Vitamin D and bone health status in beta thalassemia patients-systematic review.

Thalassemia is a chronic congenital disease characterized by a combination of endocrine and metabolic disorders. Bone disease is a very common complication related to the poor absorption of calcium, the secondary chronic renal disease with low vitamin D, as well as multiple endocrine risk factors. The aim of this systematic review was to estimate the prevalence of vitamin D deficiency in thalassemia, as well as its association with osteoporosis/low bone mass. A systematic review was carried out using PubMed/Medline, Cochrane, and EBSCO databases. The methodological quality of the included studies was assessed with the validated Newcastle-Ottawa Quality Assessment Scale adapted for cross-sectional studies and cohort studies respectfully and the Cochrane Collaboration for clinical trials. After application of predetermined exclusion criteria compatible with the PICOS process, a total of 12 suitable articles were identified. The prevalence of vitamin D deficiency varied considerably. Only five of the reviewed studies examined the correlation between vitamin D levels and BMD of which just three showed a statistically significant positive association of mild/moderate grade. Vitamin D deficiency is a common comorbidity in patients with thalassemia. However, both its prevalence and its severity vary considerably in different populations, and existing evidence is insufficient to conclude whether vitamin D supplementation is also associated with BMD improvement in this special population group.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.

Effects of short- and long-duration hypothyroidism on function of the rat hypothalamic-pituitary-adrenal axis.

The effects of hypothyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis were investigated in adult male rats. HPA axis function was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats or in thyroidectomized rats for 7 (short-term hypothyroidism) or 60 (long-term hypothyroidism) days. Peripheral ACTH and corticosterone responses to insulin-induced hypoglycemia and interleukin (IL)-1α stimulation were used to indirectly assess the hypothalamic CRH neuron. Hypothyroidism resulted in exaggerated ACTH responses to both hypoglycemic stress and IL-1α administration. The adrenal cortex of hypothyroid animals showed a significant reduction in adrenal reserves, as assessed by its response to low-dose ACTH, following suppression of the HPA axis with dexamethasone. Hypothyroid rats were also associated with significant decreases in cerebrospinal fluid corticosterone concentrations and decreased adrenal weights. The findings suggest that experimentally induced hypothyroidism is associated with a mild, yet significant, adrenal insufficiency, which involves abnormalities in all components of the HPA axis.

Facial palsy caused by an intrameatal metastatic disease - Reconstruction with an autologous sural nerve graft.

Dysfunction of the facial nerve is frequently attributed to inflammation, followed by traumatic injury. Knowledge of the complex anatomical course of the facial nerve is critical to localize the site of pathology and for successful management. The multiplicity of etiologies and its complex anatomy often make facial paralysis a diagnostic challenge. Neoplasms are a fairly rare cause of peripheral facial palsy, and are frequently overlooked in search of the more frequent traumatic or inflammatory etiologies of facial paralysis. Isolated metastatic lesions to the cerebellopontine angle (CPA) and internal auditory canal (IAC) are extremely rare. Their accurate diagnosis is difficult, since they share common clinical and radiological characteristics with vestibular schwannomas. We report a case of a 63-year-old female with a rapidly progressive left-sided hearing loss and complete facial palsy. Magnetic resonance imaging revealed a left intrameatal lesion. A provisional diagnosis of intracanalicular schwannoma or meningioma was made, although the possibility of metastasis due to her rapid neurological deterioration was considered. The patient underwent a translabyrinthine complete removal of the tumor followed by facial nerve reconstruction. The final histopathological findings revealed a metastatic breast adenocarcinoma. To our knowledge only seven prior cases of an isolated metastatic CPA lesion have been reported. In patients without a known malignancy, a rapid progression of hearing loss, disequilibrium, and facial palsy might be the first sign of a metastatic CPA lesion.

Nicotine dependence in the United States: prevalence, trends, and smoking persistence.

BACKGROUND: The prevalence of smoking in the United States has been closely monitored. However, little is known about the epidemiology of nicotine dependence. We studied DSM-III-R nicotine dependence in the United States, trends across cohorts, and the role of nicotine dependence in smoking persistence. METHODS: The Tobacco Supplement to the National Comorbidity Survey was administered to a representative subset of 4414 persons aged 15 to 54 years. The World Health Organization's Composite International Diagnostic Interview was used to assess nicotine dependence. RESULTS: Lifetime prevalence of nicotine dependence was 24%, nearly half of those who had ever smoked daily for a month or more. The highest risk for nicotine dependence occurred in the first 16 years after daily smoking began, at which point the rate declined and continued at a slower pace for several years. Nicotine dependence increased the risk of smoking persistence, with an odds ratio (OR) of 2.2 (95% confidence interval [CI], 1.6-3.0). Members of the most recent cohort, who were 15 to 24 years of age at the time of the survey, were the least likely to smoke daily, but those who smoked had the highest risk of dependence: OR for daily smoking in the most recent vs earliest cohort was 0.7 (95% CI, 0.5-0.9), and for dependence among smokers, 7.2 (95% CI, 5.0-10.4). CONCLUSIONS: Despite evidence that nicotine dependence is the leading preventable cause of death and morbidity, it remains a common psychiatric disorder. Smoking cessation and the decline in uptake in recent years varied across subgroups of the population.

Replication of ZNF804A gene variant associations with risk of heroin addiction.

Heroin addiction is heritable, but few specific genetic variants have been reproducibly associated with this disease. The zinc finger protein 804A (ZNF804A) gene is a biologically plausible susceptibility gene for heroin addiction, given its function as a transcription factor in human brain. Novel associations of two common ZNF804A single nucleotide polymorphisms (SNPs), rs7597593 and rs1344706, with heroin addiction have been reported in Han Chinese. Both SNPs have also been implicated for regulating ZNF804A expression in human brain, including the addiction-relevant dorsolateral prefrontal cortex. In this independent replication study, we tested the rs7597593 and rs1344706 SNP genotypes and their corresponding haplotypes for association with heroin addiction using cases drawn from the Urban Health Study and population controls: total N = 10 757 [7095 European Americans (EAs) and 3662 African Americans (AAs)]. We independently replicated both ZNF804A SNP associations in EAs: the rs7597593-T (P = 0.016) and rs1344706-A (P = 0.029) alleles both being associated with increased risk of heroin addiction, consistent with the prior report. Neither SNP was associated in AAs alone, but meta-analysis across both ancestry groups resulted in significant associations for rs1344706-A [P = 0.016, odds ratio (95% confidence interval) = 1.13 (1.02-1.25)] and its haplotype with rs7597593-T [P = 0.0067, odds ratio (95% confidence interval) = 1.16 (1.04-1.29)]. By showing consistent associations across independent studies and diverse ancestry groups, our study provides evidence that these two ZNF804A SNPs and their risk haplotype are among the few replicable genetic associations with heroin addiction.

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.

We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis.

Environmental events, both physical and emotional, can produce stress reactions to widely varying degrees. Stress can affect many aspects of physiology, and levels of stress, emotional status, and means of coping with stress can influence health and disease. The stress system consists of brain elements, of which the main components are the corticotropin-releasing hormone (CRH) and locus ceruleus (LC)-norepinephrine (NE)/autonomic systems, as well as their peripheral effectors, the pituitary-adrenal axis and the autonomic system, which function to coordinate the stress response. Activation of the stress system results in behavioral and physical changes which allow the organism to adapt. This system is closely integrated with other central nervous system elements involved in the regulation of behavior and emotion, in addition to the axes responsible for reproduction, growth and immunity. With current trends in stress research which focus on understanding the mechanisms through which the stress-response is adaptive or becomes maladaptive, there is a growing association of stress system dysfunction, characterized by hyperactivity and/or hypoactivity to various pathophysiological states. The purpose of this review is to 1) define the concepts of stress and the stress response from a historical perspective, 2) present a dynamic overview of the biobehavioral mechanisms that participate in the stress response, and 3) examine the consequences of stress on the physiologic and behavioral well-being of the organism by integrating knowledge from apparently disparate fields of science.

Recovery of the rat hypothalamic-pituitary-adrenal axis after discontinuation of prolonged treatment with the synthetic glucocorticoid agonist dexamethasone.

To evaluate the recovery of the hypothalamic-pituitary-adrenal (HPA) axis after discontinuation of prolonged exposure to glucocorticoids, we employed adult male Sprague-Dawley rats which were implanted sc with osmotic minipumps filled with saline (vehicle) or dexamethasone (DEX), 100 micrograms/day, for 7 days. At the end of the glucocorticoid treatment period, the minipumps were removed and both saline- and DEX-treated rats were randomly assigned to five different groups tested at 1, 3, 7, 14, and 21 days after removal of the minipumps. Each group was divided into two subgroups receiving either arecoline (ARE), or ovine CRH (oCRH) stimulation tests. ARE was chosen because it has been shown to selectively stimulate the hypothalamic CRH neuron, whereas oCRH was selected as a probe of the pituitary component of the HPA axis. ARE (0.2 mg/kg) and oCRH (10 micrograms/kg) were injected iv to catheterized, freely moving rats and serial blood samples for plasma ACTH and corticosterone determinations were drawn from the catheter before, and 5, 15, 30, and 60 min after the injection. The day after the tests were performed, the rats were killed by decapitation, and body, adrenal and thymus weights, as well as hypothalamic CRH and pituitary ACTH content were determined. On the day of the stimulation tests, basal plasma levels of ACTH and corticosterone were not different between saline- and DEX-treated rats at any time-point after discontinuation of treatment. The ACTH response to ARE, on the other hand, was suppressed one day after, but became normal 3 days after discontinuation of DEX treatment. ACTH response to oCRH normalized later, after 7 days. Interestingly, corticosterone responses to both ARE and oCRH normalized 7 days after discontinuation of glucocorticoid administration. Body, adrenal and thymus weights were significantly reduced by DEX treatment. They recovered slowly and only after 22 days there was no difference between DEX- and saline-treated rats in body and adrenal weight. In contrast, thymus weight was still low on day 8, began to increase after 15 days, and by day 22 did not reach the values recorded in saline-treated rats. Hypothalamic immunoreactive CRH content was not different between DEX- and saline-treated rats, whereas the content of ACTH in the pituitary gland was lower in the DEX-treated rats the second day after discontinuation of GC treatment, normalized after 4 days and increased significantly after 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of short and long duration hypothyroidism and hyperthyroidism on the plasma adrenocorticotropin and corticosterone responses to ovine corticotropin-releasing hormone in rats.

We report here a study of the plasma ACTH and corticosterone responses to synthetic ovine CRH (oCRH) in hypothyroid and hyperthyroid rats studied 7, 15, and 60 days after either thyroidectomy or the administration of pharmacological doses of T4. The purpose of this study was to further clarify the time-dependent effects of alterations in thyroid status on the functional integrity of the hypothalamic-pituitary-adrenal axis and to aid in the interpretation of the oCRH stimulation test in hypo- and hyperthyroid states. Our data demonstrate that hypothyroid rats have a significant reduction in the cerebrospinal fluid (CSF) levels of corticosterone and a significant decrease in adrenal weight in association with significant increases in the plasma ACTH response to oCRH. On the other hand, the corticosterone response to the ACTH released during the oCRH stimulation test was significantly reduced in hypothyroidism. With increasing duration of thyroidectomy-induced hypothyroidism, there was a progressive fall in CSF corticosterone levels, a progressive increase in the plasma ACTH response to oCRH, and a gradual normalization of the corticosterone responses to the ACTH released during oCRH stimulation. Our findings in hyperthyroid rats were generally the converse of those seen in hypothyroidism. Hence, there was a significant increase in the CSF levels of corticosterone and a significant increase in adrenal weight in association with an initial slight decrease in the ACTH response to oCRH. On the other hand, the corticosterone response to the ACTH released during oCRH stimulation was significantly increased. There was a gradual increase in the magnitude of the rise in CSF corticosterone levels with time, as well as a gradual normalization of adrenocortical responses during oCRH stimulation. The ACTH plasma clearance rates were similar in hypo-, hyper-, and euthyroid rats. Our data do not permit definitive identification of the precise locus in the hypothalamic-pituitary-adrenal axis that is principally affected by experimentally induced alterations in thyroid status. However, these data are most compatible with a subtle hypothyroid-induced centrally mediated adrenal insufficiency and a subtle hyperthyroid-induced centrally mediated hypercortisolism. These data also suggest that alterations in hypothalamic-pituitary-adrenal function in states of disturbed thyroid function become somewhat more pronounced as the duration of thyroid dysfunction increases. The fact that pituitary-adrenal responses to oCRH are consistently altered in states of thyroid dysfunction may be relevant to the clinical interpretation of oCRH stimulation tests.(ABSTRACT TRUNCATED AT 400 WORDS)

The muscarinic cholinergic agonist arecoline stimulates the rat hypothalamic-pituitary-adrenal axis through a centrally-mediated corticotropin-releasing hormone-dependent mechanism.

Several lines of experimental evidence suggest that acetylcholine and other cholinergic agonists are excitatory to the hypothalamic-pituitary-adrenal (HPA) axis. To examine the site on the HPA axis that is stimulated by cholinergic agents, we evaluated the in vivo and in vitro effects of the muscarinic cholinergic agonist arecoline in intact and pituitary stalk-transected rats as well as on isolated rat hypothalami, dispersed anterior pituicytes, and adrenocortical cells in culture. Arecoline, injected iv to catheterized, freely moving male Sprague-Dawley rats, stimulated plasma ACTH and corticosterone release in a dose-dependent fashion. The muscarinic cholinergic antagonist atropine significantly blunted the ACTH response to arecoline. Pituitary stalk transection led to diminished plasma ACTH and corticosterone responses to arecoline. Similarly, previous administration of anti-CRH serum significantly blunted these responses. These findings suggest that arecoline stimulates the HPA axis centrally, mainly via secretion of CRH. This hypothesis was confirmed by the dose-dependent ability of arecoline to cause hypothalamic CRH secretion in vitro, an effect antagonized by atropine, and its failure to elicit ACTH and corticosterone secretion by dispersed anterior pituicytes and adrenocortical cells in culture, respectively. These data suggest that the muscarinic cholinergic agonist arecoline stimulates the HPA axis in the rat and that this effect is mediated mainly by the release of endogenous CRH. Arecoline, therefore, appears to be a compound suitable to selectively evaluate the responsiveness of the central component of the HPA axis.

Cholecystokinin-octapeptide stimulates hypothalamic-pituitary-adrenal function in rats: role of corticotropin-releasing hormone.

Peripherally-administered cholecystokinin (CCK) is a profound suppressor of food intake, can promote anxiety, and causes the acute release of ACTH into plasma. Centrally administered corticotropin-releasing hormone (CRH), on the other hand, not only represents the principal stimulus to the pituitary corticotroph cell, but also has been shown to suppress appetite and to be profoundly anxiogenic. Because of the overlap in the effects of peripherally administered CCK and of centrally administered CRH, we report here a study to determine whether sulphated CCK octapeptide (CCK-8) could induce the release of CRH within the central nervous system. To accomplish this task, we first assessed the dose-related effects of CCK-8 on ACTH release. Graded doses of CCK-8 (0.1-10 micrograms/kg BW) given in an i.v. bolus to freely moving male rats, resulted in a dose-dependent increase of plasma immunoreactive (IR)-ACTH (ED50: 1-10 micrograms/kg BW). The lowest maximal stimulatory dose of CCK-8 (5 micrograms/kg BW) was used in all subsequent experiments. To evaluate whether CCK-induced ACTH secretion was mediated by a peripheral CCK receptor, an i.v. bolus injection of vehicle or L-364,718 (1 mg/kg BW), a specific, highly potent peripheral CCK receptor antagonist, was given before the i.v. administration of CCK-8 or vehicle. Plasma IR-ACTH response to CCK-8 was significantly attenuated by L-364,718. A role for the vagal afferents that contain CCK receptors in peripherally administered CCK-mediated hypothalamic-pituitary-adrenal (HPA) axis activation was examined in animals that had been pretreated with capsaicin, a potent neurotoxin that destroys vagal afferents. Plasma IR-ACTH and IR-corticosterone responses in capsaicin-treated animals were significantly lower than those in vehicle treated rats. In subsequent in vivo experiments, pituitary stalk-transected and sham-operated animals were used to evaluate whether CCK-8 stimulates the HPA axis via a centrally mediated mechanism. IR-ACTH and IR-corticosterone responses to i.v. CCK-8 were significantly reduced in the pituitary stalk-transected compared to sham-operated animals. In further effort to determine whether the central nervous system was involved in the plasma IR-ACTH response to the peripheral administration of i.v. CCK-8, we compared the effects of the i.v. administration of CRH antisera vs. normal rabbit serum on this parameter. IR-ACTH and IR-corticosterone responses to i.v. CCK-8 were significantly reduced in the context of pretreatment with CRH antisera compared to the administration of normal rabbit serum.(ABSTRACT TRUNCATED AT 400 WORDS)

Interactions between tumor necrosis factor-alpha, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat.

We studied the effects of tumor necrosis factor-alpha (TNF alpha), a macrophage-derived pleiotropic cytokine produced during the inflammatory/immune response, on the function of the hypothalamic-pituitary-adrenal (HPA) axis of the rat. Intravenous injections of TNF alpha stimulated plasma ACTH and corticosterone secretion in a dose-dependent fashion. This effect was inhibited by a rat CRH antiserum that was administered to the rats 1 h before the TNF alpha injections. This suggested that CRH is a major mediator of the HPA axis response to TNF alpha. We subsequently evaluated the ability of TNF alpha to influence CRH and ACTH secretion in vitro by explanted rat hypothalami in organ culture and by dispersed rat anterior pituicytes in primary culture respectively. Hypothalami were incubated for 40 min with graded concentrations of TNF alpha (10 pM to 1 microM). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 x 10 pM (P less than 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 microM), eicosatetraynoic acid (10 microM), or nordihydroguaiaretic acid (30 microM) resulted in inhibition of TNF alpha-stimulated CRH secretion (P less than 0.05). Interestingly, 4-h incubation with TNF alpha had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNF alpha (100 nM and 1 microM), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNF alpha represents one of the immune response mediators that directly or via stimulation of other cytokines act as activators of the HPA axis during immune/inflammatory reactions. This effect appears to be glucocorticoid suppressible and eicosanoid mediated. The primary site of action of TNF alpha appears to by the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF alpha, however, cannot be excluded.

Increased risk of learning disabilities in low birth weight boys at age 11 years.

BACKGROUND: Few studies have examined learning disabilities among low birth weight (< or =2500 g) children, and those that have, have focused on very low birth weight children (<1500 g). We tested the hypothesis that low birth weight increases the risk of reading and math disabilities, examined possible sex differences in the effect of low birth weight, and assessed risk across the entire range of low birth weight. METHODS: Low birth weight and normal birth weight children were randomly selected from the 1983-1985 newborn lists of an urban and a suburban hospital in southeast Michigan. Children with neurological impairments were excluded. Children were evaluated at age 6 years and at age 11 years. Of the 823 children in the initial assessment, 717 (87.1%) participated in the second assessment. The Wechsler Intelligence Scale for Children--Revised and the Woodcock-Johnson Psycho-Educational Battery--Revised were used to identify children with learning disabilities. Learning disabilities were estimated in 574 children with IQs of > or =85. RESULTS: Low birth weight was associated with increased risk for reading and math disability in male children (odds ratio = 3.3 and odds ratio = 6.5, respectively) but not in female children. The increased risk of learning disabilities among male children applied to the entire range of low birth weight and was observed in both the urban and suburban communities. CONCLUSIONS: The effect of low birth weight on learning disabilities appears to be specific to male children. Although this sex-specific effect is consistent with previous findings of a greater vulnerability of male children to pregnancy and birth complications, it remains to be replicated and clarified.

Psychometric evaluation of daytime sleepiness and nocturnal sleep onset scales in a representative community sample.

BACKGROUND: The public health importance of daytime sleepiness as a risk factor for accidents, interpersonal problems, and decreased productivity has been recognized. However, epidemiologic research on this topic has been limited by the reliance on laboratory measures (i.e., the Multiple Sleep Latency Test-MSLT). Two scales, daytime sleepiness and nocturnal sleep onset, have been identified from the self-report Sleep-Wake Activity Inventory (SWAI) in a clinic sample and validated against the MSLT. This study evaluates the replicability of the two scales in a population sample and assesses potential thresholds in scale scores that distinguish normal from pathologic levels of daytime sleepiness and difficulty falling asleep. METHODS: The sample consisted of 2181 subjects 18-45 years old in the Detroit metropolitan area. All sleep characteristic information covered the 2 weeks prior to interview. Split-half sample factor analyses were conducted to assess replicability of the results. Distribution of scale scores and their relation to construct validity variables were used to evaluate possible thresholds. RESULTS: A two-factor model appeared to best account for the variation among the 12 items from the SWAI. The two factors accounted for 50% of the variance in both split-half sample analyses. The revised eight-item daytime sleepiness and two-item nocturnal sleep onset scales showed good and fair internal consistency respectively across both split-half samples. There appeared to be a "natural break" in daytime sleepiness scale scores that was associated with a substantial and consistent change in number of hours slept. No breaks appeared in nocturnal sleep onset scores. CONCLUSIONS: This study replicated the results of the clinic-based study and suggested a potentially useful diagnostic threshold for self-report excessive daytime sleepiness. Epidemiology of sleep depends on the ability to move from the laboratory to population surveys in reliable and valid ways. Development of self-report is a step in that direction.

Neurologic soft signs and low birthweight: their association and neuropsychiatric implications.

BACKGROUND: We examine the relationship between neurologic soft signs and cognitive deficits, learning disorders, and psychiatric problems in low birthweight (LBW) and normal birthweight (NBW) children. METHODS: Representative samples of LBW and NBW children were selected from the 1983-1985 newborn discharges of two major hospitals in Michigan. Eight hundred-twenty three children (75% of the target sample) were evaluated at ages 6 and 11. A standardized neurologic evaluation was used by neurologists to measure neurologic soft signs at age 6 (children with frank neurologic impairment were excluded). IQ was measured by WISC-R and behavior problem lists were rated by mothers and teachers. Standard tests of academic achievement were used to identify learning disorders. All assessments were blind to LBW status. Using multiple regression analysis, applying generalized estimating equations (GEE), we estimated the effects of soft signs on 3 behavioral domains, based on information from multiple informants and times of assessment. RESULTS: LBW was associated with a two-fold increased risk for soft signs. Soft signs increased the risk for subnormal IQ and for learning disorders in children with normal IQ. Soft signs were associated with excess internalizing problems in LBW and NBW children, and with attention and externalizing problems in LBW children; the excess in externalizing problems in LBW children was observed only at age 6. CONCLUSIONS: Soft signs are a marker of high risk for cognitive and psychiatric problems. Of particular concern is their presence in LBW children, in whom they are associated with more severe cognitive deficits and more pervasive psychiatric problems.