Human evoked potentials to long duration vibratory stimuli: role of muscle afferents

The aim of this study was to evaluate the reproducibility of the circadian blood pressure (BP) change in normal healthy volunteers. The subjects were 32 healthy, young, normotensive volunteers who underwent 24 h ambulatory BP monitoring on two occasions, at least 4 weeks apart. Data were analysed using standard definitions of day and night (i.e. 07.00-22.00 for daytime and 22.00-07.00 for night time), event diaries to identify individual's day and night time and a time independent method (cusum analysis). Intraindividual variations of BP were assessed using the coefficient of variation (CV). The mean 24 h BP was very reproducible with a CV of 4.7%. Using the fixed definition of day and night, mean night time systolic blood pressure (SBP) was significantly reduced on the second visit compared to the first (P < 0.001). Using fixed times for day and night, day-night difference was poorly reproducible, with a CV of 52% for SBP and 59% for diastolic blood pressure (DBP), however this improved using diary based day-night to 40/41% and cusum analysis to 24.6/28.1%. We recommend that circadian BP changes are studied using individual definitions of day and night or time independent methods such as cusum analysis.     

Sir Harold Gillies Memorial Lecture. Aesthetic plastic surgery and the future plastic surgeon

Tissue factor pathway inhibitor (TFPI) is known to inhibit the initial reaction in the tissue factor-mediated coagulation pathway. We measured plasma free-form TFPI antigen levels and monitored 24-h Holter recordings at 06.00, 14.00 and 22.00 h in 15 patients with coronary spastic angina, 13 patients with stable exertional angina, and 11 control subjects. There was a significant circadian variation in plasma free-form TFPI antigen levels in patients with coronary spastic angina (25.8+/-2.0 ng/ml at 06.00 h, 21.1+/-1.6 ng/ml at 14.00 h, and 20.2+/-1.4 ng/ml at 22.00 h; p<0.01). Furthermore, free-form TFPI antigen levels at 06.00 h were significantly higher in coronary spastic angina patients than in patients with stable exertional angina or control subjects (p<0.01). Free-form TFPI antigen levels increased after the ischemic attacks in coronary spastic angina (p<0.01). This circadian variation correlated with the frequency of attacks, with the peak level occurring between midnight to early morning in patients with coronary spastic angina.     

Dynamic phenotypic restructuring of the CD4 and CD8 T-cell subsets with age in healthy humans: a compartmental model analysis

The incidence of ulcer perforation in 1480 patients treated in the Bergen area of Norway between 1935 and 1990 was analyzed for daily (circadian), weekly (circaseptan), and yearly (circannual) time effects. A circadian rhythm was found overall that was reproducible and fairly stable across seasons, decades, and days of the week. After subgrouping, a circadian rhythm was found in younger patients, males, and duodenal perforations, while a 12 h (circasemidian) rhythm characterized ulcer perforation for women and for gastric ulcers. Duodenal perforations showed highest incidence in the afternoon, while gastric perforations showed a major peak around noon and a secondary peak near midnight. For duodenal ulcer perforation, the circannual pattern was characterized by a 6-month rhythm, with significantly higher incidence in May-June-July and in November-December in most subgroups. A circaseptan rhythm was not found, but there was a significantly higher incidence on Thursday-Friday as compared to Sunday-Monday. The pathophysiological mechanisms underlying the perforation of an ulcer thus seemed to show pronounced circadian and 6-month rhythmic variations, much less so circaseptan or circannual rhythms. While it is likely that exogenous environmental and/or societal factors play a significant role, variations in ulcer perforation may be related to endogenous biological rhythms in pathophysiological factors since the circadian pattern of duodenal perforation follows that for gastric acidity. Knowledge of the temporal patterns in peptic ulcer perforation and associated pathophysiologic factors should prove useful in optimizing the chronotherapeutic management of ulcer disease.     

Anemia increases gastric blood flow in noncirrhotic and cirrhotic patients

BACKGROUND: Previous studies in rats have demonstrated that anemia induces a significant increment in gastric mucosal blood flow. In the present study, we investigated whether chronic anemia induces similar changes in gastric blood perfusion in humans, and if this effect is also present in cirrhotic patients in whom gastric blood flow is usually increased in basal conditions. METHODS: Gastric mucosal blood perfusion was assessed by means of laser-Doppler flowmetry and reflectance spectrophotometry applied through the endoscope. RESULTS: Anemia significantly increases laser-Doppler signal in cirrhotic (2.3 +/- 0.11 vs 2.9 +/- 0.22 volts, p < 0.05) and noncirrhotic patients (1.71 +/- 0.15 vs 2.24 +/- 0.17, p < 0.05). In anemic patients the index of hemoglobin concentration of the gastric mucosa, assessed by reflectance spectrophotometry, was significantly decreased in cirrhotic patients (107.6 +/- 4.7 vs 95.5 +/- 3.3, p < 0.05) and noncirrhotic patients (93.9 +/- 4.1 vs 76.1 +/- 4.2, p < 0.01), whereas the index of oxygen saturation was increased (36.7 +/- 0.7 vs 40.4 +/- 1.4, p = 0.05; and 36.4 +/- 1.1 vs 43.2 +/- 1.9, p < 0.01, respectively). CONCLUSIONS: In conclusion, chronic anemia is associated with an enhanced gastric blood perfusion reflected by an increased laser-doppler signal and gastric mucosal oxygen index despite a decrease in gastric hemoglobin concentration. In cirrhotic patients, anemia promotes a further increment in its basal gastric hyperemia.     

Fatal shoulder dystocia: a review of 56 cases reported to the Confidential Enquiry into Stillbirths and Deaths in Infancy

BACKGROUND: Helicobacter pylori may interfere with gastroduodenal protective mechanisms. Such effects could be due to a direct interaction with gastric epithelial cells but also to the action of a wide range of secreted and membrane-bound virulence factors. Our aim was to study the acute effects of water extracts produced from H. pylori on gastric mucosal blood flow and acid secretion and to relate them to VacA and CagA activity. METHOD: Extracts were produced from strains 88-23 and A5, both wild type; A5VacA, an isogenic mutant lacking expression of the vacuolating cytotoxin (VacA) and the immunodominant antigen (CagA); and Escherichia coli strain ATCC-25922. Bacterial extracts were applied on the exteriorized gastric corporal mucosa in inactin-anaesthetized rats after removal of as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured by means of laser-Doppler flowmetry. RESULTS: All H. pylori extracts, including the extract from 88-23 heated to 100 degrees C for 30 min, significantly reduced blood flow by 15%-19%, whereas E. coli had no significant effect on blood flow. CONCLUSION: A factor or a combination of factors, other than VacA and CagA released from H. pylori, might compromise the natural defence of the gastric corporal mucosa by reducing mucosal blood flow. The factor is heat-stable and lacking or less potent in E. coli.     

Occurrence of onchocerciasis in subjects coming from non-endemic areas and migrating to a hyperendemic area

The diurnal change in baseline fetal heart rate (FHR) of four anencephalic fetuses at 20, 23, 24 and 30 weeks of gestation were examined. The mean baseline FHR in 00.00-06.00 h, 06.00-12.00 h, 12.00-18.00 h and 18.00-24.00 h were compared by one-factor ANOVA and Scheffe's test in each case. The diurnal variations in baseline FHR were recognized in all subjects (P < 0.01). In 3/4 subjects, the lowest values were at 00.00-06.00 h. The diurnal variation in baseline FHR might be caused by maternal factors because it was present even in the anencephalic fetuses that had no central nervous system having the oscillators of the circadian rhythm.     

Pharmacokinetics of a single dose of phenylpropanolamine following oral administration at two different times of the day

Pharmacokinetics of a single oral dose of phenylpropanolamine (CAS 154-41-6) was investigated by administering 50 mg of the drug at 10.00 and 22.00 h to 8 healthy male volunteers in a crossover design with a wash-out period of 10 days. Serum samples were analysed for phenylpropanolamine using high performance liquid chromatography. Pharmacokinetic parameters were calculated using model independent method. A significant (p < 0.05) elevation in Cmax (227.45 versus 181.98 micrograms/l) was observed following the drug administration at 22.00 h as compared to 10.00 h. These variations may be due to circadian changes in gastric pH contributing to the time dependent changes in the absorption of the drug.     

Circadian gastric acidity in Helicobacter pylori positive ulcer patients with and without gastric metaplasia in the duodenum

BACKGROUND: The presence of gastric metaplasia allows helicobacter pylori to colonise the duodenum and this condition is thought to be acquired as a response to acid hypersecretion. This functional disorder, however, is present only in a subgroup of duodenal ulcer patients and, in addition, surface gastric metaplasia has been frequently found in the proximal duodenum of normal subjects and patients with non-ulcer dyspepsia, who cannot be certainly considered as acid hypersecretors. AIMS: To clarify the role of acid in inducing gastric type epithelium in the duodenum. This study aimed at assessing whether the pattern of circadian gastric acidity differs between H pylori positive duodenal ulcer patients with and without duodenal gastric metaplasia. PATIENTS: Seventy one patients with duodenal ulcer confirmed by endoscopy and who were found to be positive for H pylori infection by histology on antrum biopsy specimens were enrolled into this study. METHODS: Gastric type epithelium in the duodenum was found in 49 of 71 ulcer patients (69%). Continuous 24 hour gastric pH metry was performed in 50 healthy subjects and in the two subgroups of duodenal ulcer patients with and without gastric metaplasia in the duodenum. Gastric acidity was calculated for 24 hours (1700-1659), night (2000-0759) and day-time (0800-1959). RESULTS: Ulcer patients without gastric metaplasia showed a significantly higher gastric acidity (p < 0.001) than controls for every time interval considered, while the ulcer subgroup with gastric metaplasia was more acid than healthy subjects (p < 0.001) during the whole 24 hour period and the daytime. There was no difference between the two subgroups of duodenal ulcer patients with and without gastric metaplasia during the various time segments analysed. CONCLUSION: The findings confirm that the circadian gastric acidity of duodenal ulcer patients is higher than that of controls. As there is no difference in gastric pH between duodenal ulcer patients with and without gastric metaplasia, gastric hyperacidity is not specific to patients with duodenal gastric metaplasia. It is probable that this histological change is a non-specific response to mucosal injury resulting from various factors and not exclusively to acid.     

Circadian reactivity rhythm of rat gastric mucosa to restraint-cold stress and indomethacin: temporal variation in the protective effect of iloprost

In this study, the time-dependent ulcerogenic effects of restraint-cold stress and indomethacin on the gastric mucosa and the temporal variation in the protective effect of iloprost, a synthetic stable analog of prostacyclin, were investigated in rats synchronized to 12h light and 12h darkness, lights on at 08:00. The severity of gastric ulceration produced by either stress or indomethacin showed marked circadian variation; it was greatest at 11 HALO (hours after lights on) for restraint-cold stress and at 23 HALO for indomethacin. The severity of the induced ulcerogenesis was least at 7 HALO for both stimuli. The protective effect of iloprost against restraint-cold stress was most prominent at 15 HALO and 19 HALO with an approximately 80% protection score. On the other hand, pretreatment with iloprost reduced the indomethacin-induced mucosal injury only at 23 HALO. The circadian variation in the effect of iloprost and in the rhythmic modalities of these two experimental ulcer models are indicative of differences in their underlying mechanisms. In experimental models of ulceration, the circadian time of application of the ulcerogenic stimulus must be considered as an important experimental factor. Moreover, the protective effectiveness of antiulcer drugs can express time-dependent differences and must also be taken into account in investigative research.     

Effects of sodium pentobarbitone on serum gonadotrophin levels and on the incorporation of 35S from methionine into protein in the brain and anterior pituitary during the oestrous cycle of the rat

Ovulation was delayed for 24 h after the administration of sodium pentobarbitone (Nembutal, 35 mg/kg body weight) at 14.00 h, before the critical period on the afternoon of pro-oestrus. The expected preovulatory surge of serum LH at 18.00 h of pro-oestrus was also delayed until 21.00 h on the following day; however, increased levels (less than 12 ng/ml) were observed in 14 out of 23 animals (killed by decapitation) at 21.00 h on the day of Nembutal administration. The serum FSH rise observed on the morning of expected oestrus was extended after Nembutal treatment, and a further rise was noted 24 h later. Peak levels of incorporation of 35S from methionine into protein of the median eminence area (ME) and of the anterior pituitary (AP) which normally occur about the time of the preovulatory LH surge, were also delayed until 21.00 h on the day following Nembutal administration. Neither ovulation nor the preovulatory gonadotropin rises with their accompanying changes in incorporation in the ME and the AP, were altered by Nembutal administered after the pro-oestrous critical period. Thus Nembutal, while blocking ovulation, inhibits the circadian rhythm of incorporation of 35S from methionine in the brain as well as the peaks of incorporation in the median eminence and the anterior pituitary which accompany the normal preovulatory surges of gonadotrophin.     

Role of circadian rhythmicity in the heart rate variability preceding non-sustained ventricular tachycardia

The difference in sympathovagal activity preceding non-sustained ventricular tachycardia (NSVT) was examined between patients with and without a circadian rhythm. Thirty-three patients' Holter monitoring data (41 NSVT episodes) were analyzed regarding the frequency domain measures (low-frequency component [LF: 0.04-0.15 Hz], high-frequency component [HF: 0.15-0.4 Hz], and the ratio of LF to HF [LF/HF]) for each 15-min average from 120 min before each episode of NSVT. The presence of a circadian rhythm was accepted when the rhythm adaptation was significant by cosinor analysis and the acrophase was located at night (22.00-06.00h) in HF (HF-positive group, n=17), and during the daytime (10.00-20.00h) in LF/HF (LF/HF-positive group, n=12). The negative groups were identified by the absence of a circadian rhythm (HF-negative group, n=16; LF/HF-negative group, n=21). The serial changes in the HF power before NSVT were significantly different between the HF-positive and -negative groups (p<0.05). The HF increased from 75-60 min before NSVT in the HF-positive group, whereas the HF decreased from 60-45 min in the HF-negative group. The serial changes in the LF/HF ratio were not significantly different between the LF/HF-positive and -negative groups. Thus, the circadian rhythmicity of vagal activity seems to have an important role in the genesis of NSVT.     

Gastric mucosal blood flow response to stress in streptozotocin diabetic rats: regulatory role of nitric oxide

To investigate cytoprotection against mucosal injuries of the stomach in patients with diabetes, we investigated gastric mucosal blood flow (GMBF), its response to a burn stress, and the involvement of nitric oxide (NO) in streptozotocin (STZ) diabetic rats. GMBF was measured by laser-Doppler velocimetry (LDV) and by the hydrogen gas clearance technique (HGC). The steady-state GMBF of STZ rats decreased according to the duration of diabetes, and insulin treatment blocked this decrease. Burn stress caused a rapid decrease in the GMBF. Reduction of the GMBF and gastric mucosal leakage of Evans blue (EB) after the burn stress were greater in the STZ rats than in the controls, but insulin treatment completely blocked this increase in EB leakage in the STZ rats. There was a significant negative correlation between the percent GMBF 3 h after the burn stress and EB leakage at the same time point. In the controls and the insulin-treated STZ rats, N-nitro-L-arginine (L-NNA), an NO synthase inhibitor, enhanced the decrease in postburn GMBF and EB leakage, but was without effect in the STZ rats. These results suggest that NO may be involved in the regulation of GMBF, and that persistent hyperglycemia may impair this regulation. These findings suggest that patients with diabetes have reduced cytoprotection against a variety of gastric mucosal injuries.     

Involvement of free radicals and histamine in the potentiating action of cigarette smoke exposure on ethanol-induced gastric mucosal damage in rats

Cigarette smoking has been associated with peptic ulcer diseases. We studied the effects of cigarette smoke exposure on ethanol-induced gastric mucosal damage and its relationship with vascular integrity and the possible role of free radicals and histamine. Male Sprague-Dawley rats were exposed to cigarette smoke followed by ethanol administration (70% v/v). Smoke exposure alone dose-dependently reduced basal blood flow and increased xanthine oxidase (XO) activity but superoxide dismutase (SOD) activity remained unaffected in gastric mucosa. Cigarette smoking followed by ethanol administration significantly potentiated mucosal lesion formation along with augmentation of the mucosal blood flow, vascular permeability and myeloperoxidase (MPO) activity. The potentiating effect of smoking on ethanol-induced gastric mucosal lesion and MPO activity was abolished by pretreatment with allopurinol, terfenadine or ranitidine. Terfenadine and ranitidine also reduced the increased mucosal blood flow and vascular permeability induced by smoking and ethanol combined. These findings suggested that cigarette smoke adversely affected the defense mechanisms of the gastric mucosa by reducing the mucosal blood flow which in turn led to ischemia and increased XO activity. Activation of XO together with histamine H1 and H2 receptors stimulation could lead to neutrophil aggregation and vascular damage. However, the potentiating action of cigarette smoke on ethanol ulceration is unlikely through reduction of SOD activity in gastric mucosa.     

Gastric mucosal EGF and PDGF receptor expression with ulcer healing by ebrotidine

OBJECTIVES: Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) play important roles in the process of mucosal repair and restitution, and their biological effects are mediated by receptors located on the target cell surfaces. The purpose of this study was to assess the effect of the antiulcer agent, ebrotidine, on the expression of EGF and PDGF receptors with chronic ulcer healing. METHODS: Chronic gastric ulcers were developed in the rat by acetic acid technique. The animal were divided into two groups and were treated twice daily for 14 consecutive days, either with ebrotidine at 100 mg/kg, or placebo. At different stages of treatment, the animals were sacrificed and used for the isolation and quantification of gastric mucosal EGF and PDGF receptors. RESULTS: The binding assays revealed that ulcer healing was accompanied by an increase in mucosal expression of both types of receptors. A 1.7-1.8-fold increase in PDGF and EGF receptors occurred by the 4th day after the development of ulcer and reached a maximum of 3-fold increase by the 14th day, when the ulcer was essentially healed. Treatment with ebrotidine caused accelerated ulcer healing (7 days) which was accompanied by a significant enhancement in receptor expression. Compared to the controls, a 1.5-fold increase in EGF and 1.7-fold increase in PDGF receptor expression occurred by the 7th day of ebrotidine treatment, and a 1.4- to 1.5-fold increase was still observed at the 14th day of treatment. CONCLUSIONS: The results suggest that ebrotidine is capable of enhancement of gastric mucosal proliferative activities associated with ulcer healing through the stimulation of EGF and PDGF receptor expression.     

Influence of Helicobacter pylori on gastric mucosal adaptation to naproxen in man

Our objective was to determine whether H. pylori influences gastric mucosal injury and adaptation caused by naproxen. Twenty-four healthy volunteers, 12 H. pylori-positive and 12 H. pylori-negative, were given a 28-day course of naproxen 500 mg twice a day. They were each gastroscoped to assess gastric mucosal damage and mucosal blood flow before and at 1, 7, and 28 days during treatment. Maximal gastric mucosal damage (median grade + IQR) occurred during the first 24 hr in both groups and was of similar magnitude (H. pylori-positive: 2.5, 2.0-3.0 P < 0.01; H. pylori-negative: 2.0, 1.0-3.0 P < 0.01). This damage was associated with a fall in antral but not corpus mucosal blood flow. With continued NSAID administration, gastric damage resolved confirming adaptation (H. pylori-positive 1.0, 0-2.0, H. pylori-negative: 1.0, 0-1.0) and antral mucosal blood flow returned to baseline in both groups by day 28. These observations suggest that initial gastric mucosal injury is not influenced by H. pylori colonization and adaptation occurs regardless of its presence.     

Chronic nicotine intake causes vascular dysregulation in the rat gastric mucosa

Chronic cigarette smoking has adverse effects on peptic ulcer disease because the healing of ulcers is delayed and the incidence of relapses is enhanced. Short term intake of nicotine induces vascular damage in the rat gastric mucosa, but the pathophysiological mechanisms of nicotine's action in the stomach are largely unknown. In this study rats were treated with nicotine, added to their drinking water, for 50 days. They were then anaesthetised and their stomachs perfused with acidified acetylsalicylic acid (ASA). Chronic nicotine treatment failed to change the effects of acidified ASA to induce gastric mucosal acid back diffusion, haemorrhagic damage and bleeding. Basal blood flow in the gastric mucosa was also unchanged by chronic nicotine intake, whereas the mucosal hyperaemia evoked by ASA induced acid back diffusion was averted. The concentrations of sulfidoleukotrienes were significantly augmented in the gastric wall of nicotine treated rats. These data show that chronic nicotine intake causes dysregulation of the gastric microcirculation, an effect that is associated with biochemical changes in the stomach. This study thus substantiates the adverse effects of smoking on gastric mucosal pathophysiology. These data suggest that inappropriate regulation of gastric mucosal blood flow inhibits recovery from gastric mucosal injury in smokers.     

Modulation of cisplatin chronotoxicity related to reduced glutathione in mice

Intracellular reduced glutathione (GSH) concentrations were measured according to the tissue sampling-time along the 24 h scale in male B6D2F1 mice. A significant circadian rhythm in GSH content was statistically validated in liver, jejunum, colon and bone-marrow (P < or = 0.02) but not in kidney. Tissue GSH concentration increased in the dark-activity span and decreased in the light-rest span of mice. The minimum and maximum of tissue GSH content corresponded respectively to the maximum and minimum of cisplatin (CDDP) toxicity. The role of GSH rhythms with regard to CDDP toxicity was investigated, using a specific inhibitor of GSH biosynthesis, buthionine sulfoximine (BSO). Its effects were assessed on both tissue GSH levels and CDDP toxicity at three circadian times. BSO resulted in a 10-fold decrease of the 24 h-mean GSH in kidney. However a moderate GSH decrease characterized liver (-23%) and jejunum (-30%). BSO pretreatment largely enhanced CDDP toxicity which varied according to a circadian rhythm. Although BSO partly and/or totally abolished the tissue GSH rhythms, it did not modify those in CDDP toxicity. We conclude that GSH have an important influence on CDDP toxicity but not in the circadian mechanism of such platinum chronotoxicity.     

Circadian and ultradian rhythms of drinking behavior of albino rats maintained in constant darkness

The objective of the present study was to investigate the circadian and the ultradian rhythms of drinking behavior in Wistar rats maintained under conditions of constant darkness. Six mature male rats (weighing 270-350 g) were exposed to light-dark 12:12-h cycles (LD 12:12, light on at 12:00 h) for 35 days and then switched to constant darkness (DD) conditions for at least 2 weeks. Drinking behavior was monitored continuously with a standard drinkometer circuit and the data was stored in 5-min bins. A modification of Enright's periodogram technique was used to evaluate the free-running drinking behavior circadian rhythm. Ultradian rhythms in drinking behavior were estimated by the Fast Fourier Transform (FFT) technique. Two of the animals (rats 4 and 6) showed no statistically significant circadian or ultradian rhythms and the other four showed free-running drinking circadian rhythm behavior shorter than 24 h (ranging from 23.333 to 23.967 h). Ultradian rhythms of drinking behavior of 12- and 8-h periods were detected in 4 (rats 1, 2, 3 and 5) and 2 (rats 1 and 5) animals, respectively. The relation of the compound structure of the circadian and ultradian rhythms is discussed demonstrating that drinking behavior is a good marker for studies of physiology of temporal organization.     

Neurophysiological evaluation with multimodality evoked potentials in craniostenosis and craniofacial stenosis

OBJECTIVE: To observe the changes of gastric mucosal hemodynamics and discuss the possible regulatory factors of prehepatic portal hypertensive rat. METHOD: Prehepatic portal hypertensive (PHT) rat model was produced by various degree of portal vein constriction, and gastric mucosal hemodynamics was measured by radioactive microsphere technique. Statistical analysis was performed by ANOVA, the student t test, and linear correlation. RESULT: The gastric mucosal blood flow was significantly reduced in PHT rats, whereas the blood flow in submucosa, muscular layer prominently increased. The resistance of mucosal vasculature was elevated in PHT rats, however, that of submucosa and muscular layer was decreased remarkably. There was a negative correlation between the gastric mucosal blood flow and portal pressure. CONCLUSION: The gastric mucosa of prehepatic portal hypertensive rat model is poorly perfused prominently. It may be due to the increased mucosal vascular resistance and elevated portal pressure.