Sleep ability mediates individual differences in the vulnerability to sleep loss: evidence from a PER3 polymorphism.

Sleep deprivation is highly prevalent in our 24/7 society with harmful consequences on daytime functioning on the individual level. Genetically determined, trait-like vulnerability contributes to prominent inter-individual variability in the behavioral responses to sleep loss and adverse circadian phase. We aimed at investigating the effects of differential sleep pressure levels (high vs low) on the circadian modulation of neurobehavioral performance, sleepiness correlates, and nap sleep in individuals genotyped for a polymorphism in the clock gene PERIOD3. Fourteen homozygous long (PER3(5/5)) and 15 homozygous short (PER3(4/4)) allele carriers underwent both a 40-h sleep deprivation and multiple nap protocol under controlled laboratory conditions. We compared genotypes regarding subjective and ocular correlates of sleepiness, unintentional sleep episodes as well as psychomotor vigilance during both protocols. Nap sleep was monitored by polysomnography and visually scored according to standard criteria. The detrimental effects of high sleep pressure on sleepiness correlates and psychomotor vigilance were more pronounced in PER3(5/5) than PER3(4/4) carriers. Under low sleep pressure, both groups showed similar circadian time courses. Concomitantly, nap sleep efficiency and subjective sleep quality across all naps tended to be higher in the more vulnerable PER3(5/5) carriers. In addition, PER3-dependent sleep-loss-related attentional lapses were mediated by sleep efficiency across the circadian cycle. Our data corroborate a greater detrimental impact of sleep deprivation in PER3(5/5) compared to PER3(4/4) carriers. They further suggest that the group with greater attentional performance impairment due to sleep deprivation (PER3(5/5) carriers) is superior at initiating sleep over the 24-h cycle. This higher sleep ability may mirror a faster sleep pressure build-up between the multiple sleep opportunities and thus a greater flexibility in sleep initiation. Finally, our data show that this higher nap sleep efficiency is positively related to attentional failures under sleep loss conditions and might thus be used as a marker for inter-individual vulnerability to elevated sleep pressure.

Propofol versus combined sedation in flexible bronchoscopy: a randomised non-inferiority trial.

Combined sedation with a benzodiazepine and an opiate has been proposed as standard sedation for bronchoscopy. Propofol is a sedative-hypnotic with a rapid onset of action and fast recovery time, but carries the potential risk of respiratory failure. Consecutive patients (n = 200) were randomly allocated to receive either the combination midazolam and hydrocodone or intravenous propofol. The primary end-points were the mean lowest arterial oxygen saturation during bronchoscopy and the readiness-for-discharge score 1 h after the procedure. The mean lowest arterial oxygen saturation during bronchoscopy did not differ across treatment groups (p = 0.422), and the number of patients recording an arterial oxygen saturation of < or =90% on at least one occasion was similar in both groups (p = 0.273). The median (interquartile range) readiness-for-discharge score 1 h after the procedure was significantly higher in the propofol group than in the combined sedation group (8 (6-9) versus 7 (5-9); p = 0.035). Patients assigned propofol exhibited less tachycardia during bronchoscopy and for > or =1 h after the examination. Minor procedural complications were noted in 71 (35.5%) patients and exhibited a similar incidence in both treatment arms (p = 0.460). Propofol is as effective and safe as combined sedation in patients undergoing flexible bronchoscopy, thus representing an appealing option if timely discharge is a priority.

[Symptomatic management in amyotrophic lateral sclerosis (ALS)]. / Symptomatische Therapie der amyotrophen Lateralsklerose (ALS).

Although disease-specific treatment of amyotrophic lateral sclerosis is still unsatisfactory, a number of advances have been made in the symptomatic therapy of ALS patients within the last decade. Current data suggest that active and aggressive multidisciplinary management of ALS patients improve their quality of life and prolong their survival. Patient and caregiver communications and decisions are increasingly recognized to be a relevant part of this management. A wide range of supportive and palliative measures, in particular the widely use of symptomatic drugs for pseudobulbar affect, sialorrhea, and sleep disorders is available to relieve patients symptomatology. In addition, patients quality of life has been profoundly improved by the introduction of enteral nutrition and non-invasive ventilation.

Ceramic inserts do not generally improve resin composite margins.

summary Ceramic inserts are reported to possibly reduce polymerization shrinkage for posterior resin composite fillings. The aim of the present investigation was to evaluate the effect of different insert systems before and after thermomechanical loading. Sixty sound human third molars received occlusomesial Class II cavities, 40 with proximal margins 2 mm above and 20 with proximal margins 1 mm below the cementum-enamel junction. The specimens were randomly assigned to one of the six experimental groups (n = 10). The enamel-bordered cavities were restored with Syntac classic and Tetric Ceram (ST), Syntac classic, Tetric Ceram and beta-quartz inserts (TB), Syntac classic, Tetric Ceram and Cerana inserts (TC), Syntac classic, Tetric flow and SonicSys approx inserts (TS). The dentin-limited cavities were filled with Syntac classic and Tetic Ceram (DT), Syntac classic, Tetric flow and SonicSys approx inserts (DS). Before and after thermomechanical loading (100 000 x 50 N, 2500 x 5 degrees C/55 degrees C), replicas were made and both interfaces tooth/composite and insert/composite were examined under a scanning electron microscope at 200x. The Cerana and SonicSys insert groups showed significantly less gaps in enamel (P < 0.05). With beta-quartz inserts, no reduction of gaps was found (P > 0.05). Marginal integrity in dentine-bordered specimens could not be improved with SonicSys inserts (P > 0.05). The bonding performance insert/composite was promising for all IPS Empress inserts (Cerana, SonicSys enamel) but worse for beta-quartz inserts. Regarding gap formation between resin composite and tooth, Cerana and SonicSys inserts significantly reduced gaps. The use of SonicSys inserts in deep proximal cavities cannot be recommended.

Obstructive sleep apnea: therapies other than CPAP.

Nasal application of continuous positive airway pressure (CPAP) is the standard form of therapy for treating obstructive sleep apnea (OSA). Common difficulties associated with CPAP therapy include sense of dryness in the mouth, rhinorrhea, nasal congestion and dryness, mask discomfort, claustrophobia, irritation from device noise, aerophagy, chest discomfort and partner's intolerance. Therefore, many patients are unable to or unwilling to comply with the use of CPAP. This article discusses the various non-CPAP approaches that have been investigated in the management of OSA, which include behavioral therapy (weight loss and positional therapy), pharmacological treatment, mandibular advancement techniques and surgery. However, none of these has been shown to be superior to CPAP. In clinical practice, only selected patients will benefit from therapies other than CPAP.

Effect of surface treatment on fatigue behaviour between Tetric Ceram inlays and Variolink luting composite.

The effect of pre-treatment of composite inlays on bonding performance between a resin composite inlay and a luting composite has not been fully studied. The aim of the present study was to evaluate the influence of three different pre-treatment modes on fatigue bond strength and marginal adaptation. One hundred twenty resin composite discs (Tetric Ceram) were made as simulated inlays and randomly assigned to four groups (n=30): Without treatment (WT), hydrofluoric acid etching for 15 s + silanating (HF), roughening with a silicon carbide bur (SC), and silica coating + silanating (CO). Luting composite cylinders (Variolink II low) were bonded to the discs using Heliobond, and after 24 h in water at 37 degrees C, quasistatic shear bond strengths (n=l) and fatigue bond strengths (n=20; 5,000 cycles) were measured. Thirty-two third molars received occlusomesial Class II cavities (n=8), and direct resin composite inlays were luted with identical methods and materials. Before and after thermomechanical loading (100,000x50 N, 2,500 x +5 degrees C/+55 degrees C), replicas were made and examined (SEM, x200). CO and SC exhibited significantly higher bond strengths and adhesive fatigue limits than HF and WT (P<0.05). After thermomechanical loading, CO (98% continuous margin) and SC (95% continuous margin) demonstrated that they provide significantly more fatigue resistance than HF (88%).

Effect of midazolam on transfer function between beat-to-beat arterial pressure and inter-beat interval length.

Arterial pressure (AP) and inter-beat interval (IBI) length are under autonomic nervous system control. The control mechanisms can be investigated by transfer function analysis. It is not known if this type of analysis may be helpful in monitoring depth of sedation. In an open-label, uncontrolled investigation, the effect of midazolam on the transfer function between AP and IBI, and on spectral indices of AP and heart rate (HR) variability (APV, HRV) were assessed in the absence and presence of the benzodiazepine antagonist flumazenil. We studied 11 healthy male volunteers. After an initial control period of 60 min, we studied three consecutive periods, each of 60 min duration, with progressively increasing concentrations of midazolam (0.02, 0.06, 0.14 mg kg-1 h-1). A final 60-min period during administration of flumazenil 0.004 mg kg-1 h-1 and while the agonist was still present was also studied. To confirm midazolam-induced central nervous system effects, electroencephalography was performed and Ramsay sedation scores were determined. With increasing dose of midazolam, the high frequency (0.15-0.4 Hz) component of the transfer function between AP and IBI decreased progressively (mean 26.5 (SEM 3.7), 19.2 (2.9), 12.8 (1.7), 8.4 (1.6) ms mm Hg-1). This effect was antagonized by flumazenil (21.5 (3.2) ms mm Hg-1). Other indices (e.g. HRV, APV) did not reveal such a clear response to midazolam dose and flumazenil application. Thus in healthy male volunteers, the transfer function between AP and IBI in the parasympathetically dominated high frequency range varies according to benzodiazepine agonism and antagonism. This finding has potential implications for monitoring the effects of benzodiazepines.

Adjunctive drug treatment in severe hypoxic respiratory failure.

This article reviews the pharmacological treatment of severely hypoxaemic critically ill patients, notably those with acute respiratory distress syndrome (ARDS), acute lung injury or the sepsis syndrome. Haemodynamic support in hypotensive patients often initially requires aggressive fluid resuscitation with crystalloids or colloids, combined with vasopressors to maintain adequate end-organ perfusion. The catecholamine of choice in severe hypotension with low systemic resistance is norepinephrine (noradrenaline); dopamine is often used in mild hypotension. Once haemodynamic stabilisation is achieved, loop diuretics such as furosemide (frusemide) are used to obtain the lowest volaemia that guarantees adequate perfusion. If the fraction of inspired oxygen necessary to achieve the satisfactory haemoglobin oxygen saturation of 90% approaches 1, a trial of nitric oxide with or without almitrine is justified. Oxygen consumption can be lowered by treating fever with paracetamol (acetaminophen) and physical cooling. Occasionally, deep sedation using a combination of an opioid (most often morphine or fentanyl) and a benzodiazepine (lorazepam or midazolam) is necessary; in the presence of renal or hepatic insufficiency, propofol is a valid, although expensive, alternative. Paralysis with pancuronium or vecuronium has been associated with critical illness polyneuropathy and is used only as a last resort. Corticosteroids may be indicated in the subacute (fibroproliferative) phase of ARDS. Other anti-inflammatory treatments (such as cytokine antagonists, cyclo-oxygenase inhibitors, antioxidants or monoclonal anti-endotoxin antibodies), as well as surfactant supplementation, have failed to improve prognosis in randomised trials.

Midazolam effects on prepulse inhibition of the acoustic blink reflex.

AIMS: The eye-blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenuated by presentation of a weak stimulus before the 'startle-eliciting' stimulus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the application of benzodiazepines altered the magnitude of PPI in healthy male volunteers. METHODS: In an open-label noncontrolled investigation, the effect of the benzodiazepine agonist midazolam on PPI was assessed in the absence and presence of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing concentrations of midazolam were studied (0. 02, 0.06, 0.14 mg kg-1 h-1 ). A final 60 min period during the administration of flumazenil (0.004 mg kg-1 h-1 ) and while the agonist was still present was also studied. Drug was administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) response of the right orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were randomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 65 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calculated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects participated in the study, two of them were excluded from the statistical analysis because startle responses could not be reliably elicited (final sample size n=9). RESULTS: The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal Emax model, giving an Emax of 0.65+/-0.13, an ED50 of 33.9+/-10.9 ng ml-1 and gamma of 3.5+/-1.0. During infusion of flumazenil and in the presence of midazolam, the magnitude of PPI increased by 0.11 (95% CI, 0-0.22, P

Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure.

BACKGROUND: The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown. METHODS AND RESULTS: Thirty-six men (mean age+/-SD, 55+/-8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4+/-4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (-24.2% [-28.1% to -20.3%]) and pulmonary (-19.9% [-28.4% to -11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15. 2% [10.8% to 19.6%]) and systemic (-9.3% [-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to -3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged. CONCLUSIONS: Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.

Substance P in human hand veins in vivo: tolerance, efficacy, potency, and mechanism of venodilator action.

OBJECTIVES: To study potency, efficacy, development of tolerance, and mechanism of action of substance P, an endothelium-dependent vasodilator neurokinin, in human hand veins in vivo. METHODS: Thirty-three healthy subjects were studied with use of the hand vein compliance technique. In hand veins preconstricted with the alpha 1-agonist phenylephrine, substance P and antagonists of nitric oxide formation (L-NG-mono-methyl-arginine, L-NMMA), adenosine triphosphate (ATP)-dependent potassium channels (glyburide), angiotensin converting enzyme (enalaprilat), and cyclooxygenase (acetylsalicylic acid) were infused and the venodilator effect was measured. RESULTS: Substance P proved to be the most potent venodilator known thus far (the dose-rate exerting 50% of mean maximum dilation [ED50], geometric mean: 0.105 pmol/min). Rapid development of tolerance occurred in seven of eight volunteers studied. Glyburide decreased the venodilator action of a single dose of substance P (1.5 pmol/min) from 81% to 28% of baseline venodilation (p < 0.05), suggesting that substance P acts through release of endothelium-derived hyperpolarizing factor. The cyclooxygenase-inhibitor acetylsalicylic acid reduced substance P-induced venodilation from 53% +/- 7% to 34% +/- 8% (p < 0.05), whereas L-NMMA had no effect. CONCLUSIONS: Unlike in other vessels, substance P-induced venodilation in hand veins is not mediated through nitric oxide but to a significant extent through a glyburide-sensitive pathway. Therefore it appears likely that substance P activates ATP-dependent potassium channels on vascular smooth muscle cells through the release of endothelium-derived hyperpolarizing factor.

Neuropeptide Y in human hand veins: pharmacologic characterization and interaction with cyclic guanosine monophosphate-dependent venodilators in vivo.

The dorsal hand vein compliance technique was used to study direct vascular effects of human neuropeptide Y in vivo. Human neuropeptide Y is an endogenous vasoconstrictor peptide that is costored with norepinephrine in sympathetic nerve endings and coreleased with the catecholamine under various physiologic and pathologic conditions. Compared with the alpha 1-adrenergic agonist phenylephrine (geometric mean dose-rate that produces the half-maximal response [ED50]: 1.05 nmol/min; maximum venoconstriction [Emax] +/- SEM, expressed as a percentage of baseline compliance: 91% +/- 3%), human neuropeptide Y was nine times more potent (geometric mean ED50: 0.122 nmol/min; p < 0.001) but markedly less efficacious (Emax: 58% +/- 4%; n = 12; p < 0.001). Venoconstrictor effects of human neuropeptide Y lasted several hours and were unchanged by simultaneous administration of alpha-adrenergic antagonists but were readily reversed by nitroglycerin or bradykinin. The high responsiveness of subcutaneous veins to human neuropeptide Y indicates that human neuropeptide Y may regulate venous compliance and filling of the venous subcutaneous capacitance bed in vivo.

Indirect evidence for stimulation of nitric oxide release by tumour necrosis factor-alpha in human veins in vivo.

OBJECTIVES: The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compound, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-alpha (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF. METHODS: Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-NG-monomethyl-arginine (L-NMMA) on alpha 1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 micrograms in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure. RESULTS: Mean (+/- s.e.) maximum phenylephrine constriction (Emax) was 73 +/- 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 +/- 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 mumol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 +/- 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 +/- 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA. CONCLUSIONS: As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to alpha-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shock.

Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study.

OBJECTIVE: To evaluate efficacy and tolerability of the lipase inhibitor Orlistat (Ro 18-0647) in doses of 10, 60 and 120 mg three times a day in addition to a mild hypocaloric diet containing 30% of calories as fat. DESIGN: 4 week single-blind placebo run-in period of diet alone followed by a 12 week double-blind, placebo-controlled, randomized treatment period. SETTINGS: Five European outpatient clinics specializing in endocrinology and/or the treatment of obesity, one central laboratory. SUBJECTS: Of 237 healthy obese subjects meeting the inclusion criteria, 188 showed compliance to the diet during the run-in period and were randomized for the treatment period. MAIN OUTCOME MEASURES: Primary efficacy criterion was the difference in weight loss after 12 weeks of treatment between the Orlistat treated groups and the diet alone group. Secondary efficacy criteria were changes in serum total, HDL- and LDL-cholesterol. RESULTS: Compared to placebo a mean (+/- s.e.) additional weight loss of 0.63 +/- 0.54 kg with 30 mg a day (P = 0.246), 0.71 +/- 0.55 kg with 180 mg a day (P = 0.190) and 1.75 +/- 0.54 kg with 360 mg a day was seen (P = 0.001) or Orlistat was observed. Overall data indicated dose-dependency. Small decreases were seen in total and LDL-cholesterol (significant in the 180 and 360 mg a day groups) and LDL- to HDL-cholesterol ratio (significant in the 360 mg a day group only). Mild, mostly gastrointestinal side effects were observed more frequently in the Orlistat groups and caused premature withdrawal from the study in only four patients. No marked laboratory abnormalities were shown, including the lipid-soluble vitamins A, D and E. CONCLUSION: Orlistat, in an apparently dose-dependent manner, leads to additional weight loss compared to diet alone and overall, is well tolerated.