Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers.

BACKGROUND: Synthetic human ghrelin accelerates gastric emptying, reduces gastric accommodation, and results in numerical increases in postprandial symptom scores. The ghrelin receptor agonist, relamorelin, accelerates gastric emptying in patients with diabetic gastroparesis. AIM: To measure pharmacological effects of relamorelin on gastric accommodation, distal antral motility, and satiation in healthy volunteers. METHODS: In a placebo-controlled, double-blind, randomized study of 16 healthy volunteers, we compared effects of 30 µg subcutaneous (s.c.) relamorelin to placebo on: (i) gastric volumes measured by single photon emission computed tomography, (ii) 1-h postprandial distal antral motility index (MI) by 15-lumen perfusion gastroduodenal manometry, and (iii) satiation tested by Ensure nutrient drink test. Primary endpoints were: fasting and postprandial gastric volumes, distal antral phasic pressure activity (number of contractions, mean amplitude, and MI), and maximum tolerated volume. Results were normally distributed and the two treatment groups were compared using t-test. KEY RESULTS: Relamorelin, 30 µg s.c., significantly increased the number of contractions in the distal antrum during 0-60 min postmeal when compared to placebo (p = 0.022); this was also observed in the first two 15-min periods (p = 0.005 and 0.015 for number of contractions 0-15 and 16-30). There was borderline increase in MI0-15 (p = 0.055) and numerically increased MI0-60 (p = 0.139) and MI16-30 (p = 0.116). The amplitude of contractions was not significantly increased. Relamorelin did not significantly alter fasting or postprandial gastric volumes, gastric accommodation, or satiation volumes and symptoms. CONCLUSIONS & INFERENCES: Relamorelin increases frequency of distal antral motility contractions without significant effects on amplitude of contractions. The lack of inhibition of accommodation and absence of increase in satiation symptoms support relamorelin for the treatment of symptomatic gastroparesis (ClinicalTrials.gov NCT02466711).

Nuclear CSPP1 expression defined subtypes of basal-like breast cancer.

BACKGROUND: The multi-exon CSPP1 gene, encoding for centrosome and microtubule-associated proteins involved in ciliogenesis and cell division, is a candidate oncogene in luminal breast cancer but expression of CSPP1 proteins remained unexplored. METHODS: CSPP1 gene and protein expression was examined in normal mammary tissue, human breast cancer cell lines, and primary breast cancer biopsies from two patient cohorts. Cell type and epitope-dependent subcellular-specific CSPP1 staining pattern in normal mammary gland epithelium and cancer biopsies were correlated to molecular and clinical parameters. RESULTS: A novel, nuclear localised CSPP1 isoform was exclusively detected in luminal epithelial cells, whereas cytoplasmic CSPP-L was generally expressed in normal mammary epithelium. Luminal cell-related nuclear CSPP1 expression was preserved in type-matched cell lines and carcinomas, and correlated to gene copy number and mRNA expression. In contrast, basal-like carcinomas displayed generally lower CSPP1 mRNA expression. Yet, a subgroup of basal-like breast carcinomas depicted nuclear CSPP1 expression, displayed luminal traits, and differed from nuclear CSPP1 devoid counterparts in expression of eight genes. Eight-gene signature defined groups of basal-like tumours from an independent cohort showed significant differences in survival. CONCLUSIONS: Differential expression of a nuclear CSPP1 isoform identified biologically and clinically distinct subgroups of basal-like breast carcinoma.

Randomised clinical trial: the effects of daikenchuto, TU-100, on gastrointestinal and colonic transit, anorectal and bowel function in female patients with functional constipation.

BACKGROUND: Daikenchuto, a Japanese herbal medicine used for post-operative ileus and constipation, dose dependently stimulates gastrointestinal (GI) motility and decreases rectal compliance and sensation. Effects of TU-100 (commercial form of daikenchuto) in adults with constipation are unknown. AIM: To compare the effects of oral TU-100, 2.5 g t.d.s. or 5 g t.d.s. and placebo t.d.s. on GI and colonic transit (CT), rectal compliance (RC) and sensation thresholds (RST), anal sphincter pressures (ASP) and bowel function in female patients with functional constipation (FC). METHODS: We conducted a single-centre, randomised, parallel-group, double-blind, pharmacodynamic study; 45 female patients with FC without evidence of rectal evacuation disorder were assigned to 28 days' treatment with oral placebo or TU-100 (Tsumura USA, Princeton, NJ, USA). Demographic data and CT were measured at baseline and randomisation stratified by baseline CT (GC> or <1.9) and by BMI (<25 or ≥25 kg/m(2) ). At the end of treatment period, we measured GI and CT by scintigraphy, RST and RC by barostat, ASP by manometry, psychosensory sensations, bowel function by daily diary and quality of life (QOL). The study had power to detect effect sizes of 33% (CT), 40% (RC) and 46% (RST). Statistical analysis included BMI as covariate. RESULTS: TU-100 had no significant effects on GI or CT, RC, ASP, recto-anal pressure difference, or RST. The 5 g t.d.s./day dose was associated with lower RST for first sensation and gas (unadjusted P: 0.045 and 0.024 respectively). There were no treatment effects on psychosensory symptoms, stool frequency, stool consistency or QOL. CONCLUSION: Mechanisms underlying the observed clinical benefit of TU-100 remain unclear (ClinicalTrials.gov NCT01139216).

Results of ambulatory pH monitoring do not reliably predict response to therapy in patients with eosinophilic oesophagitis.

BACKGROUND: The consensus statements for eosinophilic oesophagitis recommend that ambulatory pH monitoring is one means of determining if gastro-oesophageal reflux is the cause of oesophageal eosinophilia and should guide pharmacological therapy. AIM: To evaluate prospectively the accuracy of pH monitoring as a predictor of endoscopic, histological and symptomatic response in patients with oesophageal eosinophilia. METHODS: We conducted a prospective trial in which patients with oesophageal eosinophilic infiltration with ≥15 eos/hpf underwent a 24-h pH study and were placed in one of two treatment arms for 6 weeks based on positive or negative results. Patients with abnormal acid exposure were treated with esomeprazole 40 mg twice daily and others were treated with oral viscous budesonide 1 g twice daily. Response to treatment was assessed by oesophageal histology (<5 eos/hpf) and symptoms. RESULTS: A total of 51 patients were enrolled in the study. The average patient age was 39 years and 31 patients (61%) were male. The average number of eosinophils per hpf, prior to study enrolment was 41.2 (range 15-140, s.d. 27.7). Nineteen (37%) had positive pH studies and 32 (63%) had negative pH studies. Eighteen patients completed treatment with esomeprazole. Only eleven (61%) had histological response and, of these eleven, five (46%) had symptomatic improvement. A total of 28 patients with normal acid exposure completed treatment with budesonide. Only 16 (57%) had histological and 11 (69%) had symptomatic improvement. CONCLUSION: In this prospective trial of pH-guided treatment, neither positive nor negative results of initial pH monitoring accurately predicted response to therapy.

Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion.

Our aim was to understand the information from differential two-sugar excretion (2-SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed-release, methacrylate-coated capsules (CAP). Both formulations were radiolabelled. Urine was collected every 2 h from 0 to 8 h, and from 8 to 24 h. Two hours after LF, gastric residual was 15.9 +/- 6.2% (SEM), and the percentage in colon was 49.6 +/- 7.8%; in 11/12 participants, liquid had entered colon within 2 h. Average CAP arrival time in colon was 5.16 +/- 0.46 h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8 h; lactulose absorption was low throughout the 24 h. After the LF, the LMR (geometric mean, 95% CI per h) in the 0-2 h urine was [0.08 (0.05, 0.11)], which was lower than in 8-24 h urine [0.32 (0.16, 0.46); P < 0.05]. Urine LMRs at 8-24 h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0-2 h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24 h. CAP delivery reduces mannitol excreted at 0-6 h, compared with LF. The 0-5 or 6 h 2-SE urine likely reflects both SI and colon permeability; the higher LMR in the 8-24 h urine relative to 0-2 h urine should be interpreted with caution and does not mean that colon is more permeable than SI.

Muscle learning therapy--efficacy of a biofeedback based protocol in treating work-related upper extremity disorders.

Work-related upper extremity disorders (WRUEDs) continue to present significant treatment and financial challenges to providers, employers, and insurers. This retrospective study reviews outcomes for 309 subjects who, between 1995 and 1999, were referred through the workers' compensation system for treatment of computer keyboard- and mouse-related WRUED injuries. The mean length of time from the recorded date of injury to the date of intake was 12.9 months. Subjects were offered a 12-visit course in muscle learning therapy (MLT). MLT is an operant conditioning program which uses surface electromyography (sEMG) to train injured workers to control their muscles during work activities. Patient response to therapy was obtained by a therapist-administered questionnaire during Visit 8 of 12. A group of 309 subjects, who had failed to respond to a previous course of therapy (typically physical therapy), reported significant improvements of pain in the neck, thorax, and upper extremities. Ninety six percent reported that they felt "more in control," 86% reported feeling "better overall," and 81% reported either "working the same and feeling better" or "working and accomplishing more." This study provides preliminary support for this approach and provides justification for controlled clinical trials in the future.

The effects of chronic effusion on knee joint proprioception: a case study.

Knee joint effusion has been shown to cause a reflex inhibition of the quadriceps musculature. However, the effect of effusion on knee joint proprioception has not been thoroughly investigated. This issue is further clouded by the debate surrounding the role of the muscle spindle and joint mechanoreceptors in providing afferent feedback to the central nervous system. This case study examines the effects of a chronic effusion on knee joint proprioception. Possible suggestions for the results are discussed, and areas for further study are offered.

Genetic counseling in a Navajo hereditary nonpolyposis colorectal cancer kindred.

BACKGROUND: Cross-cultural genetic counseling was provided to an extended Navajo Indian family in which the MLH1 gene mutation for hereditary nonpolyposis colorectal cancer (HNPCC) had been identified. The family had been observed by the authors since 1983 and over the years had been provided with intensive education regarding the natural history of HNPCC as well as recommendations for cancer surveillance and management that was responsive to this natural history. METHODS: Following identification of the MLH1 mutation, DNA from family members was evaluated by a reference laboratory (OncorMed, Gaithersburg, MD), where sequences were checked in both the forward and reverse directions against the published sequence for MLH1. The 4bp deletion beginning at the first nucleotide of codon 727 was easily visualized in the heterozygous condition in both affected and predispositional individuals. The family was reeducated as a group and then provided further education individually during genetic counseling sessions, at which time they were appraised of potential penalties, such as insurance and employer discrimination, and psychological sequelae that could result from knowledge of the MLH1 mutation. Strict confidentiality of this information was assured. RESULTS: DNA testing was performed on 51 family members. Twenty-three individuals were counseled, seven of whom were positive for MHL1. Reactions ranged from full acceptance of the genetic implications to traditional Navajo reasoning such as the family had been cursed. CONCLUSIONS: DNA-based genetic counseling requires comparison and empathy, coupled with intensive preeducation regarding potential penalties and advantages that might emanate from this knowledge. Special care must be given to patients' culture, beliefs, and traditions.

New fluorescent dyes in the red region for biodiagnostics.

The increased sensitivity together with the advent of low-cost optical sources and detectors in the visible-near IR region has led us to current efforts to develop new efficient fluorescent labels for biodiagnostics with absorption and emission beyond 600 nm. In view of the general fluorescence decrease with increasing emission wavelength, we investigated the possibility to shift the absorption of rhodamine dyes toward the region 620-670 nm. The hydrophobic nature of all known long-wavelength dyes results in the tendency to form intra- and intermolecular aggregates in hydrophilic solvents, especially in aqueous environment. Due to the aggregation with biological materials, fluorescence quenching of the dyes is often observed. New strategies for prevention of these processes are considered.

The relationships among labor-force participation, service-sector employment, and underemployment.

"In this study, it is argued [that] underemployment is both affected by and affects the labor-force participation rate (LFPR) and the level of service employment. Interestingly, the analysis reveals that service employment lowers the LFPR and raises underemployment. In turn, underemployment increases the LFPR as more secondary workers are pushed into the labor market in an effort to support their households. Thus, secondary workers are not pulled into the labor market by the availability of service jobs, but are rather pushed into these jobs by the condition of underemployment that is brought on by the growing concentration of low-paying service jobs....A three-equation simultaneous equation model is developed to test our hypotheses [and] three-stage least squares...estimates of this model for the 100 largest [U.S.] metropolitan areas are presented...."

Carpal tunnel syndrome following automobile collisions.

Seven patients developed symptoms and signs of carpal tunnel syndrome after vehicles they were driving were involved in collisions. Nerve conduction studies showed median nerve impairment at the wrist in 4 patients and suggested it in the other three. The presence of carpal tunnel syndrome was confirmed in every patient by the relief of symptoms following surgical division of the volar carpal ligament. The findings suggest that injuries inflicted on nonneural structures of the carpal tunnel when the patient was gripping the steering wheel led to chronic compression of the median nerve within the tunnel.

Bilateral projection of the canine tooth pulp to bulbar trigeminal neurons.

Unit activity was recorded extracellulary from neurons of the cat medulla following electrical stimulation of the ipsilateral and/or contralateral cannine tooth pulps. The majority of the cells (67%) were only responsive to ipsilateral stimulation. However, many (28%) responded to stimulation of either canine pulp and a few (5%) responsed to contralateral stimulation alone. The neurons were localized histologically in the necleus proprius of the rostral trigeminal nucleus caudalis (NVCaud) and in dorsal portions of the ventromedially contiguous lateral reticular formation (LRF). Cells exclusively responsive to ipsilateral stimuli had a relatively wide dorsoventral distribution. In contrast, 'bilateral' and 'contralateral' cells were situated only in the deep NVCaud-LRF border zone or in immediately adjacent portions of the LRF. Generally, ipsilateral stimuli evoked response bursts with shorter latencies, more spike potentials and briefer interspike intervals than equivalent contralateral stimuli. In experiments designed to study afferent interactions, a conditioning stimulus, applied to either the ipsilateral or the contralateral canine, preceded a test stimulus applied to the other canine at predetermined interstimulus intervals. Responses to the test stimulus were either totally or partially suppressed when intervals of moderate duration (90-500 msec) were used. However, responses to the test stimulus frequently were enhanced when the intervals were breif (less than or equal to 60 msec) or when the teeth were stimulated simultaneously. The results reveal that bilateral afferents from the pulps of the canine teeth converge upon neurons of bulbar trigeminal structures, that the neurons are differentially responsive to the activation of ipsilateral and contralateral pulpal receptors and that bilateral afferent barrages originating in the canine pulps interact to modulate the firing patterns of the neurons.

Electrical stimulation of the tooth pulp in the study of pain.

Unit activity was recorded from bulbar neurons in the immobilized, lightly anesthetized cat following bipolar, electrical stimulation of the canine tooth pulp and the immediately proximal gingiva. When feasable, variations in neuronal responding were studied subsequent to the application of a topical anesthetic to the portion of the gingiva being stimulated. The results indicate that (1) stimulation of the pulp with insulated, embedded, dental electrodes does not excite receptors in adjacent, nondental tissue and (2) stimulation of the gingiva through insulated, concentric electrodes does not activate pulpal receptors in near-by teeth. In addition, the results corroborate previous demonstrations that current spread beyond the pulpal cavity is unlikely when appropriate stimulating procedures are used. Together, the data lend support to the position that electrical stimulation of the tooth pulp provides a unique means for the selective, parametric study of a known pain sensor.