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Biomedical subjects

M A Kling

Publications and source records attributed to M A Kling.

At least 19 recordsLinked to original sources
PubMed1998

Reliability and acceptability of psychiatric diagnosis via telecommunication and audiovisual technology.

The reliability of psychiatric diagnoses made remotely by telecommunication was examined. Two trained interviewers each interviewed the same 30 psychiatric inpatients using the Structured Clinical Interview for DSM-III-R. Fifteen subjects had two in-person interviews, and 15 subjects had one in-person and one remote interview via telecommunication. Interrater reliability was calculated for the four most common diagnoses: major depression, bipolar disorder, panic disorder, and alcohol dependence. For each diagnosis, interrater reliability (kappa statistic) was identical or almost identical for the patients who had two in-person interviews and those who had an in-person and a remote interview, suggesting that reliable psychiatric diagnoses can be made via telecommunication.

Alcoholism↗
PubMed1998

Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes.

Cytokines such as interferon-alpha (IFN-alpha) are increasingly being exploited as biologic response modifiers to treat cancer. However, treatment with IFN-alpha can adversely affect mood and cognition, causing depression, memory disturbances, and other signs of central nervous system (CNS) dysfunction. The genes encoding cytokines and their receptors are expressed in the CNS under both resting and stimulated conditions, and cytokines can affect key brain functions. The physiologic effects of IFN-alpha therapy on the CNS are probably a consequence of the activation of a complex cascade of secondary cytokines both in the periphery and within the CNS. We review the neurobiology of cytokines and outline some of the potential mechanisms by which alterations of cytokine expression in the CNS could contribute to cognitive dysfunction and mood disorders during IFN-alpha therapy.

Brain↗
PubMed1998

Mood and cognitive side effects of interferon-alpha therapy.

The central nervous system side effects associated with interferon-alpha (IFN-alpha) therapy, including depression and cognitive changes, can compromise otherwise effective immunotherapy. The term "depression" has multiple meanings ranging from a feeling of sadness to a neuropsychiatric disorder with defined diagnostic criteria. A syndrome of mood disturbance with memory impairment, cognitive slowing, and impaired executive function is common with IFN-alpha therapy and is consistent with mild subcortical dementia. Cognitive deficits and mood disorder may occur independently, and in some cases depression is a reactive phenomenon. Risk factors for development of IFN-alpha neurotoxicity include duration of treatment, high-dose therapy, and prior cranial irradiation or neurologic illness. Past or current psychiatric illness also may put the patient at risk. Subtypes of major depression are associated with neuroendocrine and neurochemical alterations that are consistent with the observed activities of IFN-alpha. This may provide insight into the etiology of IFN-alpha neurotoxicity, as well as possible interventions. Assessment of the neuropsychiatric status of patients treated with IFN-alpha should be a standard of care. Possible pharmacologic interventions to decrease the neurotoxicity associated with IFN-alpha therapy include antidepressants, psychostimulants, and opioid antagonists. Preliminary clinical and research experience suggests that it is possible to effectively palliate IFN-alpha toxicity.

Cognition Disorders↗
PubMed1996

The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro.

There is increasing evidence that opiates not only have analgesic properties, but also regulate mechanisms activated during the stress response, such as the hypothalamic-pituitary-adrenal (HPA) axis. Indeed, opioid-containing neurons innervate the paraventricular nucleus and the median eminence, thus modulating inputs to ACTH-controlling neurons. In addition, dynorphin (the endogenous ligand of the kappa-opioid receptor)-like peptides have been found co-localized with corticotrophin-releasing hormone (CRH) and are believed to be co-secreted with it in the hypophyseal portal circulation to modulate ACTH release. In this study, we evaluated the effects of the selective kappa-opioid receptor agonist MR-2034 [(-)-N-(2-tetrahydrofurfuryl)-normetazocine] on the HPA axis in vivo and in vitro. MR-2034 was given intravenously to catheterized, freely moving, male Sprague-Dawley rats and serial blood samples were collected for ACTH and corticosterone (B) measurements. We evaluated also the site of MR-2034 action on the HPA axis in vivo, after the administration of alpha-helical CRH9-41, a CRH receptor antagonist, on hypothalamic CRH, pituitary ACTH, and B release in vitro. MR-2034 increased plasma ACTH and B levels in a dose-related fashion and this effect was antagonized by the selective kappa-opioid receptor antagonist MR-1452. In the presence of alpha-helical CRH9-41, the responses of plasma ACTH and B to MR-2034 were blunted significantly, suggesting that this compound activates the HPA axis through a CRH-dependent mechanism. Accordingly, MR-2034 stimulated hypothalamic CRH release in vitro in a concentration-dependent fashion and this effect was antagonized dose-dependently by MR-1452. However, the stimulatory effect of MR-2034 on plasma ACTH and B in vivo was not completely abolished by alpha-helical CRH9-41, suggesting that an additional, CRH-independent, mechanism was involved. Indeed, MR-2034 was able to stimulate basal ACTH output in a dose-dependent manner and this effect was antagonized by MR-1452 in vitro. On the other hand, MR-2034 did not have any effect on B release from adrenocortical cells or adrenal quarters in vitro. These results show that the benzomorphan MR-2034 stimulates the HPA axis in the rat by acting at the hypothalamic and the pituitary level. We hypothesize that endogenous kappa-opioid peptides not only act at the pituitary level to increase ACTH output, but may also act at the hypothalamic level to increase CRH release through an autocrine and/or ultrashort positive feedback mechanism.

Adrenocorticotropic Hormone↗
PubMed1995

Cerebrospinal fluid total protein in patients with affective disorders.

Cerebrospinal fluid (CSF) total protein was evaluated in 240 patients with affective disorders and compared with findings in 55 normal comparison subjects. Subtype diagnoses were as follows: bipolar I (n = 108, 47 men, 61 women); bipolar type II (n = 67, 26 men, 41 women); and unipolar (n = 65, 22 men, 43 women). Men had significantly elevated values compared with women. In men with bipolar I disorder, mean CSF protein levels were found to be significantly elevated over those in normal subjects, with 31.9% above the traditional normal range cutoff of 45 mg/dl. Moreover, CSF protein levels in male bipolar I patients were found to be positively correlated with severity of depression at the time of the lumbar puncture and with duration of illness. It thus appears that increased protein levels may be associated with illness severity or progression in male patients with bipolar I disorder. Although elevated CSF protein is a nonspecific marker of cerebral pathology, further search for the potential underlying pathophysiological mechanisms related to this finding would now appear to be warranted.

Adult↗
PubMed1994

Glucocorticoid treatment increases the ability of CRH to induce seizures.

We examined whether glucocorticoids could enhance the ability of corticotropin-releasing hormone (CRH) to induce seizures. Rats were treated with systemic glucocorticoids (dexamethasone, 100 micrograms) or vehicle for either 3 days (chronic) or 2 h (acute) before intracerebroventricular CRH (3 or 10 micrograms) or saline injections and then monitored for 8 h following each injection. Our results suggest that chronic, but not acute, glucocorticoid pretreatment increases the likelihood of CRH-induced seizures.

Aggression↗
PubMed1994

Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia.

OBJECTIVE: To examine basal and stimulated hypothalamic-pituitary-adrenal (HPA) axis and related hormone levels, including adrenocorticotropin (ACTH), cortisol, arginine vasopressin (AVP), and neuropeptide Y (NPY), in patients with fibromyalgia (FM). METHODS: Basal and ovine corticotropin-releasing hormone (oCRH)-stimulated HPA axis function were assessed in 12 patients with FM and in age- and sex-matched normal subjects. Basal plasma AVP levels and AVP release after postural change were assessed, and plasma NPY levels were measured in the same samples. RESULTS: Patients with FM had low 24-hour urinary free cortisol, but normal peak and elevated trough plasma cortisol levels, compared with normal subjects. The net integrated ACTH response to oCRH in FM was not significantly different from that in normal subjects, but tended toward an exaggerated response. There was a significant decrease in net integrated cortisol response to oCRH in FM patients, indicating adrenal hyporesponsiveness. AVP levels were not significantly different between FM patients and control subjects, but variability was greater among the FM patients. Plasma NPY levels were significantly lower in FM patients than in normal subjects. CONCLUSION: These data support the view that HPA axis function is perturbed in patients with FM. Further study is required to ascertain the cause of HPA axis perturbations and their relationship to symptoms in patients with FM.

Adrenocorticotropic Hormone↗
PubMed1994

CSF magnesium in affective disorder: lack of correlation with clinical course of treatment.

There has been recent renewed interest in the role of magnesium in affective disorder, particularly in the bipolar subtype. However, determinations of serum magnesium concentrations have not yielded consistent findings and little is known about cerebrospinal fluid (CSF) magnesium in these patients. We analyzed CSF magnesium levels from 173 medication-free patients with affective disorder (76 bipolar I, 54 bipolar II, and 43 unipolar) and 59 healthy volunteers. In addition, we examined CSF magnesium from 32 patients before and during carbamazepine treatment and 13 patients before and during lithium treatment. CSF magnesium levels varied significantly according to gender (with lower concentrations in women) but not with respect to age, diagnosis, mood state, or treatment with carbamazepine or lithium. An abnormality of magnesium in affective disorders, if it exists, is not readily detectable in CSF.

Adult↗
PubMed1994

Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls.

Childhood sexual abuse is associated with an increased incidence of age-concurrent and adult psychopathology. Little is known, however, about the biological manifestations and sequelae of childhood sexual abuse. In this study, we characterized the hypothalamic-pituitary-adrenal axis of a self-selected sample of sexually abused and control girls recruited from a prospective longitudinal study. Plasma ACTH and total and free cortisol responses to ovine CRH (oCRH) stimulation were measured in 13 sexually abused and 13 control girls, aged 7-15 yr. Psychiatric profiles and 24-h urinary free cortisol (UFC) measures were also obtained. Sexually abused girls had a greater incidence of suicidal ideation (chi 2 = 4.51; df = 1; P < 0.05), suicide attempts (chi 2 = 4.51; df = 1; P < 0.05), and dysthymia (chi 2 = 8.85; df = 1; P < 0.01) than control girls. Sexually abused girls showed significantly lower basal (t = 2.1; df = 24; P < 0.05), and net oCRH stimulated (t = 2.2; df = 24; P < 0.05) ACTH levels and significantly reduced total ACTH responses (t = 2.5; df = 24; P < 0.05) compared with control subjects. Their total and free basal and oCRH-stimulated plasma cortisol levels and 24-h UFC measures, however, were similar to those in controls. The attenuated plasma ACTH with corresponding robust plasma cortisol responses to oCRH stimulation and normal 24-h UFC measures in sexually abused girls suggest a dysregulatory disorder of the HPA axis in these individuals. This may reflect pituitary hyporesponsiveness to oCRH. The ability of sexually abused subjects to correct for the proposed pituitary hyporesponsiveness to CRH may be related to their young age and the presence of intact glucocorticoid feedback regulatory mechanisms.

Adolescent↗
PubMed1994

Diurnal variation of cerebrospinal fluid immunoreactive corticotropin-releasing hormone levels in healthy volunteers.

CRH is not only secreted into hypophyseal protal blood where it is believed to regulate the circadian rhythm of pituitary-adrenal activity, but is also measurable in cerebrospinal fluid (CSF). Altered CSF immunoreactive CRH (IR-CRH) levels have been found in patients with a number of neuropsychiatric disorders and have been implicated in some of the symptoms of these disorders. To further study the potential functional relevance of CRH in human CSF, we examined whether a nonuniform temporal pattern of IR-CRH levels existed in CSF using hourly sampling over a 30-h period in six healthy volunteers. CSF was withdrawn continuously at 6 mL/h through a catheter placed in the lumbar subarachnoid space and connected to a miniroller pump and fraction collector. A significant diurnal variation in CSF IR-CRH levels was observed (P < 0.001), with highest levels between 1830-2330 h and lowest levels around 0730 h. This pattern was nearly opposite that of plasma cortisol levels, which showed the expected peak around 0800 h and nadir around 2000-2200 h. In addition, CSF IR-CRH levels in three of the six volunteers showed significant negative correlations with simultaneous plasma cortisol levels. These data suggest that CSF IR-CRH concentrations are negatively modulated by peripheral cortisol secretion, which may be one factor involved in the entrainment of this rhythm. Although the functional significance of this diurnal variation in CSF IR-CRH levels is unknown, the presence of a distinct temporal organization of CRH release into the CSF in humans is compatible with the idea that CSF may play a functional role in or otherwise reflect nonsynaptic information processing in the central nervous system. Diurnal factors should be taken into account in future studies of CRH concentrations in human CSF.

Adult↗
PubMed1994

Effects of electroconvulsive therapy on the CRH-ACTH-cortisol system in melancholic depression: preliminary findings.

Hypercortisolism is one of the most consistent biological abnormalities seen in patients with major depression, particularly the melancholic subtype. We present preliminary data regarding the effects of electroconvulsive therapy (ECT) on urinary-free cortisol (UFC) excretion and on the secretion of its principal regulatory hormone, corticotropin-releasing hormone (CRH), into the cerebrospinal fluid (CSF) of patients with major depression. Our preliminary results indicate that, while acute elevations in UFC may occur with the initiation of ECT or other antidepressant treatments, successful treatment with ECT is associated with a reduction in both UFC excretion and the diurnal pattern of CSF immunoreactive CRH levels. These findings are compatible with data in experimental animals that show reductions in hypothalamic CRH expression and pituitary-adrenal function with long-term antidepressant treatments.

Adrenocorticotropic Hormone↗
PubMed1994

Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.

Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.

Adrenocorticotropic Hormone↗
PubMed1993

Facilitation of cocaine kindling by glucocorticoids in rats.

We report that glucocorticoids significantly facilitated the development of cocaine-induced kindled seizures. These results suggest that glucocorticoids may have effects on the development of kindled seizures which are similar to those of the neuropeptide, corticotropin-releasing hormone (CRH), with which they show a close functional relationship. These results may be of interest in the light of data showing that glucocorticoids increase CRH expression in the central nucleus of the amygdala, which is an important site for the development of kindling.

Animals↗
PubMed1993

Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis.

Two studies examined sex differences in responsiveness of the hypothalamic-pituitary-adrenal cortical axis, a major component of the stress response. The first measured pituitary-adrenal responses to ovine corticotropin-releasing hormone (oCRH) in 24 health men and 19 healthy women. Plasma adrenocorticotropin hormone (ACTH) response to oCRH were significantly greater among women than among men. In contrast, cortisol concentrations were similar in both groups, though elevations were more prolonged in women. Differences in corticotropin-releasing activity between men and women may help account for these findings; such differences in central components of the stress response might play a role in the known epidemiological differences in diseases of stress system dysregulation between men and women.

Adrenocorticotropic Hormone↗
PubMed1993

Quantitative electroencephalographic correlates of steroid administration in man.

Elevated levels of circulating corticosteroids are frequently associated with behavioral alterations in man, although the mechanisms by which corticosteroids may affect behavior are poorly understood. To evaluate possible effects of exogenous corticosteroids on brain electrophysiological functioning and the relationship of such effects to behavioral and biochemical changes, we administered prednisone (80 mg p.o. daily for 5 days) in a double-blind manner to 11 medically healthy volunteers. Quantitative electroencephalogram analysis was performed following 4 days of prednisone administration and during the preceding and ensuing placebo administration periods. Central theta wave brain electrical activity significantly increased following prednisone administration and returned to baseline following prednisone withdrawal. This effect was directly correlated with prednisone-induced increases in subjective sadness ratings and with decreases in self-rated energy and well-being. Prednisone-induced reductions in peak alpha wave activity were also directly correlated with increases in subjective sadness and Symptom Checklist-90 ratings and with decreases in self-rated 'hypomanic' symptoms. Further, prednisone-induced increases in theta activity were significantly correlated with prednisone-induced decreases in CSF levels of somatostatin-like immunoreactivity, and prednisone-induced decreases in peak alpha activity were significantly correlated with decreases in CSF levels of norepinephrine and with relative increases (or lesser decreases) in CSF levels of beta-endorphin and beta-lipotropic hormone. This preliminary report of the concomitant development of prednisone-induced changes in brain electrical activity, neurochemistry and behavior highlights areas for future exploration in the study of corticosteroid effects on behavior in man.

Adult↗
PubMed1993

Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion.

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing's disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing's disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing's disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-Releasing Hormone↗
PubMed1993

Effects of the glucocorticoid antagonist RU 486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers: enhancement of plasma ACTH and cortisol secretion in underweight patients.

To further explore whether the hypercortisolism of anorexia nervosa reflects an alteration in the set point for corticotropin-releasing hormone (CRH) secretion or is a manifestation of glucocorticoid resistance, we examined plasma ACTH and cortisol responses to the competitive glucocorticoid antagonist RU 486 (10 mg/kg, p.o. at 8.00 h) versus placebo (PBO) in 7 healthy female volunteers and 8 patients with DSM-III-R anorexia nervosa, all of whom were studied while underweight [64.3 +/- 2.1% average body weight (ABW), mean +/- SE] and 5 of whom were restudied longitudinally following refeeding (> or = 85% ABW, mean 87.4 +/- 0.4% ABW). Blood samples were obtained from 16.00 to 16.30 h and from 4.00 to 8.00 h following dosing. Underweight anorexics were significantly hypercortisolemic by 24 h urinary free cortisol excretion compared with controls (239 +/- 37 vs. 119 +/- 12 nmol/day, p < 0.01). Both controls and underweight anorexics had robust early morning (4.00-8.00 h) plasma cortisol responses to RU 486 (465 +/- 61 and 719 +/- 49 nmol/l) compared with PBO (370 +/- 52 and 451 +/- 31 nmol/l; p < 0.02 and p < 0.01, respectively). The underweight anorexics showed a significant mean early morning plasma ACTH response to RU compared with placebo (3.28 +/- 0.63 vs. 2.01 +/- 0.24 pmol/l, p < 0.05), while the controls showed a trend toward an increase in mean plasma ACTH after RU (3.11 +/- 0.36 pmol/l) compared with PBO (2.31 +/- 0.41 pmol/l, p < 0.13); plasma ACTH means were greater on the RU day than the placebo day at 20 of 25 sampling points (p < 0.001). However, the increment in ACTH on the RU day compared to the placebo day was greater in the underweight anorexics at the first 20 of 25 consecutive time points of the early morning sampling period (p < 0.001). Moreover, underweight anorexics showed a significant plasma ACTH and cortisol response to RU 486 at 16.00-16.30 h (8-8.5 h following administration), while the controls showed no significant response of plasma ACTH or cortisol at this time. When restudied following weight recovery, anorexic patients showed reductions in 24-hour urinary free cortisol excretion (to 191 +/- 40 nmol/day) which were no longer significantly elevated compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗