Thomas Frieling

Cardiotoxicity of the antiproliferative compound fluorouracil.

The antimetabolite fluorouracil (5-FU) is frequently administered for chemotherapy of various malignant neoplasms. The drug is well known for its adverse effects involving bone marrow, skin, mucous membranes, intestinal tract and central nervous system, whereas its cardiotoxicity is less familiar to clinicians.The pathophysiology of fluorouracil-associated cardiac adverse events is controversial and conclusions are based on clinical studies and case reports more than on solid experimental evidence. While clinical and electrocardiographic features suggest myocardial ischaemia as a main aetiological factor, possibly induced by coronary vasospasm, histomorphological and biochemical studies indicate a more direct drug-mediated cytotoxic action. Estimates of the overall incidence of fluorouracil cardiotoxicity have varied widely from 1.2 to 18% of patients. Patients may present with angina-like chest pain, cardiac arrhythmias or myocardial infarction. There is no unequivocally effective prophylaxis or treatment in this syndrome. Once fluorouracil administration is discontinued symptoms are usually reversible, although fatal events have been described. The overall mortality rate has been estimated to be between 2.2 and 13.3%. There is a high risk of relapse when patients are re-exposed to this drug following previous cardiac incidents.From the present data it is concluded that cardiotoxicity is a relevant but underestimated problem in fluorouracil treatment. Since the mechanisms of fluorouracil-associated cardiotoxicity are not yet fully understood, all patients undergoing this chemotherapy have to be carefully evaluated and monitored for cardiac risk factors and complaints. After cardiotoxic events, fluorouracil should definitely be withdrawn and replaced by an alternative antiproliferative regimen.

Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract

Background and aims: Histamine is known as a regulator of gastrointestinal functions, such as gastric acid production, intestinal motility, and mucosal ion secretion. Most of this knowledge has been obtained from animal studies. In contrast, in humans, expression and distribution of histamine receptors (HR) within the human gastrointestinal tract are unclear. Methods: We analysed HR expression in human gastrointestinal tissue specimens by quantitative reverse transcription-polymerase chain reaction and immunostaining. Results: We found that H1R, H2R, and H4R mRNA were expressed throughout the gastrointestinal tract, while H3R mRNA was absent. No significant differences in the distribution of HR were found between different anatomical sites (duodenum, ileum, colon, sigma, and rectum). Immunostaining of neurones and nerve fibres revealed that H3R was absent in the human enteric nervous system; however, H1R and H2R were found on ganglion cells of the myenteric plexus. Epithelial cells also expressed H1R, H2R and, to some extent, H4R. Intestinal fibroblasts exclusively expressed H1R while the muscular layers of human intestine stained positive for both H1R and H2R. Immune cells expressed mRNA and protein for H1R, H2R, and low levels of H4R. Analysis of endoscopic biopsies from patients with food allergy and irritable bowel syndrome revealed significantly elevated H1R and H2R mRNA levels compared with controls. Conclusions: We have demonstrated that H1R, H2R and, to some extent, H4R, are expressed in the human gastrointestinal tract, while H3R is absent, and we found that HR expression was altered in patients with gastrointestinal diseases.

Time-trends in the epidemiology of peptic ulcer bleeding

Objective. Despite the introduction of effective medical treatment of peptic ulcer disease, bleeding is still a frequent complication. The aim of this study was to investigate whether the incidence and the risk profile of peptic ulcer haemorrhage have changed within a 10-year period. Material and methods. In a prospective epidemiological and observational study the incidence and risk profile of peptic ulcer haemorrhage in Düsseldorf, Germany were compared between two time periods (period A: 1.3.89–28.2.90 and period B: 1.4.99–31.3.2000), involving nine hospitals with both surgical and medical departments. Patients with proven peptic ulcer haemorrhage at endoscopy or operation were included in the study; those with bleeding under defined severe stress conditions were excluded. Results. No differences in bleeding ulcer incidence were observed between periods A and B (51.4 per 100,000 person-years versus 48.7), or for duodenal ulcer (24.9 versus 25.7) or for gastric ulcer bleeding (26.5 versus 23.0). A marked increase in incidence rates was observed with increasing age. In period B, patients with bleeding ulcers were older (56% versus 41% 70 years or older), were usually taking non-steroidal anti-inflammatory drugs (NSAIDs) (45% versus 27%) and were less likely to have a history of ulcer (25% versus 59%) compared with patients in period A. Conclusions. The persisting high incidence of peptic ulcer disease is a superimposing of two trends: a higher incidence in the growing population of elderly patient with a higher intake of NSAIDs and a lower incidence among younger patients due to a decrease in incidence and improved medical treatment.

Different cortical organization of visceral and somatic sensation in humans.

Sensory stimuli from the visceral domain exhibit perceptual characteristics different from stimuli applied to the body surface. Compared with somatosensation there is not much known about the cortical projection and functional organization of visceral sensation in humans. In this study, we determined the cortical areas activated by non‐painful electrical stimulation of visceral afferents in the distal oesophagus, and somatosensory afferents in the median nerve and the lip in seven healthy volunteers using whole‐head magnetoencephalography. Stimulation of somatosensory afferents elicited short‐latency responses (≈ 20–60 ms) in the primary somatosensory cortex (SI) contralateral (median nerve) or bilateral (lip) to the stimulated side, and long‐latency responses (≈ 60–160 ms) bilaterally in the second somatosensory cortex (SII). In contrast, stimulation of visceral oesophageal afferents did not evoke discernible responses in SI but well reproducible bilateral SII responses (≈ 70–190 ms) in close vicinity to long‐latency SII responses following median nerve and lip stimuli. Psychophysically, temporal discrimination of successive stimuli became worse with increasing stimulus repetition rates (0.25 Hz, 0.5 Hz, 1 Hz, 2 Hz) only for visceral oesophageal, but not for somatosensory median nerve stimuli. Correspondingly, amplitudes of the first cortical response to oesophageal stimulation emerging in the SII cortex declined with increasing stimulus repetition rates whereas the earliest cortical response elicited by median nerve stimuli (20 ms SI response) remained unaffected by the stimulus frequency. Our results indicate that visceral afferents from the oesophagus primarily project to the SII cortex and, unlike somatosensory afferents, lack a significant SI representation. We propose that this cortical projection pattern forms the neurophysiological basis of the low temporal and spatial resolution of conscious visceral sensation.

Cerebral responses evoked by electrical stimulation of the esophagus in normal subjects.

Cerebral responses to electrical stimulation of the esophagus were investigated in 11 healthy male volunteers, 20-40 yr old. The stimulus was applied via a probe equipped with bipolar ring electrodes. It was positioned in the middle and distal esophagus at 20 and 37 cm from the incisors, respectively, and sucked to the mucosa. Electrical stimuli (0.1-ms duration, different stimulus voltages) were applied at frequencies of 0.1-1.0 Hz or in randomized order. Cerebral responses to electrical stimulation were recorded after 20-40 stimulations and averaged on a time base of 1000 ms. Evoked potentials consisted of successive peaks and troughs in the averaged electroencephalogram with good reproducibility within and between subjects. Amplitudes of evoked potentials showed a significant reduction with electrical stimulation at 37 cm compared with 20 cm, and with stimulation frequencies of 0.5 and 1.0 Hz compared with 0.2 and 0.1 Hz. Evoked potentials from 37 cm showed longer latencies compared with those from 20 cm. Irregular stimulation and stimulation during mental distraction did not alter these responses. It is concluded that reproducible evoked potentials can be recorded from the scalp after electrical stimulation of the esophagus and that these are transferred centrally via vagal afferents. The technique may become a useful tool in the study of visceral nervous connections to the brain in health and disease.

Comparison between intraluminal multiple electric impedance measurement and manometry in the human oesophagus.

Abstract Conventional oesophageal manometry and intraluminal electrical impedance measurement were simultaneously applied in eight healthy volunteers to study the effect of wet and semisolid bolus viscosities on oesophageal motility and bolus transit. Contraction front velocity measured by electrical impedance and manometry were identical for wet and semisolid swallows and highly associated. Bolus front velocity as measured by electrical impedance was significantly faster than contraction front velocity in both wet and semisolid swallows. Bolus front velocity during semisolid swallows was significantly slower compared to wet swallows. It is concluded that intraluminal electrical impedance measurement is a reliable technique to detect oesophageal motility as well as to differentiate between transit of wet and semisolid bolus consistencies.

Neural components of distension-evoked secretory responses in the guinea-pig distal colon

1 Using a Ussing chamber and neuronal retrograde tracing with 1,1′‐didodecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate (DiI) we characterized the afferent and efferent neuronal pathways which mediated distension‐evoked secretion in the guinea‐pig distal colon. 2 Acute capsaicin application (10 μm) to the serosal site of the Ussing chamber evoked a secretory response which was blocked by tetrodotoxin (1 μm), the combined application of the NK1 and NK3 receptor antagonists CP‐99,994–1 and SR 142801 (1 μm), and by combined application of atropine (10 μm) and the VIP receptor antagonist VIP(6–28) (10 μm). Functional desensitization of extrinsic primary afferents by long‐term application of capsaicin significantly diminished distension‐evoked secretion by 46 %. 3 After functional desensitization by capsaicin, serosal application of gadolinium (100 μm) inhibited the distension‐evoked chloride secretion by 54 %; the L‐type Ca2+ channel blocker nifedipine (1 μm) and the 5‐HT1P receptor antagonist renzapride (1 μm) had no effect. The combination of atropine and VIP(6–28) or the combination of NK1 and NK3 receptor antagonists almost abolished distension‐evoked secretion. 4 The secretory response evoked by electrical field stimulation, carbachol (1 μm) or VIP (1 μm) was not attenuated by gadolinium. Field stimulation‐evoked chloride secretion was not affected by blockade of NK1 and NK3 receptors. 5 Twelve per cent of DiI‐labelled submucosal neurones with projections to the mucosa were immunoreactive for choline acetyltransferase, substance P and calbindin and very probably represented intrinsic primary afferent neurones. 6 Distension‐evoked chloride secretion was mediated by capsaicin‐sensitive extrinsic primary afferents and by stretch‐sensitive intrinsic primary afferent neurones. Both the extrinsic and intrinsic afferents converge on common efferent pathways. These pathways consist of VIPergic and cholinergic secretomotor neurones that are activated via NK1 and NK3 receptors.

Cerebral Responses Evoked by Electrical Stimulation of Rectosigmoid in Normal Subjects

We used electroencephalographic methods to evoke and record cerebral responses to electrical stimulation of the rectosigmoid colon in eight healthy male volunteers, 20–40 years old. The stimulus was applied via a probe equipped with bipolar ring electrodes which were attached by suction to the mucosa. The probe was positioned 20 cm above the anus. Cerebral responses were recorded by EEG electrodes. Evoked potentials (EPs) in response to electrical stimulation consisted of a series of successive peaks and troughs in the EEG with good reproducibility within and between subjects. The shape and latencies of the intestinal EPs were comparable to other types of EPs reported before. It is concluded that reproducible EPs can be recorded from the scalp after electrical stimulation of the rectosigmoid. The similarity in appearance of these EPs to those previously reported suggests that visceral afferents were stimulated. The technique may become a useful tool to study visceral nervous connections to the brain in health and disease.

Association between duplex Doppler sonographic flow pattern in right hepatic vein and various liver diseases

The aim of this study was to evaluate the association between the Doppler sonographic waveforms in the right hepatic vein and various liver diseases.

Characterization and natural course of cardiac autonomic nervous dysfunction in HIV-infected patients.

Objective:To examine the degree, pattern, and natural history of cardiac autonomic nervous dysfunction in patients infected with HIV. Design:Cross-sectional and prospective longitudinal cohort study. Setting:Primary care and tertiary referral university centre. Participants:Thirty-five consecutive HIV-infected patients who had either not yet developed AIDS (15 pre-AIDS patients) or who were at the Centers for Disease Control and Prevention (CDC) AIDS stage (n = 20), and 29 healthy age- and sex- matched HIV-negative controls. Methods:Computer-aided power spectral analysis of 15 standardized parameters of heart-rate variability (HRV). Results:Pre-AIDS patients as a group did not exhibit any HRV parameters to be significantly different from healthy controls (P > 0.017), whereas AIDS patients demonstrated reduced HRV in 14 parameters (93.3%) compared with healthy subjects (P < 0.017). Median proportion of abnormal HRV parameters (< 10th percentile of controls) per individual was 9.1% in pre-AIDS patients and 61.3% in AIDS patients (P= 0.0347). Progressive CDC stages inversely correlated to 10 HRV parameters (66.7%; −0.50 ≤ r ≤ −0.36; P< 0.05). Follow-up testing in 10 pre-AIDS and six AIDS patients after 6–16 months (median, 12.5 months) did not reveal deterioration of HRV (P< 0.05). A dysautonomia symptom score correlated to 10 HRV parameters (66.7%; −0.14<r< −0.55; P< 0.05). Conclusions:Cardiac autonomic nervous dysfunction is severe in AIDS patients, although not significant in pre-AIDS patients. Cardiac autonomic nervous dysfunction proceeds with HIV disease progression, although its individual course is slow.