A quasi-nonlinear analysis of the anisotropic behaviour of human gallbladder wall.

Estimation of biomechanical parameters of soft tissues from noninvasive measurements has clinical significance in patient-specific modeling and disease diagnosis. In this work, we present a quasi-nonlinear method that is used to estimate the elastic moduli of the human gallbladder wall. A forward approach based on a transversely isotropic membrane material model is used, and an inverse iteration is carried out to determine the elastic moduli in the circumferential and longitudinal directions between two successive ultrasound images of gallbladder. The results demonstrate that the human gallbladder behaves in an anisotropic manner, and constitutive models need to incorporate this. The estimated moduli are also nonlinear and patient dependent. Importantly, the peak stress predicted here differs from the earlier estimate from linear membrane theory. As the peak stress inside the gallbladder wall has been found to strongly correlate with acalculous gallbladder pain, reliable mechanical modeling for gallbladder tissue is crucial if this information is to be used in clinical diagnosis.

Cross-bridge apparent rate constants of human gallbladder smooth muscle.

This paper studies human gallbladder (GB) smooth muscle contractions. A two-state cross-bridge model was used to estimate the apparent attachment and detachment rate constants, as well as increased Ca2+ concentration from the peak active stress during the isometric contraction. The active stress was computed from a mechanical model based entirely on non-invasive routine ultrasound scans. In the two-state cross-bridge model, the two apparent rate constants, representing the total attached/detached cross-bridges, respectively, were estimated using active stress prediction for 51 subjects undergoing cholecystokinin-provocation test, together with estimates from the four-state cross-bridge model for a swine carotid, bovine tracheal and guinea pig GB smooth muscles. The study suggests that the apparent rate constants should be patient-specific, i.e. patients with a lower stress level are characterized by smaller apparent rate constants. In other words, the diseased GB may need to develop fast cycling cross-bridges to compensate in the emptying process. This is a first step towards more quantitative and non-invasive measures of GB pain, and may provide useful insight in understanding GB motility and developing effective drug treatments.

Self-reported management among people with rotator cuff related shoulder pain: An observational study.

BACKGROUND: Rotator cuff related shoulder pain is the most common cause of shoulder pain. Whilst guidelines recommend conservative management prior to imaging, injection or surgical management, recent findings suggest that patients experience management contrary to guideline recommendations. OBJECTIVES: The aim of this study was to investigate self-reported management among people with rotator cuff related shoulder pain (RCRSP) and their beliefs towards management. MATERIALS AND METHODS: Cross-sectional survey of people with RCRSP recruited when referred for imaging (n = 120). Electronic survey about demographic factors, management people had had (including imaging, injections, surgery, exercise, adjuncts), and beliefs about treatments. The frequency of various treatments was reported (separately for each cohort and traumatic onset) as well as the timing of interventions related to first-line care. RESULTS: Most people had tried exercise (99/120, 82.5%) but only one in five people reported exercise was helpful, and one in six reported it was unhelpful or made their symptoms worse. Approximately a third of the cohort reported not receiving activity modification advice (34.2%, 41/120), those that did received inconsistent information. People with both traumatic (imaging 31/43, 72.1%; injections 13/24, 54.2%, surgery 8/21, 38.1%) and atraumatic onset pain (imaging 43/77, 55.8%; injections 31/51, 60.8%, surgery 4/19, 21.1%) had similarly high rates of intervention prior to trialling conservative management. Patient beliefs in regards to management showed trends towards interventionalist care. CONCLUSION: Patient reported management of RCRSP is often inconsistent with guideline recommended management.

Can intraoperative manometry during laparoscopic fundoplication predict postoperative dysphagia?

BACKGROUND: Many trials have used intraesophageal manometry (IEM) to measure the adequacy of fundoplication. This pilot study aimed to assess the value of IEM in predicting postoperative dysphagia. METHODS: A series of 40 patients underwent IEM studies before operative correction of gastroesophageal reflux disease and repeat studies 3 months after the procedure. During the operation, IEM studies were undertaken before pneumoperitoneum was established, after pneumoperitoneum, after pneumoperitoneum with fundoplication, and after fundoplication without pneumoperitoneum. All the patients were followed up 1, 6, and 12 months after the procedure for assessment to detect persistent reflux and postfundoplication dysphagia. RESULTS: Three patients demonstrated persistent dysphagia at the 12-month follow-up point. No statistically significant differences in preoperative manometry findings were observed in the dysphagic and nondysphagic groups, with the dysphagic group showing higher pressures. However, at the operation, statistically significant differences in the lower esophageal sphincter pressures were observed after anesthesia and no pneumoperitoneum (30.3 vs. 13.4 cm H(2)O; p =0.002), after anesthesia with pneumoperitoneum (40.3 vs. 18.3 cm H(2)O; p < 0.001), and after fundoplication with pneumoperitoneum (47.3 vs. 23.4 cm H(2)O; p = 0.001). No statistically significant differences were demonstrated in postoperative manometry at the 3-month follow-up point. CONCLUSION: Intraoperative manometry may be a useful tool compared with postoperative manometry in identifying patients who may experience postfundoplication dysphagia.

The effect of argon plasma coagulation ablation on esophageal motility and chemoreceptor sensitivity in Barrett's esophagus patients.

Patients with Barrett's esophagus usually demonstrate impaired esophageal motility, which affects acid clearance, together with reduced chemo-receptor sensitivity and symptom severity. Ablative endoscopic techniques are now used to eliminate Barrett's cells. The hypothesis for this study was that ablation with argon plasma coagulation (APC) may affect esophageal sensitivity and motility in patients with Barrett's esophagus, and the aim of this study was to assess differences in these parameters before and after APC treatment. Twenty patients with Barrett's esophagus were investigated before and after APC therapy. After standard pull through manometry, water bolus aliquots were given to assess primary peristalsis and rapid water and air bolus injections to assess secondary peristalsis. Sensitivity studies were carried out using weak solutions of either hydrochloric acid or sodium hydroxide, together with saline washouts. Onset time for typical symptoms (t), sensory intensity rating (I), and a sensory score (SS) = (t) x (I)/100 was observed. There were no significant differences in the lower esophageal sphincter pressures (13.6 mm Hg versus 12.6 mm Hg, P= 0.8) and successful test swallows (3 mm Hg versus 5 mm Hg, P= 0.5) before and after treatment, but there was a trend for secondary peristalsis to improve (air bolus 0 versus 2, P= 0.05, water bolus 0 versus 1, P= 0.07). Sensitivity studies showed a smaller sensitivity intensity rating to both acid (61 versus 31, P= 0.02) and alkaline (91 versus 64, P= 0.03) after treatment. In conclusion, we have shown no substantive changes in esophageal motility after ablation of Barrett's esophagus cells, but have demonstrated reduced sensitivity to reflux type solutions.

Physiotherapists deliver management broadly consistent with recommended practice in rotator cuff tendinopathy: An observational study.

BACKGROUND: Rotator cuff tendinopathy is a common and disabling cause of shoulder pain. While conservative treatment is recommended as initial management, recent findings suggest that general practitioners and rheumatologists do not consistently align with recommended care. This study aimed to survey Australian physiotherapists to explore the extent to which recommended management is being applied. METHODS: A cross-sectional online survey. RESULTS: Five hundred and two Australian physiotherapists completed the survey. Results demonstrated the majority of physiotherapists provide conservative management consistent with guideline recommendations, through delivery of exercise and education, comparable to management by physiotherapists in the United Kingdom, Belgium and the Netherlands. Parameters and construction of exercise treatment programs were highly variable within the cohort, qualitative analysis highlighting varied reasoning underpinning these management decisions. CONCLUSIONS: Australian physiotherapists are broadly consistent with providing recommended management, however heterogeneity exists in the methods and parameters of treatment delivery.

The NS3 proteins of global strains of bluetongue virus evolve into regional topotypes through negative (purifying) selection.

Comparison of the deduced amino acid sequences of the genes (S10) encoding the NS3 protein of 137 strains of bluetongue virus (BTV) from Africa, the Americas, Asia, Australia and the Mediterranean Basin showed limited variation. Common to all NS3 sequences were potential glycosylation sites at amino acid residues 63 and 150 and a cysteine at residue 137, whereas a cysteine at residue 181 was not conserved. The PPXY and PS/TAP late-domain motifs were conserved in all but three of the viruses. Phylogenetic analyses of these same sequences yielded two principal clades that grouped the viruses irrespective of their serotype or year of isolation (1900-2003). All viruses from Asia and Australia were grouped in one clade, whereas those from the other regions were present in both clades. Each clade segregated into distinct subclades that included viruses from single or multiple regions, and the S10 genes of some field viruses were identical to those of live-attenuated BTV vaccines. There was no evidence of positive selection on the S10 gene as assessed by reconstruction of ancestral codon states on the phylogeny, rather the functional constraints of the NS3 protein are expressed through substantial negative (purifying) selection.

The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett's oesophagus.

BACKGROUND: Barrett's oesophagus is the major risk factor for oesophageal adenocarcinoma. It is proposed that long-term re-epithelialisation, which has been achieved following ablation using 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) may reduce the risk of malignant change. However, it is not known whether PDT modifies oesophageal motility. AIM: To assess oesophageal pH and motility before and after PDT ablation in treated and untreated areas of the oesophagus. METHODS: Twelve patients (10 male) with Barrett's oesophagus, median segment length 4 cm, were treated with PDT ablation. Twenty-four hours pH assessment and oesophageal manometry were performed before and 4-6 weeks after ablation. PDT was carried out using 635 nm red light, 4-6h after administration of 30 mg/kg 5-ALA. Proximal (untreated) and distal (treated) oesophageal resting pressure, wave amplitude, percentage peristalsis and percentage study time oesophageal pH<4, were assessed. Proton pump inhibitors (PPI) were administered throughout the study. RESULTS: There were no significant differences in oesophageal motility in treated or untreated areas of the oesophagus after PDT compared to pre-treatment values. Patients who continued to experience oesophageal acid exposure required more treatments to achieve complete Barrett's ablation. CONCLUSIONS: Oesophageal motility following ALA-PDT suggests a trend toward enhanced wave propagation however continued oesophageal acid exposure may affect PDT efficacy.

Evaluation of metastatic human tumor burden and response to therapy in a nude mouse xenograft model using a molecular probe for repetitive human DNA sequences.

A sensitive DNA dot-blot assay for repetitive human DNA sequences was developed and applied to the quantitative determination of spontaneous metastases of a human melanoma in various tissues of nude mice. The assay was useful for defining the time course and pattern of tissue distribution of metastatic cells as well as for assessing response to therapy. The methodology is relatively simple, can be performed using nonradioactive DNA probes, and should be broadly applicable to studies of metastasis of human tumors in nude mice.

Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening.

Disease-oriented panels of human tumor cell lines used by the National Cancer Institute for large-scale in vitro anticancer drug screening were evaluated for multidrug-resistant phenotype at the functional (in vitro drug sensitivity) and molecular levels. The cell line panels manifested a broad range of sensitivities to drugs typically associated with multidrug resistance (MDR) as well as to drugs not associated with MDR. Individual cell lines displayed unique and characteristic profiles of response. Patterns of correlated response were observed among, but not between, MDR and non-MDR drugs. Strong evidence of correlated response was limited to drugs sharing an intracellular mechanism of action. Several tumor cell lines exhibited a high degree of resistance to MDR drugs and relative sensitivity to non-MDR drugs, contained high levels of MDR-1 mRNA, and expressed cell surface P-glycoprotein detectable with one or more monoclonal antibodies. Parallel expression of all of these features representing the classic MDR phenotype was observed among members of the colon and renal tumor panels. Certain individual cell lines among other panels (lung, ovarian, melanoma, and central nervous system) also manifested some aspects of the MDR phenotype to various extents. Identification of MDR cell lines used for large-scale in vitro anticancer drug screening will facilitate interpretation of data in a way which may allow identification of new drug leads of potential value in treatment of MDR tumor cell populations.

Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer.

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 and histamine receptor 2 blockers. Other side effects were mild and predictable. Biodistribution studies showed a rapid and intensive hepatic uptake. At the 50 mg/m2 level the half-life and maximum serum concentration were 81 +/- 15 h and 7.9 microg/ml, respectively. One patient developed a low-level human anti-c30.6 response. Tumor response was assessed by computed tomography, positron emission tomography scanning, and serial carcinoembryonic antigen measurements. There were no partial responses, although positron emission tomography scanning demonstrated some reduction in tumor activity in three individuals. The chimerized c30.6 antibody is not immunogenic in humans and appears worthy of further study. It does, however, produce a unique profile of side effects that can be well controlled with premedication.

Atropine resistant excitation of the urinary bladder: the possibility of transmission via nerves releasing a purine nucleotide.

1. The possibility that a purine nucleotide is involved in excitatory transmission to the urinary bladder has been tested. All the purine compounds tested which contained a pyrophosphate bond produced contraction, adenosine triphosphate (ATP) being the most potent. Adenosine and adenosine monophosphate caused relaxation.2. The response to ATP closely mimicked the nerve-mediated contraction, both being characterized by a rapid contraction which was not maintained. A lack of sensitivity to ATP was noted in some preparations of the rat urinary bladder.3. Both nerve-mediated contractions and contractions caused by ATP were blocked by quinidine, while the response to acetylcholine persisted.4. Nerve-mediated responses were depressed during tachyphylaxis produced by high concentrations of ATP. Tachyphylaxis did not occur when low concentrations were used. Possible explanations for these results are discussed.5. The results are consistent with the hypothesis that non-cholinergic excitatory nerves to the guinea-pig bladder release a purine nucleotide, but do not provide critical evidence for it.

A comparison of the excitatory and inhibitory effects of non-adrenergic, non-cholinergic nerve stimulation and exogenously applied ATP on a variety of smooth muscle preparations from different vertebrate species.

1. The responses to non-adrenergic, non-cholinergic nerve stimulation have been compared with those to exogenously applied ATP on seventeen different tissues from a number of vertebrate classes.2. Stimulation of all the mammalian gut preparations studied (with the exception of the guinea-pig ileum) after blockade of the effects of adrenergic and cholinergic nerve stimulation by guanethidine (3.5 muM) and hyoscine (1.3 muM) caused inhibition; exogenously applied ATP mimicked this inhibitory response.3. Stimulation of the guinea-pig ileum in the presence of hyoscine and guanethidine, usually caused a diphasic response, relaxation followed by contraction; exogenously applied ATP mimicked this response, in contrast to acetylcholine and noradrenaline which caused excitation and relaxation respectively.4. Stimulation of preparations of lower vertebrate gut and guinea-pig bladder in the presence of hyoscine and guanethidine caused contraction; exogenously applied ATP mimicked this contractile response.5. In each preparation the time course of the response to ATP was similar or identical to the response to non-adrenergic, non-cholinergic nerve stimulation.6. The results are consistent with the hypothesis that a purine nucleotide may be the transmitter substance released from non-adrenergic, non-cholinergic nerves supplying smooth muscle preparations from a number of vertebrate classes.

Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut.

1. Stimulation of the vagal non-adrenergic inhibitory innervation caused the release of adenosine and inosine into vascular perfusates from the stomachs of guinea-pigs and toads.2. Stimulation of portions of Auerbach's plexus isolated from turkey gizzard caused the release of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP).3. ATP, added to solutions perfused through the toad stomach vasculature, was broken down to adenosine, inosine and adenine.4. Of a series of purine and pyrimidine derivatives tested for inhibitory activity on the guinea-pig isolated taenia coli, ATP and ADP were the most potent.5. ATP caused inhibition of twelve other gut preparations previously shown to contain non-adrenergic inhibitory nerves. The inhibitory action of ATP was not prevented by tetrodotoxin.6. Quinidine antagonized relaxations of the guinea-pig taenia coli caused by catecholamines or adrenergic nerve stimulation. Higher concentrations of quinidine antagonized relaxations caused by ATP or non-adrenergic inhibitory nerve stimulation.7. When tachyphylaxis to ATP had been produced in the rabbit ileum, there was a consistent depression of the responses to non-adrenergic inhibitory nerve stimulation but not of responses to adrenergic nerve stimulation.8. It is suggested that ATP or a related nucleotide is the transmitter substance released by the non-adrenergic inhibitory innervation of the gut.

Neonatal islet cell transplantation in the diabetic rat: effect on hepatic enzyme activity and glucose homeostasis.

Intraperitoneal transplantation of collagenase-digested, isogeneic, neonatal rat pancreatic tissue successfully reversed streptozotocin-induced diabetes in 77% of recipients. The low serum immunoreactive insulin, hyperglycaemia, glycosuria and weight loss, characteristic of the diabetic animal, were corrected and the reduced activities of hepatic glucokinase and pyruvate kinase, and the low glycogen concentration of the liver of diabetic rats were restored to normal. Forty-three per cent of the successfully transplanted rats became normoglycaemic within 1 month of transplantation whereas 57% took from 1 to 6 months to achieve normoglycaemia and displayed a mild glucose intolerance when subjected to a glucose load. The rats which had not become normoglycaemic 6 months after transplantation showed some amelioration of the diabetic state, as shown by increased serum immunoreactive insulin and hepatic glycogen concentration and a slow weight gain compared with diabetic controls.

Maternal metabolic alterations secondary to terbutaline therapy for premature labor.

The metabolic changes in pregnant patients treated with subcutaneous terbutaline for premature labor were studied. Arterial lactic acid, serum electrolyte, and glucose concentrations were measured in 29 patients. Samples were obtained before and 1 hour after the initial dose of terbutaline. Data included statistically significant changes in arterial pH and lactate levels and in serum glucose and potassium. In all patients tested, lactic acid and glucose concentrations increased and the potassium level significantly decreased. An increase occurred in the mean insulin level of 6 patients. It was therefore concluded that significant metabolic alterations occur in normal pregnant patients undergoing subcutaneous terbutaline treatment for premature labor. Hypokalemia, hyperglycemia, and an increase in lactic acid occur and, although these changes are handled readily and corrected rapidly in the normal pregnant patient, all patients, especially those with underlying metabolic alterations or cardiac disease, should have baseline electrolyte and glucose levels evaluated before consideration of terbutaline therapy for premature labor.

Pregnancy in women over forty.

In a retrospective review of 440 pregnancies occurring in women over the age of 40, increased frequencies of both perinatal and maternal complications were noted. The perinatal mortality rate of the study group was three times greater than that of the general obstetric population. There were increased incidences of both low and high birthweight infants. Neonatal morbidity was increased. Congenital abnormalities were noted in 12 infants, including 2 infants with cytogenetic abnormalities. Hypertensive disorders complicated one-third of the pregnancies. Diabetes mellitus and abruptio placentae occurred with increased frequency. Cesarean section was required in 12.2% of the deliveries.

Levels of messenger-RNA coding for DNA topoisomerase-ii isoforms do not correlate with in-vitro drug-sensitivity.

The relationship between cellular levels of mRNA coding for DNA topoisomerase II, both the alpha and beta isoforms, and in vitro sensitivity to anticancer drugs were evaluated. Using a sensitive RNA-polymerase chain reaction technique, the levels of mRNA coding for the alpha and beta isoforms of topoisomerase II were estimated relative to beta-actin mRNA. A relatively narrow range of expression was observed across a broad range of approximately 60 human tumor cell lines representing eight major histological types which have been characterized in detail with respect to their in vitro sensitivity to standard anticancer drugs. No significant correlations were observed between mRNA level and cellular response to drugs thought to inhibit topoisomerase II or any of the other drugs studied. These results suggest that predictive tests for response to topoisomerase II-related drugs can not be based on estimation of levels of mRNA.

Effect of cisapride on oesophageal motility and duodenogastro-oesophageal reflux in patients with Barrett's oesophagus.

OBJECTIVE: Both gastric acid and duodenal juice have been implicated in Barrett's oesophagus. The aim of this study was to look at duodenal reflux in the oesophagus together with motility characteristics in a group of patients with Barrett's oesophagus and compare them with a mild oesophagitis group and to assess the effect of cisapride on any abnormalities. DESIGN: A prospective study comparing the two groups of patients was carried out. METHODS: Twenty patients with histologically proven Barrett's oesophagus and 20 patients with Savary-Miller grade 2 oesophagitis were studied. Standard oesophageal manometric measurements were carried out and on a separate occasion duodenogastro-oesophageal reflux (DGOR) was measured over a 4-h period using a sodium ion selective electrode. Patients with more than 5% DGOR were given cisapride (10 mg four times daily) and the studies repeated after 7 days of treatment. RESULTS: Barrett's patients showed more DGOR, 12.2% of the study time compared to 5.1% in the mild oesophagitis group, P = 0.012, but manometric findings were not significantly different. Sixteen patients were treated with cisapride. DGOR was reduced in 8 out of 12 Barrett's patients and 2 out of 4 oesophagitis patients, and proximal amplitude and distal oesophageal pressures were significantly elevated (P = 0.05 and P = 0.03, respectively). CONCLUSION: Monitoring of sodium ions in the oesophagus shows that patients with Barrett's oesophagus have significantly more DGOR than patients with uncomplicated oesophagitis and cisapride may be effective in removal of this reflux.

Bethanechol provocation testing does not predict symptom relief after cholecystectomy for acalculous biliary pain.

BACKGROUND: The currently accepted hypothesis to explain acalculous gallbladder pain is the lack of contractile co-ordination between the body and neck. We have previously shown that bethanechol, a muscarinic stimulant causes differential stimulation of these two regions. AIM: To evaluate the reliability of bethanechol-induced gallbladder contraction in predicting symptom relief after cholecystectomy in patients with acalculous gallbladder disease. METHODS: Fifty-one patients underwent a bethanechol provocation test together with serial ultrasound to determine gallbladder emptying. McGill pain questionnaires were completed, and patients positive for pain (bethanechol provocation test +ve) were offered cholecystectomy, and patients negative for pain (bethanechol provocation test -ve) were reassessed at 6 months and offered cholecystectomy if symptoms persisted. All patients answered pain questionnaires either 6 months after surgery or as follow-up. RESULTS: There was no difference in the percentage of gallbladder emptying between the bethanechol provocation test +ve and bethanechol provocation test -ve groups. Fifty-three percent of bethanechol provocation test +ve patients and 54% of bethanechol provocation test -ve patients still remained symptomatic 6 months after surgery. Conclusion. Gallbladder pain provoked by bethanechol does not predict symptom relief after cholecystectomy.