Rectal sensorimotor dysfunction in women with fecal incontinence

The rate and pattern of rectal distension affect rectal distensibility, perception, and anal relaxation in health. Because rectal urgency is a prominent symptom in fecal incontinence (FI), we assessed rectal distensibility, contractions, perception, and anal pressures during rectal distention in 21 healthy, asymptomatic women (age 61 +/- 2 yr, mean +/- SE) and 51 women with FI (60 +/- 2 yr). Rectal staircases (0-32 mmHg, 4-mm steps) and ramp distensions [0-200 ml at 25, 50, and 100 ml/min with a phase of sustained distension (SD), lasting 1 min, between inflation and deflation]. The rectum was stiffer during rapid than slow ramp distention. This effect was more prominent at a lower volume (50 ml) and was also more pronounced in older subjects and in FI. A rectal contractile response was observed not only during inflation but also during SD and during deflation. During inflation, this contractile response was rate dependent in controls but not in FI. During staircase but not ramp distentions, the threshold for the desire to defecate was lower in FI. During ramp distentions, the duration of perception was significantly longer in FI. The rate of distention did not affect rectal perception (i.e., sensory thresholds or duration of perception) during ramp distentions. Baseline anal pressures and the magnitude of anal relaxation during rectal distention were also reduced in FI. In addition to reduced rectal capacity and compliance, women with FI had an exaggerated rate-dependent reduction in rectal distensibility, lower sensory thresholds, and more prolonged perception, indicative of rectoanal dysfunctions.     

慢性应激致肠易激综合征大鼠模型的建立与评价

目的建立一种模拟肠易激综合征临床症状的动物模型,为相关药物的研究提供实验基础。方法采用孤养附加慢性不可预见性刺激建立IBS模型,每只大鼠受到的刺激因子包括:24h禁水、24h禁食、昼夜颠倒、4℃冰水游泳15min、45℃高温5min、钳尾致痛1min、束缚制动5～8h、高速震荡15min等共8种,每种刺激因子出现5次,共40d。用腹部回撤反射压力阈值(AWR)和排便粒数检测动物的内脏感觉和胃肠运动功能变化;用敞箱行为评分和蔗糖水偏嗜度评价动物神经精神活动变化。结果造模2～3周腹部回撤反射压力阈值明显降低,排便粒数明显增加;造模3～4周模型组动物敞箱实验行为评分和蔗糖水偏嗜度明显降低。造模40d时,上述变化趋势仍存在。结论慢性应激加孤养可诱导动物胃肠运动亢进、内脏感觉致敏和神经精神活动的改变,模拟IBS患者的临床特征,可作为一种有效的IBS动物模型,用于评价相关药物。     

Diminished mechanosensitivity and chemosensitivity in patients with achalasia

The pathogenesis of achalasia involves the degeneration of enteric and autonomic nervous systems with resultant effects on esophageal motility. The neural degeneration could affect visceral sensation in achalasia. The aim of this study was to examine mechanosensitivity and chemosensitivity in patients with achalasia. Perceptual responses to esophageal distension and acid perfusion were assessed in nine achalasia patients and nine healthy subjects. Mechanosensitivity was evaluated using a barostat with a double-random staircase distension protocol. Responses were graded as follows: 0, no sensation; 1, initial sensation; 2, mild discomfort; 3, moderate discomfort; and 4, pain. Chemosensitivity was graded along a visual analog scale after perfusion of saline and 0.1 N HCl. Barostat pressure-volume relationships were used to report esophageal body compliance. Barostat pressures for initial sensation and mild discomfort were not significantly different for patients and controls. The pressures for moderate discomfort (37.9 +/- 3.5 vs. 25.7 +/- 2.4 mmHg; P < 0.05) and pain (47.8 +/- 2.3 vs. 32.2 +/- 3.5 mmHg; P = 0.002) were significantly higher in achalasics than controls. Seven of the eight achalasia patients never reached pain thresholds at the maximum distension pressure (50 mmHg). Sensation to acid perfusion was significantly lower in achalasics compared with controls (2.2 +/- 1.2 vs. 6.7 +/- 1.7 cm; P < 0.05). Compliance was significantly increased in patients with achalasia compared with controls. We conclude that both mechanosensitivity and chemosensitivity are significantly diminished in achalasia patients compared with controls. Also, initial sensation and pain sensation are differentially affected in achalasics. These findings suggest that neuropathic defects in achalasia may manifest themselves in visceral sensory and motor dysfunction.     

Modification of Electrical Pain Threshold by Voluntary Breathing-Controlled Electrical Stimulation (BreEStim) in Healthy Subjects

Background

Pain has a distinct sensory and affective (i.e., unpleasantness) component. BreEStim, during which electrical stimulation is delivered during voluntary breathing, has been shown to selectively reduce the affective component of post-amputation phantom pain. The objective was to examine whether BreEStim increases pain threshold such that subjects could have improved tolerance of sensation of painful stimuli.

Methods

Eleven pain-free healthy subjects (7 males, 4 females) participated in the study. All subjects received BreEStim (100 stimuli) and conventional electrical stimulation (EStim, 100 stimuli) to two acupuncture points (Neiguan and Weiguan) of the dominant hand in a random order. The two different treatments were provided at least three days apart. Painful, but tolerable electrical stimuli were delivered randomly during EStim, but were triggered by effortful inhalation during BreEStim. Measurements of tactile sensation threshold, electrical sensation and electrical pain thresholds, thermal (cold sensation, warm sensation, cold pain and heat pain) thresholds were recorded from the thenar eminence of both hands. These measurements were taken pre-intervention and 10−min post-intervention.

Results

There was no difference in the pre-intervention baseline measurement of all thresholds between BreEStim and EStim. The electrical pain threshold significantly increased after BreEStim (27.5±6.7% for the dominant hand and 28.5±10.8% for the non-dominant hand, respectively). The electrical pain threshold significantly decreased after EStim (9.1±2.8% for the dominant hand and 10.2±4.6% for the non–dominant hand, respectively) (F_{[1, 10]} = 30.992, p = .00024). There was no statistically significant change in other thresholds after BreEStim and EStim. The intensity of electrical stimuli was progressively increased, but no difference was found between BreEStim and EStim.

Conclusion

Voluntary breathing controlled electrical stimulation selectively increases electrical pain threshold, while conventional electrical stimulation selectively decreases electrical pain threshold. This may translate into improved pain control.     

Mechanosensory properties in the human gastric antrum evaluated using B-mode ultrasonography during volume-controlled antral distension

The aims of this study were to evaluate gastric antral mechanical behavior and distension-induced sensorimotor responses in the human gastric antrum using transabdominal ultrasound scanning. Ten healthy volunteers underwent volume-controlled ramp inflation of a bag located in the antrum with volumes up to 125 ml. The active and passive circumferential tensions and stresses were calculated from measurements of pressure, diameter, and wall thickness before and during the administration of the anticholinergic drug butylscopolamine. The bag distensions elicited contractions in the antrum and sensory responses below the pain threshold. Butylscopolamine abolished the contractions and significantly reduced the sensory response. The length-tension diagram known from in vitro studies of smooth muscle strips could be reproduced as tension-volume diagrams in the human gastric antrum. The number of induced contractions and the contraction pressure amplitude (afterload) showed a parabolic behavior as function of the distension volume (preload), with maximum approximately at 70 ml. At the sensation threshold, the luminal circumference showed the lowest variation coefficient (13-25%), whereas the variation coefficient was more than 100% for the pressure, tensions, and stresses. We conclude that the muscle length-tension diagram and typical preload-afterload curves ad modem the Frank-Starling cardiac law can be obtained in the human gastric antrum. The sensory responses were most closely associated with the luminal circumference, indicating that the sensation during antral distension depends on deformation rather than on tension.     

Quantification of gender specific thermal sensory and pain threshold before and after laser needle stimulation]

Quantitative thermal sensory and pain threshold testing (QST) was performed in 29 adult healthy volunteers (mean age 24.2 +/- 2.7 years; range: 18-29 years; 20 females, 9 males) using the Thermal Sensory Analyser TSA-II (Medoc Advanced Medical Systems, Ramat Yishai, Israel, and Minneapolis, Minnesota, USA) before and after laser needle acupuncture and placebo stimulation, respectively. Significant (p < or = 0,001; t-test) gender-specific differences were seen on cold pain threshold analysis. No significant changes in parameters of thermal sensory and pain thresholds were found before and after laser needle or placebo stimulation at acupuncture points for acute pain. However, a trend towards change in the median value of cold pain sensation after laser needle stimulation (p = 0.479; paired t-test; n.s.) was seen within the group of healthy females. The influence of stimulation of acupuncture points for chronic pain on the various parameters needs to be clarified in future studies.     

Effect of the α2δ ligand, pregabalin, on colonic sensory and motor functions in healthy adults

Pregabalin, an α2δ ligand, is used clinically to treat somatic pain. A prior study suggested that pregabalin reduces distension-induced pain while increasing rectal compliance. We aimed to quantify effects of pregabalin on colonic sensory and motor functions and assess relationships between sensory effects and colonic compliance. We conducted a randomized, double-blind, placebo-controlled, parallel-group study of a single oral administration of 75 or 200 mg of pregabalin in 62 healthy adults (aged 18-75 yr). Subjects underwent left colon intubation. We assessed "stress-arousal symptoms", compliance, sensation thresholds, sensation ratings averaged over four levels of distension, fasting and postprandial colonic tone, and phasic motility index (MI). Analysis of covariance (adjusted for age, sex, body mass index, and corresponding predrug response) and proportional hazard models were used. There were no clinically important differences among treatment groups for demographics, predrug compliance, tone, MI, and sensation. Treatment was associated with reduced energy and increased drowsiness but no change in tension or relaxation. Sensation ratings averaged over the four distension levels were lower for gas sensation [overall effect P = 0.14, P = 0.05 (pregabalin 200 mg vs. placebo)] and for pain sensation [overall effect P = 0.12, P = 0.04 (pregabalin 200 mg vs. placebo)]. The magnitude of the effect of 200 mg of pregabalin relative to placebo is on average a 25% reduction of both gas and pain sensation ratings. Pregabalin did not significantly affect colonic compliance, sensation thresholds, colonic fasting tone, and MI. Thus 200 mg of pregabalin reduces gas and pain sensation and should be tested in patients with colonic pain.     

Candidate genes and sensory functions in health and irritable bowel syndrome

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (GI) function; these effects are mediated through G protein transduction. Candidate genetic variations in ADR-SER were significantly associated with somatic scores in irritable bowel syndrome (IBS) and gastric emptying but not small bowel or colonic transit. Our aim was to assess whether candidate ADR-SER genes are associated with motor and sensory GI functions in IBS and subgroups on the basis of bowel dysfunction. In 122 patients with IBS and 39 healthy controls, we assessed gastrointestinal somatic symptoms and affect by validated questionnaires. We measured: gastric volume (GV), maximum tolerated volume, rectal compliance, sensation thresholds and ratings, and genetic variations including alpha2A (C-1291G), alpha2C (Del 332-325), GNbeta3 (C825T), and 5-HTTLPR. Demographics and genotype distributions were similar in the patients with IBS subgrouped on bowel function. There were significant associations between 5-HTTLPR SS genotype and absence of IBS symptoms and between 5-HTTLPR LS/SS genotype and increased rectal compliance and increased pain ratings, particularly at 12 and 24 mmHg distensions. GNbeta3 was associated only with fasting GV; we did not detect associations between alpha2A genotype and the gastrointestinal sensory or motor functions tested. We concluded that 5-HTTLPR LS/SS genotype is associated with both increased pain sensation and increased rectal compliance though the latter effect is unlikely to contribute to increased pain sensation ratings with LS/SS genotype. The data suggest the hypotheses that the endophenotype of visceral hypersensitivity in IBS may be partly related to genetic factors, and the association of GNbeta3 with fasting GV may explain, in part, the reported association of GNbeta3 with dyspepsia.     

Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain

Mechanical probes of various sizes and shapes were used to determine thresholds for the perception of pressure, sharpness, and pain on the human finger. As force increased, perception changed from dull pressure to sharp pressure to sharp pain. With the smallest probe (0.01 mm2), sharpness threshold was very close to pressure threshold. As probe size increased, sharpness and pain threshold expressed in terms of force) increased in proportion to probe circumference (not probe area), whereas pressure threshold increased relatively little. Pain and sharpness thresholds also increased as probe angle became obtuse. There was a statistically significant increase in both thresholds with a probe angle change of 15 degrees. Thus, both size and shape are necessary to describe a mechanical stimulus adequately, and pressure (force/area) is not a sufficient metric for pain studies. Thresholds varied at different skin sites on the finger. The dorsal surface had lower thresholds than the volar surface, but the difference between the two areas was not always statistically significant. The compliance of the skin (e.g., the amount of indentation produced by a given force) exhibited no relation to sharpness or pain threshold, whether considered within subjects at various skin sites, or across subjects at the same skin site. Comparison of the perceptual thresholds with the thresholds for nociceptors determined in electrophysiological studies indicates that the sensation of nonpainful sharpness is likely to be mediated by nociceptors. Furthermore, considerably more than threshold activation of nociceptors is necessary for normal pain perception.     

The influence of chemical gustatory stimuli and oral anaesthesia on healthy human pharyngeal swallowing

This study explored the effects of taste and oral anaesthesia on human sequential swallowing. Subjects were healthy adults (n = 42, mean age 28 years, 21 females), investigated by means of a water swallow test. Taste stimuli comprised quinine, glucose, citrus and saline solutions compared with neutral water. Oral anaesthesia comprised topical lidocaine at doses of 10, 20 and 40 mg and compared with placebo. Data were collected on swallowing speed (volume per second), inter-swallow interval and swallowing capacity (volume per swallow). Compared with water, glucose, citrus and saline reduced swallowing speed (10.94 +/- 0.89 versus 9.56 +/- 0.79, 9.33 +/- 1.19, 9.37 +/- 0.92 ml/s respectively, P < 0.05). Inter-swallow interval was increased only by quinine and saline (1.47 +/- 1.11 versus 2.13 +/- 0.34 and 1.92 +/- 0.31 s, P < 0.04). Swallowing capacity was only marginally increased by quinine (P = 0.0759). Compared with the placebo, only 40 mg of lidocaine altered swallowing, immediately reducing the swallowing speed (7.89 +/- 2.34 versus 10.11 +/- 3.26 ml/s, P < 0.05) and increasing inter-swallow interval (1.67 +/- 0.38 versus 1.45 +/- 0.29 s, P < 0.01) without affecting capacity. By 15 min all measures except sensory thresholds had returned to baseline values. Thus, swallowing function is highly influenced by chemosensory input, providing insight into how oral sensation regulates pharyngeal swallowing.     

Right ventricular function in the hypoxaemic fetal sheep

Right ventricular function was investigated in seven fetal sheep (125-130 days gestation) hypoxaemic at a mean of 5 days postoperation, and were compared to nine normoxaemic fetal sheep of the same gestation. Arterial O2 and CO2 tensions, pH, and haematocrit values for the hypoxaemic and normoxaemic fetuses were 15.6 +/- 1.0 vs. 20.6 +/- 1.8 torr, 49.4 +/- 4.1 vs. 46.1 +/- 1.6 torr, 7.38 +/- 0.02 vs. 7.39 +/- 0.02, and 29 +/- 7.5 vs. 31 +/- 5.3%, respectively. Right ventricular output and stroke volume were similar in the two groups, 241 +/- 57 vs. 247 +/- 75 ml X min-1 X kg-1 and 1.5 +/- 0.4 vs. 1.5 +/- 0.4 ml X kg-1, respectively. Filling and afterload pressures were also similar in the hypoxaemic and normoxaemic fetuses with right atrial pressure of 3.0 +/- 1.0 vs. 3.7 +/- 1.2 mmHg, and arterial pressure of 42 +/- 5 vs. 43 +/- 4 mmHg, respectively. Ventricular function curves were produced by rapid withdrawal and re-infusion of fetal blood producing curves with a steep ascending limb and a plateau phase. The breakpoint joining the limbs of the control function curve for the hypoxaemic and normoxaemic fetuses were right atrial pressure 2.9 +/- 1.0 vs. 3.4 +/- 1.2 mmHg and a stroke volume of 1.5 +/- 0.5 vs. 1.5 +/- 0.4 ml X kg-1, respectively. Linear regression of stroke volume against arterial pressure from 30-90 mmHg during infusions of nitroprusside and phenylephrine at right atrial filling pressures greater than breakpoint was stroke volume = 0.018 ml X kg-1 X mmHg-1 arterial pressure +/- 2.25 ml X kg-1. This equation is not different from that calculated in normoxaemic fetuses, and demonstrates that the fetal right ventricle is quite sensitive to changes in arterial pressure. These data indicate that reduction in fetal oxygen content by an estimated 40% does not affect fetal right ventricular function.     

Defective regulation and action of atrial natriuretic peptide in type 2 diabetes.

Increased plasma atrial natriuretic peptide (ANP) levels and impaired ANP action have been reported in patients with diabetes or insulin resistance. The aim of this study was to assess the interaction between insulin and ANP in type 2 diabetes. In 12 normotensive, normoalbuminuric type 2 diabetics, we infused insulin at a high (6.6 pmol/min/kg) or, on a different day, at a low rate (0.6 pmol/min/kg) during 4 hours of isoglycemia under isovolumic, isoosmolar conditions. The normal response was established in 12 healthy volunteers using an identical protocol. Despite higher baseline ANP levels (17.7 +/- 2.8 vs. 10.8 +/- 1.8 pg/ml, p = 0.04), urinary sodium excretion was similar in diabetics and controls (113 +/- 8.5 vs. 102 +/- 8.8 mEq/24 hours, p = ns). In both groups, hyperinsulinemia caused a decrease in blood volume (0.33 +/- 0.10 l, p < 0.01), diastolic blood pressure (6 %, p < 0.02), and natriuresis. However, plasma ANP decreased in controls (from 12.7 +/- 1.9 to 8.6 +/- 1.4 pg/ml, p = 0.01) but not in type 2 diabetics (15.1 +/- 2.7 vs. 17.2 +/- 3.8 pg/ml, p = ns). We conclude that ANP release is resistant to volume stimulation in type 2 diabetic patients, and natriuresis is resistant to ANP action. This dual disruption of ANP control may play a role in blood pressure regulation in diabetes.     

C- and Adelta-fibre mediated thermal perception: response to rate of temperature change using method of limits

Studies investigating the effect of rate of temperature change on thermal thresholds have used a variety of different methods and threshold combinations, and many display incomplete reporting of statistical analyses. It has been suggested that C- and Adelta-fibre mediated thresholds differ in their reaction to different rates of temperature change. Ten healthy female volunteers (aged 18-26 years; mean 21 +/- S.D. 2.53) undertook cold sensation (CS), warm sensation (WS), cold pain (CP) and heat pain (HP) threshold determinations on the thenar eminence of the dominant hand. Rates of temperature change of 0.5, 1, 2.5 and 4 degrees C/s were used, with a modified method of limits. Adaptation temperature was 32 degrees C and thermode size 3 cm x 3 cm. Results showed a significant increase in WS, HP and CP thresholds with increased rates of temperature change (all p < 0.001), but no significant change for CS (p = 0.653). These results suggest that thresholds with a C-fibre component (WS, HP and CP) and those that are Adelta-fibre mediated (CS) behave differently. A traditional explanation of measurement artefact alone is insufficient in rationalizing these results, with additional factors potentially involved. Slow rates of temperature change were shown to reduce mean intra-individual differences in recorded threshold values, and also to abolish ceiling effects with HP threshold determinations. Clinically, therefore, using slow rates of temperature change with method of limits has a range of benefits over and above simply minimizing measurement artefact.     

Swallowing function and upper airway sensation in obstructive sleep apnea.

The objective of this study was to determine whether impaired upper airway (UA) mucosal sensation contributes to altered swallowing function in obstructive sleep apnea (OSA). We determined UA two-point discrimination threshold (2PDT) and vibratory sensation threshold (VST) in 15 men with untreated OSA and 9 nonapneic controls (CL). We then assessed swallowing responses to oropharyngeal fluid boluses delivered via a catheter. The threshold volume required to provoke swallowing and the mean latency to swallowing were determined, as was the phase of the respiratory cycle in which swallowing occurred [expressed as percentage of control cycle duration (%CCD)] and the extent of prolongation of the respiratory cycle after swallowing [inspiratory suppression time (IST)]. 2PDT and VST were significantly impaired in OSA patients compared with CL subjects. 2PDT was positively correlated with swallowing latency and threshold volume in CL subjects, but not in OSA patients. Threshold volume did not differ between the groups [median value = 0.1 ml (95% confidence interval = 0.1-0.2) for OSA and 0.15 ml (95% confidence interval = 0.1-0.16) for CL], whereas swallowing latency was shorter for OSA patients [3.3 (SD 0.7) vs. 3.9 (SD 0.8) s, P = 0.04]. %CCD and IST were similar for OSA patients and CL subjects. However, among OSA patients there was a significant inverse relation between VST and IST. These findings suggest that oropharyngeal sensory impairment in OSA is associated with an attenuation of inhibitory modulating inputs to reflex and central control of UA swallowing function.     

Effects of Acupuncture on Sensory Perception: A Systematic Review and Meta-Analysis

Background

The effect of acupuncture on sensory perception has never been systematically reviewed; although, studies on acupuncture mechanisms are frequently based on the idea that changes in sensory thresholds reflect its effect on the nervous system.

Methods

Pubmed, EMBASE and Scopus were screened for studies investigating the effect of acupuncture on thermal or mechanical detection or pain thresholds in humans published in English or German. A meta-analysis of high quality studies was performed.

Results

Out of 3007 identified articles 85 were included. Sixty five studies showed that acupuncture affects at least one sensory threshold. Most studies assessed the pressure pain threshold of which 80% reported an increase after acupuncture. Significant short- and long-term effects on the pressure pain threshold in pain patients were revealed by two meta-analyses including four and two high quality studies, respectively. In over 60% of studies, acupuncture reduced sensitivity to noxious thermal stimuli, but measuring methods might influence results. Few but consistent data indicate that acupuncture reduces pin-prick like pain but not mechanical detection. Results on thermal detection are heterogeneous. Sensory threshold changes were equally frequent reported after manual acupuncture as after electroacupuncture. Among 48 sham-controlled studies, 25 showed stronger effects on sensory thresholds through verum than through sham acupuncture, but in 9 studies significant threshold changes were also observed after sham acupuncture. Overall, there is a lack of high quality acupuncture studies applying comprehensive assessments of sensory perception.

Conclusions

Our findings indicate that acupuncture affects sensory perception. Results are most compelling for the pressure pain threshold, especially in pain conditions associated with tenderness. Sham acupuncture can also cause such effects. Future studies should incorporate comprehensive, standardized assessments of sensory profiles in order to fully characterize its effect on sensory perception and to explore the predictive value of sensory profiles for the effectiveness of acupuncture.     

Thermal perception thresholds recorded using method of limits change over brief time intervals

Quantitative Sensory Testing (QST) of thermal perception thresholds assesses small afferent nerve function. QST has also been widely used to investigate the effects of interventions on the perception of activity within these nerve fibres, often over brief time periods. The natural variation in perception thresholds over brief time periods has not been determined, however, complicating accurate identification of induced changes. The present study therefore investigated changes in thermal perception threshold values within a 1-h period. Twenty-four healthy women volunteers aged 18-28 years (mean 20.6, SD 2.8) undertook cold sensation (CS), warm sensation (WS), cold pain (CP), and hot pain (HP) perception threshold measurements on the thenar eminence of the dominant hand during six 8-min experimental cycles. The order of stimulus presentation was randomized within pre-selected criteria. An adaptation temperature of 32 degrees C, a rate of temperature change of 0.5 degrees C/s, a 3 cm x 3 cm thermode, and a method of limits algorithm were used. Separate two-way ANOVAs with repeated measures showed statistically significant changes over time for WS, CS, and HP (p < 0.05), but not for CP (p = 0.232). The results indicate that WS, CS, and HP perception thresholds change significantly with repeated testing over a 1-h period. These results should be carefully considered when assessing the importance of observed changes in thermal perception thresholds. In research trials exclusion of a control group would be a fundamental flaw.     

Distinct neurophysiological profiles in irritable bowel syndrome

The objective of this study was to determine whether cortical evoked potentials (CEPs) can define neurophysiological patterns in irritable bowel syndrome (IBS). In this prospective study of consecutive patients attending secondary and tertiary centers, patients with Rome II-defined IBS underwent rectal sensory and pain threshold (RST and RPT, respectively) testing with electrical stimulation on three separate visits. CEPs were collated for 75% pain thresholds, and anxiety [Spielberger State-Trait Anxiety Inventory (SSTAI)] questionnaires were completed. Subjects were 33 IBS patients (27 female, mean age 40.1 yr) and 21 healthy controls (14 female, mean age 31.4 yr). At visit 3, RPT was significantly lower [mean (95% CI)] in IBS patients than in control subjects: 58.2 mA (48.0-68.5) vs. 79.5 mA (69.3-89.6) (P < 0.01). No significant differences were observed in CEP latencies and amplitudes between visits 1, 2, and 3 within each group, except P2 latency for controls (P = 0.04) and N2 latency (P = 0.04) and N2 amplitude (P = 0.02) for IBS patients. Group comparisons showed significant differences in 3-day mean RPT, CEP amplitudes, and CEP latencies between IBS patients and controls. RPT <50 mA and P1 latency >106 ms were identified four IBS subgroups: 24% were hypersensitive, 12% were hypervigilant, 15% were hyposensitive, and 49% exhibited normal P1 latency and pain threshold. CEPs are reliable and reproducible measures of early sensory processing. Identification of four IBS neurophysiological patterns highlights its heterogeneous nature. These findings mark the first step toward personalized medicine in IBS, whereby therapy may be directed at the underlying physiological process.     

Age-related thermoregulatory differences during core cooling in humans

The current study assessed sympathetic neuronal and vasomotor responses, total body oxygen consumption, and sensory thermal perception to identify thermoregulatory differences in younger and older human subjects during core cooling. Cold fluid (40 ml/kg, 4 degrees C) was given intravenously over 30 min to decrease core temperature (Tc) in eight younger (age 18-23) and eight older (age 55-71) individuals. Compared with younger subjects, the older subjects had significantly lower Tc thresholds for vasoconstriction (35.5 +/- 0.3 vs. 36.2 +/- 0.2 degrees C, P = 0.03), heat production (35.2 +/- 0.4 vs. 35.9 +/- 0.1 degrees C, P = 0.04), and plasma norepinephrine (NE) responses (35.0 vs. 36.0 degrees C, P < 0.05). Despite a lower Tc nadir during cooling, the maximum intensities of the vasoconstriction (P = 0.03) and heat production (P = 0.006) responses were less in the older compared with the younger subjects, whereas subjective thermal comfort scores were similar. Plasma NE concentrations increased fourfold in the younger but only twofold in the older subjects at maximal Tc cooling. The vasomotor response for a given change in plasma NE concentration was decreased in the older group (P = 0.01). In summary, aging is associated with 1) a decreased Tc threshold and maximum response intensity for vasoconstriction, total body oxygen consumption, and NE release, 2) decreased vasomotor responsiveness to NE, and 3) decreased subjective sensory thermal perception.     

Systemic Inflammation Decreases Pain Threshold in Humans In Vivo

Background

Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods.

Methods and Results

Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20±4 % and 13±3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7±3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques.

Conclusions and Significance

In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.     

Effect of nitric oxide on basal and stretch-induced release of atrial natriuretic factor (ANF) from isolated perfused rat atria

We investigated the effect of the NO donor SNAP (6.7 nM) on basal and stretch-induced ANF release from isolated perfused rat atria. There was no significant difference in basal ANF secretion between the vehicle- and SNAP-infused atria (SNAP: 388+/-63 pg. 100 microl(-1), n = 13 vs. vehicle: 349+/-26 pg. 100 microl(-1), n = 5). Atrial distention caused an increase in ANF secretion in both the buffer- and SNAP-treated groups. SNAP greatly attenuated the stretch-induced increase in ANF (SNAP: 225+/-7 pg. 100 microl(-1), n = 5 vs. vehicle: 448+/-72 pg. 100 microl(-1), n = 13, P < 0.05). The compliance of atria treated with SNAP was lower than that of the vehicle-perfused atria (P < 0.05). Thus, although SNAP appeared to attenuate stretch-induced ANF secretion, there was in fact no significant difference in the ratio of Delta[ANF] to Deltaintraluminal volume (SNAP: 5.8+/-1.3 pg. 100 microl(-1). microl(-1) vs. vehicle: 8.2+/-1.4 pg. 100 microl(-1). microl(-1).). In conclusion, we found no evidence that NO alters the control of basal or stretch-induced ANF secretion. NO can however reduce ANF release by shifting the pressure-volume curve, so that a given increase in atrial pressure is associated with a smaller increase in intraluminal volume and reduced atrial distention.