Intimate stimuli result in fronto-parietal activation changes in anorexia nervosa.

BACKGROUND: Intimacy is a key psychological problem in anorexia nervosa (AN). Empirical evidence, including neurobiological underpinnings, is however, scarce. OBJECTIVE: In this study, we evaluated various emotional stimuli including intimate stimuli experienced in patients with AN and non-patients, as well as their cerebral response. METHODS: Functional magnetic resonance imaging was conducted using stimuli with positive, neutral, negative and intimate content. Participants (14 AN patients and 14 non-patients) alternated between passive viewing and explicit emotion regulation. RESULTS: Intimate stimuli were experienced less positively in AN patients compared to non-patients. AN patients showed decreased cerebral responses in superior parietal cortices in response to positive and intimate stimuli. Intimate stimuli led to stronger activation of the orbitofrontal cortex, and lower activation of the bilateral precuneus in AN patients. Orbitofrontal responses decreased in AN patients during explicit emotion regulation. CONCLUSIONS: These results show that intimate stimuli are of particular importance in AN patients, who show experiential differences compared to non-patients and altered activation of orbitofrontal and parietal brain structures. This supports that AN patients have difficulties with intimacy, attachment, self-referential processing and body perception. LEVEL OF EVIDENCE: Level III, case-control study.

Differential effects of long-chain alcohols in long- and short-sleep mice.

Observations that the long-sleep (LS) and short-sleep (SS( mouse lines differ in their depressant response to barbiturates, and that the difference between lines becomes greater as lipid solubility increases, prompted this investigation of the effects of alcohols that differ in lipid solubility. Results indicate that LS and SS mice differ significantly in their sleep time responses to propanol, butanol, and 3-methyl butanol, as well as ethanol: their hypothermic responses showed a similar pattern, but only the response to ethanol differed significantly between lines. For both sleep time and hypothermia, the difference between lines decreased with increasing lipid solubility. In all cases, the LS mice were more sensitive than the SS to the depressant effects of the alcohol. Similar ratios of SS:LS waking brain ethanol and butanol levels indicated that CNS sensitivity to long-chain alcohols is similar to that for ethanol. A pharmacokinetic study revealed higher ethanol levels for LS than for SS mice at all time points in blood, fat, and brain body compartments. Blood ethanol elimination curves showed that the SS mice eliminate ethanol at a faster rate than do the LS.

Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study.

N-methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood-brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid-induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose-limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self-limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half-life of 117.5 minutes (+/-53.2), and a clearance of 38.8 L/hr (+/-17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.

Thromboelastogram fails to predict postoperative hemorrhage in cardiac patients.

To determine the clinical usefulness of the thromboelastogram in the prediction of postoperative hemorrhage in cardiac patients, we related the results of routine coagulation tests (RCTs) and thromboelastography with the amount of chest tube drainage postoperatively in 101 patients requiring cardiopulmonary bypass. Our data indicated that there was no correlation between RCT results and thromboelastographic variables. No single variable of RCTs and thromboelastography correlated well with the amount of chest tube drainage postoperatively. Before the onset of cardiopulmonary bypass, the most frequent abnormalities detected by thromboelastograms were fibrinolysis and hypocoagulability resulting from factor deficiency. Hypercoagulability detected by thromboelastograms occurred in 13% of patients after cardiopulmonary bypass and usually was not detected by RCTs. The incidence of false-negative thromboelastograms and RCT results in patients who had excessive hemorrhage of unknown cause was 46% and 52%, respectively. The incidence of fibrinolysis as detected by thromboelastograms was similar before and after bypass, but only 2 of the 18 patients with fibrinolysis had excessive hemorrhage postoperatively. Our results indicate that neither RCTs nor thromboelastography predicts the likelihood of excessive hemorrhage in patients after cardiopulmonary bypass. The thromboelastographic results should be interpreted cautiously because of the high rate of unreliable results.

Components of the GABA system in mice selectively bred for differences in open-field activity.

Mice selectively bred for differences in open-field activity were utilized to test the hypothesis that differences in open-field behaviour are mediated at least in part by components of the GABA system, including brain glutamic acid decarboxylase activity (V, Vmax, and Km), as well as glutamate and GABA concentrations. Enzyme velocity was found to be inversely correlated with open-field activity, but it accounted for less than 15% of the variance. Moreover, the rank order of the lines was not as predicted for a genetically correlated character and the magnitude of the differences in enzyme activity among the lines was not large. It was therefore concluded that the GABA system is not an important mediator of differences in open-field behaviour in these lines of mice.

Effects of pentobarbital in mice selected for differential sensitivity to ethanol.

Two lines of mice have been genetically selected for differential sensitivity to ethanol. These lines have been designated long sleep (LS) and short sleep (SS) on the basis of their hypnotic response to the ethanol selection dose. Earlier studies of these mice suggested that this difference was limited to alcohols and did not extend to other classes of hypnotics. The present study examined hypnotic and hypothermic responses produced by pentobarbital in recent generations of these mice. Dose-dependent differences in sleep time and in hypothermia were found, with SS mice affected to a greater degree than LS mice. Pharmacokinetic studies showed that the half-life of pentobarbital disappearence from SS blood was twice that reported for SS mice of the 18th generation. The half-life in the LS line had not changed. The volumes of distribution and waking brain concentrations were identical in LS and SS mice. An altered rate of elimination (not differential CNS sensitivity) appeared to be the major factor responsible for the differences observed between these lines.

Chronic scopolamine treatment and brain cholinergic function.

Scopolamine was either continuously infused or injected once daily into C3H mice. Chronic infusion resulted in mice that were supersensitive to the hypothermia and tremor produced by the muscarinic agonist, oxotremorine. Chronic scopolamine infusion did not alter brain acetylcholinesterase (AChE) or choline acetyltransferase (ChAT) activities but it did produce an increase in brain muscarinic receptors, as measured by quinuclidinyl benzilate (QNB) binding. The maximal increase in QNB binding was seen at the 0.2 mg/kg/hr dose. Further increase in dose resulted in a return to control QNB binding in all brain regions studied except cortex. These animals were still supersensitive to oxotremorine, suggesting a dissociation between receptor number and response to agonist. Animals injected once daily for 10 days with 5 mg/kg exhibited an increase in QNB binding while no increase was seen at 20 mg/kg/day. Chronic oxotremorine infusion resulted in tolerance to the hypothermia-producing effects of oxotremorine. This was accompanied by a decrease in brain QNB binding. Coinfusion of scopolamine with oxotremorine blocked both the tolerance development and receptor changes. These experiments demonstrate that chronic scopolamine treatment can elicit an increase in brain muscarinic receptors which is accompanied by supersensitivity to agonists. However, this effect is not clearly dose related, and a strict relationship between receptor number and agonist response does not exist.

Rabbit cerebral cortex 5HT1a receptors.

Selective 5HT1a agonist binding to membranes from rabbit cerebral cortex was concentration-dependent and saturable; the Kd was 1.1 nM and Bmax of 480 fmols/mg protein. Scatchard as well as Hill plots were linear; the Hill coefficient was 0.96, suggesting a single, non-interacting binding site. Agonist binding was inhibited in a concentration-dependent fashion by gamma S GTP, a result consistent with the coupling of this binding site to the G protein signal transduction system. In competition experiments involving agonist and a series of agents with known affinities and specificities at 5HT1a receptors, a rank order relationship was found consistent with this binding site being a 5HT1a binding site. Direct comparisons of agonist and antagonist binding at rat cerebral cortex 5HT1a receptors and cloned human 5HT1a receptors also suggested that the rabbit binding site belongs to the 5HT1a class. The only rank order anomalies were with methiothepin in rabbit cerebral cortex, where a comparatively high Ki was observed and with buspirone in cloned human 5HT1a receptor, where a low Ki was determined; these anomalies bear further study in light of the comparative pharmacology of 5HT1a receptors. Finally, the natural product parthenolide was tested for affinity in the rabbit, rat, and human systems, where it uniformly was unable to displace agonist, suggesting that the 5HT1a receptor is not a target for this compound. Overall, these results suggest that a functional 5HT1a receptor exists in rabbit cerebral cortex.

Links between behavioral factors and inflammation.

This review focuses on the biobehavioral factors that show robust associations with markers of inflammation and discusses the following variables: diet, smoking, coffee, alcohol, exercise, and sleep disruption. Each of these variables has been assessed in large-scale epidemiological studies, and many of them have been assessed in clinical and experimental studies as well. Treatment strategies that target biobehavioral factors have the potential to complement and enhance the benefit of anti-inflammatory medicines.

A comparison of the inductive effects of phenobarbital, methaqualone, and methyprylon on hepatic mixed function oxidase enzymes in the rat.

The effects of equal doses of three sedative-hypnotics, phenobarbital, methaqualone, and methyprylon, on the hepatic mixed function oxidase enzymes of the rat were investigated and compared. After 5 days of pretreatment, phenobarbital and methyprylon significantly increased aminopyrine demethylation, aniline hydroxylation, and cytochrome P-450 content in hepatic microsomes. Methaqualone pretreatment only increased hepatic aminopyrine demethylase activity and wet liver weights. After 29 days of pretreatment, phenobarbital significantly increases aminopyrine demethylase, aniline hydroxylase activity, liver weight and cytochrome P-450 content. Methaqualone only produced a significant increase in wet liver weight.

Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation.

BACKGROUND: Conous infusions of sedative drugs in the intensive care unit may prolong the duration of mechanical ventilation, prolong the length of stay in the intensive care unit and the hospital, impede efforts to perform daily neurologic examinations, and increase the need for tests to assess alterations in mental status. Whether regular interruption of such infusions might accelerate recovery is not known. METHODS: We conducted a randomized, controlled trial involving 128 adult patients who were receiving mechanical ventilation and continuous infusions of sedative drugs in a medical intensive care unit. In the intervention group, the sedative infusions were interrupted until the patients were awake, on a daily basis; in the control group, the infusions were interrupted only at the discretion of the clinicians in the intensive care unit. RESULTS: The median duration of mechanical ventilation was 4.9 days in the intervention group, as compared with 7.3 days in the control group (P=0.004), and the median length of stay in the intensive care unit was 6.4 days as compared with 9.9 days, respectively (P=0.02). Six of the patients in the intervention group (9 percent) underwent diagnostic testing to assess changes in mental status, as compared with 16 of the patients in the control group (27 percent, P=0.02). Complications (e.g., removal of the endotracheal tube by the patient) occurred in three of the patients in the intervention group (4 percent) and four of the patients in the control group (7 percent, P=0.88). CONCLUSIONS: In patients who are receiving mechanical ventilation, daily interruption of sedative-drug infusions decreases the duration of mechanical ventilation and the length of stay in the intensive care unit.

A bioactive peptide from the transmembrane 5-intracellular loop 3 region of the human 5HT1a receptor.

15 amino acid peptide from the transmembrane 5-intracellular loop 3 region of the human 5HT1a receptor produced concentration-dependent decreases in agonist binding. This result is consistent with a competitive interaction between peptide, receptor, and G protein at the receptor-G protein interface. Bombesin and a 13 amino acid peptide from the carboxyl terminus region of the receptor were inactive. Additionally, the peptide decreased forskolin-mediated cAMP elevation. Overall, these results suggest that amino acid residues from this region of the receptor are involved in receptor-G protein coupling and that G protein is activated by the receptor.

Propofol in an emulsion of long- and medium-chain triglycerides: the effect on pain.

IMPLICATIONS: In a test of two formulations of propofol for induction, patients experienced less pain with the formulation in Intralipid (Propofol-Lipuro 1%) than with Diprivan 1%.

Lipid solubility is correlated with hypnotic and hypothermic responses of long-sleep (LS) and short-sleep (SS) mice to various depressant drugs.

The long-sleep (LS) and short-sleep (SS) lines of mice have been selected for a difference in duration of ethanol-induced sleep time. In our previous study, recent generations of the two lines were found to exhibit differential hypnotic and hypothermic responses to pentobarbital which appear to be explained by differences in elimination. Casual observation that the LS mice were fatter than the SS suggested that this discrepancy may influence the responses of these animals to sedative-hypnotic drugs which differ in lipid solubility. The present study was designed to determine whether the LS and SS mice differ in hypnotic and hypothermic responses to two barbiturates which differ in lipid solubility; to the highly lipid soluble tertiary alcohol, ethchlorvynol; and to the water soluble depressant, methyprylon. Mice of the SS line were more responsive to the lipid soluble depressants than were LS mice, and increasing the lipid solubility of the barbiturates resulted in a greater difference between the lines. LS mice were more responsive to the water soluble depressant, apparently due to differential central nervous system sensitivity rather than to differences in elimination. The whole-body lipid content of the LS mice is double that of the SS mice. The influence of body lipid content on drug disposition may accentuate the elimination differences that result in the lesser responsivity of LS mice to barbiturates and possibly ethchlorvynol. This study indicates that sedative-hypnotic drugs of varying lipid solubilities may not share common mechanisms of action.

Clinical examination reliably detects intrinsic positive end-expiratory pressure in critically ill, mechanically ventilated patients.

Critically ill patients requiring mechanical ventilation often develop intrinsic positive end-expiratory pressure (PEEPi). Methods for its detection include an expiratory flow waveform display (not always available), an esophageal pressure transducer (invasive), or a relaxed or paralyzed patient. We sought to determine the accuracy of clinical examination for detecting PEEPi. Examiners blinded to waveform analysis assessed patients for the presence of PEEPi by inspection/palpation and auscultation. If either inspection/palpation or auscultation demonstrated PEEPi, it was said to be present by clinical exam. Clinicians with various levels of experience (attending, resident, student) made 503 observations of 71 patients. Sensitivity (SENS), specificity (SPEC), positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios were determined for inspection/palpation, auscultation, and clinical exam. PEEPi was present during 69.8% of observations. SENS, SPEC, and PPV of clinical exam were 0.72, 0.91, and 0.95 respectively for the examiners as a whole. Likelihood ratio for PEEPi detection by clinical exam was 8.35. Attending intensivists displayed SPEC and PPV of 1.0. NPV was only 0.58 (likelihood ratio 0.31). We conclude that the clinical exam is very good for detecting PEEPi at all experience levels; and further, that the clinical exam is only modestly useful for ruling out PEEPi, therefore, other tests should be used if PEEPi is not detected by clinical exam.

A genetic analysis of ethanol, pentobarbital, and methyprylon sleep-time response.

The sleep-time responses to ethanol, pentobarbital, and methyprylon were assessed in various generations derived from crossing the long-sleep (LS) and short-sleep (SS) mouse lines in order to assess whether common or different genes regulate response to these agents. The LS and SS mice were selectively bred for differences in duration of ethanol-induced sleep time. Ethanol and pentobarbital responses segregate in a different fashion into F1 and F2 generations derived from the LS and SS lines, indicating different genic control and probably different mechanisms of action for these two agents. Ethanol and methyprylon response segregated similarly but fewer genes seem to influence methyprylon response. These results support the notion that water-soluble depressants have common mechanisms of action.

Systemic and gut O2 extraction during endotoxemia. Role of nitric oxide synthesis.

Endotoxin administration decreases intrinsic responsiveness of arteries to contractile agonists, both in vivo and in vitro. Endotoxin also impairs systemic and intestinal ability to increase microvascular O2 extraction in response to decreases in O2 delivery. During endotoxemia, contractile responsiveness can be increased by stereospecific inhibitors of nitric oxide (NO) synthase, suggesting that the hypotension and loss of microvascular function caused by endotoxin may result from increased nitric oxide biosynthesis. This study tested whether inhibition of NO synthesis could reverse the systemic and intestinal oxygen extraction defects seen after endotoxin challenge in the dog. Oxygen extraction and hemodynamic responses to progressive decreases in O2 delivery (stagnant hypoxia) were measured systemically and in isolated autoperfused intestine segments in anesthetized dogs. Systemic and intestinal O2 extractions at the onset of O2 supply dependency were significantly impaired in endotoxin-challenged (n = 6) compared with control (n = 7) animals. Inhibition of NO synthase activity with N omega-nitro-L-arginine methyl ester (L-NAME), 50 mg/kg + 100 mg/kg/h, completely inhibited endothelium-dependent vasodilation responses evaluated in vitro, and significantly but incompletely reversed the systemic hypotension in animals previously given endotoxin (n = 9). Despite this improvement, critical O2 extraction ratios remained significantly reduced. Administration of L-NAME in the absence of endotoxin (n = 8) significantly increased systemic vascular resistance and decreased cardiac output and O2 delivery, but it did not impair critical O2 extraction ratios in whole body or isolated intestine. We conclude that inhibition of NO synthesis in this model of endotoxemia can improve arterial pressure without improving those microvascular functions that may influence tissue O2 extraction efficacy.

Cardiopulmonary bypass produces greater pulmonary than systemic proinflammatory cytokines.

Cardiopulmonary bypass (CPB) impairs pulmonary endothelial injury in part by increasing expression of adhesion molecules that results in neutrophil influx. Although numerous proinflammatory cytokines up-regulate these responses, the extent to which systemic and pulmonary proinflammatory cytokines increase remains unknown. We therefore examined systemic and pulmonary gene expression and production of proinflammatory cytokines during CPB. Bronchoalveolar lavage and peripheral blood sampling were performed just after the induction of anesthesia and at the end of surgery in 80 patients undergoing CPB. RNA was extracted from harvested cells and cDNA was synthesized by reverse transcription. The expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) was measured by semiquantitative polymerase chain reaction using beta-actin as an internal standard. We also measured these cytokines in cultured alveolar macrophages and plasma monocytes in standard medium alone, or in the presence of lipopolysaccharide. We found 2- to 20-fold increases in gene expression for these cytokines in both plasma and alveolar leukocytes at the end of surgery. However, the increases were 4-8 times greater in alveolar than plasma leukocytes. Alveolar macrophages obtained at the end of surgery produced 1.5-3 times more IL-6, IL-8, and TNF-alpha than those obtained at the beginning (P < 0.0001). Although plasma monocytes produced more IL-8 at the end of surgery (P < 0.001), TNF-alpha and IL-6 did not increase. The production of all cytokines was 1.5-3 times greater in alveolar macrophages obtained at the end of surgery than in plasma monocytes obtained simultaneously (P < 0.005). Our data thus suggest that CPB provokes a greater pulmonary than systemic inflammatory response.

Neutrophil number and interleukin-8 and elastase concentrations in bronchoalveolar lavage fluid correlate with decreased arterial oxygenation after cardiopulmonary bypass.

Atelectasis is a major cause of decreased arterial oxygenation after cardiopulmonary bypass (CPB). There is a close relationship between atelectasis and inflammatory responses. We therefore tested the hypothesis that neutrophil number and the concentrations of proinflammatory cytokines and elastase in plasma and bronchoalveolar lavage fluid correlate with changes in arterial oxygenation. Bronchoalveolar lavage was performed just after the induction of anesthesia and at the end of surgery in 80 patients undergoing CPB. Peripheral blood was sampled simultaneously. Arterial oxygenation was quantified by PaO(2)/fraction of inspired oxygen (FIO(2)) and intrapulmonary shunt (Q(s)/Q(t)). PaO(2)/FIO(2) and Q(s)/Q(t) decreased significantly at the end of surgery, whereas neutrophil number, interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and elastase concentrations in the lavage fluid increased significantly. The increase in neutrophil count from the lavage fluid correlated significantly with the increases in IL-8 and elastase concentrations. The increase in neutrophil number and IL-8 and elastase concentrations in the lavage fluid correlated significantly with PaO(2)/FIO(2) and Q(s)/Q(t) at the end of surgery. In contrast, none of the plasma values correlated with these variables. Significant correlation between immune mediators and decreased arterial oxygenation suggests that inflammatory responses in the distal airway are strongly related to a decrease in arterial oxygenation after CPB.