Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Utilization of wireless pH monitoring technologies: a summary of the proceedings from the esophageal diagnostic working group.

Gastroesophageal reflux disease (GERD) can be difficult to diagnose - symptoms alone are often not enough, and thus, objective testing is often required. GERD is a manifestation of pathologic levels of reflux into the esophagus of acidic, nonacidic, and/or bilious gastric content. However, in our current evidence-based knowledge approach, we only have reasonable outcome data in regards to acid reflux, as this particular type of refluxate predictably causes symptoms and mucosal damage, which improves with medical or surgical therapy. While there are data suggesting that nonacid reflux may be responsible for ongoing symptoms despite acid suppression in some patients, outcome data about this issue are limited. Therefore, this working group believes that it is essential to confirm the presence of acid reflux in patients with 'refractory' GERD symptoms or extraesophageal symptoms thought to be caused by gastroesophageal reflux before an escalation of antireflux therapy is considered. If patients do not have pathologic acid reflux off antisecretory therapy, they are unlikely to have clinically significant nonacid or bile reflux. Patients who do not have pathologic acid gastroesophageal reflux parameters on ambulatory pH monitoring then: (i) could attempt to discontinue antisecretory medications like proton pump inhibitors and H2-receptor antagonists (which are expensive and which carry risks - i.e. C. diff, etc.); (ii) may undergo further evaluation for other causes of their esophageal symptoms (e.g. functional heartburn or chest pain, eosinophilic esophagitis, gastroparesis, achalasia, other esophageal motor disorders); and (iii) can be referred to an ear, nose, and throat/pulmonary/allergy physician for assessment of non-GERD causes of their extraesophageal symptoms.

Frontal brain asymmetry as a biological substrate of emotions in patients with panic disorders.

BACKGROUND: Right frontal hemisphere activation, as indicated by reduced frontal alpha amplitude, seems to represent activation of an avoidance-withdrawal system and seems to be associated with negative emotions. Since patients with panic disorder are characterized by both negative emotions and avoidance-withdrawal behavior, we expected them to show greater right than left frontal hemisphere activation. METHODS: Spontaneous electroencephalography was recorded from the left and right frontal and parietal scalp regions of 23 patients with panic disorder patients without a diagnosis of depression and from 25 healthy control participants during the following conditions: rest, confrontation with neutral, panic-relevant, anxiety-relevant but panic-irrelevant, or anxiety-irrelevant but emotionally relevant stimuli, and performance of a motor task. Their emotional state during these conditions was assessed by the Self-Assessment Manikin. RESULTS: In patients with panic disorders, there were asymmetries in frontal hemisphere activation during resting phases and when confronted with anxiety-relevant stimuli. Their right frontal alpha power was significantly decreased compared with the left, while control participants did not show frontal brain asymmetry during these phases. There was no frontal brain asymmetry when patients observed an emotionally neutral picture or performed a motor task. Under these conditions, left and right frontal hemisphere alpha activation of patients with panic disorder and healthy participants were comparable. CONCLUSIONS: These data support the hypothesis that patients with panic disorder are characterized by greater activation of a right frontal avoidance-withdrawal system in negatively valenced situations. The findings are interpreted as biological evidence for a disturbed cortical processing in patients with panic disorder.

Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells.

We have selected a panel of human tumor xenografts for in vitro and in vivo studies that allows an indication of selectivity of action of novel chemotherapeutic agents. We report here the antitumor activity of the flavone flavopiridol (previously designated L86-8275), which has been selected for further studies based in part on its behavior in the anticancer drug screening system of the United States National Cancer Institute. Eighteen human tumor and five cell line-derived xenografts established by serial passage in nude mice in our laboratory were used as tumor models for in vitro investigations using a modified double-layer soft agar assay. In vivo investigations were completed in nude mice bearing advanced-stage s.c. growing prostate cancer xenografts. Antitumor activity in vitro (test/control

Cycloplatam: a novel platinum compound exhibiting a different spectrum of anti-tumour activity to cisplatin.

Cycloplatam is a novel platinum compound which has shown anti-tumour activity in murine tumour models. In this study, cycloplatam was found to have anti-tumour activity in vitro and in vivo in human tumour models. In 15 cell lines (mainly ovarian), cycloplatam showed similar cytotoxicity as cisplatin, using the sulphorhodamine B assay. Determination of the resistance factor (IC50 of cisplatin-resistant divided by IC50 of parental cell line) clearly showed lower values for cycloplatam than for cisplatin. In the parental ovarian cell line CH1 and the cisplatin-resistant CH1 cisR model, we observed no cross-resistance of cycloplatam and cisplatin. The in vitro anti-tumour activity was confirmed in human tumour xenografts using the clonogenic assay. Mean IC70 values of cycloplatam were 0.54 microgram/ml (1.25 microM) and of cisplatin 0.42 microgram/ml (1.4 microM), respectively. In the murine subcutaneously implanted ADJ/PC6 plasmacytoma in vivo cycloplatam showed less activity than cisplatin, with a 2-fold smaller therapeutic index than cisplatin. In ovarian cancer xenografts cycloplatam was less active than cisplatin. However, anti-tumour activity of cycloplatam in lung cancer xenografts was quite different from cisplatin. In LXFS 538, a model moderately sensitive to cisplatin, a partial remission was observed, but in LXFL 529, a cisplatin-sensitive model, cycloplatam was inactive, cycloplatam thus demonstrating a different spectrum of anti-tumour activity. Based on these results, further preclinical investigations with other tumours, such as cisplatin-sensitive and -resistant gastric cancer models, are warranted with cycloplatam.

Cytotoxicity of TGF alpha-PE40 and correlation to expression of epidermal growth factor receptor.

TGF alpha-PE40 is a chimeric protein composed of transforming growth factor alpha (TGF alpha) linked to a modified Pseudomonas exotoxin (PE40). We tested the in vitro cytotoxicity of TGF alpha-PE40 on 23 different solid human tumour xenografts established in nude mice and human bone marrow cells from healthy donors, utilising a modified clonogenic assay. In order to distinguish non-specific toxicity from the targeted effects of TGF alpha-PE40, epidermal growth factor receptor (EGFR) expression of the tumours studied was assessed by Northern blot, slot blot and immunohistochemistry. TGF alpha-PE40 demonstrated differential cytotoxicity on human tumour xenografts in the clonogenic assay. No toxicity on human bone marrow cells was observed. In vitro activity of TGF alpha-PE40 showed a significant correlation with the expression of EGF receptors as determined by immunohistochemistry and slot blot. Further studies will be performed in order to determine the in vivo activity of this compound in tumour-bearing nude mice.

Behavioral and neurophysiological evidence for altered processing of anxiety-related words in panic disorder.

Body-related and nonsomatic words were presented tachistoscopically to 15 panic patients and 15 healthy controls at each participant's threshold for correctly identifying 50% of neutral words. Behavioral (proportion of words correctly recognized) and electrocortical (event-related brain potentials [ERPs]) measures were registered. Panic patients recognized more body-related than nonsomatic words, and body-related as compared with nonsomatic words elicited, in these patients, significantly larger P300 amplitudes and enhanced positive slow waves (600 to 800 ms after stimulus presentation). In healthy controls, the number of correct recognized words and the ERPs were not differentially affected by the 2 word types. These results are grossly consistent with cognitive models of panic disorders, assuming that certain bodily sensation are perceived and processed in an affective manner that differentiates panic patients from healthy controls.

Decreased duration and altered topography of electroencephalographic microstates in patients with panic disorder.

The topography and temporal sequence of scalp electrical fields were analyzed by adaptive segmentation of the continuous electroencephalogram (EEG) in 27 patients with panic disorder and 28 control subjects during rest phases and during the viewing of a neutral (mushroom) or an emotionally relevant (casualty) picture. The results indicate decreased duration of brain microstates in panic patients during all conditions. Comparison of the resting phases with the viewing conditions revealed a significant acceleration of EEG microstates in both the patients and the control subjects. Patients and control subjects differed in the topography of the fields during rest: control subjects showed a left-anterior/right-posterior orientation, while panic patients showed a predominantly right-anterior/left-posterior orientation. Neither group displayed any topographic changes when viewing the mushroom picture. However, when viewing the anxiety-specific casualty picture, panic patients shifted fields in a different way than did control subjects. Centroid topography does not permit clear localization of the cortical generators. It is concluded that panic patients show a generally increased cortical activation compared with healthy control subjects, and activate different neuronal arrays when viewing an anxiety-specific stimulus.

A priori expectancy bias in patients with panic disorder.

BACKGROUND: Several studies have indicated that phobic participants tend to overassociate fear-relevant stimuli and aversive outcomes, i.e, they show a covariation bias. Such a bias seems to be a powerful way to confirm danger expectations and enhance fear. Therefore, a covariation bias might be an important factor in the maintenance of fear. METHODS: To investigate a covariation bias in patients with panic disorder, we had 29 patients and 29 healthy control participants rate the a priori probabilities with which they would expect pictures of mushrooms, spiders, erotic scenes, and emergency situations to be paired with a tone, shock, or nothing. RESULTS: This is the first study to show that patients with panic disorder specifically overestimate the association between panic-relevant stimuli and a following negative consequence. This distorted contingency expectancy represents a panic-specific covariation bias, since it was not observable for other stimuli-consequence combinations and only to a significantly lesser degree in control participants. CONCLUSIONS: The underpinning hypothesis is that overestimation of threat plays a casual role in the origins and maintenance of anxiety. Thus anxiety may induce a covariation bias, which in turn may enhance the perceived threat, which in turn may intensify the anxiety etc. This reciprocal relationship between covariation bias and anxiety may have clinical implications for prediction and treatment in patients with panic disorder.

Right paraduodenal hernia in childhood: a case report.

A 7-year-old patient was recently treated surgically for a right paraduodenal hernia. Paraduodenal hernia is a rare cause of chronic abdominal complaints, as well as acute obstruction, and although it is not typical, it can manifest in childhood. The term "hernia" is a misnomer since this condition results from anomalous intestinal rotation. Knowledge of this embryology will prevent injury to vital mesenteric vessels during "repair" of a right paraduodenal hernia.

Associations between cortical slow potentials and clinical rating scales in panic disorder: a 1.5-year follow-up study.

In a previous study of 15 panic patients, we demonstrated that body-related (somatic) word stimuli elicited an enhanced positive cortical slow wave compared to non-somatic word stimuli. Healthy controls did not show this difference. The present paper reports on psychometric ratings in relation to cortical slow waves in these patients. Patients were clinically reexamined after about 1.5 years. Although no significant correlations between neurophysiology and psychometric measures could be found at the onset of the study, there was a significant correlation between improvement over the follow-up period and neurophysiology. A decline in the Hamilton Anxiety Scale (HAMA), which proved to be the best estimate for improvement, was associated with the relative magnitude of the positive slow wave elicited by somatic stimuli. Our findings support cognitive models of panic disorder, which stress that abnormal processing of bodily symptoms is relevant for the development and/or maintenance of the disorder.

A priori expectancy bias and its relation to shock experience and anxiety: a naturalistic study in patients with an automatic implantable cardioverter defibrillator.

Patients with an automatic implantable cardioverter defibrillator (AICD) may offer an unique naturalistic opportunity to study whether expectancy biases develop because of precipitating aversive or traumatic experiences and/or because of elevated anxiety. An expectancy bias and its associations with AICD discharge and anxiety was examined in 24 AICD patients with a thought experiment. While patients without AICD discharge exhibited no expectancy bias, patients with discharge experiences were found to expect that stimuli depicting medical emergency situations will be followed by an aversive consequence. The magnitude of their expectancy bias was positively correlated with their anxiety level. In the group with AICD discharge, patients with low anxiety levels exhibited no bias, while patients with high anxiety levels exhibited a rather strong bias. It seems that the experience of an aversive or traumatic event, here an AICD discharge, is a necessary (but not sufficient) precipitating event for the development of an expectancy bias. If such an event happens, trait anxiety level presumably determines if and how strong the expectancy bias will be.

Pursuit opposite to the vestibulo-ocular reflex (VOR) during sinusoidal stimulation in humans.

Pursuit opposite to a simultaneously activated vestibulo-ocular reflex (VOR) was tested during passive sinusoidal body oscillations (0.1-1.0 Hz, amplitudes 10-80 degrees) about the vertical axis in 4 healthy humans, while subjects were asked to pursue a small target moving in phase with the rotating chair with about half its amplitude relative to the head and 1.5 times its amplitude with respect to space. The decrease in gain of the pursuit opposite to the VOR occurred at lower stimulus frequency, stimulus velocity and stimulus acceleration than pure visual pursuit when gain was calculated in relation to target motion in head coordinates. It resembles that of pure pursuit when calculated in relation to target motion in space (earth coordinates, sum of the displacements of the mirror image and of the chair) thus taking the oppositely directed VOR into account. The data fit the assumption of a linear interaction of the VOR (in counterphase) and pursuit.

Fixation suppression of the vestibulo-ocular reflex (VOR) during sinusoidal stimulation in humans as related to the performance of the pursuit system.

Fixation suppression (FS) of the vestibulo-ocular reflex (VOR) was tested during passive sinusoidal body rotation with a frequency of 0.1 to 1.0 Hz and stimulus amplitudes ranging from 10 degrees to 240 degrees. To test whether FS can be explained by an internal pursuit signal opposite to the VOR, pursuit and the VOR under different instructional sets were studied. Both pursuit and FS decrease with increasing frequency and stimulus amplitude and seem to be limited by stimulus acceleration. Gains in FS calculated on the basis of the VOR during mental arithmetic correspond closely to the frequency and amplitude dependent pursuit gain, suggesting that an internal pursuit signal plays a major role in VOR suppression.

[Kleine-Levin syndrome. The provocation of manic symptoms by an antidepressant and a therapeutic trial of carbamazepine]. / Kleine-Levin-Syndrom. Provokation manischer Symptome durch ein Antidepressivum und Therapieversuch mit Carbamazepin.

A 17-year-old adolescent had a recurrent episode of somnolence and morbid hunger (Kleine-Levin syndrome) three years after a first attack, from which he had spontaneously recovered. He was treated with 50 mg daily of clomipramine for the somnolence accompanied by disturbance of attention and memory. Under this treatment he developed thymoleptic symptoms with polyphagia, logorrhea and hyperactivity. Placed on a trial dose of at first 600 mg, then 400 mg carbamazepine daily the abnormal findings disappeared within a few days, and there has been no recurrence after some months. It is postulated, based on the observations of this case, that the Kleine-Levin syndrome, presumably a functional hypothalamic disorder, is closely related to the endogenous psychoses.

No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone.

In a recent study we demonstrated that recombinant human growth hormone (r-hGH; Saizen) delayed tumor-induced cachexia in human tumor xenografts in vivo. Such a therapeutic effect could have a great impact in the supportive care of advanced cancer patients. Before large clinical studies are initiated possible growth stimulation should be excluded. This question was investigated in vitro in 20 human tumor models, which had been established in serial passage in nude mice. The effect of continuous exposure of r-hGH was investigated at dose levels ranging from 0.3 ng/ml up to 0.1 microg/ml in colorectal (n=2), gastric (n=1), non-small cell lung (n=4), small cell lung (n=1), mammary (n=3), ovarian (n=2), prostate (n=2) and renal cancers (n=2), and melanoma (n=3) using a modified Hamburger and Salmon clonogenic assay. The results show that there was neither tumor growth inhibition nor any evidence for tumor growth stimulation in any of the tumors studies. Therefore this preclinical study in 20 human tumor models indicated no direct risk for tumor growth enhancement.

[Self-reported substance abuse related emergencies: frequency and nature]. / Drogennotfälle: Häufigkeit und Umstände aus der Sicht der Betroffenen.

OBJECTIVE: The aim of this study was to estimate the frequency and nature of self-reported and drug-related emergencies. METHODS: 47 patients of a ward for opiate detoxification were interviewed about their experiences with drug-related emergencies. Typical categories had to be found like overdoses, seizures, accidents and suicide attempts respectively. RESULTS: 68% had own experience with drug-related emergency. A majority suffered opiate overdose with different extensions as unconsciousness or breath-depression. Alcohol and polydrug use was associated with overdose. Drug-related accidents were only reported by men. Half the number of drug-related emergencies were treated in hospital. Most emergencies occurred alone either in a home environment or outside. CONCLUSION: Harm reduction interventions like observed user rooms should be established. Furthermore other strategies to reduce the number of emergencies as sharing naloxon or resuscitation programs in wards for detoxification could also be an effective method to prevent near fatal or fatal overdoses in dependent subjects.

Targeted inhibition of tumor-cell growth by recombinant heregulin-toxin fusion proteins.

Fusion of functional domains of proteins by in vitro recombination of gene fragments can be used to generate novel anti-tumor agents. The combination of tumor-cell-recognition functions and toxic functions results in cytotoxic molecules with a high specificity for tumor cells. Human adenocarcinomas are frequently characterized by over-expression of members of the epidermal-growth-factor (EGF) receptor family (ErbB-1, 2, 3 and 4), when compared with normal cells. These tumors are particularly suited to treatment with recombinant toxins. The human heregulins (HRG) and their rat counterparts (neu differentiation factor, NDF) have been identified as ligands for these receptors. Two chimeric heregulin-toxin fusions consisting of the EGF-like receptor recognition domain of the heregulin isoforms HRG alpha and HRG beta I, and the domains II, Ib and III of the Pseudomonas exotoxin A (ETA) were constructed. HRG beta I-ETA is highly cytotoxic for the mammary carcinoma cell lines SK-BR-3 and MDA-MB-453. HRG alpha-ETA was less active than HRG beta I-ETA. The killing activity of the recombinant toxins correlated with the expression levels of ErbB-3 and/or ErbB-4 in the cell lines studied. High expression of ErbB-2 is not sufficient to confer sensitivity towards the HRG-ETA. Treatment of mice with 0.4 mg/kg/day of HRG beta I-ETA caused growth retardation of transplanted human breast tumor cells. Higher levels of HRG beta I-ETA administration resulted in acute hemorrhagic necrosis of the liver.

Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow.

Hepsulfam (1,7-heptanediol disulfamate, NSC 329680) is a new antineoplastic alkanesulfonate agent which has demonstrated a broader preclinical activity than busulfan. The compound is currently undergoing clinical trials. We have studied the activity of hepsulfam and busulfan simultaneously in human tumor xenografts in vitro in a clonogenic assay and in vivo in tumor-bearing animals in order to assess the activity of both compounds in model systems of slowly growing malignancies. In a total of 37 different tumors of various histologies, both agents demonstrated broad spectrum in vitro activity. The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively. At a concentration of 1.0 micrograms/ml, hepsulfam was active in eight of 37 tumors (22%) in the clonogenic assay, whereas busulfan effected inhibition of colony formation in one of 37 lines (3%). At the same concentration, however, hepsulfam demonstrated a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors, whereas busulfan did not reveal a myelosuppressive effect. Evaluation of equitoxic concentrations in vitro revealed a higher activity of hepsulfam, especially in non-small cell lung cancer. In tumor-bearing nude mice, the approximate LD10 dose was determined as 150 mg/kg single bolus injection given i.p. on day 1 for both compounds. Hepsulfam demonstrated superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)