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Recent studies in transition metal catalysis employing chelating phosphines have suggested a role for partial ligand oxidation in formation of the catalytically active species, with potentially widespread relevance in a number of catalytic systems. We examine the internal redox reaction of PdII(bisphosphine)X2(X = Cl, OAc, etc.) complexes to reveal previously underexplored aspects of bisphosphine monoxides (BPMOs), including evaluation of ligand structure and development of general reaction conditions to access a collection of structurally diverse BPMO precatalysts based on organopalladium oxidative addition complexes. In particular, a series of PdII(BPMO)(R)(X) (R = aryl, alkyl; X = I, Br) oxidative addition complexes bearing 24 different BPMO ligands were characterized by NMR and X-ray crystallography. Comparison of the catalytic performance of the oxidative addition complexes of bisphosphine versus bisphosphine monoxides as precatalysts is demonstrated to be an enabling diagnostic tool in Pd catalytic reaction development. Finally, the differences in catalytic behavior between bisphosphine and bisphosphine monoxide complexes were rationalized through solid-state parametrization and stoichiometric experiments.

In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.

Cyclopropanes are a common motif in many pharmaceutically relevant compounds, and methods for the synthesis of these strained rings have relevance throughout the pharmaceutical development process. Among the many options, the Corey–Chaykovsky cyclopropanation stands out due to its broad substrate scope, high functional group tolerance, and mild conditions. Despite these benefits, its application to the synthesis of cyclopropanes, specifically in the context of large-scale syntheses, has been limited. In this review, the scope and limitations of the Brønsted-base-promoted Corey–Chaykovsky cyclopropanation with sulfur ylides will be examined. Through this discussion, gaps in the scope and understanding of the transformation will be highlighted to promote further application and advancement of this powerful and useful methodology.

Quality of life (QoL) is inversely associated with alcohol misuse and is a key measure by which recovery from alcohol use disorder (AUD) might be assessed. Yet, the determinants of QoL are scarcely known. The authors examined three ways through which demographic characteristics, familial and early life factors, and psychopathology conferred risks for QoL, including unique direct effects, developmental pathways, and clinical risk Profiles. Cross‐sectional data from 1095 adults (50.4% without AUD; 49.6% with AUD) who participated in the NIAAA Natural History Protocol from January 2015 to March 2022 were analyzed. Multivariable regressions, path analysis, and latent Profile analysis were conducted. AUD was uniquely associated with lower QoL, and adverse effects of child maltreatment history and psychopathology symptoms on QoL were of similar or larger magnitudes. Mediation analysis indicated family history of AUD and child maltreatment history were indirectly associated with lower QoL through higher attention‐deficit/hyperactivity disorder symptoms, higher depressive symptoms, and positive AUD diagnosis. Latent Profile analysis of an enriched set of clinical characteristics identified four latent Profiles capturing the full range of alcohol use behavior. Latent Profiles with greater severity of familial and early life factors, psychopathology, and problematic drinking showed dose‐response associations with lower levels of physical, psychological, social, and environment QoL. A constellation of developmental and clinical characteristics disproportionately affects individuals with AUD and is negatively associated with QoL domains. To improve QoL, prevention and intervention need to target multiple factors, including history of child maltreatment, comorbid psychopathology, and problematic drinking itself. Quality of life can be conceptualized as a multidimensional construct, encompassing the domains of physical, psychological, social, and environment quality of life. This study showed multiple ways early life factors and clinical characteristics could individually and collectively confer risk for low quality of life across these four domains.Early life and familial factors were indirectly associated with lower quality of life through heightened psychopathology symptoms and alcohol use disorder. Four latent Profiles that captured the severity of developmental and clinical characteristics were inversely associated with domains of quality of life. Developmental risk factors and clinical indicators underlying the latent Profiles should be assessed to inform case conceptualization in the treatment of alcohol use disorder.Several demographic characteristics, including older age, male gender, other marital status, fewer years of education, and lower household income, were linked to increased risk of membership in latent Profiles with greater clinical severity. These findings could inform targeted prevention and intervention efforts among at risk populations and highlight the importance of investigating health disparities in the context of alcohol and quality of life research. Quality of life can be conceptualized as a multidimensional construct, encompassing the domains of physical, psychological, social, and environment quality of life. This study showed multiple ways early life factors and clinical characteristics could individually and collectively confer risk for low quality of life across these four domains. Early life and familial factors were indirectly associated with lower quality of life through heightened psychopathology symptoms and alcohol use disorder. Four latent Profiles that captured the severity of developmental and clinical characteristics were inversely associated with domains of quality of life. Developmental risk factors and clinical indicators underlying the latent Profiles should be assessed to inform case conceptualization in the treatment of alcohol use disorder. Several demographic characteristics, including older age, male gender, other marital status, fewer years of education, and lower household income, were linked to increased risk of membership in latent Profiles with greater clinical severity. These findings could inform targeted prevention and intervention efforts among at risk populations and highlight the importance of investigating health disparities in the context of alcohol and quality of life research.

Interindividual variation in responses to alcohol is substantial, posing challenges for medical management and for understanding the biological underpinnings of alcohol use disorders (AUD). It is important to understand whether diverse alcohol responses such as sedation, which is predictive of risk and partly heritable, occur concurrently or independently from responses such as blackouts and withdrawal. We hypothesized that latent factors accounting for sources of variance in diverse alcohol response phenotypes could be identified in a large, deeply phenotyped sample of patients with AUD. We factor analyzed 17 alcohol response related items from the Alcohol Dependence Scale (ADS) in 938 individuals diagnosed with AUD via structured clinical interviews. Demographic, genetic, and clinical characteristics were tested as predictors of the latent factors by multiple indicators, multiple causes analysis. The final factor solution included three alcohol response factors: Physical Symptoms, Perceptual Disturbances, and Neurobiological Effects. Both gender and genetic ancestry were identified as variables influencing alcohol response. Major depressive disorder positively predicted physical symptoms and aggression negatively predicted physical symptoms. Barratt's Impulsivity Scale total score predicted the Physical and Perceptual domains. Family history, average drinks per drinking day, and negative urgency (an impulsivity measure) predicted all three domains. Diverse items from the ADS concurrently load onto three correlated alcohol response factors rather than loading independently. Genetic ancestry and clinical characteristics predicted the severity of items that define the alcohol response factors even after accounting for degree of alcohol consumption. Co‐occurring phenotypes point towards an underlying shared physiology of diverse alcohol responses. Three common factors relevant for diverse alcohol responses are identified: Physical Symptoms, Perceptual Disturbances, and Neurobiological EffectsAlcohol response items from the Alcohol Dependence Scale concurrently load onto these three factors rather than loading independentlyThe three factors are correlated; patients presenting to clinical settings with a problem such as blackout are likely to experience several other problems either acutely or in the future Three common factors relevant for diverse alcohol responses are identified: Physical Symptoms, Perceptual Disturbances, and Neurobiological Effects Alcohol response items from the Alcohol Dependence Scale concurrently load onto these three factors rather than loading independently The three factors are correlated; patients presenting to clinical settings with a problem such as blackout are likely to experience several other problems either acutely or in the future

A new catalytic radical-polar crossover annulation between two unsaturated carbonyl compounds is described. The annulation proceeds under exceptionally mild conditions and provides direct and expedient access to complex terpenoid motifs. Application of this chemistry allows for synthesis of forskolin, a densely functionalized terpenoid, in 14 steps from commercially available material.

Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol‐induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex‐related differences in these parameters in alcohol‐dependent individuals admitted to an alcohol treatment program. A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. Sixty‐nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor‐alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. The study documented the association of mild alcohol‐induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program. The study demonstrated that mild alcohol‐induced liver injury (alcohol‐dependent individuals with slightly elevated ALT [Group 2] versus normal ALT [Group1]) was associated with endotoxemia, which improved with 2 weeks of abstinence. Liver damage and endotoxemia were greater in females than males, although they had fewer drinks/day and shorter lifetime duration of heavy drinking. The study provides further evidence for the role of the gut:liver axis in the development of ALD and a rationale for LPS‐targeted therapies for early ALD.

A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase (FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses. Forty‐nine patients with PTSDand ADwere admitted for 4 weeks to an experimental medicine unit at the National Institutes of Health Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid (eCB) levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSDsymptom severity. FAAHC385A allele carriers showed a marked increase in serum anandamide levels at baseline and throughout the stress challenge procedure compared with C allele homozygotes, while levels of eCBs primarily metabolized through other enzymatic activity, such as 2‐arachidonoylglycerol, did not differ between genotype groups. FAAHC385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAHC385A genotype were found at the level of clinical PTSDsymptom severity, in particular in the arousal domain. This is to our knowledge the first study showing that FAAHC385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the eCB pathway as a promising target for future antistress therapeutics. In patients with PTSDand comorbid alcohol dependence, a common single nucleotide polymorphism (C385A) in the fatty acid amide hydrolase (FAAH) gene is associated with a marked increase in serum anandamide levels and with faster decline of the anxiety responses to a stressor. These findings indicate that FAAH385A variation facilitates habituation to and extinction of chronic stress response, without influencing response to acute stress. This points to the endocannabinoid pathway as a promising target for future antistress therapeutics.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21–65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Heavy alcohol consumption frequently causes liver inflammation/injury, and certain fatty acids (FAs) may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking and the changes in the FA levels involved in the ω‐6 (pro‐inflammatory) and ω‐3 (anti‐inflammatory) state in alcohol‐dependent (AD) patients who had no clinical manifestations of liver injury. We aimed to identify sex‐based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. A total of 114 heavy drinking ADfemale and male patients aged 21 to 65 years without clinical manifestations of liver injury, who were admitted to an alcohol dependence treatment program, were grouped by the alanine aminotransferase (ALT) levels: ≤40 IU/l, as no liver injury (GR.1), and >40 IU/l, as mild liver injury (GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic panel, comprehensive FA panel, and drinking history data were evaluated. Elevated ALTand aspartate aminotransferase (AST) showed close association with markers of heavy alcohol intake. In the patients with mild biochemical liver injury (GR.2), females showed significantly higher ASTlevel than males. Significant association of ASTand total drinks in past 90 days (TD90) in females, and ASTand heavy drinking days in past 90 days (HDD90) in males was observed. The ω‐6:ω‐3 ratio showed a significant pro‐inflammatory response only in females with mild liver injury (GR.2) when adjusted by drinking history marker, TD90. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were increased in males with liver injury, while females did not show any comparable rise in EPA; and DHAlevels were lower. Measures of heavy drinking, TD90 and HDD90, predicted changes in liver injury. Changes in the ω‐3 and ω‐6 FA levels and the ω‐6:ω‐3 ratio showed a pro‐inflammatory shift in patients with biochemical liver injury with a significant effect in females. Changes in FAs involved in the inflammatory state may represent one mechanism for liver inflammation/injury in response to heavy alcohol drinking. EPA levels were significantly increased in male alcohol‐dependent patients who exhibited mild liver injury; however, there was no response change in females. On the other hand, DHA levels were reduced in females who exhibited mild liver injury, while in males with mild liver injury, there was an increase in DHA levels supporting protective or anti‐inflammatory response.

Background: Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought.

Objective: Alcoholism and aggression have each been associated with neurochemical measurements suggestive of decreased serotonin synaptic transmission. We measured densities of the serotonin transporter (SERT) in a moderate‐sized sample of alcoholic patients who were assessed for aggressive characteristics.

Background: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic‐pituitary‐adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long‐term sober alcoholics.

BACKGROUND: We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. METHODS: We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monoamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. RESULTS: A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. CONCLUSION: Among treatment-seeking alcoholics, early age at onset is generally associated with a more severe course of alcoholism and lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.

• To avoid the confounding influences of malnutrition or weight loss, we studied patients with anorexia nervosa at normal weight and stable dietary intake. Compared with 15 controls, 17 long-term weight-restored anorectic subjects had elevated concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid, the major serotonin metabolite, whereas levels of cerebrospinal fluid homovanillic acid, the major dopamine metabolite, were normal. Elevated levels of cerebrospinal fluid 5-hydroxyindoleacetic acid may indicate increased serotonin activity. Such activity could contribute to pathological feeding behavior. Most importantly, this study raises the question as to whether increased cerebrospinal fluid 5-hydroxyindoleacetic acid levels are associated with overly inhibited, anxious, or obsessive traits.

• We assessed the plasma corticotropin (adrenocorticotropic hormone) and cortisol responses to ovine corticotropin releasing hormone (oCRH) and the cerebrospinal fluid levels of CRH and corticotropin in alcoholics at various durations of abstinence and compared these variables with age-equivalent controls. Alcoholics who were tested at 1 week of abstinence (n = 11) demonstrated a significantly attenuated corticotropin response to oCRH compared with their response at 3 weeks of abstinence. Nine of these alcoholic patients demonstrated a significantly blunted corticotropin response at both 1 and 3 weeks of abstinence compared with controls (n =15). A markedly exaggerated corticotropin response to oCRH, associated with tachycardia, was exhibited by 2 alcoholics at both 1 and 3 weeks of abstinence. Alcoholics who were abstinent greater than 3 weeks did not differ in their response to oCRH compared with controls. Controls demonstrated a significant inverse correlation between baseline cortisol levels and the cortisol response to oCRH. This correlation was not evident in any of the alcoholic groups, including those patients who were abstinent greater than 6 months. There was a positive correlation between cerebrospinal fluid concentrations of CRH and corticotropin in all patient groups. These findings indicated that alcoholics have significantly altered hypothalamic-pituitary-adrenal axis functioning up to 3 weeks following the cessation of drinking, with a more subtle impairment present for greater than 6 months following abstinence.

• The related central nervous system peptides neuropeptide Y and peptide YY have been found to be among the most potent endogenous stimulants of feeding behavior. We measured these neuropeptides in cerebrospinal fluid to determine whether they contributed to the pathophysiologic characteristics of anorexia and bulimia nervosa. Cerebrospinal fluid neuropeptide Y concentrations were significantly elevated in underweight anorectic patients and in many of the anorectic patients studied at intervals after weight restoration. These levels normalized in long-term weight-restored anorectic patients who had a return of normal menstrual cycles. Increased neuropeptide Y activity may contribute to several characteristic disturbances in anorexia, including menstrual dysregulation. Cerebrospinal fluid peptide YY concentrations were significantly elevated in normal-weight bulimic patients abstinent from pathological eating behavior for a month compared with themselves when actively bingeing and vomiting or compared with healthy volunteers. Increased peptide YY activity may contribute to a drive to overfeed in normal-weight bulimic patients.

The effects of fluvoxamine (50 or 100 mg), alone and in combination with ethanol (0.8 g/kg), on psychomotor and cognitive performance and on autonomic nervous system reactivity were studied in healthy male volunteers. Fluvoxamine produced neither serious psychomotor or cognitive impairment nor alterations in autonomic nervous system functioning at these doses. There was no evidence that fluvoxamine exacerbated, or improved, ethanol-induced impairments of memory or any other measures evaluated. Fluvoxamine tended to improve recognition, but not free recall, of words.

George, David T., Stuart A. Binder-Macleod, Thomas N. Delosso, and William P. Santamore. Variable-frequency train stimulation of canine latissimus dorsi muscle during shortening contractions. J. Appl. Physiol.83(3): 994–1001, 1997.—In cardiomyoplasty, the latissimus dorsi muscle (LDM) is wrapped around the heart ventricles and electrically activated with a constant-frequency train (CFT). This study tested the hypotheses that increased mechanical performance from the LDM could be achieved by activating the muscle with variable-frequency trains (VFTs) of shorter duration or containing fewer stimulus pulses than the CFT now used. The mechanical performance of the canine LDM (n= 7) during shortening contractions was measured while the muscle was stimulated with 5- and 6-pulse CFTs (of duration 132 and 165 ms, respectively) and 5- and 6-pulse VFTs (of duration 104 and 143 ms, respectively) that were designed to take advantage of the catchlike property of skeletal muscle. Measurements were made from fresh and fatigued muscles. For the fresh muscles, the VFTs elicited significantly greater peak power than did the 6-pulse CFT. When the muscles were fatigued, VFT stimulation significantly improved both the peak and mean power produced compared with stimulation by CFTs. These results show that stimulation of the LDM with shorter duration VFTs is potentially useful for application in cardiomyoplasty.

Pharmacologic enhancement of central nervous system serotonin and dopamine functions has been postulated to improve maintenance of abstinence in patients with alcoholism. To test this hypothesis, patients with alcoholism who completed a 42-day inpatient treatment program were randomized to be administered, in a double-blind fashion, either 5-hydroxytryptophan and carbidopa, levodopa and carbidopa, or placebo for 1 year. Eight of 31 patients who entered the analysis remained abstinent from alcohol for 1 year; however, there was no significant effect of the treatment condition on maintenance of abstinence. Baseline psychologic measures showed that patients who abstained from alcohol had more education and higher scores on memory function tests. Measures of cerebrospinal fluid obtained before the start of the study indicated that all patients who had higher concentrations of the dopamine metabolite homovanillic acid relapsed, suggesting that further research is needed to elucidate the role of dopamine in alcoholism.Clinical Pharmacology and Therapeutics (1992) 52, 553–560; doi:10.1038/clpt.1992.184

• To explore the relationship of central and peripheral adrenocorticotropic hormone (ACTH, or corticotropin) levels to hypothalamo-pituitary-adrenal axis dysfunction in patients with eating disorders, levels of cerebrospinal fluid (CSF) and plasma ACTH, cortisol, and 24-hour urinary free cortisol were measured in 16 patients with anorexia nervosa (60% ±1.1% of ideal body weight), 14 patients with bulimia (93.2% ±4.6% of ideal body weight), and 11 healthy age-matched women volunteers. The CSF, plasma, and urinary free cortisol levels were elevated in underweight anorexic patients and showed declines following weight recovery. Cortisol-binding globulin levels were similar in anorexics and controls. In contrast, underweight anorexics showed low CSF ACTH levels that returned to normal following weight recovery, and their plasma ACTH levels were normal. On hospital admission, bulimic patients demonstrated normal ACTH and cortisol levels. After their abstinence from binge-purge episodes, the CSF ACTH levels decreased significantly. Positive relationships were found among CSF, plasma, and urinary cortisol levels, and inverse relationships were seen between cortisol measures and CSF ACTH levels in patients with eating disorders. Secretion of ACTH into the CSF may respond to feedback by cortisol or, alternatively, may be suppressed by the hypersecretion of corticotropin-releasing hormone, leading to the depletion of the pro-opiomelanocortin molecule.

• Many aspects of panic attacks, eg, palpitations, tremor, sweating, and an emotional sense of "fear," have been theorized to arise from sympathetic nervous system activation. However, most studies have not demonstrated clearly increased levels of catecholamines during an attack, which is contrary to this hypothesis. To explore another possible cause for the physiological changes known to occur during a panic attack, we assessed parasympathetic nervous system activity by measuring vagal tone during treatments known to produce panic symptoms: sodium lactate administration and hyperventilation. Our findings showed a marked reduction in vagal tone during both procedures. We postulate that withdrawal of parasympathetic activity may explain some of the physiological changes occurring in panic attacks and be contributing to the origin of panic.

• β-Adrenergic receptor binding on circulating lymphocytes was evaluated in young female bulimic patients (n =12) and age- and sex-matched normal control volunteers (n =10). Using iodine 125—labeled cyanopindolol, antagonist binding was evaluated (number of receptors [Bmax] and dissociation constant [KD]), and using isoproterenol competition of cyanopindolol binding, the concentration required to inhibit binding by 50% (IC50) for isoproterenol and the agonist affinity measure of KL/KH (ratio of dissociation constants for the low- and highaffinity states of the receptor) were determined. Plasma norepinephrine (NE) level was also measured. There was a trend toward lower plasma NE levels in the bulimic patients. The KL/KH ratio in bulimic patients was significantly greater than that for the normal volunteers, indicating increased receptor coupling. The KL/KH ratio was not significantly correlated with plasma NE level. Neither Bmax nor KD was different between the two groups. These findings suggest that β-adrenergic receptors in bulimic patients may be more responsive than in normal subjects, without alteration of the traditional measures of receptor responses, a difference that cannot be explained on the basis of plasma NE. These findings provide another line of evidence for altered regulation of the noradrenergic system in bulimic patients during a controlled phase of their illness.

To help characterize the l-dopa-mediated release of glucagon, rats were given either L-dopa or dopamine (10 mg/kg) intravenously; portal plasma levels of insulin, glucagon, and glucose were measured in the presence and absence of adrenergic and ganglionic blockers.The α-adrenergic blocker (phentol-amine) suppressed the glucagon and glucose responses to l-dopa and increased plasma insulin levels. β-Adrenergic blockade with propranolol ameliorated the l-dopa-mediated glucagon and glucose responses but had no effect on plasma insulin levels.Ganglionic blockade with pentolinium tartrate was ineffective and did not alter any of the L-dopa-mediated responses of glucagon, insulin, or glucose.These data indicate that l-dopa and dopamine probably act via the sympathetic nervous system through known pathways enhancing the release of glucagon. Furthermore they substantiate the fact that the adrenergic nervous system is involved in the regulation of the endocrine pancreas.

In patients with congestive heart failure, medical treatment has a high rate of mortality and morbidity, and transplantation is limited by the availability of donor hearts. Dynamic cardiomyoplasty is being investigated as surgical therapy to improve left ventricular function in these patients. To evaluate the early postoperative effects of this procedure on left ventricular diastolic function, we studied seven dogs through the use of sonomicrometry and micromanometry in a canine model of dynamic cardiomyoplasty. Left ventricular diastolic parameters were determined before wrapping the latissimus dorsi muscle (baseline), after latissimus dorsi muscle wrap but without stimulation, and with synchronous left ventricular contraction-latissimus dorsi muscle stimulation. End-diastolic pressure was increased in both conditions after latissimus dorsi muscle wrap (without stimulation, 5 ± 1; with stimulation, 6 ± 2 mm Hg; p < 0.05) compared with baseline (3 ± 2 mm Hg). The peak rate of diastolic pressure decay was greater at baseline (1560 ± 370 mm Hg/sec) than after latissimus dorsi muscle wrap, both without (1260 ± 330 mm Hg/sec, p < 0.01) and with (1120 ± 420 mm Hg/sec, p < 0.01) stimulation. The constant of pressure decay was prolonged both without (53 ± 10 seconds, p < 0.05) and with (62 ± 11 seconds, p < 0.01) latissimus dorsi muscle stimulation compared with the baseline (38 ± 5 seconds). Compared with baseline (0.2 ± 0.2 cm–2), the constant of passive chamber stiffness increased after the latissimus dorsi muscle was wrapped around the heart (1.6 ± 0.7 cm–2, p < 0.05) and with stimulation (2.1 ± 1.0 cm-2, p < 0.01). The maximal diastolic filling rate (baseline, 18.1 ± 6.7; without stimulation, 16.6 ± 8.9; with stimulation, 16.6 ± 4.1 cm2/sec, not significant) and end-diastolic short-axis area (baseline, 7.3 ± 2.3; without stimulation, 7.4 ± 2.1; with stimulation, 7.5 ± 2.3 cm2, not significant) were similar among the three conditions. The latissimus dorsi muscle wrap prolonged relaxation and increased left ventricular passive stiffness. Synchronous latissimus dorsi muscle stimulation with left ventricular contraction did not improve diastolic function in this model. The results suggest that in the early postoperative period, dynamic cardiomyoplasty impairs diastolic function.

Ethanol may downregulate G-protein–coupled beta-adrenoreceptors (βAR). βAR may also be dysregulated in panic disorder (PD). In clinical samples, many patients have comorbid alcohol dependence (AD) and PD. Therefore, we investigated βAR coupling in patients with these disorders. We harvested polymorphonuclear leukocytes from 24 healthy volunteers (Vs), and from 22 abstinent AD patients, 7 PD patients, and 9 patients with comorbid AD/PD. βAR were assayed using saturation and agonist-displacement experiments. Group differences were tested using one-way analysis of variance (ANOVA). All βAR binding parameters were similar in AD patients and Vs. The ratio of the agonists′ dissociation constant from the receptor in the low affinity state (KL) to that in the high affinity state (KH) was significantly higher in PD patients than in AD patients and Vs (930.97 ± 440.80 vs. 226.2 ± 94.47 vs. 197.05 ± 61.03, respectively, p < .01). This finding suggests that βAR are supercoupled to GSin patients with PD. There was a trend for higher total receptor density (RT) in AD/PD and PD patients (Vs = 39.06 ± 42.57 vs. AD = 27.93 ± 23.07 vs. AD/PD = 66.85 ± 79.02 vs. PD = 68.36 ± 49.20, p < .08). There were no differences between AD/PD and PD patients, who combined had a significantly higher RTthan Vs and AD patients (Vs = 38.95 ± 8.81 vs. AD = 29.63 ± 5.07 vs. AD/PD = 67.51 ± 17.00, fmol/mg protein, p < .04). Finally, AD/PD patients had a significantly higher receptor density in the low-affinity conformational state than Vs and AD patients, but not PD patients (25.96 ± 11.59 vs. 10.69 ± 1.53 vs. 7.62 ± 1.08 vs. 17.07 ± 5.26 fmol/mg protein, respectively, p < .005). βAR function in polymorphonuclear leukocytes is normal in abstinent alcoholics. The previously reported abnormal βAR regulation in alcoholism may be state dependent. The higher RTand KLKHratio in AD/PD and PD, but not in AD patients, suggest that increased βAR function may be important in the pathophysiology of PD.Neuropsychopharmacology (1997) 16 69–76.

Disturbances in central nervous system serotonin (5‐HT) have been implicated in the pathophysiology of alcoholism. To test the hypothesis that increasing 5‐HT function could promote treatment compliance, we randomized patients who had completed a 5‐week inpatient treatment program for alcoholism to receive either buspirone or placebo for 1 year. Ten of the 49 patients remained in the study for the entire year. The days to relapse did not differ significantly between patients receiving buspirone or placebo. Regardless of the medication, late‐onset alcoholics had a longer time to relapse than early‐onset alcoholics. Cerebrospinal fluid showed that patients with high concentrations of both the 5‐HT metabolite, 5‐hydroxyindoleacetic acid, and the dopamine metabolite, homovanillic acid, were more likely to relapse, compared with patients with low concentrations of cerebrospinal fluid 5‐hydroxyindoleacetic acid and homovanillic acid.

This study investigated the validity of the Christian Orthodoxy Scale of Fullerton and Hunsberger for 125 male and 125 female college students, who identified their religious preference and rated the importance of their religion. They were administered the scale and Allport and Ross's Religious Orientation Scale. Subjects were grouped by gender, Christian or NonChristian and importance of religion. Data for Christian and NonChristian groups were separately subjected to a 3 × 2 analysis of variance. Scores on the Christian scale and on the Orientation scale were correlated for the total sample. The Christian scale discriminated between subjects reporting greater or less importance of religion in their lives. Also, positive relationships were found between the Christian scale and an Intrinsic religious orientation.

TO THE EDITOR.— Alcoholic patients have lower levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid1; decreased availability of the serotonin precursor, tryptophan2; and reduced serotonin concentrations in platelets.3 These findings have led to the hypothesis that a dysregulation in serotonin metabolism may be involved in the pathogenesis of alcoholism. To further explore this hypothesis, we studied alcoholic patients who abstained from alcohol. Behavioral, physiological, and endocrine responses to the metabolite of trazodone hydrochloride, meta-chlorophenylpiperazine (m-CPP) hydrochloride, were used as indexes of serotonin receptor function in alcoholic patients.4Twenty-one male patients who fulfilled DSM-III-R criteria for alcohol dependence and Research Diagnostic Criteria for alcoholism were selected for the study. They were in good physical health, euthymic, and abstinent from alcohol for at least 3 weeks when the study began. After written, informed consent was obtained, normal saline solution (the placebo) was administered intravenously. Thirty minutes later, m-CPP (0.08