Development and validation of a nomogram to predict poor short-term response to recombinant human growth hormone treatment in children with growth disorders.

PURPOSE: The purpose of this study was to develop and validate a clinical predictive model for predicting the likelihood of a poor therapeutic response during the first year of recombinant human growth hormone (rhGH) treatment in children with growth disorders. METHODS: A total of 627 pediatric patients with growth disorders (GHD, ISS, TS, SGA) from The LG Growth Study cohort were evaluated. Restricted cubic splines (RCS) were utilized to investigate the association between predictors and the risk of poor rhGH response. Variables were selected using LASSO regression, and multivariate logistics regression models were established. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC) were used to assess the predictive model's accuracy and clinical value. The predictive accuracy of the model was validated on the testing set. RESULTS: Two predictive models containing 8 baseline predictors (diagnosis, age, height SDS, bone age minus chronological age, rhGH dosage, distance from mid-parental height in SDS, weight SDS, IGF-1 SDS) and 1 post-treatment predictor (height SDS gain at 6 months) were constructed by multivariate logistic regression analyses. The nomogram was built based on the multivariate predictive model and showed good discrimination and model fit effects in both the training set and the testing set. DCA and CIC analyses presented good clinical usability. CONCLUSION: The clinical predictive model for predicting the probability of poor short-term response of rhGH treatment in pediatric patients with growth disorders is useful and can assist physicians in making clinical decisions.

Protein-protein interaction network construction for cancer using a new L1/2-penalized Net-SVM model.

Identifying biomarker genes and characterizing interaction pathways with high-dimensional and low-sample size microarray data is a major challenge in computational biology. In this field, the construction of protein-protein interaction (PPI) networks using disease-related selected genes has garnered much attention. Support vector machines (SVMs) are commonly used to classify patients, and a number of useful tools such as lasso, elastic net, SCAD, or other regularization methods can be combined with SVM models to select genes that are related to a disease. In the current study, we propose a new Net-SVM model that is different from other SVM models as it is combined with L1/2-norm regularization, which has good performance with high-dimensional and low-sample size microarray data for cancer classification, gene selection, and PPI network construction. Both simulation studies and real data experiments demonstrated that our proposed method outperformed other regularization methods such as lasso, SCAD, and elastic net. In conclusion, our model may help to select fewer but more relevant genes, and can be used to construct simple and informative PPI networks that are highly relevant to cancer.

The central mechanism of hypothalamic-pituitary-adrenocortical system hyperfunction in depressed patients.

While hypercortisolemia is commonly observed in depression, exactly where in the hypothalamic-pituitary-adrenocortical (H-P-A) axis this dysfunction arises remains undefined. In attempting to distinguish between central or peripheral locus of dysfunction, we studied in 12 patients (10 females, two males) with primary major depression and eight age-matched controls (six females, two males) in their adrenal cortisol response to infused adrenocorticotropic hormone (ACTH) (cosyntropin 0.05 microg/kg bodyweight) while endogenous ACTH was suppressed with 1 mg of dexamethasone. Compared with the control group, pre-dexamethasone plasma baseline cortisol level was significantly higher in depressed patients while ACTH level remained normal. Post-dexamethasone responses of both hormones were greatly non-suppressed in the depressed group. Exogenous cosyntropin-elicited rise in plasma cortisol was significantly lower in depressed patients while the ACTH response was not significantly different. These findings suggest that an adrenal cortisol response to ACTH was significantly decreased during depression as compared with normals in Chinese depressed patients. Therefore, the central mechanism of hyperfunctioning H-P-A axis causing hypercortisolemia should be emphasized.

Non-steroidal anti-inflammatory drugs with adverse psychiatric reactions: five case reports.

Adverse drug reactions of non-steroidal anti-inflammatory drugs (NSAIDs) are quite prevalent, but there are few reports about possible adverse psychiatric reactions, which may be ignored or underestimated. We describe here five psychiatric outpatients, two with major depressive disorders, one bipolar disorder, one schizophrenic disorder and one anxiety disorder, who were treated with NSAIDs for pain due to rheumatoid arthritis, osteoarthritis or other painful neuromuscular conditions. All five patients developed a moderate to severe depressive state, three patients became obviously paranoid, and four had either thoughts of suicide or an attempt while undergoing co-administration of NSAIDs. The psychiatric symptoms remitted when the NSAIDs were stopped. The depressive and paranoid symptoms returned on seven occasions of re-use or re-challenge with the same or a different type of NSAID in all five patients. When the NSAIDs were stopped again, the patients had another remission of the adverse psychiatric reactions, and eventually recovered to their baseline mental states in clear temporal relationships. The cases presented suggest that NSAIDs can induce or exacerbate idiosyncratic reproducible adverse psychiatric symptoms in certain vulnerable patients, including those with a variety of psychotic or neurotic disorders, and also in elderly persons, but these undesirable side-effects were generally transient and disappeared on withdrawal of the NSAIDs.

A prospective one-year follow-up study of patients with bipolar affective disorder.

BACKGROUND: Patients with affective disorder often have a poorer than expected prognosis for functional outcome between episodes. Previously, these patients were thought to have a better outcome between episodes, particularly Chinese patients. The aim of our study was to prospectively monitor symptoms, and vocational and residential functions of a group of patients with bipolar affective disorder one year after hospitalization. This study compare these data with index, admission data and discuss the relationship between patients' symptoms and functional outcome. METHODS: The Brief Psychiatric Rating Scale (BPRS), Modified Manic State Rating Scale (MMS) and Hamilton Depression Rating Scale (HDRS-21 items) were used to measure the patients' general psychiatric condition, manic and depressive symptoms, respectively. A modified Vocational State Index and modified Location Code Index Scale were used to determine levels of functioning. RESULTS: One-year follow-up measurements indicated that 75% of patients were free of symptoms or had mild psychiatric symptoms and 95% of patients were asymptomatic or mildly symptomatic for affective-manic condition. There was significant improvement in symptom outcome. However, only 46% of patients were employed at the one-year follow-up assessment, and as few as 12% worked at their expected level of employment, while 42% were rated as being unable to work and remained at an incapacitated occupational function. There was a significant tendency for increased independent living at one year of follow-up (74.6% vs 45.8%). More than 40% of patients were solely responsible for themselves, while over 50% required others to be responsible for them in terms of daily living. Additionally, 70% of first-admission subjects were employed at some level at one-year follow-up assessment, compared with only 31.8% of subjects with multiple admissions; 70% of first-admission patients were living independently compared with only 40% of subjects with multiple admissions. CONCLUSIONS: The results showed that the symptom outcome was superior to the functional outcome. These findings indicate that variable factors other than psychotic symptoms are related to the functional outcome in Chinese patients with bipolar affective disorder. Although treatment reduced the symptom intensity of affective episodes, a long-range rehabilitative program and strategy for prevention relapse is required to help functional outcome catch up with symptomatic amelioration.

Diurnal melatonin and cortisol secretion profiles in medicated schizophrenic patients.

Although melatonin and/or cortisol secretions have been suggested as markers for both circadian and noradrenaline dysfunctions in psychiatric illnesses, especially in affective disorders, studies of melatonin and cortisol in schizophrenic patients are rare. We evaluated the circadian profiles of melatonin and cortisol secretion in schizophrenic patients and control subjects. A total of 21 medicated Taiwanese male paranoid schizophrenic inpatients (mean age, 27.3 +/- 7.2 yr) and 21 age- and sex-matched controls underwent 24-hour neuroendocrine screening. Melatonin and cortisol concentrations were measured at 2-hour intervals from 0800 h to 2200 h, and at 1-hour intervals from 2300 h to 0700 h. The standard dexamethasone suppression test was performed the next day to provide an index of hypothalamic-pituitary-adrenal axis (HPA) function. The results showed that the circadian rhythm of plasma melatonin secretion was disrupted in schizophrenics compared with controls, whereas the 24-hour profile of plasma cortisol was preserved. The melatonin to cortisol ratio was significantly higher in control subjects than in schizophrenic patients. Results of the dexamethasone suppression tests indicated that there were no functional changes in the HPA axis in schizophrenic patients. Five drug-naive schizophrenic patients studied simultaneously, but whose data were not included in the above analyses, had results consistent with those of the maintenance-medicated patients. Our findings suggest the presence of abnormal melatonin metabolism in Taiwanese schizophrenics, which may possibly be related to the pathophysiologic process itself. However, broader pathogenetic aspects of these neuroendocrine interrelations remain to be clarified.

Regulation of tyrosine hydroxylase gene expression in depolarized non-transformed bovine adrenal medullary cells: second messenger systems and promoter mechanisms.

Activation of the tyrosine hydroxylase (TH) gene in the adrenal medulla during stress is mediated by trans-synaptic mechanisms and may involve cholinergic receptors. Stimulation of nicotinic receptors in adrenal medullary cells induces cell depolarization, influx of Ca2+ ions and increases levels of cAMP. We have shown that both cAMP and membrane depolarization produce an increase in the expression of the TH gene in cultured bovine adrenal medullary cells (BAMC). Others have proposed that transcriptional activation of the TH gene by cAMP is mediated through the sequence homologous to a cAMP responsive element (CRE) located in the proximal region of the TH gene promoter. In the present study we have examined the mechanisms by which membrane depolarization increases the TH gene activity. Treatment of serum-free BAMC cultures with the depolarizing agent, veratridine, increased the extracellular concentration of catecholamines, Met5-enkephalin, and the relative abundance of TH mRNA. Veratridine treatment also increased the levels of mRNAs for the catecholamine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT), and proenkephalin A (PEK). Treatment for longer than 3 h was required to increase TH mRNA levels. By contrast, our previous studies indicated that cAMP stimulation for 2 h produces a maximal increase in TH mRNA levels in BAMC. The effects of veratridine and forskolin on TH mRNA levels were additive, further indicating that depolarization and cAMP activate TH gene expression via different pathways. Calmidazolium, an antagonist of calmodulin, had no effect on the veratridine-induced increase in TH mRNA levels. Similarly sphingosine treatment or preincubation with PMA, which reduce protein kinase C (PKC) activity and attenuate the induction of TH mRNA by PMA or the hormone, angiotensin II, did not affect the induction by veratridine. To identify promoter mechanisms of TH gene activation in depolarized cells we transfected BAMC with a plasmid pTHgoodLuc and treated with veratridine for 24 h. pTHgoodLUC contains a luciferase reporter gene linked to a -428/+21 bp fragment of the bovine TH gene promoter (relative to the transcription start site). Veratridine increased the expression of luciferase from the TH promoter 2.5-fold. Deletion of the -194/-54 bp promoter region containing SP-1 and POU/Oct sites reduced veratridine stimulation by 40%. Additional deletion of the -269 to -190 bp promoter segment, including an AP-1 element, further reduced veratridine stimulation to a statistically non-significant level. In conclusion, activation of TH gene expression upon depolarization is not mediated by calmodulin and PKC. Promoter sequences involved in this activation are located upstream from the CRE. Depolarization may activate TH gene transcription by acting on more than one regulatory region.

Role of plasma catecholamines, autonomic, and left ventricular function in normotensive and hypotension prone dialysis patients.

The current study looked at plasma catecholamines, clinical autonomic function tests, and hemodynamic parameters in 10 ESRD patients (five men and five woman, aged 56.4 +/- 3.6) with dialysis hypotension and 10 patients (five men and five women, aged 58.6 +/- 4.2) without dialysis hypotension. Catecholamines were measured using high performance liquid chromatography--electrochemical detection (HPLC-ECD). Dialysis led to a significant decrease in mean arterial pressure (MAP) in the hypotensive group as compared with the normotensive group. Significantly higher basal (predialysis) plasma norepinephrine (NE) and dopamine levels (DA) were found in the hypotensive uremic group as compared with the normotensive group. Levels of plasma epinephrine (EP) were not significantly different between the normotensive and hypotensive groups. In response to postural stimulation, blood pressure fell in both groups, but the fall in the hypotensive group was significantly greater. Percentage increments of plasma catecholamines in response to postural stimulation in both groups were similar, however. Among the measured hemodynamic parameters, including total peripheral vascular resistance and left ventricular function (cardiac index and fractional shortening), only the cardiac index showed significantly lower values in the hypotensive group after dialysis, as compared with the normotensive group. Results of four tests of autonomic function indicated that although both groups responded similarly to hand-grip and cold-pressor tests, impaired responses to orthostasis and Valsalva maneuver after dialysis were observed in the hypotensive group. The MAP changes in dialysis in the hypotension prone group correlated inversely with predialysis plasma NE, but not with EP and DA.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dopamine D-1 and D-2 receptor subtype agonists on nigrostriatal opioid dynorphin and enkephalin immunostaining in 6-hydroxydopamine lesioned rats.

Using selective neurotoxin lesioning and immunocytochemical techniques, the effects of dopamine receptor subtypes stimulation by selective subtype agonists in the modulation of striatal opioid dynorphin and enkephalin were characterized in the rat basal ganglia. Tissue staining with specific antibodies against either dynorphin A (1-17) or [Met5]-enkephalin was examined in the striatum and substantia nigra following unilateral nigrostriatal dopaminergic lesioning by the neurotoxin 6-hydroxydopamine (6-OHDA). Two weeks later three groups of five 6-OHDA lesioned rats were repeatedly treated with either the dopamine D-1 receptor agonist SKF-38393 (5 mg.kg, i.p.), D-2 receptor agonist LY-171555 (1 mg/kg, i.p.) or saline for 7 days and similar immunostaining procedures were employed. The results indicated that 6-OHDA lesioning alone led to reduction in dynorphin A (1-17) immunostaining in substantia nigra and striatum when compared to the sham-lesioned contralateral side. However, SKF-38393 treatment reversed that pattern and caused more intense dynorphin A (1-17) immunostaining than the lesion side, while LY-171555 had no effect. In contrast, enkephalin immunostaining was increased by 6-OHDA lesioning, and the effect was abolished by SKF-38393 but not LY-171555. These results are in agreement with previously reported radioimmunoassay findings and are compatible with the proposal that dopamine D-1 receptors mediate the excitatory effect on the dynorphinergic system while inhibiting the enkephalinergic system.

Regulation of proenkephalin gene expression by angiotensin in bovine adrenal medullary cells: Molecular mechanisms and nature of the second messenger systems.

The purpose of this study was to examine the effects of angiotensin on the release of enkephalin peptides and the expression of the proenkephalin (pEK) gene. Incubation of cultured bovine adrenal medullary (AM) cells in serum-free medium resulted in calcium- and time-dependent accumulation of [Met(5)]-enkephalin (MEK) in the medium. Fifteen minutes to three hours of incubation with 2 nM [Sar(1)]-angiotensin II (s(1)-AII) did not affect basal secretion of MEK; however, longer incubations (24 h) resulted in four- to fivefold increases. Northern and dot blot analyses with bovine pEK cDNA demonstrated increases in the relative abundance of pEK mRNA in angiotensin-treated cells, suggesting that the long-term increases in MEK release may reflect increased expression of pEK gene and MEK synthesis. Stimulation of MEK release and induction of pEK mRNA were concentration dependent (ED(50) approximately 1 nM. Changes in pEK mRNA levels were not observed until 12 h of incubation with s(1)-AII and continued to increase during an additional 12 h of incubation. Addition of an angiotensin antagonist, saralasin, at 0-16 h, but not at 18-20 h, to cells incubated continuously for 24 h with s(1)-AII inhibited changes in pEK mRNA and MEK release. These observations demonstrate the absence of apparent desensitization of angiotensin receptor function and indicate that long-term receptor-ligand interactions are required to induce changes in gene expression and MEK release. Induction of pEK mRNA and stimulation of MEK release were additive to the effects of veratridine and forskolin, respectively, indicating that the effects of angiotensin were not due to membrane depolarization or increased cyclic AMP levels. Angiotensin-induced increases in pEK mRNA were partially inhibited by nifedipine and also by dantrolene and TMB-8, drugs that inhibit voltage-dependent calcium channels and mobilization of calcium from intracellular stores, respectively. s(1)-AII-induced changes in pEK mRNA were inhibited with calmidazolium, suggesting involvement of calmodulin. The participation of protein kinase C in the induction of pEK gene and long-term stimulation of MEK release was indicated by inhibition of the s(1)-AII effects by pretreatment of cells with protein kinase C inhibitor sphingosine. Effects of s(1)-AII on induction of pEK mRNA by angiotensin and by nicotine were prevented by the translational inhibitor cycloheximide. In conclusion, angiotensin receptors were found to control expression of the pEK gene and secretion of MEK. Unlike nicotinic receptors, which may control secretion of enkephalin peptides directly by stimulating exocytosis and indirectly by controlling peptide synthesis, the effects of angiotensin appear to be mediated indirectly at the level of pEK gene expression.

Influence of nigrostriatal dopaminergic tone on the biosynthesis of dynorphin and enkephalin in rat striatum.

The purpose of this study was to obtain direct evidence that the nigrostriatal dopamine (DA) pathway modulates the metabolism of striatal dynorphin and [Met5]-enkephalin. This was achieved by repeated injections of apomorphine (APO) or D-amphetamine (AMP) in unilateral nigral 6-hydroxydopamine (6-OHDA)-lesioned rats. Three weeks after a 6-OHDA lesion, dynorphin A(1-8)-like immunoreactivity (DN-LI) and the level of mRNA encoding prodynorphin in the striatum on the lesioned side were decreased compared with the contralateral control side. Activation of DA receptors by 7 daily injections of APO (5 mg/kg, Bid, s.c.), however, caused a large increase (3- to 4-fold of saline control) in striatal levels of DN-LI and prodynorphin mRNA on the 6-OHDA lesioned side, which is far greater than the increase on the contralateral side (2-fold of saline control). Presumably, the potentiated effect of APO in 6-OHDA lesioned rats is due to hypersensitivity of DA receptors resulting from DA denervation. Seven daily injections of AMP (5 mg/kg, Bid, s.c.), a DA-releasing agent, increased striatal DN-LI (187% of saline control) on the non-lesioned side, but not on the 6-OHDA-lesioned side. Taken together, the data indicate that the nigrostriatal pathway exerts a tonic excitatory influence over the biosynthesis of dynorphin and that this influence is not maximal since an additional increase in dopaminergic tone further increases the expression of dynorphin. In contrast, [Met5]-enkephalin-like immunoreactivity (ME-LI) in the striatum was increased by a 6-OHDA-lesion (145% of contralateral control), which was blocked by repeated administration of APO but not AMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Short and long term regulation of catecholamine biosynthetic enzymes by angiotensin in cultured adrenal medullary cells. Molecular mechanisms and nature of second messenger systems.

The purpose of this study was to examine the effects of angiotensin on the enzyme activities and gene expression of two catecholamine synthesizing enzymes, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT), in bovine adrenal medullary (AM) cells. Short term (15 min) incubation of cultured AM cells with 2 nM [Sar1]angiotensin II (s1-AII) did not increase basal secretion of catecholamines; however, longer incubations (3, 24, or 72 h) produced 4-10-fold increases. To determine whether angiotensin affects synthesis of catecholamines, the activities of TH and PNMT were examined. Incubation with s1-AII (15-30 min) decreased the Km of TH for its biopterine cofactor [6R)-5,6,7,8-tetrahydro-1-biopterin dihydrochloride (BH4] without affecting the Vmax, suggesting activation of TH. After long term incubation (72 h) the Km value was identical to that of control, while increases in the apparent Vmax were observed. PNMT activity was unaffected during a 30-min treatment with s1-AII; however, 2-fold increases occurred after a 48-72-h incubation. s1-AII (24 h) increased the relative abundance of TH and PNMT mRNAs, suggesting that the long term increase in enzyme activities reflected increased expression of TH and PNMT genes. Maximal increases were observed at 2 nM s1-AII and the changes were antagonized by saralasin. Induction of TH mRNA by s1-AII was additive to the effects of veratridine or forskolin indicating that effects of angiotensin were not due to membrane depolarization or increased cyclic AMP levels. Incubation with Ca2+ ionophore A23187 increased TH and PNMT mRNA levels in AM cells raising the possibility that the increase in cellular [Ca2+] could mediate effects of angiotensin. Angiotensin-induced increases in TH and PNMT mRNA were inhibited by nifedipine indicating involvement of voltage-dependent Ca2+ channels. In addition, the increases in TH, but not PNMT mRNA, were antagonized by dantrolene, which inhibits mobilization of Ca2+ from intracellular stores. Calmodulin involvement was suggested by the inhibition of s1-AII induced changes in mRNA with 1 microM calmidazolium.(ABSTRACT TRUNCATED AT 400 WORDS)

Stimulation of adrenal medullary cells in vivo and in vitro induces expression of c-fos proto-oncogene.

The nuclear proto-oncogene, c-fos, has been implicated in the coordinated regulation of gene expression during cell proliferation and differentiation. In this study, we have demonstrated the induction of the c-fos gene products in differentiated cells of the adrenal medulla by non-mitogenic signals. Activation of adrenal medullary cells in vivo by insulin-induced hypoglycemia, and in vitro by nicotine or angiotensin resulted in the rapid and transient elevation of c-fos mRNA levels. Induction of the c-fos mRNA by angiotensin and nicotine were accompanied by the appearance of the c-fos protein. The increase in c-fos protein occurred initially in the cytoplasm and, later, in the nucleus, and it was co-localized with tyrosine hydroxylase. Nuclear expression of the c-fos protein was also induced by veratridine, forskolin and the calcium ionophore A231287. The role of calcium in the regulation of the c-fos gene by angiotensin with nifedipine and inhibition of the effects of angiotensin with nifedipine and sphingosine, a protein kinase C inhibitor. Activation of the c-fos gene may play a role in the coordinated induction of genes involved in the long-term adaptation of adrenal medullary cells to increased functional demands.

Differential modulation of striatonigral dynorphin and enkephalin by dopamine receptor subtypes.

Previous studies indicate that dopaminergic transmission inhibits the biosynthesis of enkephalin and stimulates that of dynorphin in the striatonigral pathway of intact rat. The purpose of this study was to determine which dopamine (DA) receptor subtype(s) mediate the modulatory actions of DA. We measured striatal and nigral levels of enkephalin and dynorphin in: (1) intact rats repeatedly injected with D1 (SKF-38393, 5 mg/kg, i.p.) or D2 (LY-171555, 1 mg/kg, i.p.) agonists, alone or in combination, (2) 6-hydroxydopamine (6-OHDA)-lesioned rats repeatedly injected with the same D1 or D2 agonists, and (3) intact rats repeatedly injected with D1 (SCH-23390, 0.05 mg/kg, s.c.) or D2 (sulpiride, 100 mg/kg, s.c.) antagonists, given alone or in combination with the mixed D1/D2 agonist apomorphine (5 mg/kg, i.p.). Repeated injections of the D1 agonist to intact rats (twice daily for 7 days) produced a small but not statistically significant increase in striatal levels of dynorphin; similar treatment with the D2 agonist did not affect dynorphin levels at all. Combined treatments with D1 and D2 agonists did not potentiate the effect of the D1 agonist. 6-OHDA lesions of the nigrostriatal DA pathway alone decreased the level of dynorphin in both the striatum and substantia nigra. However, repeated D1 agonist, but not D2, injections not only reversed the decrease in dynorphin levels, but caused a significant increase above control levels. In intact rats, repeated injections of the D1 or D2 antagonist alone failed to alter the levels of dynorphin, but the D1 antagonist, not the D2 antagonist, attenuated the apomorphine-induced increase in striatal dynorphin.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated dynorphin in the hippocampal formation of aged rats: relation to cognitive impairment on a spatial learning task.

Radioimmunoassay revealed increased dynorphin A(1-8)-like immunoreactivity [dynA(1-8)LI] in the aged rat brain. Among a number of brain regions examined, an age-related dynA(1-8)LI elevation was found only in the hippocampal formation and frontal cortex. Moreover, the increase in dynA(1-8)LI in the aged hippocampus was associated with a decline in spatial learning ability: dynA(1-8)LI distinguished aged rats that were behaviorally impaired from aged cohorts that learned the spatial task as rapidly as younger animals. Northern blot hybridization using a 32P-labeled complementary RNA probe encoding rat prodynorphin indicated that the abundance of prodynorphin mRNA was also significantly increased in the hippocampal formation of aged rats with identified spatial learning impairments.

Regulation of the metabolism of striatal dynorphin by the dopaminergic system.

The purpose of this study was to explore the dopaminergic control of the striatonigral dynorphin system. Seven daily injections of a dopamine (DA) agonist, apomorphine (APO, 5 mg/kg, b.i.d., s.c.), caused a significant increase of dynorphin A (1-8)-like immunoreactivity (DN-LI) in the striatum (140% over control) and substantia nigra (41% over control) without changing DN-LI in frontal cortex, hypothalamus and hippocampus. Immunocytochemistry revealed intense dynorphin A (1-17)-like immunostaining in striatal "patch" neurons and striatonigral fibers after APO treatment. In order to understand the mechanism of increase in the peptide level, the abundance of preprodynorphin mRNA was quantified by Northern blot hybridization with a 32P-labeled cRNA probe coding for rat preprodynorphin. Seven daily injections of APO increased the abundance of striatal preprodynorphin mRNA by 60%. In another experiment, rats received a single injection of various doses of APO (0.5-2.5 mg/kg s.c.). Striatal DN-LI was decreased by 15% 1 hr after injection of a dose of 2.5 mg/kg of APO. Seven daily injections or a single injection of D-amphetamine produced effects similar to those elicited by APO. These studies reveal that the nigrostriatal DA system plays an important role in modulating the metabolism of striatonigral dynorphin-containing neurons.

Cortisol response to ACTH infusion in depressed patients: comparison with age-, sex-, and weight-matched normal subjects.

Adrenal responsiveness to Cosyntropin (synthetic ACTH) was investigated in five patients with major depression and five individually matched normal subjects. Three hours following suppression of endogenous ACTH secretion with dexamethasone (1 mg orally), the adrenal response to a 10-min infusion of Cosyntropin (0.05 micrograms/kg body weight) was monitored for 2 1/2 hr by plasma cortisol measured at 15-min intervals. The depressed patients had significantly higher baseline plasma cortisol, but not higher baseline ACTH, than the controls. During the 3-hr post-dexamethasone (and prior to Cosyntropin infusion), the depressed patients maintained significantly higher cortisol secretion, but not higher ACTH secretion, than the controls. After Cosyntropin infusion, there were no differences in ACTH and cortisol increases between the two groups. These findings stand in contrast to previous reports of enhanced adrenal responsiveness to the administration of much larger amounts of Cosyntropin in major depression.