatic smooth muscle cells QAPB-associated fluorescence binding exhibited specific high-affinity binding properties (FK(D) = 0.63 +/- 0.02 nM), which was 3- to 4-fold higher compared with recombinant cells (FK(D) = 2. 1-2.3 nM). Internal consistency in the data showed that affinity is greater, in general, in membrane preparations than in cells but also greater in the native prostatic tissues or cells than in equivalent recombinant receptors. Fluorescence revealed binding sites both on the plasmalemmal membrane and on intracellular compartments: at all locations RS100329 inhibited QAPB binding identifying the sites as alpha(1A)-ARs. Quantitative three-dimensional mapping of QAPB-associated fluorescence binding in native human cells showed that 40% of high-affinity-binding sites was in intracellular compartments. This provides a potential new site for physiological agonism and makes intracellular access a potential differentiator of drug action.

Single-cell recombinant pharmacology: bovine alpha(1a)-adrenoceptors in rat-1 fibroblasts release intracellular ca(2+), display subtype-characteristic agonism and antagonism, and exhibit an antagonist-reversible inverse concentration-response phase.

Phe-activated Ca(2+) signals recorded from single rat-1 fibroblasts stably expressing the bovine alpha(1a)-adrenoceptor (AR) were characterized and used to analyze functional agonist-antagonist interactions. The response to Phe was initiated by the mobilization of stored Ca(2+) and subsequently sustained by receptor-regulated Ca(2+) influx. The selective alpha(1A)-AR agonist (R)-A-61603 was 141-fold more potent as an agonist than Phe. This potency ratio was consistent with the pharmacology of the native alpha(1A)-ARs. Functional responses evoked by concentrations of Phe of more than 0. 3 microM displayed fade, which could be explained by agonist-dependent depletion of Ca(2+) stores. The antagonists tested did not conform to the predictions of the Schild equation for competitive antagonism as expected from the nonequilibrium nature of the response. The antagonist potency series WB4101 > or = prazosin >> BMY7378, however, was consistent with alpha(1A)-ARs. Antagonism exhibited by WB4101 and prazosin was compatible with a model in which antagonists dissociate so slowly from the receptor that this is a major factor in their inhibition of the transient agonist-mediated response, leading to the appearance of insurmountable antagonism. A consequence of this phenomenon was that an inverse concentration-response relationship at high agonist concentrations was abolished by low concentrations of antagonists. Overall, the results indicate that quantitative pharmacology can be studied successfully in single cells even though equilibrium could not be achieved in the agonist-antagonist-response relationship in this particular cell phenotype. The study also showed a form of fade that could be readily explained.

Importance of agonists in alpha-adrenoceptor classification and localisation of alpha1-adrenoceptors in human prostate.

alpha-Adrenoceptor blocker drugs are commonly used in the clinical (non-surgical) treatment of BPH. alpha1-adrenoceptors were originally sub-divided using agonists but, subsequently, were sub-divided using only antagonists in ligand-ligand interactions, which did not require agonists at all. Ultimately, proof that adrenoceptors are functional receptors for the natural ligands, noradrenaline and adrenaline, requires that agonists be used. The earlier excitement engendered by finding varying agonist potency series in different tissues has not been revisited to place it in the context of current concepts of alpha1-adrenoceptor subtypes. This review will consider the advantages and limitations of different agonists for the study of alpha1-adrenoceptor subtypes including 'extreme' examples where the archetypal alpha1-adrenoceptor agonist phenylephrine activates alpha2-adrenoceptors and others where UK14304, often the alpha2-adrenoceptor agonist of choice, activates alpha1-adrenoceptors. New work will also be presented showing the interaction between agonists and the fluorescent alpha1-adrenoceptor antagonist QAPB. This introduces the novel point of view of studying the displacement of antagonists by agonists. Possible errors in antagonist classification arising from complexity in the actions of agonists and the recently developed method of fluorescent ligand binding on isolated living human prostatic smooth muscle cells will be discussed.

Pharmacological implications of cellular localization of alpha1-adrenoceptors in native smooth muscle cells.

1. This study examines the cellular localization of alpha1-adrenoceptors and demonstrates that binding to intracellular receptive binding sites in native smooth muscle cells may influence the pharmacological profile of agonists or antagonists. The example tissue studied was rat basilar artery. 2. An alpha1-adrenoceptor antagonist and fluorescent analogue of prazosin, BODIPY-FL prazosin (QAPB) allowed visualization, with high resolution, of both plasma membrane and cytosolic binding sites on live native cells, as previously shown in cells harbouring recombinant receptors. QAPB-associated fluorescence binding was both time- and concentration-dependent in rat basilar smooth muscle cells and affinity for alpha1-adrenoceptors was calculated from specific binding curves as 1.1 nM. 3. Concentration-dependent binding of QAPB detected in smooth muscle cells dissociated from rat basilar arteries was composed of diffuse and clustered fluorescence. Visually the diffuse component of fluorescence was the more evident up to a concentration of 5 nM QAPB. Confocal visualization of an optical section through the cell showed that the clustered component was located mainly intracellularly. In rat basilar artery smooth muscle cells the intracellular binding sites were located in close proximity to the nuclear membrane. 4. 3D models of QAPB-associated fluorescence demonstrate that a high proportion of effective binding sites are intracellular, showing not only that a high proportion of receptors are located inside the cell but also that in this location they can bind ligands. This has implications for pharmacological analysis in relation to the consequences of intracellular binding per se and for differential effects upon the pharmacology of particular ligands according to whether they can enter the cell.

Push enteroscopy.

Push enteroscopy has superseded sonde enteroscopy principally because of its ability to provide therapy, as well as diagnosis. An overtube limits gastric looping and allows deeper jejunal insertion. A working channel allows therapeutic intervention. The technique is increasingly used to the diagnosis and treatment of small intestinal disorders, particularly in obscure gastrointestinal bleeding. The wider acceptance of push enteroscopy into routing practice requires further clinical effectiveness data.

Cellular localization and pharmacological characterization of functioning alpha-1 adrenoceptors by fluorescent ligand binding and image analysis reveals identical binding properties of clustered and diffuse populations of receptors.

A fluorescent quinazoline derivative was shown to retain high affinity for, and act as a competitive antagonist at, alpha-1 adrenoceptors. This allowed it to be used in live cells to localize receptors and to quantify receptor binding characteristics. The technique was demonstrated and validated on fibrobasts transfected with a recombinant alpha-1d adrenoceptor. Using confocal laser scanning microscopy and image analysis methods both diffuse and clustered binding sites were found: their binding characteristics were assessed and found comparable to radioligand binding on membrane preparations. This approach should have widespread applicability in nonradioactive assays determining the location, quantity and binding properties of receptors and other biological molecules on live tissue.

Heterogeneity of endothelin-B receptors in rabbit pulmonary resistance arteries.

We have previously shown that endothelin-B (ETB) receptors mediate contraction in human and rat pulmonary resistance arteries (PRAs). Here we characterize the endothelin (ET) receptors in rabbits PRAs. PRAs (approximately 150 microns i.d.) were studied using wire myography. Vasoconstrictor effects to ET-1, ET-3, and the ETB-selective agonist sarafotoxin S6c (S6c) were studied in the presence and absence of the ETA receptor antagonist FR139317, the ETB-selective antagonist BQ788, and the mixed ETA/ETB antagonist SB209670. The effect of SB209670 was also studied in human PRAs (approximately 250 microns i.d.). Competitive ET-1 binding studies were also carried out on rabbit small pulmonary artery homogenates. The potencies of the agonists were in the following order: S6c > ET-3 = ET-1. Concentration-response curves (CRCs) to ET-1 were biphasic, with a gradual slope up to approximately 1 nM and a steeper component at higher concentrations of ET-1. Neither FR139317 (1 microM) nor BQ788 (1 microM) inhibited responses to ET-1. BQ788 inhibited S6c- and ET-3 induced contractions with pKb values of 6.8 +/- 0.1 and 6.3 +/- 0.2, respectively. SB209670 inhibited responses to ET-1 in the higher concentration component of the CRC and inhibited responses to S6c in a competitive fashion. pKb values for ET-1 and S6c were 6.8 +/- 0.2 and 7.5 +/- 1, respectively. SB209670 (0.1-1 microM) totally abolished responses to ET-1 in human PRAs. The binding assay established two ET binding sites in rabbit PRAs, one low affinity (Ki = 480 pM) and one high affinity (Ki = 64 fM). The study provides evidence for a heterogeneous population of ETB-like receptors in pulmonary resistance arteries, including an atypical ETB receptor sensitive to SB209670.

Push enteroscopy and heater probe therapy for small bowel bleeding.

BACKGROUND: Blood loss from the small bowel is a significant cause of obscure gastrointestinal bleeding. Small bowel angiodysplasia may be the source of bleeding in 30% to 40% of patients with this problem. In other areas of the bowel, angiodysplasia has been effectively treated by endoscopic methods. METHODS: We used a 1.7 meter push enteroscope and heater probe ablation to examine and treat 11 transfusion-dependent patients with significant bleeding from small bowel angiodysplasia. Patients had push enteroscopy to target all lesions identified and had follow-up hemoglobin and fecal occult blood tests for a minimum of 6 months after final enteroscopy. RESULTS: There were a median of 2 (range 1 to 7) small bowel lesions per patient. Patients required a median of 1 (range 1 to 5) examination to treat lesions identified at enteroscopy. Following therapy, hemoglobin levels rose significantly from a median of 8.5 (range 5.3 to 10.6) gm/dL) to a median of 13.5 (range 7.6 to 16.5) gm/dL (p < 0.01 Wilcoxon matched pair signed rank test). CONCLUSION: Push enteroscopy and heater probe ablation offer potential therapy for bleeding from small bowel angiodysplasia and result in reduction of blood loss and transfusion requirements along with a significant improvement in levels of hemoglobin.

Push enteroscopy in the investigation of small-intestinal disease.

We report our experience with small-bowel push enteroscopy in 50 patients. The indications for push enteroscopy were: anaemia/occult gastrointestinal bleeding (22 patients); overt gastrointestinal bleeding (17 patients); abnormal small-bowel radiology (8 patients) and miscellaneous (3 patients). In those with undiagnosed gastrointestinal bleeding/anaemia, abnormalities were detected in 24/39 patients (62%): small bowel arteriovenous malformations (AVMs) were detected in 19 (49%), and five (13%) had lesions in the upper gastrointestinal tract. Seventeen patients had heater-probe ablation therapy of vascular lesions: nine patients had small-intestinal lesions, four patients gastric lesions, and four patients combined gastric and small-intestinal lesions. In those with abnormal small-bowel radiology, abnormalities were detected in 6/8 patients. We conclude that (i) push enteroscopy can establish a diagnosis in a high proportion of patients with gastrointestinal bleeding; (ii) heater-probe ablation therapy of vascular lesions can be performed routinely at the time of enteroscopy; (iii) a significant proportion of patients (9/50) referred for enteroscopy with undiagnosed gastrointestinal bleeding have lesions in the stomach/proximal duodenum missed at diagnostic endoscopy. Push enteroscopy is a valuable diagnostic and therapeutic endoscopic procedure.

Short report: the effect of misoprostol on the anaemia of NSAID enteropathy.

BACKGROUND: Small bowel ulceration is an increasingly recognised complication of therapy with non-steroidal anti-inflammatory drugs (NSAID). The ulceration is a potent site of blood loss contributing to unexplained iron deficiency anaemia in patients with arthritis. No drug is currently available to treat NSAID small bowel ulcers. METHODS: We have retrospectively examined the effect of therapy with the prostaglandin E1 analogue misoprostol on the anaemia of patients with enteroscopically proven NSAID small bowel enteropathy. RESULTS: All of the patients had proven iron deficiency anaemia. Eleven patients received misoprostol and ten received no treatment. Haemoglobin in the misoprostol-treated group rose significantly from median (range) 9.1 (6.2-10.6) g/dL (95% confidence intervals 8.76, 10.13) to 10.6 (6.5-16.8) g/dL (95% confidence intervals 10.06, 11.82); P = 0.004). Those patients who did not receive misoprostol had no significant change in their haemoglobin: 9.1 (7.5-10.6) g/dL to 8.1 (5.6-14.7) g/dL (P = N.S.). CONCLUSION: Misoprostol therapy was associated with an improvement in the anaemia in patients with proven NSAID enteropathy.

Small bowel enteroscopy in undiagnosed gastrointestinal blood loss.

Sixty five of 70 consecutive patients with undiagnosed gastrointestinal blood loss were examined using the new technique of small bowel enteroscopy. Using a balloon driven sonde enteroscope (SIF-SW) extended views of the small bowel were obtained as far as the distal ileum. Medium length of small bowel examined was 140 cm (range (30-200 cm). All patients studied had a normal upper gastrointestinal endoscopy. Nineteen (41%) of 46 anaemic rheumatoid arthritis patients taking non-steroidal antiinflammatory drugs (NSAID) and three (27%) of 11 patients with unexplained iron deficiency, were found to have small bowel lesions to account for their anaemia. Small bowel lesions were found in a further three of eight (37%) patients with acute gastrointestinal bleeding. The procedure failed or was terminated in five patients. Small bowel enteroscopy has considerable potential in the investigation of undiagnosed gastrointestinal blood loss and deserves more widespread application.

Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs.

15 patients with rheumatoid arthritis who were receiving non-steroidal anti-inflammatory drugs (NSAIDs) and who had chronic occult gastrointestinal bleeding underwent extended small bowel examination with a Sonde enteroscope. 7 patients (47%) were found to have jejunal or ileal ulceration. Small bowel enteroscopy may be a valuable technique for the investigation of undiagnosed gastrointestinal bleeding.

Magnesium deficiency in patients on home enteral nutrition.

Home enteral nutrition (HEN) is an established method of long term nutritional support. Many patients receiving HEN have Crohn's disease complicated by intestinal failure and malnutrition, including magnesium deficiency. It is unknown if HEN can correct magnesium deficiency or if patients on HEN can become magnesium deficient. We measured total magnesium intake in nine patients receiving HEN, and assessed their magnesium status. Two patients had magnesium intakes below the recommended dietary allowance of 15 mmol/day. Four patients (44%) had biochemical evidence of magnesium deficiency, although no patient had clinical signs of magnesium deficiency. Several magnesium deficient patients used a liquid feed which had a low magnesium content. Patients on HEN should have their magnesium status checked regularly and may require magnesium supplements.

Achalasia-like syndrome in systemic sclerosis.

Two methods of quantifying oesophageal emptying for liquids have been used to assess the dysphagia of patients with systemic sclerosis: the oesophageal infusion scintiscan and the timed Gastrografin swallow. Upper gastrointestinal endoscopy and oesophageal manometry were also performed. Thirteen patients with oesophageal symptoms were studied. Eight had dysphagia, and all of these had endoscopies with no evidence of oesophagitis or stricture. Four of these eight subjects had gross delay of oesophageal emptying for fluids, and manometry showed absence of oesophageal peristalsis and incomplete relaxation of the lower oesophageal sphincter. This abnormality is similar to achalasia. Two of these four patients have benefited from pneumatic dilatation with improvement in their severe dysphagia. We believe that pneumatic dilatation should be considered in patients with systemic sclerosis and severe dysphagia where reflux oesophagitis is not apparent.