Effect of dietary restriction on body condition, composition and welfare of overweight and obese pony mares.

REASONS FOR PERFORMING STUDY: Increased prevalence of obesity among UK horses and ponies demands evidence-based advice to promote weight loss. HYPOTHESIS: Restriction of dry matter intake (DMI) to 1% of body mass (BM, 67% [corrected] of predicted maintenance digestible energy [DE] requirements) would promote weight loss without compromise to health. METHODS: Five mature (mean ± s.e. 10 ± 2 years), overweight/obese pony mares (BM, 257 ± 20 kg: body condition score [BCS] 6.8/9 ± 0.5) were studied over 12 weeks. Animals were individually housed. Daily provision of a chaff-based, complete diet (measured DE, 8.5 MJ/kg DM) was restricted to 1% of actual BM as DMI daily. BCS, girth measurements and ultrasound-derived measures of subcutaneous fat depth overlying the gluteal region and 12th intercostal space (rib-eye) were recorded weekly. Body fat content was estimated at the beginning and end of the study by deuterium oxide dilution methods. Clinical biochemistry was monitored weekly. Behaviour was observed (24 h, 3/5 ponies) on 3 occasions. RESULTS: BM decreased by 4.3 ± 1.1% during the first week and thereafter by 0.7 ± 0.1% of BM at end of Week 1 each week. BCS remained constant. Heart and belly girths, rump width and subcutaneous fat depth at rib-eye decreased significantly with time and BM. Fat comprised 45 ± 19% of BM loss. Fatter animals lost relatively more fat. With decreased feeding activity, time spent in 'play' and rest increased by 36 ± 11% and 438 ± 95%, respectively. CONCLUSIONS: This plane of nutrition resulted in an overall rate of weight loss of 1% of outset BM weekly. BCS was not a useful index of early weight loss but heart and belly girths and subcutaneous rib-eye fat were identified as alternative markers. POTENTIAL RELEVANCE: This study provides an evidence-base for the management of weight loss in obese animals, especially those for which exercise may be contra-indicated.

Impact of feeding and housing systems on disease incidence in dairy calves.

Contentious issues in calf rearing include milk feeding level and single versus group housing. The current study was performed on a high-producing 170 Holstein cow dairy farm to investigate the impact of nutrition and housing on disease incidence. Calves (n=100) were allocated in birth order to one of two commonly used feeding strategies. Group A calves were group housed from birth and fed ad libitum milk replacer (MR) via a computerised machine using a single teat, with weaning commencing at 63 days. Group R calves were initially housed in individual pens receiving 2.5 litres of MR twice daily via a bucket until three weeks of age when they were group housed and fed 3 litres of MR twice daily via a group trough with weaning commencing at 56 days. In total, 80 (80 per cent) calves suffered from at least one incident of disease during the period from birth to 12 weeks. Group A calves had a greater risk of disease than group R calves (diarrhoea: OR 3.86 (95 per cent CI 1.67 to 8.9); pneumonia: OR 5.80 (95 per cent CI 2.33 to 14.44)). There was a 5.1 per cent incidence of failure of passive transfer of Ig assessed via measurement of plasma total protein concentrations at 48 hours of age. It is hypothesised that the increased diarrhoea risk in group A calves was most likely associated with group housing, while the increased pneumonia risk was associated with the use of a single teat allowing increased transmission of pathogens from calf to calf.

Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction.

The regulation of hypothalamopituitary-adrenal (HPA) function in depressed patients was studied by a midnight dexamethasone suppression test. By using an observation period of 24 hours postadministration of dexamethasone, a graded series of abnormal test responses was identified. Depressed patients show abnormal early escape from suppression rather than absolute resistance to HPA suppression by dexamethasone. With increasing severity of depression, this escape occurs progressively more early on the day after administration of dexamethasone. These abnormalities were strongly related to the presence of HPA hyperactivity before dexamethasone was given. The essential disturbance of neuroendocrine regulation in depression is a failure of the normal brain inhibitory influence on the HPA system. This disinhibition of HPA activity suggests that there is an abnormal limbic system drive on the HPA axis in primary depressive illness.

Hypothalamic-pituitary-adrenal axis activity in panic disorder. 24-hour secretion of corticotropin and cortisol.

BACKGROUND: Oversecretion of corticotropin-releasing hormone and/or dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to pathophysiologic processes in panic disorder, but documentation of HPA axis disturbance in panic has been inconsistent. In the current study we examined HPA axis activity in panic disorder over a full circadian cycle, using frequent blood sampling to provide detailed assessment of corticotropin and cortisol secretion. METHODS: Twenty patients with panic disorder and 12 normal control subjects were studied. Blood samples were drawn every 15 minutes for 24 hours and assayed for corticotropin and cortisol levels. RESULTS: Patients with panic disorder had elevated overnight cortisol secretion and greater amplitude of ultradian secretory episodes. Patients who entered the study through clinical referral channels had greater cortisol secretion than those recruited by advertisements. Patients with panic disorder who had a low frequency of panic attacks had elevated daytime corticotropin levels and elevated corticotropin ultradian amplitude. Patients with a high frequency of attacks had shifted corticotropin circadian cycles. CONCLUSIONS: Patients with panic disorder demonstrate subtle alterations in HPA axis activity, characterized by overnight hypercortisolemia and increased activity in ultradian secretory episodes, but HPA axis alterations in panic are modulated by illness severity and treatment seeking. It remains unclear whether HPA axis dysregulation in panic represents a pathogenic defect within the axis itself. Inconsistencies in prior work may reflect the subtlety of the abnormalities seen, differences in clinical characteristics of patients studied, and the use of different probes and measurement contexts.

Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients.

Forty-two patients with endogenomorphic depression (ED) and 42 patients with other psychiatric disorders received an overnight dexamethasone test of hypothalamopituitary-adrenal (HPA) suppressibility. Plasma and urinary cortisol measures showed that the ED patients had significantly greater HPA activity before dexamethasone and less complete HPA suppression after dexamethasone. High cortisol vlaues after dexamethasone correlated strongly with spontaneous HPA disinhibition, as indicated by high baseline midnight plasma cortisol levels. Criteria for defining normal suppression responses were developed. All patients with depressive neuroses and most patients with other nondepressive disorders had completely normal responses to dexamethasone. About half of the ED patients had abnormal responses, whether or not they were receiving other drugs at the time of the test. Drug-free patients with depressive neuroses or other disorders showed no abnormal responses to dexamethasone. The effects of psychotropic drugs on the test require further study. Patients with two or more abnormal cortisol values after administration of dexamethasone were identified correctly as ED at confidence levels close to 100%. The dexamethasone suppression test may be of value as a laboratory aid in the diagnosis of "endogenous" depression.

Blunted growth hormone response to clonidine in patients with generalized anxiety disorder.

Patients with panic disorder or depression have abnormal responses to the alpha 2-adrenergic receptor partial agonist clonidine. Evidence linking anxiety to noradrenergic dysfunction and the presence of anxiety symptoms in both depression and panic suggest that abnormal responses to clonidine in these disorders could be due to the anxiety symptoms. To explore a possible link between "nonspecific" anxiety symptoms and abnormal responses to clonidine, patients with DSM-III-defined generalized anxiety disorder were given intravenous infusions of clonidine hydrochloride. Responses of plasma growth hormone, 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, and psychological states were determined in 11 patients with generalized anxiety disorder and 14 healthy subjects. Clonidine produced significantly smaller growth hormone responses in patients than in healthy controls. The two groups did not differ in 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, or psychological responses to clonidine. These results are compared with data from similar studies on patients with panic disorder and depression. The blunting of the growth hormone response to clonidine in all three disorders could be due to the presence of generalized anxiety symptoms. Subsensitivity of postsynaptic alpha 2-adrenoreceptors may be present in all three disorders; however, there are alternative interpretations of growth hormone blunting in response to clonidine. Blunting was observed in DSM-III-defined generalized anxiety disorder, whether or not the DSM-III-R criterion of excessive worry was also present.

Platelet alpha 2-adrenergic receptor binding and plasma catecholamines. Before and during imipramine treatment in patients with panic anxiety.

Specific binding of tritiated clonidine, an alpha 2-adrenergic receptor agonist, and tritiated yohimbine, an alpha 2-adrenergic receptor antagonist, to platelet membranes was measured in persons with panic attacks or major depression and in normal subjects. Plasma catecholamine levels were measured in patients with panic attacks and in normal subjects. The number of binding sites in patients with panic attacks, as measured with tritiated clonidine, was lower than in depressed persons and was the same as in normal subjects. The number in patients with panic attacks, as measured with tritiated yohimbine, was lower than in either depressives or normal subjects. Catecholamine levels were somewhat higher in patients with panic attacks than in normal subjects. Treatment with imipramine hydrochloride decreased the number of sites, as measured with either ligand, in both patient groups and increased catecholamine levels in patients with panic attacks.

Adrenergic function in patients with panic anxiety.

Increased beta-adrenergic receptor sensitivity could account for many aspects of panic disorder. We tested this hypothesis by comparing 14 patients with six normal control subjects. The controls and eight patients had 14 blood samples taken, and heart rate and BP measured, during a four-hour protocol that included supine rest, a posture and isometric exercise stimulus, and a series of up to seven logarithmically increasing bolus intravenous doses of isoproterenol hydrochloride. The other six patients were studied only at rest. Patients had markedly elevated resting heart rate, substantially elevated levels of plasma epinephrine, cortisol, and growth hormone, mildly elevated plasma norepinephrine levels, and decreased heart rate responses to isoproterenol. These results suggest that beta-adrenergic receptor response is not increased, and may be decreased, in patients with panic disorder. Receptor down-regulation could result from the increased adrenergic function that these patients demonstrate, even in the absence of panic attacks.

Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia.

The present study was undertaken to clarify some of the conflicting findings of previous reports on the effect of state anxiety on cerebral blood flow (CBF). Seven subjects with simple phobia of small animals were studied to permit the generation of wide ranges of anxiety. Each subject received five positron emission tomography (PET) scans in a rest-fear-rest-fear-rest, repeated-measures paradigm. A population of eight normal controls was employed. The phobic stimuli produced significant increases in state anxiety during fear and significant differences in physiologic measurements between the fear and rest scans. Absolute global and regional CBF was significantly lower during fear scans than during rest scans; however, when hypocapnia resulting from anxiety-induced hyperventilation was taken into account, the pattern vanished, and all global and regional CBF differences among scans became not significant. Resting global and regional CBF values in the phobic subjects did not significantly differ from those of the normal controls. That a relationship between anxiety and CBF was not found in 35 scans among seven subjects strongly suggests that CBF changes induced by state anxiety are either not presently measurable by PET techniques or that such a relationship may not exist. These findings should also reduce concerns that subject anxiety may confound CBF measurements during routine PET scanning.

Adrenocorticotropic hormone and cortisol responses to corticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment.

This study applied the corticotropin-releasing hormone (CRH) stimulation test to patients with panic disorder, before and during treatment with alprazolam, and to control subjects. In contrast to some, but not all prior studies, untreated, nondepressed panic disorder patients failed to show blunted adrenocorticotropic hormone or cortisol responses to CRH. In fact, the responses were subtly enhanced in that they were more rapid than those of controls. After 12 weeks of alprazolam treatment, repeat testing gave results that were indistinguishable from those of controls. Inconsistency among reports of CRH testing in panic disorder may be related to interactions among illness mechanisms, concurrent subthreshold depressive symptoms, the chronic stress of the illness, and hyperresponsiveness of panic patients to the acute stress of experimental manipulations. Pretreatment abnormalities in hypothalamic-pituitary-adrenal axis function appear to resolve with alprazolam treatment. Preliminary observations suggest that pretreatment dysregulation of the hypothalamic-pituitary-adrenal system may predict a more difficult or less satisfactory treatment.

Endocrine, cardiovascular, and behavioral responses to clonidine in patients with panic disorder.

We examined adrenergic regulation in patients with panic disorder by challenging 10 patients and 14 age-matched and sex-matched controls with intravenous infusions of clonidine hydrochloride (2 micrograms/kg), an alpha 2-adrenoreceptor agonist. Growth hormone, 3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure, heart rate, and behavioral (anxiety, sedation) responses were monitored. The data replicated the previously reported finding of blunted growth hormone (GH) responses to clonidine in patients with panic disorder. Reported abnormalities in MHPG, cardiovascular, and behavioral responses of panic patients to clonidine infusion were not replicated. The robustly blunted GH response to clonidine in panic patients supports the adrenergic dysregulation hypothesis of panic disorder, but alternative interpretations of this finding are available and further study is needed.

Persistent respiratory irregularity in patients with panic disorder.

BACKGROUND: Dysregulated respiratory control may play a role in the pathophysiology of panic disorder. This could be due to abnormalities in brain stem respiratory nuclei or to dysregulation at higher brain levels. Results from previous studies using the doxapram model of panic have yielded an unclear picture. A brief cognitive manipulation reduced doxapram-induced hyperventilation in patients, suggesting that higher level inputs can substantially alter their respiratory patterns. However, respiratory abnormalities persisted, including a striking irregularity in breathing patterns. METHODS: To directly study respiratory irregularity, breath-by-breath records of tidal volume (V(t)) and frequency (f) from previously studied subjects were obtained. Irregularity was quantified using von Neumann's statistic and calculation of "sigh" frequency in 16 patients and 16 matched control subjects. Half of each group received a standard introduction to the study and half received a cognitive intervention designed to reduce anxiety/distress responses to the doxapram injection. RESULTS: Patients had significantly greater V(t) irregularity relative to control subjects. Neither the cognitive intervention nor doxapram-induced hyperventilation produced significant changes in V(t) irregularity. The V(t) irregularity was attributable to a sighing pattern of breathing that was characteristic of panic patients but not control subjects. Patients also had somewhat elevated f irregularity relative to control subjects. CONCLUSIONS: The irregular breathing patterns in panic patients appear to be intrinsic and stable, uninfluenced by induced hyperventilation or cognitive manipulation. Further study of V(t) irregularity and sighs are warranted in efforts to localize dysregulated neural circuits in panic to brain stem or midbrain levels.

Adrenergic status in anxiety disorders: platelet alpha 2-adrenergic receptor binding, blood pressure, pulse, and plasma catecholamines in panic and generalized anxiety disorder patients and in normal subjects.

In order to evaluate adrenergic function in anxiety disorders, platelet alpha 2-adrenergic binding parameters and supine and standing blood pressure, pulse, and venous plasma epinephrine and norepinephrine were determined in patients with panic attacks or generalized anxiety disorder and in normal subjects. The maximum number of binding sites (Bmax) for the partial agonist tritiated clonidine was significantly lower for both patient groups than for normal subjects, and the Bmax for the antagonist tritiated yohimbine was significantly lower for panic patients. There were no other substantive differences across groups. Prior exposure to psychotropic drugs might account for the results for clonidine binding, but not for yohimbine. The Bmax for clonidine was correlated with norepinephrine increases upon standing and, for panic patients, with the severity of full unexpected panic attacks. These data provide further evidence of adrenergic receptor abnormalities in people with anxiety disorders.

Alpha 2-adrenoreceptor status in obsessive-compulsive disorder.

Ten patients with obsessive-compulsive disorder (OCD) and 13 normal control subjects received intravenous infusions of 2 X 10(-6) g/kg of clonidine and normal saline on separate days. Responses to the drug relating to plasma growth hormone (GH), 3-methoxy-4-hydroxyphenylglycol (MHPG), heart rate, blood pressure, and several symptoms were determined. Additionally, platelet alpha 2-adrenoreceptor binding was measured in most of the subjects. GH, MHPG, blood pressure, and heart rate responses to clonidine did not differ between groups. As expected, patients reported more symptoms than normal subjects, and clonidine was sedating for both groups. Patients did not differ from normal subjects in the symptom response to clonidine. The maximum number of binding sites (Bmax) for tritiated clonidine was significantly greater in OCD patients than in normals. This pattern of alpha 2-adrenoreceptor status is different than the patterns in major depression and panic anxiety.

Sensory experiences during treatment of phobias by in vivo exposure.

The author describes several patients undergoing in vivo exposure therapy for simple phobias who reported transient sensory distortions without other evidence of psychosis. The experiences occurred mainly in the tactile, kinesthetic, and visual modes. Their nature and significance are undetermined, but they appear to resemble conversion symptoms, hypnotic sensory distortions, and other nonpsychotic sensory experiences stimulated by emotionally charged ideas.

Hypothalamic-pituitary-adrenal axis activity in panic disorder: prediction of long-term outcome by pretreatment cortisol levels.

OBJECTIVE: The authors sought to determine whether hypothalamic-pituitary-adrenal (HPA) axis activity in patients before their treatment for panic disorder can predict follow-up functional status. Although baseline HPA axis disturbances in patients with panic disorder appear to attenuate with treatment, there is evidence that they may be linked to poorer long-term outcomes. METHOD: Follow-up clinical data were obtained for 18 of 20 patients with panic disorder who participated in a detailed study of HPA axis activity in panic, both before and during their treatment with alprazolam. HPA axis assessment included monitoring of adrenocorticotropin and cortisol over a full circadian cycle. The relationships between disability and clinical status at 2-year follow-up and HPA axis overactivity at entry were examined. RESULTS: Mean 24-hour cortisol levels before treatment provided a strong, positive predictor of disability scores at follow-up. Those patients who achieved the treatment goal of medication-free remissions had less evidence of HPA axis overactivity at entry than those who were not in remission. CONCLUSIONS: HPA axis activity before treatment did predict outcome 2 years later. This relationship appears robust and reproducible. Further work is needed to define the neuroendocrine mechanisms underlying the HPA axis markers that are linked to long-term functioning and to determine the biological, psychological, and social processes that link HPA axis disturbance to poorer outcomes.

Fainting on exposure to phobic stimuli.

Two patients with phobias for medical procedures and trauma developed "vasovagal syncope" with hypotension and bradycardia while viewing a videotape of a venous cutdown. Eleven hours of exposure therapy per patient eliminated both the phobic and fainting responses. These facts support existing hypotheses that phobias of this type and vasovagal fainting are associated and that vasovagal syncope is a diphasic response. They do not support hypotheses that vasovagal syncope follows sudden cessation of anxiety, that that counter-conditioning is necessary for successful treatment, or that novel symptoms emerge following behavioral treatment of these phobias.

Paradoxical response to dopamine agonists in tardive dyskinesia.

The authors conducted an extensive pharmacological analysis of a patient severely affected by tardive dyskinesia. No drug treatment gave lasting clinical improvement. Several agents recently recommended for this condition, dimethyl aminoethanol, clozapine, and thioridazine, failed to modify the dyskinesia. Reserpine caused a worsening of the symptoms. A paradoxical and unexpected improvement was observed with apomorphine injections and with low-dosage oral L-dopa. These two drugs may have acted by stimulating presynaptic inhibitory dopamine receptors.

Plasma growth hormone: effect of anxiety during flooding in vivo.

The treatment of phobias by rapid in vivo exposure to the feared situation was accompanied by an increase in plasma growth hormone levels on at least one of two occasions in 8 of 11 subjects. The average growth hormone response was greater on the second occasion, even though subjective anxiety was less. Plasma growth hormone was not elevated during the subjects' adaptation to the laboratory. Strong subjective and behavioral anxiety responses failed to elevate plasma growth hormone levels in some subjects. The probability of a growth hormone response was the same whether or not baseline levels were elevated prior to exposure.

The dexamethasone suppression test in panic disorder and agoraphobia.

Reports that imipramine and phenelzine prevent panic attacks in agoraphobia suggest the possibility that agoraphobia and/or panic disorder might be a clinical manifestation of underlying depression. To test this hypothesis, dexamethasone suppression tests (DSTs) were performed in 10 patients meeting DSM-III criteria for agoraphobia with panic attacks, 6 for panic disorder, and 4 whose diagnosis could have been either panic disorder or agoraphobia except that another axis I disorder precluded such a diagnosis. Abnormal DSTs were observed in only 3 patients and appeared to be attributable to causes other than panic attacks or agoraphobia. The results suggest that panic attacks and endogenous depression are separate disorders and that the antipanic properties of imipramine and phenelzine are separate from their antidepressant actions.