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Biomedical subjects

Philip W Gold

Publications and source records attributed to Philip W Gold.

9 recordsLinked to original sources
PubMed2003

Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa.

Studies have shown that ghrelin plays a major role in energy homeostasis and modulation of feeding behavior. However, little is known about the influence of food consumption on plasma ghrelin levels in humans. Therefore, we investigated responses of plasma ghrelin to food intake, meal volume and meal nutritional value in healthy volunteers and women with anorexia nervosa (AN). After overnight fasting, all subjects received either a standardized breakfast or fiber. Plasma ghrelin levels were measured before and after the meal. Fasting plasma ghrelin was significantly higher in AN patients than in controls (1,800.6 +/- 47.0 vs. 795.9 +/- 24.3 pg/ml, P < 0.001) (606.8 +/- 15.8 vs. 268.2 +/- 8.2 pmol/l, P < 0.001), and correlated negatively with percentage of body fat in both groups. Ghrelin levels markedly fell after consumption of either a standardized meal or fiber in controls, but not in anorexic women. Thus, we concluded that the acute plasma ghrelin response to food intake, which in healthy individuals is independent of meal caloric value, is impaired in women with AN. This abnormality may be part of a chronic adaptation to prolonged food restriction, which attempts to restore a normal feeding conduct by maintaining the drive to eat.

Adipose Tissue↗
PubMed2003

Antithyroid antibody-linked symptoms in borderline personality disorder.

Circulating thyroid autoantibodies are more prevalent in patients with mood disorders than in the general population, but longitudinal clinical data that establish a relationship between thyroid antibody status and the course of any psychiatric syndrome have been lacking. In addition, scant attention has been paid to thyroid hormones and autoimmunity in borderline personality disorder (BPD). We report a case of a patient with classic BPD whose fluctuating mood and, especially, psychotic symptoms-rated using a double-blind method-were directly linked to antithyroglobulin antibody titers serially determined over an inpatient period of 275 d. Significantly lower psychosis and depression ratings were seen during a 4-wk period of relatively low antithyroid antibody titers, during blinded treatment with carbamazepine, than were observed during two high autoantibody epochs. The significant positive correlations between nurse- and patient-rated depression and thyroid autoantibodies over the entire period of inpatient study were similar to those also observed between urinary free cortisol levels and depression; the positive correlation between antithyroglubulin antibody titers and psychotic symptoms was stronger (r = +0.544; p < 0.002). Although this patient had biochemical indices of primary hypothyroidism, she showed only marginal improvement to triiodothyronine (T3) and no apparent clinical response to sustained levorotatory thyroxine (T4) administration; neither were antithyroid antibody titers significantly associated with changes in T3, free T4, or thyroid-stimulating hormone concentrations. She clinically deteriorated during a 50-d fluoxetine trial. The present data demonstrate a clinically significant, longitudinal correlation between fluctuating antithyroid antibody titers and symptoms of borderline psychopathology in our patient. It will be of interest to determine the prevalence, pathophysiologic mechanisms, and treatment implications of this putative autoimmune- BPD link.

Adult↗
PubMed2002

Regulatory role of glucocorticoids and glucocorticoid receptor mRNA levels on tyrosine hydroxylase gene expression in the locus coeruleus during repeated immobilization stress.

Sustained responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis during chronic or repeated stress is associated with continuous activation of ascending noradrenergic neurons from the brainstem to the hypothalamic paraventricular nucleus (PVN). The fact that glucocorticoid receptor (GR) exists in the brainstem noradrenergic neurons including locus coeruleus (LC) suggests that glucocorticoids play a modulatory role in maintaining the activity of these neurons during chronic stress. To determine whether alterations in the sensitivity of noradrenergic neuronal activity to endogenous CORT occur during chronic or repeated stress, tyrosine hydroxylase (TH) and GR mRNA expressions in the LC were examined in acute (2 h) and repeated (2 h daily, 14 days) immobilization stress, using sham-operated rats and adrenalectomized rats with a moderate dose of CORT replacement (ADX+CORT group). In acute stress, TH mRNA in the LC increased in the ADX+CORT rats, but not in sham operated rats. In repeated stress, however, elevated endogenous CORT failed to inhibit TH mRNA responses in sham rats; LC TH mRNA in sham rats responded to the same extent as in ADX+CORT rats. A reduction of GR mRNA in the LC was observed in the acutely stressed and repeatedly stressed sham group, but not in the ADX+CORT groups. The decrease in LC GR mRNA levels in sham rats tended to be greater after repeated than after acute stress. LC GR mRNA levels decreased in response to systemic CORT treatment (200 mg pellet sc, for 14 days) and increased in response to adrenalectomy; neither CORT treatment nor adrenalectomy influenced TH mRNA levels in the LC. These results suggest that glucocorticoid responses to acute immobilization prevent LC TH mRNA levels from rising significantly, while glucocorticoids appear to decrease their capacity to restrain LC TH mRNA during repeated immobilization. Although the results clearly show glucocorticoid-dependent alterations in LC GR mRNA expression, the association between increased TH mRNA and decreased GR mRNA in the LC remains to be elucidated.

Adrenalectomy↗
PubMed2002

Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress.

Stress-associated disorders such as melancholic depression are characterized by persistent hypothalamic-pituitary-adrenocortical (HPA) axis activation and intensive anxiety. Corticotropin-releasing hormone (CRH) appears to play an essential role in pathophysiology of such disorders. In an attempt to elucidate possible mechanisms underlying persistent activation of CRH in the central nervous system (CNS), we examined responses of hypothalamic and extrahypothalamic CRH systems to the stressors (immobilization stress or psychological stress) and interactions between these CRH systems and glucocorticoids in rats. We propose multiple feedback loops activating central CRH system: (1) attenuation of glucocorticoid-induced negative feedback on the activity of the hypothalamic and brainstem nuclei during chronic stress, (2) autoregulation of CRH biosynthesis in the hypothalamic paraventricular nucleus (PVN) through up-regulation of Type-1 CRH receptor (CRHR-1), and (3) glucocorticoid-mediated positive effects on the amygdaloid CRH system. Stress initially activates the hypothalamic CRH system, resulting in the hypersecretion of glucocorticoids from the adrenal gland. In addition, the psychological component of the stressor stimulates the amygdaloid CRH system. In the chronic phase of stress, down-regulation of GR in the PVN and other brain structures such as the locus coeruleus (LC) fails to restrain hyperfunction of the HPA axis, and persistent activation of the HPA axis further up-regulates the amygdaloid CRH system. Thus, the hypothalamic and the amygdaloid CRH systems cooperatively constitute stress-responsive, anxiety-producing neurocircuitry during chronic stress, which is responsible for the clinical manifestations of stress-associated disorders. Effects of tricyclic antidepressants (TCAs), which appear to mitigate the above mentioned multiple feedback loop forming the vicious circle to activate central CRH systems, will also be discussed.

Animals↗
PubMed2002

Divergent endocrine abnormalities in melancholic and atypical depression: clinical and pathophysiologic implications.

Mediators of neuroendocrine and autonomic function seem to play important roles in the core symptoms of major depression. Although centrally directed corticotropin-releasing hormones and norepinephrine contribute to core symptoms such as alterations in anxiety, arousal, and mood, they also exert significant potentially clinically relevant effects on key processes that proceed in the periphery. Thus, the core clinical manifestations of major depression may represent a fraction of a complicated systemic illness that not only influences thought and feeling, but also the processes involved in premature cardiovascular disease, osteoporosis, and premature death. Subdividing patients with major depression into meaningful biologic subgroups will facilitate the elucidation of the mechanisms that underlie the central and peripheral manifestations of major depressive illness.

Amygdala↗
PubMed2002

CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists.

A series of compounds related to N-butyl-N-ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (1, antalarmin) have been prepared and evaluated for their CRHR1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (delta-hydroxy or bis-beta-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor. Introducing an amino group or shortening the alkyl side chain was detrimental to CRHR1 affinity. The alcohol 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]butan-1-ol (3), bearing a terminal hydroxyl group on an N-alkyl side-chain, showed the highest CRHR1 binding affinity among these compounds (K(i)=0.68 nM), and is one of the highest affinity CRHR1 ligands known. Compounds 3-5, and 8, which are likely to be less lipophilic than 1, have high CRHR1 affinity and may be valuable probes to further study the CRH system.

Animals↗
PubMed2002

Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation.

OBJECTIVE: To determine whether a corticotropin releasing hormone (CRH) type 1-specific receptor antagonist, antalarmin, would alter the progression of inflammation in adjuvant induced arthritis (AIA) susceptible LEW/N rats by blocking local CRH mediated inflammatory responses or render AIA resistant F344/N rats more susceptible to AIA by blocking central CRH, thus reducing secretion of endogenous glucocorticoids. METHODS: F344/N and LEW/N rats were assigned to either drug or vehicle groups and treated with 20 mg/kg antalarmin or vehicle alone BID for 25 days by intraperitoneal injection. Arthritis was induced in both antalarmin and vehicle treated LEW/N and F344/N rats by subcutaneous injections at the base of the tail of incomplete Freund's adjuvant containing 10 mg/ml heat killed Mycobacterium tuberculosis. Control F344/N and LEW/N rats were maintained on either antalarmin or vehicle. RESULTS: Chronic blockade of CRH-R1 with systemic antalarmin significantly ameliorated AIA in LEW/N rats, reducing the severity of inflammation in peripheral joints, evidenced by clinical and histopathology scores, and weight loss associated with disease onset. Antalarmin neither induced nor exacerbated arthritis expression in F344/N or LEW/N rats, despite suppression of levels of adjuvant induced corticosterone, the major antiinflammatory glucocorticoid in rats. CONCLUSION: Systemic blockade of CRH-RI appeared to predominantly block peripheral proinflammatory effects of immune CRH, rather than the systemic glucocorticoid mediated antiinflammatory effects of hypothalamic CRH. Results indicate that chronic treatment with a CRH antagonist attenuates progressive inflammation induced degeneration of synovia, cartilage, and bone in arthritic joints, suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders.

Animals↗
PubMed1979

Manic-depressive illness: psychodynamic features of multigenerational families.

Psychodynamic features of families with multigenerational bipolar manic-depressive illness are described. Repetitive maladaptive patterns, including avoidance of affect, unrealistic standards of conformity, absence of intimate relationships apart from family, displaced parental low self-esteem, and fears related to illness heritability, may influence the maintenance of family pathology.

Adolescent↗