Growth hormone secretion in children and adolescents at high risk for major depressive disorder.

BACKGROUND: Decreased growth hormone (GH) response to pharmacologic stimulation has been found in children and adolescents during an episode of major depressive disorder and after recovery. In this study, we sought to determine whether GH secretion is similarly altered in children and adolescents who had never experienced depression but were at high risk of developing depression. METHODS: Subjects were 8 through 16 years of age and selected for high- and low-risk status according to familial loading for mood disorders. Sixty-four high-risk and 55 low-risk healthy subjects participated in the study, which assessed the following GH measures: (1) GH before growth hormone-releasing hormone (GHRH) infusion, every 15 minutes for 30 minutes; (2) GH response after intravenous infusion of GHRH (0.1 microg/kg), every 15 minutes for 90 minutes; and (3) nocturnal GH every 20 minutes from 9 PM until morning awakening. RESULTS: After stimulation with GHRH, the high-risk subjects secreted significantly less GH compared with the low-risk healthy controls (effect sizes for mean and peak GH, 0.52 [P =.007] and 0.40 [P =.04], respectively). In contrast, there were no between-group differences in the pre-GHRH and nocturnal GH secretion levels. Exposure to recent stressors was not associated with GH secretion. CONCLUSIONS: Taken together with previous evidence of decreased GH after GHRH infusion in acutely depressed and recovered children, these results indicate that the decreased GH response found in high-risk subjects may represent a trait marker for depression in children and adolescents.

Serotonergic functioning in depressed abused children: clinical and familial correlates.

BACKGROUND: The goal of this study was to examine serotonergic functioning and concomitant clinical and familial correlates in depressed abused children. METHODS: L-5-Hydroxytryptophan (L-5-HTP) (0.8 mg/kg) was administered intravenously to 10 depressed abused (MDD-AB), 10 depressed nonabused (MDD-NA), and 10 normal control nonabused (NC-NA) children. The children in the two nonabused cohorts represent a small matched subset of children from a larger interlocking study of the psychobiology of depression. Blood samples for prolactin and cortisol were collected from 30 min before to 2.5 hours after L-5-HTP infusion. RESULTS: The MDD-AB children secreted significantly more prolactin post-L-5-HTP than the children in the other two groups. There were no differences in baseline prolactin or any of the cortisol measures. Total prolactin post-L-5-HTP was significantly correlated with clinical ratings of aggressive behavior (rho = .48). In addition, children with a family history positive for suicide attempt (MDD-AB: n = 7; MDD-NA: n = 5; NC-NA: n = 2) secreted significantly more prolactin post-L-5-HTP than children with no family history of suicide. CONCLUSIONS: Dysregulation in the serotonergic system in abused children appears to be related to both familial and experiential factors.

Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder.

BACKGROUND: Altered serotonergic function has been observed in prepubertal children and adults with an acute episode of major depressive disorder (MDD). However, it is not known whether these alterations are present prior to the onset of MDD. METHODS: A serotonergic precursor, 5-hydroxy-L-tryptophan (L-5HTP) (oxitriptan) (0.8 mg/kg), was administered through an indwelling catheter to 36 children at high risk of MDD (with high family loading for MDD), 31 children with MDD, and 23 low-risk normal controls (with low family loading for mood disorders and no history of psychopathology). Blood samples for cortisol, prolactin (PRL), and growth hormone were obtained every 15 minutes for 180 minutes, beginning 30 minutes before L-5HTP infusion. RESULTS: Children at high risk of MDD and children with MDD had similar hormonal responses following L-5HTP infusion. After controlling for baseline values, both groups secreted significantly less cortisol and more PRL than did the low-risk normal controls, with the PRL finding being limited to girls. There were no between-group differences in baseline cortisol, PRL, or growth hormone secretion measures. CONCLUSIONS: Before the onset of affective illness, high-risk children had the same pattern of neuroendocrine response to the L-5HTP challenge as did children with MDD. These results extend earlier findings of altered serotonergic regulation in association with early-onset depression and indicate that these alterations may represent a trait marker for depression in children.

Adult tube feeding formulas.

Adult tube feeding formulas vary considerably with respect to composition, administration, and cost. Selecting the best product for patients requires a careful analysis of specific patient requirements and resources.

Corticotropin-releasing hormone challenge in prepubertal major depression.

This study investigates cortisol and ACTH (corticotropin) responses to an infusion of human CRH (corticotropin-releasing hormone) in prepubertal children with major depressive disorder (MDD). Following a period of 24 hours of adaptation to the laboratory environment with an intravenous catheter in place, 34 children with MDD and 22 healthy controls received 1 microgram/kg of human CRH at 5:00 PM. Blood samples for cortisol and ACTH were measured at baseline and post-CRH. Overall, there were no significant differences between the MDD and the normal controls in baseline or post CRH stimulation values of either cortisol or ACTH. Melancholic (n = 4) patients had significantly higher baseline cortisol levels than nonmelancholic (n = 24) patients. Compared with the outpatients and the nonmelancholics, the inpatients (n = 10) and the melancholics showed significantly lower total ACTH secretion (effect size: 0.9 and 1.4, respectively) after CRH infusion. These results are consistent with a broad literature suggesting that the HPA axis abnormalities occur less frequently in early-onset depression than reported in adult studies. The pattern of results in the subgroups of inpatients and in melancholic children, however, raise questions about possible continuities with adult studies.

Fenfluramine challenge test as a predictor of outcome in major depression.

It has been reported that low pretreatment cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels may correlate with better clinical response to selective serotonin reuptake inhibitors (SSRI) compared to non-serotonergic antidepressant drugs. We examined the hypothesis that serotonergic system status, as measured by the prolactin (PRL) response to fenfluramine (FEN), may predict outcome in a heterogenous sample treated with various types of antidepressant treatment. Higher PRL response predicted a favorable outcome for males and females treated with either pharmacotherapy, psychotherapy [milieu therapy with or without cognitive behavior therapy (CBT)], or electroconvulsive therapy (ECT). All patients in the high PRL response group responded to antidepressant therapies. Patients receiving ECT had the highest proportion of treatment responders, the highest degree of treatment response, and, unlike drug or psychotherapy treatment, improved significantly whether in the high or low PRL response group. PRL response to a single dose fenfluramine challenge may be a useful predictor of response to pharmacological or psychotherapeutic treatments in major depression. By contrast, ECT is an effective short-term treatment independent of pretreatment serotonergic responsivity.

Induction of granulomatous experimental autoimmune thyroiditis in mice with in vitro activated effector T cells and anti-IFN-gamma antibody.

Experimental autoimmune thyroiditis (EAT) can be induced in mice after the transfer of mouse thyroglobulin (MTg)-sensitized donor spleen cells that have been activated in vitro with MTg. CD4+ T cells are required for the transfer of EAT in this model. Because CD4+ T cells produce various lymphokines, such as IFN-gamma, that may be involved in the activation or regulation of the immune response to MTg and the development of EAT, the present study was undertaken to determine whether a neutralizing mAb to IFN-gamma could modulate the induction or expression of EAT. The anti-IFN-gamma mAb XMG-1.2 had no effect on sensitization of donor cells. However, addition of XMG-1.2 mAb during in vitro activation of MTg-primed spleen cells resulted in more severe EAT in recipient mice. The thyroid lesions in recipients of cells cultured with MTg and XMG-1.2 mAb also exhibited granulomatous changes, which differed qualitatively from the predominantly lymphocytic cell infiltrates in recipients of cells cultured with MTg alone. Recipients of MTg-activated spleen cells also developed severe granulomatous EAT when they were given injections of XMG-1.2 mAb. The effects of XMG-1.2 could be neutralized by IFN-gamma. Recipients of cells cultured in the presence of XMG-1.2 mAb had augmented autoantibody responses, although there were no apparent differences in the IgG subclass distribution of the anti-MTg autoantibody responses. These studies suggest that neutralization of endogenous IFN-gamma results in increased activity of cells capable of inducing granulomatous EAT in mice.

Hormonal responses to dextroamphetamine in depressed and normal adolescents.

Because of its neuroendocrine effects, amphetamine infusion has been used as a probe to investigate neurobiological correlates of depressive illness. In two separate studies, a total of 72 adolescents with major depressive disorder and 66 normal adolescents were given dextroamphetamine, 0.15 mg/kg, intravenously. Their cortisol, growth hormone, and prolactin responses were measured. These endocrine responses did not reliably distinguish adolescents with major depressive disorder from those without it, nor did they reliably delineate any specific depressive subgroup. These findings are compared with those from similar studies of adult depression.

Identification and mapping of an immunogenic region of Mycoplasma hyopneumoniae p65 surface lipoprotein expressed in Escherichia coli from a cloned genomic fragment.

A previously characterized lipid-modified amphiphilic surface protein of Mycoplasma hyopneumoniae, p65, has been defined by its reaction with a surface-binding monoclonal antibody (MAb) and by its exclusive partitioning into the detergent phase during Triton X-114 phase fractionation (K. S. Wise and M. F. Kim, J. Bacteriol. 169:5546-5555, 1987). In the current study, polyclonal mouse antibody (PAb) to gel-purified p65 was used to identify recombinant phage plaques expressing p65-related epitopes. Several characteristic partial tryptic fragments of p65 were recognized by both PAb and p65 and MAb to p65, but the PAb population specifically eluted from recombinant phage plaques bound only epitopes restricted to the largest of these fragments. Graded carboxypeptidase-Y digestion of intact M. hyopneumoniae generated C terminally truncated peptides that were recognized by PAb to p65 and MAb to p65, indicating that the C terminus and much of the adjoining region of p65 were present and accessible on the external face of the membrane. However, antibody eluted from recombinant phage plaques bound only to the largest truncated polypeptide, suggesting that a recombinant product corresponding to the C-terminal region of p65 was expressed in Escherichia coli. A 19-kilodalton recombinant protein (p19), which was recognized by PAb to p65 but not by MAb to p65, was detected in recombinant phage lysates. Serum antibodies from swine taken after, but not before, experimentally induced M. hyopneumoniae pneumonia preferentially recognized the native, amphiphilic p65 lipoprotein and also bound specifically to the p19 recombinant product. This confirmed that the p65 lipoprotein is a major immunogen of M. hyopneumoniae recognized during disease and identified its C-terminal region as an immunogenic domain.

Effects of anti-I-A and anti-I-E monoclonal antibodies on the induction and expression of experimental autoimmune thyroiditis in mice.

Susceptibility to experimental autoimmune thyroiditis (EAT) in mice is linked to the I-A subregion of the major histocompatibility complex (MHC). The present study was undertaken to assess the effectiveness of anti-I-Ak monoclonal antibody (MAb) 10-2.16 in preventing or arresting the development of EAT. Spleen cells from CBA/J or (CBA/J x Balb/c) F1 mice given 10-2.16 prior to sensitization with mouse thyroglobulin (MTg) and adjuvant could not transfer EAT to normal recipients, and cells from these mice did not proliferate in vitro to MTg. Donor CBA/J mice given 10-2.16 before immunization and recipients of cells from such mice produced little MTg-specific IgG1 or IgG2b antibody but did produce nearly as much IgG2a as controls. The effects of in vivo treatment with 10-2.16 appear to be due to elimination of Ia + cells rather than to modulation of Ia or induction of suppressor T cells. When 10-2.16 was added to in vitro cultures it also prevented the proliferation and activation of sensitized CBA/J or F1 effector cell precursors. Other mAb specific for MHC class II gene products, but not associated with disease susceptibility, expressed by CBA/J (I-Ek) or F1 (I-Ad) mice (14-4-4S or MK-D6 respectively), also prevented in vivo sensitization, but did not block in vitro activation. Anti-I-Ak was also effective in preventing EAT if multiple injections of mAb were given to recipients of sensitized EAT effector cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention and reversal of experimental autoimmune thyroiditis (EAT) in mice by administration of anti-L3T4 monoclonal antibody at different stages of disease development.

Experimental autoimmune thyroiditis (EAT) can be induced in CBA/J mice following the transfer of spleen cells from mouse thyroglobulin (MTg)-sensitized donors that have been activated in vitro with MTg. Since L3T4+ T cells are required to transfer EAT in this model, the present study was undertaken to assess the effectiveness of the anti-L3T4 monoclonal antibody (mAb) GK1.5 in preventing or arresting the development of EAT. Spleen cells from mice given mAb GK1.5 prior to sensitization with MTg and adjuvant could not transfer EAT to normal recipients and cells from these mice did not proliferate in vitro to MTg. Donor mice given GK1.5 before immunization did not develop anti-MTg autoantibody and recipients of cells from such mice also produced little anti-MTg. GK1.5 could also prevent the proliferation and activation of sensitized effector cell precursors when added to in vitro cultures. When a single injection of mAb GK1.5 was given to recipients of in vitro-activated spleen cells, EAT was reduced whether the mAb was given prior to cell transfer or as late as 19 days after cell transfer. Whereas the incidence and severity of EAT was consistently reduced by injecting recipient mice with GK1.5, the same mice generally had no reduction in anti-MTg autoantibody. Since EAT is consistently induced in control recipients by 14-19 days after cell transfer, the ability of mAb GK1.5 to inhibit EAT when injected 14 or 19 days after cell transfer indicates that a single injection of the mAb GK1.5 can cause reversal of the histopathologic lesions of EAT in mice. These studies further establish the important role of L3T4+ T cells in the pathogenesis of EAT in mice and also suggest that therapy with an appropriate mAb may be an effective treatment for certain autoimmune diseases even when the therapy is initiated late in the course of the disease.

Pharmacokinetics of pimozide in adults and children with Tourette's syndrome.

Pimozide is a neuroleptic drug with dopamine receptor and calcium channel blocking activity that is used in the treatment of Tourette's syndrome. A comparison of the pharmacokinetics of pimozide was made in children and adults with Tourette's syndrome. Seven adults (ages 23-39) and four children (ages 6-13) received a single 2-mg oral dose of pimozide and a minimum of nine blood samples were collected over a four-day period. Mean elimination half-life of pimozide in children was 66 hours compared with 111 hours in adults with Tourette's syndrome. Significant interindividual variability of pimozide pharmacokinetics was found in both adults and children with Tourette's syndrome. The pharmacokinetics of pimozide in patients with Tourette's syndrome differs from that reported in adult populations with chronic schizophrenia.

Regulation of bone marrow cell survival in short-term cultures: a new macrophage function.

The involvement of macrophages (M phi) in the regulation of bone marrow (BM) cell survival in short-term cultures was studied. We developed a system to measure the survival of fresh BM cells in vitro, by evaluating 111indium (111In) release from prelabeled BM cells. 111In release was proportional to cell death and inversely related to the number of trypan blue excluding cells. Upon 24 hr of culture in conventional medium, more than 50% of BM cells died. In order to investigate whether BM cell death could be reduced by coculture with other cell types, 111In-labeled BM cells were incubated for 24 hr with peritoneal M phi, thymocytes (THY), or polymorphonuclear cells (PMN) and then assayed for their survival. We found that coculture of BM cells with M phi dramatically increased BM survival, whereas THY or PMN consistently failed to enhance BM survival. The ability to promote BM cell survival, here designated nurse activity, represented a novel function of M phi and was further characterized. The stage of activation of M phi did not influence their nurse activity, since M phi elicited in vivo by proteose-peptone, thioglycollate, or Bacillus Calmette-Guérin, as well as resident M phi unstimulated or activated in vitro with lipopolysaccharide, equally sustained survival of BM cells. BM-derived M phi (adherent cells from BM cultures maintained in 20% L-cell-conditioned medium for 14 days) were equally effective in exerting nurse activity. Moreover, nurse activity was also exerted across the histocompatibility barriers. Supernatants from M phi cultures or killed M phi were ineffective. We propose that the nurse effect of M phi on BM is a primitive function that may play an important role in the development of the hemopoietic system.

Referendum rescues county ambulances.

A hospital joins with ambulance paramedics and citizens, labor, and business groups to wage a successful campaign for tax support of a new county emergency ambulance service.