Time course of continuous positive airway pressure effects on central sleep apnoea in patients with chronic heart failure

Continuous positive airway pressure (CPAP) causes a variable immediate reduction in the frequency of central apnoeas and hypopnoeas in patients with congestive heart failure (CHF) and central sleep apnoea (CSA), but has beneficial mid-term effects on factors known to destabilize the ventilatory control system. We, therefore, tested whether CPAP therapy leads, in addition to its short-term effects on CSA, to a significant further alleviation of CSA after 12 weeks of treatment on the same CPAP level in such patients. CPAP therapy was initiated in 10 CHF patients with CSA. During the first night on CPAP, the pressure was stepwise increased to a target pressure of 8–12 cmH₂O or the highest level the patients tolerated (<12 cmH₂O). Throughout the second night (baseline CPAP), the achieved CPAP of the first night was applied. After 12 weeks of CPAP treatment, we performed a follow-up polysomnography (12 weeks CPAP) on the same CPAP level (8.6 ± 1.1 cmH₂0). We found a significant reduction of the apnoea-hypopnoea index (AHI) between the diagnostic polysomnography and baseline CPAP night (41.8 ± 19.2 versus 22.2 ± 12.6 events per hour; P  = 0.005). The AHI further significantly decreased between the baseline CPAP night and the 12 weeks CPAP night on the same CPAP level (22.2 ± 12.6 versus 12.8 ± 11.0 events per hour; P  = 0.028). We conclude that, in addition to its immediate effects, CPAP therapy leads to a time-dependent alleviation of CSA in some CHF patients, indicating that in such patients neither clinical nor scientific decisions should be based on a short-term trial of CPAP.     

Association of cardiac autonomic function measures with severity of sleep-disordered breathing in a community-based sample

The goal of this study was to test the hypothesis that spectral indices of heart rate variability, such as high-frequency power (HFP), low-to-high frequency power (LHR), and their respiration-adjusted counterparts (HFPra, LHRra) are correlated with severity of sleep-disordered breathing (SDB), as quantified by the respiratory disturbance index (RDI). A total of 436 subjects, non-smoking, normotensive, and free of cardiovascular disease and diabetes were selected from the Sleep Heart Health Study (SHHS). Of these, 288 records with sufficiently high quality electrocardiogram signals were selected for further analysis [males/females: 221/67; age: 46.1 to 74.9 years; body mass index (BMI): 21.5 to 46.4 kg m⁻²; 0.3 < RDI < 85.0⁻¹]. From each polysomnogram, the respiration channels (thoracic and abdominal) and R-R interval (RRI) derived from the electrocardiogram were subjected to spectral analysis and autoregressive moving average modeling in consecutive 5-min segments. After adjusting for age and BMI, mean RRI was found to be negatively correlated with RDI in men in all sleep-wake states (all P  < 0.001). HFP and HFPra were negatively correlated with RDI in men only during wakefulness (all P  < 0.01). In women, LHR and LHRra were not correlated with RDI during wakefulness, but were positively correlated during non-rapid eye movement Stage 1 and 2 sleep (all P  < 0.01). These findings suggest that the indices of cardiac autonomic control are correlated with SDB severity, but gender and state affect the nature of these correlations. In both genders, however, vagal modulation of heart rate increases while sympathetic modulation decreases from wakefulness to sleep.     

Evolution of upper airway resistance syndrome

The question of whether upper airway resistance syndrome (UARS) is a distinct disease or an initial feature of obstructive sleep apnoea syndrome is still a matter of debate. We evaluated a retrospective group of UARS patients to determine the evolution of UARS over time and the relationship between clinical evolution and subjects' phenotype. Investigations were performed in 30 patients, in whom UARS was diagnosed between 1995 and 2000 by the use of full polysomnography (PSG) without oesophageal pressure (Pes) measurement. The time between initial and follow-up investigations was 6.6 ± 2.6 years. All subjects had full PSG with Pes measurement and completed a sleep questionnaire, including the Epworth Sleepiness Scale. In 19 subjects, PSG results were compatible with UARS. In nine subjects, obstructive sleep apnoea–hypopnoea syndrome (OSAHS) was diagnosed. In two subjects, PSG did not demonstrate breathing abnormalities. The mean ± SD apnoea–hypopnoea index in the UARS group was 1.5 ± 1.7 h⁻¹ and 25.2 ± 19 h⁻¹ in the OSAHS group ( P  <   0.01). The increase in body mass index (BMI) between initial and follow-up investigations in the UARS group was from 29.4 ± 4 to 31 ± 5.7 kg m⁻² ( P  =   0.014) and in the OSAHS group from 30 ± 4.1 to 32.4 ± 4.7 kg m⁻²( P  =   0.004). Amplitude of Pes swings during respiratory events was significantly higher in OSAHS than that in UARS ( P  =   0.014). Our results suggest that UARS is part of a clinical continuum from habitual snoring to OSAHS. Progression from UARS to OSAHS seems to be related to an increase in the BMI.     

Cyclic movement stimulates hyaluronan secretion into the synovial cavity of rabbit joints

The novel hypothesis that the secretion of the joint lubricant hyaluronan (HA) is coupled to movement has implications for normal function and osteoarthritis, and was tested in the knee joints of anaesthetized rabbits. After washing out the endogenous synovial fluid HA (miscibility coefficient 0.4), secretion into the joint cavity was measured over 5 h in static joints and in passively cycled joints. The net static secretion rate (11.2 ± 0.7 μg h⁻¹, mean ± s.e.m. , n = 90) correlated with the variable endogenous HA mass (mean 367 ± 8 μg), with a normalized value of 3.4 ± 0.2 μg h⁻¹ (100 μg)⁻¹     . Cyclic joint movement approximately doubled the net HA secretion rate to 22.6 ± 1.2 μg h⁻¹ ( n = 77) and raised the normalized percentage     to 5.9 ± 0.3 μg h⁻¹ (100 μg)⁻¹. Secretion was inhibited by 2-deoxyglucose and iodoacetate, confirming active secretion. The net accumulation rate underestimated true secretion rate due to some trans-synovial loss. HA turnover time (endogenous mass/secretion rate) was 17–30 h (static) to 8–15 h (moved) The results demonstrate for the first time that the active secretion of HA is coupled to joint usage. Movement–secretion coupling may protect joints against the damaging effects of repetitive joint use, replace HA lost during periods of immobility (overnight), and contribute to the clinical benefit of exercise therapy in moderate osteoarthritis.     

Economy of locomotion in high-altitude Tibetan migrants exposed to normoxia

High-altitude Tibetans undergo a pattern of adaptations to chronic hypoxia characterized, among others, by a more efficient aerobic performance compared with acclimatized lowlanders. To test whether such changes may persist upon descent to moderate altitude, oxygen uptake of 17 male Tibetan natives lifelong residents at 3500–4500 m was assessed within 1 month upon migration to 1300 m. Exercise protocols were: 5 min treadmill walking at 6 km h⁻¹ on increasing inclines from +5 to +15% and 5 min running at 10 km h⁻¹ on a +5% grade. The data (mean ± s.e.m. ) were compared with those obtained on Nepali lowlanders. When walking on +10, +12.5 and +15% inclines, net     of Tibetans was 25.2 ± 0.7, 29.1 ± 1.1 and 31.3 ± 0.9 ml kg⁻¹ min⁻¹, respectively, i.e. 8, 10 and 13% less ( P < 0.05) than that of Nepali. At the end of the heaviest load, blood lactate concentration was lower in Tibetans than in Nepali (6.0 ± 0.9 versus 8.9 ± 0.6 m m ; P < 0.05) . During running,     of Tibetans was 35.1 ± 0.8 versus 39.3 ± 0.7 ml kg⁻¹ min⁻¹ (i.e. 11% less; P < 0.01). In conclusion, during submaximal walking and running at 1300 m, Tibetans are still characterized by lower aerobic energy expenditure than control subjects that is not accounted for by differences in mechanical power output and/or compensated for by anaerobic glycolysis. These findings indicate that chronic hypoxia induces metabolic adaptations whose underlying mechanisms still need to be elucidated, that persist for at least 1 month upon descent to moderate altitude.     

Protein synthesis rates in human muscles: neither anatomical location nor fibre-type composition are major determinants

In many animals the rate of protein synthesis is higher in slow-twitch, oxidative than fast-twitch, glycolytic muscles. To discover if muscles in the human body also show such differences, we measured [¹³C]leucine incorporation into proteins of anatomically distinct muscles of markedly different fibre-type composition (vastus lateralis, triceps, soleus) after an overnight fast and during infusion of a mixed amino acid solution (75 mg amino acids kg⁻¹ h⁻¹) in nine healthy, young men. Type-1 fibres contributed 83 ± 4% (mean ± s.e.m. ) of total fibres in soleus, 59 ± 3% in vastus lateralis and 22 ± 2% in triceps. The basal myofibrillar and sarcoplasmic protein fractional synthetic rates (FSR, % h⁻¹) were 0.034 ± 0.001 and 0.064 ± 0.001 (soleus), 0.031 ± 0.001 and 0.060 ± 0.001 (vastus), and 0.027 ± 0.001 and 0.055 ± 0.001 (triceps). During amino acid infusion, myofibrillar protein FSR increased to 3-fold, and sarcoplasmic to 2-fold basal values ( P < 0.001). The differences between muscles, although significant statistically (triceps versus soleus and vastus lateralis, P < 0.05), were within ∼15%, biologically probably insignificant. The rates of collagen synthesis were not affected by amino acid infusion and varied by < 5% between muscles and experimental conditions.     

Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep

Prenatal exposure to elevated maternal glucocorticoids (dexamethasone (DEX) or cortisol (CORT)) for 2 days early in pregnancy can 'programme' alterations in adult offspring of sheep, including elevated arterial pressure. DEX treatment also results in greater angiotensin II type 1 (AT₁) receptor expression in the medulla oblongata in late gestation fetuses than in saline (SAL)- or CORT-exposed animals. We hypothesized that this would result in functional changes in brainstem angiotensinergic control of cardiovascular function in DEX- but not CORT-exposed animals. To test this hypothesis, cardiovascular responses to intracerebroventricular ( i.c.v. ) angiotensin II were examined in adult male offspring exposed to DEX (0.48 mg h⁻¹; n = 7), CORT (5 mg h⁻¹, n = 6) or SAL ( n = 9) from 26 to 28 days of gestation. Increases in mean arterial pressure during i.c.v. infusion of angiotensin II (1 or 10 μg h⁻¹) were significantly greater in the DEX group (10 ± 1 mmHg at 1 μg h⁻¹) compared with SAL (6 ± 1 mmHg) or CORT (6 ± 1 mmHg) animals ( P < 0.05). i.c.v. infusion of the AT₁ antagonist losartan significantly decreased cardiac output and heart rate in DEX animals, but not in SAL or CORT animals. Thus, increased expression of brainstem AT₁ receptor mRNA after prenatal DEX is associated with increased responsiveness of cardiovascular control to activation of brain AT receptors by exogenous and endogenous angiotensin II. The altered role of the brain RAS in sheep exposed prenatally to DEX was not observed in sheep exposed prenatally to cortisol, suggesting these two glucocorticoids have distinct programming actions.     

Automatic CPAP based on impedance-comparison of constant CPAP with an individual pressure range

Summary Introduction   Self-adjusting positive airways pressure treatment based on the impedance of the airways (APAP_FOT) has proven effective in obstructive sleep apnoea syndrome. To avoid patient discomfort during periods of high treatment pressure we lowered the upper pressure limit with APAP_FOT and investigated whether this provided equally as effective treatment as constant CPAP. Methods   37 patients (33 males, 57.9 ± 9.9 years, BMI 32.5 ± 3.8 kg/m²) underwent after diagnostic polysomnography and manual nCPAP titration two treatment nights in randomized order, one with constant nCPAP (mode 1), one with APAP_FOT (mode 2). Under APAP_FOT treatment pressure varied between 4 hPa (set lower limit for all patients) and 13.3 ± 1.4 hPa (individually variable upper pressure limit). Results   AHI was reduced from 32.8 ± 18.1/h to 4.6 ± 4.9/h (mode 1, p < 0.01) and to 5.0 ± 4.1/h (mode 2, p < 0.01). Rapid eye movement sleep (REM) and respiratory arousals improved significantly with both modes. With APAP_FOT, the mean pressure was 5.7 ± 1.7 hPa as compared to 8.3 ± 1.4 hPa with constant nCPAP (p < 0.01). Conclusions   APAP_FOT with a reduced upper pressure is as effective as constant nCPAP for OSAS. With APAP_FOT the mean pressure is substantially reduced.     

Prenatal hypoxia impairs circadian synchronisation and response of the biological clock to light in adult rats

The present study was undertaken to investigate the fate of blood-borne non-esterified fatty acids (NEFA) entering contracting and non-contracting knee extensor muscles of healthy young individuals. [U-¹³C]-palmitate was infused into a forearm vein during 5 h of one-legged knee extensor exercise at 40 % of maximal work capacity and the NEFA kinetics, oxidation and rate of incorporation into intramuscular triacylglycerol (mTAG) were determined for the exercising and the non-exercising legs. During 4 h of one-legged knee extensor exercise, m tag content decreased by 30 % (   P < 0.05  ) in the contracting muscle, whereas it was unchanged in the non-contracting muscle. The uptake of plasma NEFA, as well as the proportion directed towards oxidation, was higher in the exercising compared to the non-exercising leg, whereas the rate of palmitate incorporation into m tag was fourfold lower (0.70 ± 0.14 vs. 0.17 ± 0.04 μmol (g dry wt)⁻¹ h⁻¹; P lt; 0.05), resulting in fractional synthesis rates of 1.0 ± 0.2 and 3.8 ± 0.9 % h⁻¹ ( P lt; 0.01) for the contracting and non-contracting muscle, respectively. These findings demonstrate that mTAG in human skeletal muscle is continuously synthesised and degraded and that the metabolic fate of plasma NEFA entering the muscle is influenced by muscle contraction, so that a higher proportion is directed towards oxidation at the expense of storage in mTAG.     

Attenuated vascular responsiveness to noradrenaline release during dynamic exercise in dogs

During dynamic exercise, there is reduced responsiveness to α₁- and α₂-adrenergic receptor agonists in skeletal muscle vasculature. However, it is desirable to examine the sympathetic responsiveness to endogenous release of neurotransmitter, since exogenous sympathomimetic agents are dependent upon their ability to reach the abluminal receptor. Therefore, to further our understanding of sympathetic control of vasomotor tone during exercise, we employed a technique that would elicit the release of endogenous noradrenaline (norepinephrine) during dynamic exercise. Mongrel dogs ( n = 8, 19-24 kg) were instrumented chronically with transit time ultrasound flow probes on both external iliac arteries. A catheter was placed in a side branch of the femoral artery for intra-arterial administration of tyramine, an agent which displaces noradrenaline from the nerve terminal. Doses of 0.5, 1.0 and 3.0 μg ml⁻¹ min⁻¹ of iliac blood flow were infused for 1 min at rest and during graded intensities of exercise. Dose-related decreases in iliac vascular conductance were achieved with these concentrations of tyramine. The reductions in iliac vascular conductance (means ± s.e.m .) were 45 ± 6 %, 30 ± 4 %, 26 ± 3 % and 17 ± 2 %, for the 1.0 μg ml⁻¹ min⁻¹ dose at rest, 3.0 miles h⁻¹, 6.0 miles h⁻¹ and 6.0 miles h⁻¹, 10 % gradient, respectively. At all doses, the magnitude of vasoconstriction caused by administration of tyramine was inversely related to workload. We conclude that there is a reduced vascular responsiveness to sympathoactivation in dynamically exercising skeletal muscle.     

The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse

We hypothesized that rates of myofibrillar and patellar tendon collagen synthesis would fall over time during disuse, the changes being accompanied in muscle by decreases in focal adhesion kinase (FAK) phosphorylation and in gene expression for proteolytic enzymes. We studied nine men (22 ± 4 years, BMI 24 ± 3 kg m⁻² (means ± s.d. ) who underwent unilateral lower leg suspension for 23 days; five were studied between 0 and 10 days and four between 10 and 21 days. Muscle and tendon biopsies were taken in the postabsorptive state at days 0, 10 and 21 for measurement of protein synthesis, gene expression and protein phosphorylation. Muscle cross-sectional area decreased by 5.2% at 14 days and 10.0% (both P < 0.001), at 23 days, i.e. 0.5% day⁻¹, whereas tendon dimensions were constant. Rates of myofibrillar protein synthesis fell ( P < 0.01) from 0.047% h⁻¹ at day 0 to 0.022% h⁻¹ at 10 days without further changes. Tendon collagen synthetic rates also fell ( P < 0.01), from 0.052 to 0.023% h⁻¹ at 10 days and then to 0.010% h⁻¹ at 21 days. FAK phosphorylation decreased 30% ( P < 0.01) at 10 days. No changes occurred in the amounts/phosphorylation of PKB–P70s6k–mTOR pathway components. Expression of mRNA for MuRF-1 increased ∼3-fold at 10 days without changes in MAFbx or tripeptidyl peptidase II mRNA, but all decreased between 10 and 21 days. Thus, both myofibrillar and tendon protein synthetic rates show progressive decreases during 21 days of disuse; in muscle, this is accompanied by decreased phosphorylation of FAK, with no marked increases in genes for proteolytic enzymes.     

Sleep-disordered breathing in a general heart failure population: relationships to neurohumoral activation and subjective symptoms

The aim of this study was to determine the prevalence of sleep-related breathing disorders (SDB) in a UK general heart failure (HF) population, and assess its impact on neurohumoral markers and symptoms of sleepiness and quality of life. Eighty-four ambulatory patients (72 male, mean (SD) age 68.6 (10) yrs) attending UK HF clinics underwent an overnight recording of respiratory impedance, SaO2 and heart rate using a portable monitor (Nexan). Brain natriuretic peptide (BNP) and urinary catecholamines were measured. Subjective sleepiness and the impairment in quality of life were assessed (Epworth Sleepiness Scale (ESS), SF-36 Health Performance Score). SDB was classified using the Apnoea/Hypopnoea Index (AHI). The prevalence of SDB (AHI > 15 events h(-1)) was 24%, increasing from 15% in mild-to-moderate HF to 39% in severe HF. Patients with SDB had significantly higher levels of BNP and noradrenaline than those without SDB (mean (SD) BNP: 187 (119) versus 73 (98) pg mL(-1), P = 0.02; noradrenaline: 309 (183) versus 225 (148) nmol/24 h, P = 0.05). There was no significant difference in reported sleepiness or in any domain of SF-36, between groups with and without SDB (ESS: 7.8 (4.7) versus 7.5 (3.6), P = 0.87). In summary, in a general HF clinic population, the prevalence of SDB increased with the severity of HF. Patients with SDB had higher activation of a neurohumoral marker and more severe HF. Unlike obstructive sleep apnoea, SDB in HF had little discernible effect on sleepiness or quality of life as measured by standard subjective scales.     

Long-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats

In vivo biotelemetry studies have demonstrated that short-term streptozotocin (STZ)-induced diabetes is associated with a reduction in heart rate (HR) and heart rate variability (HRV) and prolongation of QT and QRS intervals. This study investigates the long-term effects of STZ-induced diabetes on the electrocardiogram (ECG), physical activity and body temperature. Transmitter devices were surgically implanted in the peritoneal cavity of young adult male Wistar rats. Electrodes from the transmitter were arranged in Einthoven bipolar lead II configuration. ECG, physical activity and body temperature data were continuously recorded with a telemetry system before and following the administration of STZ (60 mg kg⁻¹) for a period of 22 weeks. HR, physical activity and body temperature declined rapidly 3–5 days after the administration of STZ. The effects became conspicuous with time reaching a new steady state approximately 1–2 weeks after STZ treatment. HR at 4 weeks was 268 ± 5 beats min⁻¹ in diabetic rats compared to 347 ± 12 beats min⁻¹ in age-matched controls. HRV at 4 weeks was also significantly reduced after STZ treatment (18 ± 3 beats min⁻¹) compared to controls (33 ± 3 beats min⁻¹). HR and HRV were not additionally altered in either diabetic rats (266 ± 5 and 20 ± 4 beats min⁻¹) or age-matched controls (316 ± 6 and 25 ± 4 beats min⁻¹) at 22 weeks. Reduced physical activity and/or body temperature may partly underlie the reductions in HR and HRV. In addition, the increased power spectral low frequency/high frequency ratio from 4 weeks after STZ treatment may indicate an accompanying disturbance in sympathovagal balance.     

Arousals bei Patienten mit obstruktivem Schlafapnoe-Syndrom—Untersuchung zur Häufigkeit in Abhängigkeit von Lebensalter,Geschlecht und Schweregrad der Erkrankung

Zusammenfassung Die nächtlichen Arousals, die als Folge obstruktiver Ereignisse auftreten, werden als wesentliche Ursache der vermehrten Tagesschläfrigkeit bei Patienten mit obstruktivem Schlafapnoe-Syndrom (OSAS) angesehen. Ziel dieser Untersuchung war es, die Häufigkeit von Weckreaktionen, nach der American Sleep Disorders Association (ASDA) klassifiziert, bei Patienten mit OSAS zu ermitteln und festzustellen, ob eine Beziehung zwischen anthropometrischen Daten oder Schweregrad des OSAS und den Arousals besteht. 215 Patienten (Alter: 53,3 ± 10,8 Jahre, BMI: 31,3 ± 5,5 kg/m², AHI: 36,3 ± 22,9/h, 192 Männer) mit einem AHI ≥ 10 und der anamnestischen Angabe von Hypersomnolenz, wurden konsekutiv polysomnographisch untersucht. Es fand sich eine signifikante Korrelation zwischen dem AHI und dem BMI (r: 0,47, p < 0,001). Die Gesamtzahl der Arousals lag initial bei 151,3 ± 82,6 und der Index der Weckreaktionen bei 28,9 ± 16,2/h (Männer 29,8 ± 16,7/h, Frauen 20,8 ± 7,2/h, p < 0,01). Der Arousal-Index (ArI) zeigte eine signifikante Korrelation mit dem AHI (r: 0,62, p < 0,001), dem BMI (r: 0,27, p < 0,001) und dem Score der Epworth Sleepiness Scale (r: 0,13, p < 0,05), nicht jedoch mit dem Lebensalter (r: 0,07, n. s.). Unter Berücksichtigung des AHI als Kontrollvariable war eine signifikante Korrelation zwischen BMI und ArI und Alter und ArI nicht nachweisbar. Wir schliessen daraus, dass bei OSAS die Anzahl der Arousals vor allem mit dem Schweregrad der Erkrankung zusammenhängt, nicht jedoch mit dem Lebensalter. Trotz vergleichbarer Tagesschläfrigkeit zeigen Frauen weniger Arousals.     

以短时心率变异性反映充血性心力衰竭患者自主神经活动的改变

基于短时心率变异性（HRV）分析,探讨充血性心力衰竭（CHF）患者自主神经活动的变化和影响。选用THEW数据库中正常人子数据库作为正常对照组（n=189）,对于PhysioNet中两个CHF子数据库的样本（n=44）,按照NYHA等级,将NYHA I-II级划分轻度CHF 组（n=12）,NYHA III-IV级为重度CHF组（n=32）。对每一个Holter记录选取日间和夜间安静态各5 min的RR间期（RRI）序列,分别进行时域、基于AR模型的频域和去趋势波动（DFA）分析。在正常组、轻度CHF组和重度CHF组等三组中,CHF患者日间的短时分形尺度指数（(α₁)_d）两两比较均有显著性差异,并存在下降趋势（依次分别为1.35±0.21、1.03±0.29和0.81±0.29）,反映心率动力学从分形特性转向更随机化的结构。同时,日间HFn((HFn)_d)在三组间的两两比较中均存在显著性差异,并存在上升趋势（依次分别为23.89%±12.78%、37.22%±11.24%和56.30%±15.28%）, 表明CHF导致交感神经和迷走神经交互作用趋于消失。利用夜间RRI（RRI_n）,(HFn)_d 和 (α₁)_d等3个指标进行Fisher线性判别,区分正常人和CHF患者的灵敏性和特异性分别为90.91%和92.06%,而区分轻度和重度CHF患者的灵敏性和特异性分别为84.38%和100%。所进行的研究将HRV非线性方法与传统方法相结合评估自主神经状态, 为监测CHF病情或观察治疗效果等潜在的临床应用提供了依据。     

Variation in Gut-Homing CD27-Negative Lymphocytes in Inflammatory Colon Disease

Prolonged antigenic stimulation results in lymphocyte shedding of CD27, a member of the tumour necrosis factor receptor (TNFR) family, and transformation to a stable phenotype capable of synthesizing interleukin-4 (IL-4). Co-expression of α4β7 identifies those cells with gut-homing potential. We have investigated these cell populations in patients with inflammatory colonic disease. Circulating and lamina propria mononuclear cells were isolated from patients with Crohn's disease (CD), ulcerative colitis (UC), non-inflammatory bowel disease (non-IBD) colonic inflammation and healthy controls. Double and triple colour flow cytometry for CD3, CD4, CD27, α4β7 and intracellular cytokines was performed. Circulating CD4+CD27– populations were increased in patients with CD (8.8 ± 0.8%, P  < 0.001), UC (12.2 ± 1.9%, P  < 0.001) and non-IBD colitis (10.5 ± 1.3%, P  < 0.01) as compared with controls (6.1 ± 0.5%). CD4⁺CD27⁻α4β7⁺ cells were increased in CD ( P  < 0.01). Lamina propria CD4⁺CD27⁻ populations were depressed significantly in CD ( P  < 0.05), UC ( P  < 0.02) and non-IBD colitis ( P  < 0.03). Mucosal CD4⁺CD27⁻ cells synthesized IL-4 in preference to interferon-γ. Thus, colonic inflammation is associated with alterations in gut-tropic circulating and mucosal populations of differentiated memory T cells with the phenotype of predominantly IL-4-synthesizing cells.     

Furosemide-induced renal medullary hypoperfusion in the rat: role of tissue tonicity, prostaglandins and angiotensin II

Furosemide (frusemide)-induced renal medullary hypoperfusion provides a model for studies of the dependence of local circulation on tissue tonicity. We examined the role of medullary prostaglandins (PG) and adenosine (Ado) as possible mediators of the response to furosemide. Furosemide was infused i.v. at 0.25 mg kg⁻¹ h⁻¹ in anaesthetized rats, untreated or treated with intramedullary indomethacin (Indo) or Ado. An integrated set-up was used to measure renal medullary laser-Doppler flux (MBF) and medullary ionic tonicity (electrical admittance, Y), and to infuse Indo and Ado directly into the medulla. The cortical flux was measured on kidney surface. The excretion of water, sodium and total solute was also determined. Intramedullary Indo (1 mg kg⁻¹ h⁻¹) decreased MBF 18 ± 5% and increased tissue Y 14 ± 3% (both significant); the treatment abolished the post-furosemide decrease in MBF (−22% in untreated group) and enhanced slightly the increase in renal excretion. Intramedullary Ado (5 mg kg⁻¹ h⁻¹) did not change baseline MBF or Y; the post-furosemide decreases in MBF (−22%) and Y, and the increase in renal excretion were preserved. We conclude that a decrease in intramedullary PG activity secondary to decreased medullary hypertonicity mediates the fall in medullary perfusion in response to furosemide; the hypoperfusion may help restore the initial tonicity. Together with the earlier evidence on the dependence of post-furosemide medullary hypoperfusion on angiotensin II, the study exposes its interaction with PG in the control of medullary circulation. Adenosine is not involved in medullary vascular responses to decreased tissue hypertonicity.     

Diagnosis of sleep-disordered breathing in patients with chronic heart failure: evaluation of a portable limited sleep study system

Sleep-disordered breathing (SDB) is common in chronic heart failure (CHF), affects disease progression and presents a potential therapeutic target. This study was designed to test the hypothesis that there would be good agreement in diagnostic outcome between home limited sleep studies and in-laboratory polysomnography (PSG) in the identification of SDB in patients with CHF. We performed synchronous in-laboratory Embletta and PSG, and home Embletta studies, prospectively in 20 consecutive patients with stable symptomatic CHF (ejection fraction 33 +/- 12%) on optimal medical therapy. Sleep efficiency was poor at 57 +/- 21%. Unlike synchronous in-laboratory Embletta (kappa coefficient 0.63, P < 0.01), home Embletta showed poor agreement with PSG (kappa coefficient 0.27, P = 0.06). Positive and negative predictive values for home Embletta in detecting SDB were 83% and 57% respectively. In this relatively small study, agreement in diagnostic outcome between home Embletta and PSG, and negative predictive value for the home Embletta, were poor. We explore possible explanations for this, both technical and situational, which should be taken into consideration when considering potential screening or diagnostic tools for SDB in patients with CHF.     

Neural drive to human genioglossus in obstructive sleep apnoea

One postulated mechanism for obstructive sleep apnoea (OSA) is insufficient drive to the upper-airway musculature during sleep, with increased (compensatory) drive during wakefulness. This generates more electromyographic activity in upper airway muscles including genioglossus. To understand drives to upper airway muscles, we recorded single motor unit activity from genioglossus in male groups of control ( n = 7, 7 ± 2 events h⁻¹) and severe OSA ( n = 9, 54 ± 4 events h⁻¹) subjects. One hundred and seventy-eight genioglossus units were recorded using monopolar electrodes. Subjects were awake, supine and breathing through a nasal mask. The distribution of the six types of motor unit activity in genioglossus (Inspiratory Phasic, Inspiratory Tonic, Expiratory Phasic, Expiratory Tonic, Tonic and Tonic Other) was identical in both groups. Single unit action potentials in OSA were larger in area (by 34%, P < 0.05) and longer in duration (by 23%, P < 0.05). Inspiratory units were recruited earlier in OSA than control subjects. In control subjects, Inspiratory Tonic units peaked earlier than Inspiratory Phasic units, while in OSA subjects, Inspiratory Tonic and Phasic units peaked simultaneously. Onset frequencies did not differ between groups, but the peak discharge frequency for Inspiratory Phasic units was higher in OSA (22 ± 1 Hz) than control subjects (19 ± 1 Hz, P = 0.003), but conversely, the peak discharge frequency of Inspiratory Tonic units was higher in control subjects (28 ± 1 Hz versus 25 ± 1 Hz, P < 0.05). Increased motor unit action potential area indicates that neurogenic changes have occurred in OSA. In addition, the differences in the timing and firing frequency of the inspiratory classes of genioglossus motor units indicate that the output of the hypoglossal nucleus may have changed.