Radar plots: A novel modality for displaying disparate data on the efficacy of eluxadoline for the treatment of irritable bowel syndrome with diarrhea.

BACKGROUND: Patients with irritable bowel syndrome with diarrhea (IBS-D) experience a range of abdominal and bowel symptoms; successful management requires alleviation of this constellation of symptoms. Eluxadoline, a locally active mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, is approved for the treatment of IBS-D in adults based on the results of 2 Phase 3 studies. Radar plots can facilitate comprehensive, visual evaluation of diverse but interrelated efficacy endpoints. METHODS: Two double-blind, placebo-controlled, Phase 3 trials (IBS-3001 and IBS-3002) randomized patients meeting Rome III criteria for IBS-D to twice-daily eluxadoline 75 or 100 mg or placebo. Radar plots were prepared showing pooled Weeks 1-26 response rates for the primary efficacy composite endpoint (simultaneous improvement in abdominal pain and stool consistency), stool consistency, abdominal pain, urgency-free days, and adequate relief, and change from baseline to Week 26 in IBS-D global symptom score, abdominal discomfort, abdominal pain, abdominal bloating, and daily number of bowel movements. KEY RESULTS: The studies enrolled 2428 patients. Eluxadoline increased Weeks 1-26 responder proportions vs placebo for the composite endpoint, stool consistency, abdominal pain, urgency-free days, and adequate relief. Changes from baseline to Week 26 in IBS-D global symptom score, abdominal discomfort, abdominal pain, abdominal bloating, and number of bowel movements were greater with eluxadoline vs placebo. CONCLUSIONS AND INFERENCES: Data presentation in radar plot format facilitates interpretation across multiple domains, demonstrating that eluxadoline treatment led to improvements vs placebo across 13 endpoints representing the range of symptoms experienced by patients with IBS-D.

Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor.

Expression of apolipoprotein E (apoE) and ciliary neurotrophic factor (CNTF), a pleiotropic neuron survival factor, increases in the CNS in response to injury. Although CNTF is believed to act as a survival factor after injury in the CNS, the functions of apoE in the CNS remain mainly unknown. Similarities between apoE and CNTF, including coinciding patterns of postinjury expression, extracellular localization, homologous tertiary structure, and ability to form homodimers led us to examine the possibility that apoE and CNTF directly associate and thereby facilitate the neurotrophic activity of CNTF. We identified two binding interactions between apoE and CNTF: (1) reversible binding of both the apoE3 and apoE4 isoforms to CNTF under nondenaturing conditions, and (2) a higher avidity, SDS-stable binding of apoE3 with CNTF. Purified lipid-free apoE, as well as apoE in cerebrospinal fluid, binds CNTF. We demonstrate here that the survival-promoting activity of CNTF on cultured hippocampal neurons is potentiated by apoE. In the absence of apoE, survival of hippocampal neurons with 1 ng/ml CNTF was 20% above control survival values. In contrast, in the presence of apoE, survival of hippocampal neurons with 1 ng/ml CNTF was 40% above control survival values. These data, which indicate a novel function for apoE in the nervous system, support the hypothesis that apoE secreted locally at sites of injury can facilitate neural repair by promoting the activity of certain growth factors, in particular CNTF.

Frequency analysis of catecholamine axonal morphology in human brain. I. Effects of postmortem delay interval.

The diverse morphologies of catecholamine axons in the human brain were examined by using tyrosine hydroxylase immunocytochemistry. Human brain tissue was obtained by either rapid autopsy (mean postmortem delay < 1 h) or routine autopsy (mean postmortem delay 5 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus and the calcarine cortex (Brodmann area 17) were processed for tyrosine hydroxylase immunoreactivity. First, a quantitative method was developed to reliably identify differing morphologies of catecholamine axons in human brain tissue. A total of 625 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct morphological categories. These categories were based upon axonal morphologies which were readily distinguished by trained observers, and moreover, further investigations demonstrated that entire tissue sections could be reliably re-sampled at intervals of up to six months. Second, regional variations in axonal distribution and the effects of increasing postmortem delay in tissue processing on the categories of tyrosine hydroxylase immunoreactive axon morphologies were examined. Postmortem delays of up to 6.5 hours were found to decrease the frequency of fine axons with varicosities (axon type 2) and increase thick-caliber straight axons (axon type 5) in all regions examined. The frequency of other morphological axon types did not change as a function of postmortem delay. In summary, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to be reliable and valid. It was furthermore demonstrated that postmortem delays affect selected morphological types of catecholamine axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency analysis of catecholamine axonal morphology in human brain. II. Alzheimer's disease and hippocampal sympathetic ingrowth.

We have examined the various diverse morphologies of catecholamine axons in the brains of patients with Alzheimer's disease. Alzheimer's disease and aged control brain tissue were obtained by a rapid autopsy protocol (mean postmortem delay < 1 h). Tissue blocks from the superior frontal cortex (Brodmann area 9), the hippocampal gyrus, and the calcarine cortex (Brodmann area 17) were processed for identification of catecholamine axons using tyrosine hydroxylase immunocytochemistry. A total of 1275 tyrosine hydroxylase immunoreactive axons were randomly sampled from coded sections and classified into one of six distinct axon-type categories. The axon classification from patients with Alzheimer's disease significantly differed from those of an age-matched control population in the hippocampus. The Alzheimer's disease brains were decreased in the frequency of very long, thin, tyrosine hydroxylase immunoreactive axons (type 1) and had an increased frequency of shorter, tortuous, axons (type 3). These selective quantitative shifts in hippocampal catecholaminergic axon morphology are consistent with the hypothesis that sympathetic noradrenergic axons invade the hippocampus of patients with Alzheimer's disease. Multivariate modeling of the frequency sampling data found that the axon type classification scheme successfully predicted the presence of Alzheimer's disease. In particular, the use of quantitative neuroanatomical measures of the catecholaminergic system in human brain tissue was found to have errorless predictive ability with respect to late onset (> 75 years) Alzheimer's disease. In summary, the use of quantitative neuroanatomical measures of catecholamine axonal morphologies in Alzheimer's disease brain tissue identified a specific frequency shift which may represent hippocampal sympathetic ingrowth and this unique measure was found to have predictive utility with respect to Alzheimer's disease.

Organization of motor pools supplying axial muscles in the chicken.

Intramuscular injections of the retrograde tracers 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and horseradish peroxidase (HRP) were used to map the motor pools innervating axial muscles in the cervical and thoracic regions of the chicken. We found that motor pool position is well correlated with the muscle's embryonic origin, and not necessarily with its position. Muscles of myotomal (exclusively somitic) origin were innervated by medially positioned motoneurons in the median motor column, and the motor pools supplying these muscles were somatotopically organized. Muscles having a dual embryonic origin, from the somites and lateral plate, were innervated by motoneurons positioned further laterally within the median motor column. The relationship between motor pool position and embryonic origin of the muscle may be a general principle of ventral horn organization.

Changing trends in surgery for acute cholecystitis.

Surgery for acute cholecystitis has become the most frequent abdominal surgery in most hospitals, yet aspects of its management remain controversial. The aim of this study was to focus on the recent trends by demonstrating the principal differences between 2 series of patients operated on during 10-year intervals. Two hundred fifty-six consecutive operations for acute cholecystitis were performed from 1970 to 1977 (group O) and were compared to 260 cases operated from 1980 to 1987 (group N). Thirty-six variables were recorded in each case. All data obtained were computer recorded and analyzed. Several trends were observed in group N: 1. The population was significantly older with a higher proportion of males and diabetics. 2. There was a marked increase in common bile duct stones, acalculous cholecystitis, and gangrenous changes in the gallbladder. 3. There was a significant increase in patients operated on within 48 hours of admission. 4. There was a significant increase in the number of patients without previous history of biliary symptoms. 5. There was a significant decrease in the rate of wound infections and no statistically significant differences in mortality (N: 3.0%, O: 2.7%). 6. A decrease of the average postoperative hospital stay of 3.2 days was observed. In spite of the older and sicker population in group N, no significant increase in mortality occurred and the postoperative hospital stay was reduced.