Hospitalist Value in an ACO World.

The accountable care organization (ACO) concept is advocated as a promising value-based payment model that could successfully realign the current payment system to financially reward improvements in quality and efficiency. Focusing on the care of hospitalized patients and controlling a substantive portion of variable hospital expenses, hospitalists are poised to play an essential role in system-level transformational change to achieve clinical integration. Especially through hospital and health system quality improvement (QI) initiatives, hospitalists can directly impact and share accountability for measures ranging from care coordination to implementation of evidence-based care and the patient and family caregiver experience. Regardless of political terrain, financial constraints in healthcare will foster continued efforts to promote formation of ACOs that aim to deliver coordinated, evidence-based, and patient-centered care. Hospitalists possess the clinical experience of caring for complex patients with multiple comorbidities and the QI skills needed to lead efforts in this new ACO era.

The Fear-Avoidance Components Scale (FACS): Responsiveness to Functional Restoration Treatment in a Chronic Musculoskeletal Pain Disorder (CMPD) Population.

OBJECTIVES: To assess the clinical validity and factor structure of the Fear-Avoidance Components Scale (FACS), a new fear-avoidance measure. MATERIALS AND METHODS: In this study, 426 chronic musculoskeletal pain disorder patients were admitted to a Functional Restoration Program (FRP). They were categorized into 5 FACS severity levels, from subclinical to extreme, at admission, and again at discharge. Associations with objective lifting performance and other patient-reported psychosocial measures were determined at admission and discharge, and objective work outcomes for this predominantly disabled cohort, were assessed 1 year later. RESULTS: Those patients in the severe and extreme FACS severity groups at admission were more likely to "drop out" of treatment than those in the lower severity groups (P=0.05). At both admission and discharge, the FACS severity groups were highly and inversely correlated with objective lifting performance and patient-reported fear-avoidance-related psychosocial variables, including kinesiophobia, pain intensity, depressive symptoms, perceived disability, perceived injustice, and insomnia (Ps<0.001). All variables showed improvement at FRP discharge. Patients in the extreme FACS severity group at discharge were less likely to return to, or retain, work 1 year later (P≤0.02). A factor analysis identified a 2-factor solution. DISCUSSION: Strong associations were found among FACS scores and other patient-reported psychosocial and objective lifting performance variables at both admission and discharge. High discharge-FACS scores were associated with worse work outcomes 1 year after discharge. The FACS seems to be a valid and clinically useful measure for predicting attendance, physical performance, distress, and relevant work outcomes in FRP treatment of chronic musculoskeletal pain disorder patients.

The Fear-avoidance Components Scale (FACS): Development and Psychometric Evaluation of a New Measure of Pain-related Fear Avoidance.

Pain-related fear avoidance (FA), a common problem for patients with painful medical conditions, involves pain-related catastrophizing cognitions, hypervigilance, and avoidance behaviors, which can ultimately lead to decreased functioning, depression, and disability. Several patient-reported instruments have been developed to measure FA, but they have been criticized for limited construct validity, inadequate item specificity, lack of cutoff scores, and missing important FA components. The Fear-Avoidance Components Scale (FACS) is a new patient-reported measure designed to comprehensively evaluate FA in patients with painful medical conditions. It combines important components of FA found in prior FA scales, while trying to correct some of their deficiencies, within a framework of the most current FA model. Psychometric evaluation of the FACS found high internal consistency (α = 0.92) and high test/retest reliability (r = 0.90-0.94, P < 0.01). FACS scores differentiated between 2 separate chronic pain patient samples and a nonpatient comparison group. When clinically relevant severity levels were created, FACS severity scores were highly associated with FA-related patient-reported psychosocial and objective lifting performance variables. These results suggest that the FACS is a psychometrically strong and reliable measure that can help healthcare providers assess FA-related barriers to function and recovery.

The Potential Utility of the Patient Health Questionnaire as a Screener for Psychiatric Comorbidity in a Chronic Disabling Occupational Musculoskeletal Disorder Population.

OBJECTIVES: The patient health questionnaire (PHQ) is designed for screening psychopathology in primary care settings. However, little is known about its clinical utility in other chronic pain populations, which usually have high psychiatric comorbidities. DESIGN: A consecutive cohort of 546 patients with chronic disabling occupational musculoskeletal disorder (CDOMD) was administered and compared upon psychosocial assessments, including the PHQ and a structured clinical interview for DSM-IV (SCID). Four PHQ modules were assessed: major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder (PD), and alcohol use disorders (AUD) [including both alcohol abuse and dependence]. Based on the SCID diagnosis, sensitivity and specificity were determined. RESULTS: The specificity of the PHQ ranged from moderate to high for all 4 PHQ modules (MDD, 0.79; GAD, 0.67; PD, 0.89; AUD, 0.97). However, the sensitivity was relatively low: MDD (0.58); GAD (0.61); PD (0.49); and AUD (0.24). The PHQ was also associated with psychosocial variables. Patients whose PHQ showed MDD, GAD, or PD reported significantly more depressive symptoms and perceived disability than patients who did not (Ps < 0.001). Patients with MDD or GAD reported significantly higher pain than those without (Ps < 0.001). CONCLUSIONS: The strong specificity of the PHQ appears to be its primary strength for this cohort. Due to its high specificity, the PHQ could be employed as an additional screening tool to help rule out potential psychiatric comorbidity in patients with CDOMD. The low sensitivity of the PHQ in this population, however, remains a weakness of the PHQ.

What is the best screening test for depression in chronic spinal pain patients?

BACKGROUND CONTEXT: High prevalence rates of depression have been found in patients with chronic spinal disorder (CSD). The biopsychosocial model has become widely adopted and, with it, the role of psychopathology in the development and/or exacerbation of CSD has become increasingly recognized. Standardized diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), have been used to diagnose major depressive disorder (MDD). Many measures of MDD (and depressive symptom inventories) have been developed during the past 50 years, but their comparative utility in CSD populations is still unclear. PURPOSE: To systemically compare the performance of depression screening questionnaires in detecting MDD among a large sample of patients with CSD. STUDY DESIGN/SETTING: Prospective cohort study comparing the screening ability of four popular depression measures for diagnosing MDD against the "gold standard" Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), using a receiver operating characteristic (ROC) analysis in a CSD population. PATIENT SAMPLE: A consecutive cohort of 546 patients with CSD admitted to an interdisciplinary functional restoration program. OUTCOME MEASURES: Sensitivity, specificity, ROC curves, area under the curve (AUC), and optimal cutoff points that are most closely related to the prevalence rates of MDD, with balanced sensitivity and specificity analysis. METHODS: Using the SCID-I diagnosis as a "gold standard," the ability of four screening measures in detecting MDD were compared. These included: the Beck Depression Inventory (BDI); Hamilton Rating Scale for Depression (HRSD); 9-Item Patient Health Questionnaire Depression Module (PHQ-9); and the Short Form-36 (SF-36). RESULTS: Of 542 CSD patients, 331 (61.1%) were diagnosed with MDD by the SCID-I. Results of the ROC analysis revealed that the BDI (AUC 0.768), HRSD (AUC 0.796), and PHQ-9 (AUC 0.768) have similar abilities to discriminate between depressed and nondepressed patients in this population. These depression measures outperformed the two mental health scales derived from the SF-36 (Mental Component Summary score/5-Item Mental Health Index; AUC 0.679-0.715). The optimal cut-off scores of 15 (for the BDI), 17 (for the HRSD), and 10 (for the PHQ-9) were also determined. Although the greatest overall accuracy (sensitivity of 81.3% and specificity of 65.4%) was obtained with the HRSD, it is the only clinician-administered instrument. Self-report measures of depression (the BDI and PHQ-9) showed comparable abilities to detect depression, only slightly less than the HRSD. CONCLUSIONS: Compared to the HRSD, both BDI and PHQ-9 are relatively short and easy to self-administer. The cut-off scores established in this study may be used to reliably determine whether a person should be evaluated more thoroughly for an MDD diagnosis. Using an acknowledged "gold standard," the HRSD, BDI and PHQ-9 showed similar validity to recommend their use for future clinical and research purposes. The SF-36 is less appropriate for diagnosing MDD.

Differences in regional cerebral blood flow response to a 5HT3 antagonist in early- and late-onset cocaine-dependent subjects.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients.

The development and psychometric validation of the central sensitization inventory.

Central sensitization (CS) has been proposed as a common pathophysiological mechanism to explain related syndromes for which no specific organic cause can be found. The term "central sensitivity syndrome (CSS)" has been proposed to describe these poorly understood disorders related to CS. The goal of this investigation was to develop the Central Sensitization Inventory (CSI), which identifies key symptoms associated with CSSs and quantifies the degree of these symptoms. The utility of the CSI, to differentiate among different types of chronic pain patients who presumably have different levels of CS impairment, was then evaluated. Study 1 demonstrated strong psychometric properties (test-retest reliability = 0.817; Cronbach's alpha = 0.879) of the CSI in a cohort of normative subjects. A factor analysis (including both normative and chronic pain subjects) yielded 4 major factors (all related to somatic and emotional symptoms), accounting for 53.4% of the variance in the dataset. In Study 2, the CSI was administered to 4 groups: fibromyalgia (FM); chronic widespread pain without FM; work-related regional chronic low back pain (CLBP); and normative control group. Analyses revealed that the patients with FM reported the highest CSI scores and the normative population the lowest (P < 0.05). Analyses also demonstrated that the prevalence of previously diagnosed CSSs and related disorders was highest in the FM group and lowest in the normative group (P < 0.001). Taken together, these 2 studies demonstrate the psychometric strength, clinical utility, and the initial construct validity of the CSI in evaluating CS-related clinical symptoms in chronic pain populations.

Time to Relapse Questionnaire (TRQ): a measure of sudden relapse in substance dependence.

BACKGROUND: Relapse may occur suddenly, following a short period of craving, or after extended consideration. The time to relapse may reveal underlying mechanisms of relapse and have important implications for treatment. OBJECTIVE: The Time to Relapse Questionnaire (TRQ), a self-administered questionnaire, was designed to assess the time from the initial thought of drug use to actual use. METHODS: Psychometric properties of the TRQ were evaluated in two distinct populations (n = 183 and 194) with DSM-IV primary substance use disorders. RESULTS: Factor analysis and item refinement led to a 9-item TRQ with a three-factor solution accounting for 63% of the total variance. Three discrete types of relapse style were identified: Sudden Relapse, Short Delay Relapse, and Long Delay Relapse. The TRQ demonstrated good construct validity and adequate internal consistency for the total (alpha = .61) and individual factor (alpha = .64-.75) scores. Measures to assess convergent validity of the TRQ suggest that Sudden Relapse may not reflect more generalized deficits of inhibitory control. CONCLUSIONS AND SIGNIFICANCE: The TRQ may provide a useful self-report measure to discriminate between addicted patients who relapse without forewarning compared to those with a period of delay. Clinical interventions may be targeted towards different relapse styles.

Altered neural cholinergic receptor systems in cocaine-addicted subjects.

Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

Adrenocortical and pituitary glucocorticoid feedback in abstinent alcohol-dependent women.

BACKGROUND: The long-term ingestion of alcohol diminishes hypothalamic-pituitary-adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone. METHODS: Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 microg/kg), a synthetic ACTH (1-24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes. RESULTS: Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone. CONCLUSION: Significant differences in pituitary-adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness.

Neural response to lidocaine in healthy subjects.

Recent studies suggest that some of cocaine's central nervous system (CNS) effects may be mediated through its sodium channel inhibiting local anesthetic properties. Local anesthetics that lack cocaine's strong affinity for the dopamine transporter (DAT) also produce sensory and mood effects, further suggesting a role for this neural pathway. Due to an absence of affinity at the DAT, the local anesthetic lidocaine may offer the potential to assess sodium channel activity in vivo in humans. To assess the utility of lidocaine as a CNS probe, we determined regional cerebral blood flow (rCBF) with single photon emission computed tomography (SPECT) following the intravenous administration of lidocaine (0.5 mg/kg) and compared this response to procaine (0.5 mg/kg and 1.0 mg/kg), a local anesthetic with partial affinity for the DAT, and saline. Infusions were administered in nine healthy female controls over a 10-day period with at least 2 days between each scan. Increased rCBF was observed following lidocaine, relative to saline, in the insula, caudate, thalamus, and posterior cingulate. Decreased rCBF was detected in a different region of the posterior cingulate. In general, increases in rCBF were more marked following lidocaine relative to procaine. Mood and sensory changes following lidocaine were limited and significantly less than those induced by either dose of procaine. There were no significant changes in blood pressure or heart rate following either medication. These findings suggest that lidocaine can be safely used to assess sodium channel function in persons with addictive and other psychiatric disorders.

The role of acetylcholine in cocaine addiction.

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Impulsivity, neural deficits, and the addictions: the "oops" factor in relapse.

Impulsive behaviors are observed in a wide range of psychiatric disorders, including substance use, bipolar, attention-deficit hyperactivity, antisocial and borderline personality, gambling, and eating disorders. The shared phenotype of impulsivity is thought to significantly contribute to both the etiology and perpetuation of these disorders. In this review, we focus upon the relevance of impulsivity to the addictive disorders, particularly substance use disorders. First, the literature supporting the presence of impulsive behaviors prior to the onset of drug use and addiction is discussed. The relevance of impulsivity to relapse is then presented, with a focus on three distinct neurocognitive constructs: automaticity, response inhibition, and decision making. Automaticity is a quickly occurring relapse process resulting from the learned habits induced by persistent drug use. Addicted persons with response inhibition deficits are unable to suppress these previously reinforced behaviors. Decision-making deficits contribute to relapse through a poorly considered assessment of the consequences of drug use. The brain regions associated with each model of impulsive behavior are described, and relevant neurobiologic disruptions in addicted subjects are discussed in the context of their specific neurocognitive deficit(s). Descriptive confusions in the terminology and confounds inherent in the study of impulsivity are described. Empirical investigations documenting the hypothesized relationship between specific deficits in impulsive behaviors, coupled with their neurobiological correlates, and relapse should be the focus of future studies.

Sex differences in medial and lateral orbitofrontal cortex hypoperfusion in cocaine-dependent men and women.

BACKGROUND: The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making. OBJECTIVE: This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls. METHODS: Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men. RESULTS: In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P=0.001), right lateral (P=0.002), and medial (P<0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (P

Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 1: adrenocortical and pituitary glucocorticoid responsiveness.

BACKGROUND: Long-term ingestion of alcohol produces marked alterations in hypothalamic-pituitary-adrenal axis activity. The authors engaged in a series of studies to determine the distinct role of the hypothalamus and the pituitary and adrenal glands in the disturbances observed in abstinent alcohol-dependent subjects. In this first of a two-part study, the authors report on (1) the basal secretory profile of corticotropin and cortisol from 2000 to 0800 hrs, (2) adrenocortical sensitivity in both the presence and absence of endogenous pituitary activation, and (3) pituitary glucocorticoid sensitivity to dexamethasone. METHODS: Eleven male, 4 to 6 weeks abstinent, alcohol-only-dependent subjects and 10 age-matched male healthy controls were studied. Basal circulating concentrations of corticotropin and cortisol were obtained from 2000 to 0800 hr. A submaximal dose of cosyntropin (0.01 microg/kg), a corticotropin analogue was then administered to assess adrenocortical sensitivity. In a separate session, cosyntropin was administered following high-dose dexamethasone (8 mg iv) to assess adrenocortical sensitivity in the relative absence of endogenous corticotropin. In addition, the corticotropin response to dexamethasone was measured to determine pituitary glucocorticoid responsiveness. RESULTS: Cortisol, but not corticotropin, pulse amplitude (p < 0.05) and mean concentration (p= 0.05) was significantly lower in alcohol-dependent subjects compared with controls. The cortisol response to cosyntropin was lower in alcohol-dependent subjects following endogenous corticotropin suppression by high-dose dexamethasone (p <0.04) but not without dexamethasone pretreatment. Mean corticotropin (p <0.004) and cortisol (p <0.05) concentrations in response to dexamethasone were attenuated in the patients compared to controls. Basal concentrations of 11-deoxycortisol, the precursor to cortisol, were also decreased in alcohol-dependent subjects (p <0.05). CONCLUSION: Attenuated basal and stimulated adrenocortical concentrations in abstinent alcohol-dependent men are coupled with a nonhomeostatic increase in pituitary glucocorticoid inhibition. A decrease in stress-axis responsivity in alcohol dependence may have implications for treatment outcome.

Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 2: response to ovine corticotropin-releasing factor and naloxone.

BACKGROUND: Pituitary and adrenal responsiveness is suppressed in abstinent alcohol-dependent individuals. To clarify the specific organizational disruption in hypothalamic-pituitary-adrenal functioning during early abstinence, the authors separately assessed each level of the stress-response axis. In this second of a two-part study, ovine corticotropin-releasing factor (oCRH) was used to stimulate the pituitary corticotrophs, and naloxone was used to activate the axis at the hypothalamic level. In addition, pulsatile characteristics of corticotropin and cortisol were assessed over a 12-hr period (0800 to 2000 hr). METHODS: Eleven abstinent alcohol-dependent men and 10 healthy comparison participants were assessed. All participants were between the ages of 30 and 50 years, and alcohol-dependent patients were abstinent from 4 to 6 weeks. Basal concentrations of corticotropin and cortisol were obtained every 10 min from 0800 to 2000 hr and subjected to pulsatile analysis. Plasma corticotropin and cortisol concentrations were then obtained every 5 to 10 min after low-dose, intravenously administered doses of oCRH (0.4 microg/kg) or naloxone (0.125 mg/kg). Medications were administered at 2000 hr and the two challenge studies were separated by 48 hr. RESULTS: Pulsatile analysis revealed that the mean corticotropin amplitude was increased in alcohol-dependent patients relative to controls (p <0.05). Other pulsatile characteristics of corticotropin and all cortisol pulsatile measures were not significantly different between the two groups. The integrated cortisol response to oCRH was significantly lower in alcohol-dependent patients compared with controls (p <0.01), but the integrated corticotropin response was not significantly different. In contrast, neither the corticotropin nor the cortisol response to naloxone was significantly different between groups. CONCLUSIONS: Adrenocorticoid hyposensitivity persists after oCRH infusion for at least 1 month after cessation of drinking, whereas hyporesponsiveness of the pituitary corticotrophs to CRH seems to resolve with continued abstinence. The authors suggest that adrenocortical hyporesponsiveness during prolonged abstinence may impact relapse risk.

Regional cerebral blood flow in female cocaine-addicted subjects following limbic activation.

BACKGROUND: Cocaine dependence follows a different disease course in men and women, possibly as a consequence of sex-specific neurobiologic responses to chronic cocaine use. We have previously reported that male cocaine-dependent subjects demonstrate a significantly different limbic response to the limbic-stimulus procaine, as measured by regional cerebral blood flow (rCBF), compared with male controls. In this study, we assessed the limbic rCBF response to procaine in female cocaine-addicted subjects (n=10) and female controls (n=10). METHODS: Subjects were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Single photon emission computed tomography (SPECT) was used to compare the rCBF response to procaine. RESULTS: Female cocaine-dependent subjects demonstrate a markedly muted, and distinctly different, limbic response to procaine compared with matched healthy controls. CONCLUSIONS: The rCBF response to procaine in female cocaine-dependent subjects suggests significant CNS differences compared with non-addicted female controls. Coupled with findings previously observed in male cocaine-dependent subjects, these biologic differences suggest that both male and female subjects experience alterations in limbic responsiveness following the chronic use of cocaine.

Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men.

BACKGROUND: Cortisol, the primary glucocorticoid in humans, is intimately involved in the regulation of such varied and critical biological processes as emotion, cognition, reward, immune functioning, and energy utilization. A persistent increase in cortisol concentration as a result of chronic intoxication could therefore result in alcohol-related disorders such as sleep disruption, cognitive deficits, diabetes, and mood disturbances. Although moderate levels of acute alcohol ingestion are reported to produce an increase in cortisol levels, it is uncertain whether cortisol remains persistently increased during long-term chronic intoxication. METHODS: Salivary cortisol and breath alcohol concentrations (BAC) were obtained on 73 subjects with primary alcohol dependence on initial presentation for treatment and 22 alcohol-dependent subjects participating in a residential treatment program. RESULTS: Both intoxicated alcohol-dependent subjects (n = 38) and nonintoxicated subjects in acute alcohol withdrawal (n = 30) demonstrated significantly increased salivary cortisol concentrations compared with abstinent subjects (n = 27; p < 0.001). Nonintoxicated subjects in acute withdrawal demonstrated significantly increased salivary cortisol concentrations compared with highly intoxicated subjects (BAC >100 mg/dl) but were similar to subjects with lower levels of intoxication (BAC, 10-100 mg/dl). CONCLUSIONS: Chronic alcohol-dependent subjects experience continuously increased concentrations of cortisol during both intoxication and withdrawal. Increased levels of cortisol during chronic intoxication seem to progressively increase with the onset of withdrawal. This suggests a daily cycle of hypercortisolemia during the active drinking phase, with further increases on the cessation of drinking and the emergence of withdrawal symptoms. Persistently increased levels of cortisol may extract a costly allostatic load, resulting in significant central nervous system and peripheral organ morbidity.

Gender differences in limbic responsiveness, by SPECT, following a pharmacologic challenge in healthy subjects.

Limbic system functioning is integral to the control and modulation of affect, motivation, reward, and memory. Neuropsychiatric disturbances involving disruptions in these cognitive and emotional dimensions exhibit different prevalence rates for men and women. Gender-specific differences in this integrated brain area may therefore be important in understanding both normal behavioral functioning and the etiologic underpinnings of neuropsychiatric disorders. To further explore such differences in limbic system function, we assessed regional cerebral blood flow, by SPECT, in men and women following the administration of procaine. Procaine is a local anesthetic that preferentially stimulates limbic structures. Psychiatrically and medically healthy, age-matched women (n = 15, 33.2 +/- 6.9 years) and men (n = 15, 32.8 +/- 6.9 years) were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Using voxel-based analyses (P < 0.001), males significantly activated the bilateral insular cortex following procaine, whereas females more strongly activated the bilateral anterior and mesial temporal cortex. Both groups demonstrated significant anterior cingulate activation. Subjective responses to procaine did not significantly differ between the men and women. To our knowledge, this is the first report demonstrating gender-specific responses in limbic activation following a pharmacologic challenge. These findings suggest that men and women can activate different limbic structures following the same provocative pharmacologic stimulus, despite sharing a similar subjective experience. Studies assessing pharmacologic challenges of limbic system structures should consider gender as a critical variable in assessing biologic responsiveness.

Thoracic Aortic Aneurysm Presenting as Pulmonary Vein Stenosis: A Case Presentation and Review of the Literature.

We present the case of a 66-year-old woman presenting with pulmonary vein stenosis with a large descending thoracic aortic aneurysm. Pulmonary vein stenosis is a rare condition and can be caused by extrinsic compression, as well as by inflammatory diseases, congenital anomalies and related surgical repair, tuberculosis, and pulmonary veno-occlusive disease. With obstruction to pulmonary vein flow, the velocity increases and becomes continuous. The finding of turbulent antegrade flow in the left atrium through the use of transthoracic color flow Doppler and pulsed-Doppler warrants further investigation to evaluate known causes of pulmonary vein stenosis. We believe this is the first reported case of a patient with an aortic aneurysm causing pulmonary vein stenosis.