bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative Evaluation of Catecholamine Enzymes Gene Expression in Adrenal Medulla and Sympathetic Ganglia of Stressed Rats
Authors: KVETNANSKY R , MICUTKOVA L , RYCHKOVA N , KUBOVCAKOVA L , MRAVEC B , FILIPENKO M , SABBAN E L , KRIZANOVA O
Published: July 2004

Abstract: Stress‐induced changes in mRNA levels of tyrosine hydroxylase (TH), dopamine‐β‐hydroxylase (DBH), and phenylethanolamine N‐methyltransferase (PNMT) have been expressed as relative arbitrary units compared with a control group. The aim of this study was to quantify basal and stress‐induced levels of TH, DBH, and PNMT mRNAs in rat adrenal medulla (AM) and stellate ganglia (SG) by the RT‐competitive PCR method using corresponding competitors of known concentration. In rats stressed by immobilization (IMO) once for 2 h, the concentration of mRNAs was determined in various intervals after the end of stress stimulus. In SG, the basal concentration of TH mRNA was 0.017 amol/ng of total RNA, which is approximately 30 times lower than in the AM (0.460 amol/ng RNA). The basal concentration of DBH mRNA in SG was 2.60 amol/ng of total RNA, which is about 150 times more than TH mRNA in SG but only two times less than DBH mRNA in the AM in which PNMT mRNA is present in the highest concentration. After a single 2‐h IMO, the peak elevation of TH and DBH mRNA concentration in SG occurred 24 h after the termination of stress stimulus, when their AM mRNA concentrations were already at control values. Presence of PNMT mRNA levels in the SG, of control and stressed rats has been demonstrated for the first time. Repeated IMO (7 days, 2 h daily) did not produce further increase in the mRNA concentrations compared with the elevated values found in adapted control groups. Levels of TH protein were significantly increased only after repeated IMO in SG and AM. Thus, our data show for the first time the exact concentrations of TH, DBH, and PNMT mRNA in SG and AM of rats under control and stress conditions. The lowest concentration of TH mRNA in the AM and SG supports the hypothesis that tyrosine hydroxylation is the rate‐limiting step in catecholamine biosynthesis.
Molecular Regulation of Gene Expression of Catecholamine Biosynthetic Enzymes by Stress: Sympathetic Ganglia versus Adrenal Medulla
Authors: SABBAN ESTHER L. , NANKOVA BISTRA B. , SEROVA LIDIA I. , KVETNANSKY RICHARD , LIU XIAOPING
Published: July 2004

Abstract: Stress induces tyrosine hydroxylase (TH) and dopamine β‐hydroxylase (DBH) gene expression in sympathetic ganglia and adrenal medulla (AM). However, distinct molecular mechanisms appear to regulate these genes in these locations. The elevation of TH mRNA in response to single immobilization stress (IMO) in AM is robust, but transient, while the induction of TH and DBH mRNAs in sympathetic ganglia is slower and more long lasting. Injections of adrenocorticotropic hormone (ACTH) elicited induction of TH and DBH gene expression in rat sympathetic ganglia, but not in AM. The superior cervical (SCG) and stellate (StG) ganglia, but not AM, were found to express mRNA for the MC‐2 receptor, the major ACTH responsive receptor in adrenal cortex. IMO led to increase in MC‐2 receptor mRNA levels in SCG. Thus, ACTH, via the MC‐2 receptor, may be directly involved in the stress‐elicited regulation of norepinephrine biosynthesis in sympathetic ganglia. The signaling pathways triggered by IMO differed in these locations. In AM, IMO triggered activation of the MAP kinase, JNK, and induction of AP1 factors, Egr1 and phosphorylation of CREB. In contrast in the SCG, with IMO we did not observe changes in JNK and little binding to the AP1 motif of the TH promoter. However, there was an increase in CREB binding to the CRE site of the TH promoter. The results reveal differential mechanisms of regulation of catecholamine biosynthetic enzymes by stress in two components of the sympathoadrenal system and should provide basis for possible selective pharmacologic interventions.
Changes in the Concentrations of Tetrahydrobiopterin, the Cofactor of Tyrosine Hydroxylase, in Blood under Physical Stress and in Depression
Authors: HASHIMOTO R , NAGATSU T , OHTA T , MIZUTANI M , OMURA I
Published: July 2004

Abstract: This paper studies changes in the concentrations of tetrahydrobiopterin (BH4), the cofactor of tyrosine hydroxylase, in blood under physical stress and in depression. BH4 was found to be transiently released from the sympathetic nerves under severe physical stress but continuously released in depression with an increased oxidation rate of BH4 to B.
Localization and Regulation of Phenylethanolamine N‐Methyltransferase Gene Expression in the Heart of Rats and Mice during Stress
Authors: KVETNANSKY RICHARD , MICUTKOVA LUCIA , KUBOVCAKOVA LUCIA , SABBAN ESTHER L. , PALKOVITS MIKLOS , KRIZANOVA OLGA
Published: July 2004

Abstract: Recently we have described the existence of phenylethanolamine N‐methyltransferase (PNMT) mRNA in the heart of adult rats. In this study, we report the first data on distribution of the PNMT protein in rat hearts, which follows the distribution of PNMT mRNA (high levels in the atria and low levels in ventricles). The main aim of this study was to determine the localization of the PNMT mRNA in the heart and to examine whether gene expression of this enzyme is affected by immobilization (IMO) stress in a time‐dependent manner. PNMT mRNA levels were detected in all seven studied parts of the heart (atria without and with intramural ganglion cells, ventricles, and septum), with the highest levels in the left atrium and its ganglionic part. Both Southern blot and sequencing verified the specificity of PNMT detected by RT‐PCR. Single IMO for 2‐h increased gene expression of PNMT, as determined by both RT‐PCR and Real‐Time PCR in the right and left atria. Surprisingly, the ganglionic parts of the atria did not respond to stress stimulation. Peak levels of PNMT mRNA were found in the 3‐h interval after the IMO terminated, and also 24 h after the first or sixth IMO. Expression of aromatic L‐amino acids decarboxylase and dopamine‐beta‐hydroxylase has also been detected in the heart of control and stressed rats. In the atria, the effect of stress is clearly modulated by glucocorticoids, since in mice with corticotrophin‐releasing hormone knocked out gene the immobilization‐induced increase in the PNMT mRNA levels seen in wild‐type animals was abolished. Thus, our data have shown that gene expression of the PNMT is localized, not predominantly in cardiac ganglion cells, but in a wide range in atrial cardiomyocytes. Mechanism responsible for the regulation of stress‐induced increase of PNMT gene expression in cardiac atria is clearly dependent on the presence of glucocorticoids.
Generating Mouse Models for Studying the Function and Fate of Intrinsic Cardiac Adrenergic Cells
Authors: PFEIFER KARL , BOE STEVE P. , RONG QI , EBERT STEVEN N.
Published: July 2004

Abstract: Embryos lacking the ability to synthesize epinephrine and norepinephrine die (probably due to cardiac failure) without exogenous supplementation while mutant neonates can grow into fertile adults without supplementation. These experiments define a critical period during embryogenesis, when norepinephrine and/or epinephrine are essential for mouse development. The critical period is prior to sympathetic innervation of the heart and prior to synthesis of catecholamines by the adrenal medullae. Recent work indicates that the developing heart is likely to be a major source of catecholamines in the developing mammalian embryo. The spatial pattern of biosynthetic enzymes suggests an association of the intrinsic cardiac adrenergic cells with the developing pacemaker and cardiac conduction cells. To address the functional characteristics and the fate of these cardiac adrenergic cells, we have developed two mouse models that allow us to identify and to characterize the adrenergic cells and their descendants.
Mouse Mutants for the Study of Corticotropin‐Releasing Hormone Receptor Function: Development of Novel Treatment Strategies for Mood Disorders
Authors: KECK MARTIN E. , HOLSBOER FLORIAN , MÜLLER MARIANNE B.
Published: July 2004

Abstract: In today's psychiatry there is a great deal of interest in the development of compounds with a novel mechanism of action that diverge from the classical catecholaminergic neurotransmitter system targets. Within the last few years, it has become increasingly evident that the neuroendocrine and behavioral phenotypes of mood and anxiety disorders are at least in part mediated by modulation of corticotropin‐releasing hormone (CRH) neurocircuitries and that normalization of an altered neurotransmission after treatment may lead to restoration of disease‐related changes. Although this concept was originally derived from peripheral hypothalamic‐pituitary‐adrenocortical (HPA) assessments in depressed patients, central CRH neuropeptidergic circuits other than those driving the peripherally accessible HPA system may be overactive and could be therapeutic targets of antagonist actions. Genetically engineered mice provide a novel and useful tool to study the endogenous mechanisms underlying aberrant behavior and CRH neurocircuitry regulation. The results obtained from conventional and conditional mutant mice indicate that CRH type 1 receptors may be the primary target to which to direct selective nonpeptide compounds. Moreover, beyond the encouraging preclinical studies, the first clinical open trial supports the notion that CRH type 1 receptors can be safely and effectively antagonized.
GABAergic Mechanisms Constraining the Activity of the Hypothalamo‐Pituitary‐Adrenocortical Axis
Authors: KOVÁCS K J , MIKLÓS I H , BALI B
Published: July 2004

Abstract: There are two major inhibitory mechanisms that constrain the activity of the hypothalamo‐pituitary‐adrenocortical axis: the hormonal negative feedback and the neural inhibition including that posed by the GABAergic neurons. This chapter summarizes our recent morphologic and functional findings on the role of γ‐aminobutyric acid (GABA) in the transcriptional regulation of hypophyseotropic neuropeptide genes in the parvocellular neurosecretory cells of the hypothalamic paraventricular nucleus (PVH). We used organotypic hypothalamic slice cultures and in vivo microinjection protocols in combination with in situ histologic and ultrastructural procedures to address the role of local interneurons in the regulation of hypothalamic effector neurons. Under basal conditions, an intrinsic GABAergic mechanism in the PVH microenvironment was revealed that by itself, without limbic contribution, impinged a tonic inhibitory influence on the parvocellular corticotropin‐releasing hormone (CRH) neurons in vitro. In vivo, remote inputs were superimposed on the local circuit, allowing differential transcriptional regulation of CRH and arginine vasopressin (AVP) genes in the hypophyseotropic neurons. During stress, GABAergic cells that are known to project to the PVH become activated and are involved in restraining the cellular, transcriptional, and hormonal responses to stress.
Maternal Genotype Can Influence the Outcome of a Study on Mutant Animals
Authors: ZELENA DÓRA , MERGL ZSUZSA , MAKARA GÁBOR B.
Published: July 2004

Abstract: The hypothalamo‐pituitary‐adrenal (HPA) axis plays a crucial role in stress. One of its central regulatory components is arginine‐vasopressin (AVP). We studied the role of AVP in acute restraint in AVP‐deficient mutant Brattleboro rats (AVP−), but our results were variable. The early life period is important in the later stress reactivity of the animals. We realized that our AVP− pups could be born from AVP+ (heterozygous) or from AVP− mothers. Therefore, we asked whether the genotype of the mother could explain the variability. Adult rats from AVP+ and AVP− mothers were stressed with 60 min of restraint. Trunk blood was collected for measuring hormone content by radioimmunoassay. All offspring of AVP+ mothers had similar adrenocorticotropic hormone (ACTH) responses to restraint, whereas the AVP− rats born to AVP− mothers showed reduced ACTH reactivity. Our results show that the AVP− genotype of the mother can decrease the stress reactivity of AVP− Brattleboro rats. In mutant/knockout animals, family background should be taken into account as well as the genotype of the studied animals.
Cardiovascular Responses to Stress after Carotid Baroreceptor Denervation in Humans
Authors: TIMMERS HENRI J L M , WIELING WOUTER , KAREMAKER JOHN M. , LENDERS JACQUES W.M.
Published: July 2004

Abstract: Iatrogenic bilateral denervation of carotid sinus baroreceptors may occur as a complication of carotid body tumor resection and radiation therapy of the neck. The acute phase of the resulting syndrome of baroreflex failure is characterized by a limited blood pressure buffering capacity against excessive rise or fall in response to emotional and physical stimuli like sexual arousal and cold. Paroxysms of severe hypertension and tachycardia, accompanied by excessive increments in sympathetic tone and catecholamine plasma levels, were ascribed to loss of tonic inhibitory influence of baroreceptors on sympathetic tone. Bilateral anesthetic blockade of baroreceptor afferent nerves was shown to result in a strong increase in muscle sympathetic nerve activity and disruption of its normal patterning. This chapter reviews our findings on the long‐term effects of iatrogenic baroreflex trauma on the hemodynamic responses to pharmacological, physical, and emotional stress in the autonomic function laboratory as well as under daily life conditions. Chronic attenuation of baroreflex sensitivity after carotid body tumor resection and neck irradiation results in an increased blood pressure variability. However, unopposed sympathetic activation in response to physical and emotional stress appears to be limited to the acute phase of baroreflex failure.
Congenital Dopamine‐β‐Hydroxylase Deficiency in Humans
Authors: Timmers H J L M , Deinum J , Wevers R A , Lenders J W M
Published: July 2004

Abstract: Dopamine‐β‐hydroxylase (DβH) deficiency is a rare autosomal dominant disorder. Due to the absence of DβH, there is a blocked conversion of dopamine into norepinephrine. The biochemical hallmark of this syndrome consists of a complete absence of plasma norepinephrine and epinephrine levels in conjunction with an increased plasma dopamine level. Several mutations in the gene that encodes for DβH have been described. Up to now, worldwide, 12 patients have been reported. The most important clinical feature is a severe orthostatic hypotension. In addition, several other clinical features like blepharoptosis, hyperflexible joints, high palate, sluggish deep tendon reflexes, and a mild normocytic anemia have been described. The only effective treatment of DβH deficiency is L‐threo‐3,4‐dihydroxyphenylserine (DOPS). DOPS is converted directly into norepinephrine. Treatment with DOPS results in a sustained relief of orthostatic symptoms.
Oxidative Stress to Dopaminergic Neurons as Models of Parkinson's Disease
Authors: GILLE G , HUNG S‐T , REICHMANN H , RAUSCH W‐D
Published: July 2004

Abstract: The effects of exogenous toxins (MPP+, rotenone) and potentially neurotoxic properties of levodopa (L‐DOPA) on the survival rate of dopaminergic neurons in dissociated primary culture are presented. Dopamine agonists show a capacity to counteract MPP+‐toxicity. Moreover, a preserving potential of the antioxidant and bioenergetic coenzyme Q10 (CoQ10) on the activities of tyrosine hydroxylase (TH), complexes I and II of the respiratory chain, and hexokinase activity in striatal slice cultures against MPP+ is demonstrated.
Effects of Endurance Training on Endocrine Response to Physical Exercise after 5 Days of Bed Rest in Healthy Male Subjects
Authors: KOŠKA JURAJ , KŠINANTOVÁ LUCIA , KVETŇANSKÝ RICHARD , HAMAR DUŠAN , MARTINKOVIČ MIROSLAV , VIGAŠ MILAN
Published: July 2004

Abstract: The study was designed to evaluate how a bout of endurance training (ET) influences the endocrine response after head‐down bed rest (HDBR). Eleven healthy males completed the study, which consisted of a 6‐wk ET followed by 5 days of −6° head‐down HDBR. Treadmill exercise at 80% of pretraining maximal aerobic capacity (VO2max) was performed before and after ET as well as after HDBR. ET increased VO2max by 13%. The response of norepinephrine was attenuated after ET and exaggerated after HDBR (P < 0.001). The differences in epinephrine responses were not statistically significant. The responses of cortisol and plasma renin activity (PRA) were unchanged after ET and were enhanced after HDBR (P < 0.001). The response of growth hormone after HDBR was reduced (P < 0.05). Only the change in cortisol response was associated with the increment of VO2max after ET (r= 0.68, P < 0.01). Endurance training failed to completely prevent changes in endocrine responses seen after HDBR. Improvement of physical fitness was associated with an enhancement of the cortisol response to exercise following the period of bed rest.
Development of Enantioselective Immunoassays for Free Plasma Metanephrines
Authors: MANZ BERNHARD , KUPER MATTHIAS , BOOLTINK ESSY , FISCHER‐BRÜGGE ULRICH
Published: July 2004

Abstract: The development of an enantioselective radioimmunoassay (RIA) and enzyme immunoassay (EIA) for L‐normetanephrine (NM) and L‐metanephrine (M) were studied. Prior to the immunoassay, the protein matrix of the ethylenediaminetetraacetic acid (EDTA) plasma samples was removed by acid precipitation, followed by derivatization of the L‐metanephrines to N‐acyl‐L‐metanephrines. For the EIA, N‐acyl‐L‐NM and N‐acyl‐L‐M were bound to the surface of microtiter plates. Acylated L‐metanephrines from the sample and solid‐phase‐bound N‐acyl‐L‐NM or N‐acyl‐L‐M competed for a fixed number of rabbit anti‐N‐acyl‐NM or anti‐N‐acyl‐M antibody binding sites. When the system was in equilibrium, free antigens and free antigen‐antibody complexes were removed by washing. The antibodies bound to the respective solid‐phase N‐acyl‐L‐NM or N‐acyl‐L‐M were detected by a goat anti‐rabbit IgG‐peroxidase conjugate using tetramethyl benzidine (TMB) as a substrate. The RIAs were conventional double antibody tests using the above rabbit antisera and specific 125I‐N‐acyl‐L‐metanephrine tracers. Chiral recognition of the L‐enantiomers was observed not only for the native molecules but for all N‐acyl derivatives tested. The cross‐reactivity to the corresponding D‐enantiomers was always <1%. The detection limits were found to be approximately 0.04 nmol/L (7.5 pg/mL) for M and 0.08 nmol/L (15 pg/mL) for NM in RIA and EIA.
Plasma Ghrelin in Obesity before and after Weight Loss after Laparoscopical Adjustable Gastric Banding
Authors: Hanusch-Enserer Ursula , Cauza Edmund , Brabant Georg , Dunky Attila , Rosen Harald , Pacini Giovanni , Tüchler Heinz , Prager Rudolf , Roden Michael
Published: July 2004

Weight reduction after gastric bypass surgery has been attributed to a decrease of the orexigenic peptide ghrelin, which may be regulated by insulin and leptin. This study examined effects of long-term weight loss after laparoscopical adjustable gastric banding on plasma ghrelin and leptin concentrations and their relationship with insulin action. Severely obese patients (15 women, three men, 36 ± 12 yr) underwent clinical examinations every 3 months and modified oral glucose tolerance tests to assess parameters of insulin sensitivity and secretion every 6 months. After surgery, body mass index fell from 45.3 ± 5.3 to 37.2 ± 5.3 and 33.6 ± 5.5 kg/m2 at 6 and 12 months, respectively (P < 0.0001). This was associated with lower (P < 0.0001) plasma glucose, insulin, insulin resistance, waist circumference, and blood pressure. Plasma leptin decreased from 27.6 ± 9.5 to 17.7 ± 9.8 (P = 0.0005) and 12.7 ± 5.1 ng/ml (P < 0.0001). Plasma ghrelin was comparable before and at 6 months (234 ± 53; 232 ± 53 pmol/liter) but increased at 12 months (261 ± 72 pmol/liter; P = 0.05 vs. 6 months). At 6 and 12 months, ghrelin levels correlated negatively with fasting plasma insulin levels and hepatic insulin extraction but not with body mass or insulin action.

In conclusion, prolonged weight loss results in a rise of fasting ghrelin concentrations that correlates with fasting insulin concentrations but not improvement of insulin sensitivity.
Longitudinal Study on Growth and Body Mass Index before and after Diagnosis of Childhood Craniopharyngioma
Authors: Müller Hermann L. , Emser Angela , Faldum Andreas , Bruhnken Gina , Etavard-Gorris Nicole , Gebhardt Ursel , Oeverink Rudolf , Kolb Reinhard , Sörensen Niels
Published: July 2004

We analyzed whether childhood craniopharyngioma predisposes to obesity and growth impairment. Height/length, body mass index (BMI), and hypothalamic involvement were evaluated in 90 patients at standardized ages and time points before, after, and at the time of diagnosis. Relevant decreases in height sd score (SDS) started at 10–12 months of age and persisted until diagnosis of childhood craniopharyngioma. Relevant increases in BMI SDS were detectable between 4 and 5 yr of age. Postoperative BMI SDS (yr 1–6) had a weak positive correlation with BMI SDS at the time of diagnosis. In linear regression analysis, hypothalamic tumor involvement (P < 0.001), ponderal index at birth (P = 0.014), and BMI SDS at age 6–7 months (P = 0.029) and at age 5 yr (P < 0.001) had relevant and independent impacts on the development of obesity. Patients with hypothalamic involvement (n = 48) presented lower ponderal index and BMI SDS at birth and higher BMI SDS at the time of diagnosis (P < 0.001) as well as during annual follow-up (P < 0.001) compared with patients without hypothalamic involvement (n = 42). From childhood (3.5–4 yr) to the time of diagnosis, growth rates were reduced for patients with hypothalamic tumor involvement. Patients without hypothalamic involvement presented reduced growth rates in early infancy (age 10–12 months) that persisted until diagnosis. We conclude that reduced growth rates occur quite early in history; BMI SDS increases occur later and are predictive of obesity. Hypothalamic involvement is the major risk factor for obesity in patients with childhood craniopharyngioma.
Impaired Leydig Cell Function in Infertile Men: A Study of 357 Idiopathic Infertile Men and 318 Proven Fertile Controls
Authors: Andersson A.-M. , Jørgensen N. , Frydelund-Larsen L. , Rajpert-De Meyts E. , Skakkebæk N. E.
Published: July 2004

To investigate whether an impaired Leydig cell function is present in severely oligospermic men, serum testosterone (T), LH, estradiol (E2), and SHBG levels in 357 idiopathic infertile men were compared with levels in 318 proven fertile men. In addition, the T/LH ratio, E2/T ratio, and calculated free T index (cFT) were compared between the two groups.

A shift toward lower serum T levels, cFT, and T/LH ratio and higher serum LH, E2, and E2/T levels was observed in the group of infertile men. On average, the infertile men had 18, 26, and 34% lower serum T, cFT, and T/LH levels, respectively, and 19, 18, and 33% higher serum LH, E2, and E2/T levels, respectively, than the fertile men. Twelve percent of the infertile men had a serum T level that fell below the 2.5 percentile of the fertile levels, and 15% of the infertile men had a LH level that was above the 97.5 percentile of the fertile levels.

Thus, the group of infertile men showed significant signs of impaired Leydig cell function in parallel to their impaired spermatogenesis. The association of decreased spermatogenesis and impaired Leydig cell function might reflect a disturbed paracrine communication between the seminiferous epithelium and the Leydig cells, triggered by distorted function of the seminiferous epithelium. On the other hand, the parallel impairment of spermatogenesis and Leydig cells may reflect a congenital dysfunction of both compartments caused by a testicular dysgenesis during fetal/infant development.
Protein-Tyrosine Phosphatase, Nonreceptor Type 11 Mutation Analysis and Clinical Assessment in 45 Patients with Noonan Syndrome
Authors: Yoshida Rie , Hasegawa Tomonobu , Hasegawa Yukihiro , Nagai Toshiro , Kinoshita Eiichi , Tanaka Yoko , Kanegane Hirokazu , Ohyama Kenji , Onishi Toshikazu , Hanew Kunihiko , Okuyama Torayuki , Horikawa Reiko , Tanaka Toshiaki , Ogata Tsutomu
Published: July 2004

We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1–15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [−0.6 ± 2.2 sd (n = 10) vs. −0.6 ± 1.4 sd (n = 21); P = 0.95], childhood height [−2.6 ± 1.1 sd (n = 14) vs. −2.1 ± 1.6 sd (n = 23); P = 0.28], or target height [−0.4 ± 0.9 sd (n = 14) vs. −0.2 ± 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.
Medication Adherence and Associated Hemoglobin A1c in Type 2 Diabetes
Authors: Krapek Kimberley , King Kathleen , Warren Susan S , George Karen G , Caputo Dorothy A , Mihelich Karen , Holst Elizabeth M , Nichol Michael B , Shi Sheng G , Livengood Kevin B , Walden Steve , Lubowski Teresa J
Published: July 2004

BACKGROUND:

Tight blood glucose control has been correlated with a reduction in diabetes complications. Adherence to antidiabetic medications is crucial to achieving blood glucose control.

OBJECTIVE:

To assess the relationship between good glucose control [glycosylated hemoglobin (HbA1c) levels] and adherence to prescribed treatment in patients on a stable medication regimen for type 2 diabetes.

METHODS:

The Morisky survey, a 4–item questionnaire that predicts patient medication-taking behavior, was used to assess adherence in 301 patients. The relationship of HbA1c to Morisky score was evaluated, controlling for other variables related to patient demographics and clinical characteristics. Data were analyzed using a general linear model on log (HbA1c).

RESULTS:

Unadjusted mean HbA1c values (capped at 14.0%) for patients with Morisky scores of 0 or 1, 2, 3, and 4 were 8.92%, 8.67%, 7.74%, and 7.60%, respectively. Of all patients, 13.0%, 14.0%, 24.3%, and 48.8% had scores of 0 or 1, 2, 3, and 4, respectively. Good adherence (Morisky score ≥3) was associated with a 10% lower total HbA1c (p = 0.0003) adjusted for all other factors in the model. Duration of diabetes (5–10 y) and presence of diabetes complications were also significantly associated with HbA1c (p = 0.026 and 0.002, respectively). Adherence was poor in 27% of patients.

CONCLUSIONS:

This study found that patients with a higher score on the Morisky scale had a lower associated HbA1c measurement. The Morisky score may be an efficient tool for identifying patients with poor medication-taking behavior who can then be targeted for directed adherence counseling services.
Odorant-Evoked Nitric Oxide Signals in the Antennal Lobe ofManduca sexta
Authors: Collmann Chad , Carlsson Mikael A. , Hansson Bill S. , Nighorn Alan
Published: July 2004

The gaseous signaling molecule nitric oxide (NO) can affect the activities of neurons and neural networks in many different systems. The strong expression of NO synthase (NOS) in the primary synaptic neuropil (the antennal lobe in insects and the olfactory bulb in vertebrates) of the olfactory system of most organisms, and the unique spheroidal geometry of olfactory glomeruli in those neuropils, have led to suggestions that NO signaling is important for processing olfactory information. No direct evidence exists, however, that NO signals are produced in olfactory glomeruli. We investigated the production of NO in the antennal lobe of the moth,Manduca sexta, by using immunocytochemistry and real-time optical imaging with a NO-sensitive fluorescent marker, diaminofluorescein diacetate. We confirmed that NOS was expressed in the axons of olfactory receptor neurons projecting to all glomeruli. Soluble guanylyl cyclase, the best characterized target of NO, was found in a subset of postsynaptic antennal lobe neurons that included projection neurons, a small number of GABA-immunoreactive neurons, and a serotonin-immunoreactive neuron. We found that odorant stimulation evoked NO signals that were reproducible and spatially focused. Different odorants evoked spatially distinct patterns of NO production. Increased concentrations of pheromone and plant odorants caused increases in peak signal intensity. Increased concentrations of plant odorants also evoked a dramatic increase in signal area. The results of these experiments show clearly that odorant stimulation can evoke NO production in the olfactory system. The NO signals produced are likely to play an important role in processing olfactory information.
Dendroarchitecture and Lateral Inhibition in Thalamic Barreloids
Authors: Lavallée Philippe , Deschênes Martin
Published: July 2004

Thalamic cells that relay vibrissa information to barrel cortex are clustered within whisker-related modules termed barreloids. Each barreloid receives input from one principal whisker and inhibitory inputs from reticular thalamic neurons with receptive fields that correspond to that same whisker. Although the proximal dendrites of relay cells are confined to their home barreloid, distal dendrites often extend into surrounding barreloids representing adjacent whiskers on the mystacial pad. It was proposed that this arrangement provides a substrate for a mechanism of lateral inhibition that operates remotely on extrabarreloid dendrites. In the present study, we identified adjacent whiskers that suppressed activity below background levels in barreloid cells, and we used a double-labeling protocol to relate the efficacy of inhibition to the dendroarchitecture of the cells. Significant suppression of background discharges was produced by 92% of adjacent whiskers within rows, by 48% of adjacent whiskers within arcs, but was never observed after deflection of nonadjacent whiskers. The magnitude of lateral inhibition increases linearly as the cumulated length of dendrites increases in the barreloid representing an adjacent whisker (R2= 0.86;p< 0.0001). As distance between cell bodies and the border of an adjacent barreloid increases, dendritic length in that adjacent barreloid diminishes and so does inhibition. Considering time differences between the arrival of principal and adjacent whisker inputs in barreloids, our data suggest that inhibition operating distally on dendrites acts as a spatial filter that primarily suppresses adjacent whisker inputs and so contributes to enhance edge detection.
Passive Amyloid Immunotherapy Clears Amyloid and Transiently Activates Microglia in a Transgenic Mouse Model of Amyloid Deposition
Authors: Wilcock Donna M. , Rojiani Amyn , Rosenthal Arnon , Levkowitz Gil , Subbarao Sangeetha , Alamed Jennifer , Wilson David , Wilson Nedda , Freeman Melissa J. , Gordon Marcia N. , Morgan Dave
Published: July 2004

The role of microglia in the removal of amyloid deposits after systemically administered anti-Aβ antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-Aβ antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-Aβ antibody but not in those treated with a control antibody. We found that Fcγ receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum Aβ levels and anti-Aβ antibody levels were elevated to similar levels at all three survival times in mice given anti-Aβ injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the Aβ and resulting in Fcγ receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-Aβ antibody-mediated amyloid removal can be simultaneously active.
Fibroblast Growth Factor Receptor 1 Is Required for the Proliferation of Hippocampal Progenitor Cells and for Hippocampal Growth in Mouse
Authors: Ohkubo Yasushi , Uchida Ayumi O. , Shin Dana , Partanen Juha , Vaccarino Flora M.
Published: July 2004

Fibroblast growth factor receptor 1 (Fgfr1) is expressed at high levels by progenitor cells of the ventricular zone (VZ) within the hippocampal primordium. To investigate the role ofFgfr1in these cells,in vivoCre recombination of “floxed” Fgfr1 alleles was directed to cells of the radial glial lineage by using the human glial fibrillary acidic protein promoter. Radial glial-like cells of the hippocampal VZ are the progenitors of pyramidal neurons and granule cells of hippocampal dentate gyrus (DG). Mice carrying nullFgfr1alleles (Fgfr1Δflox) in cells of this lineage showed a dramatic loss ofFgfr1gene expression throughout the embryonic dorsal telencephalon. TheseFgfr1Δfloxmice exhibited a ∼30% decrease in dividing radial glial progenitor cells in the hippocampal VZ and DG in the late embryonic period, progressing to a ∼50-60% loss at birth, without any changes in cell survival. In addition, no FGF2-sensitive neural stem cells could be isolated from theFgfr1Δfloxhippocampal neuroepithelium, whereas epidermal growth factor-sensitive neural stem cells were not affected. The number of hippocampal pyramidal neurons and DG granule cells was ∼30-50% decreased from the perinatal period through adulthood, and the number of parvalbumin-containing interneurons was similarly decreased in both the DG and pyramidal cell fields. We conclude thatFgfr1is necessary for hippocampal growth, because it promotes the proliferation of hippocampal progenitors and stem cells during development.
Fast and Slow Voltage-Dependent Dynamics of Magnesium Block in the NMDA Receptor: The Asymmetric Trapping Block Model
Authors: Vargas-Caballero Mariana , Robinson Hugh P. C.
Published: July 2004

The NMDA receptor (NMDAR) produces a long-lasting component of the glutamatergic EPSC in mammalian central neurons. The current through NMDARs is voltage dependent as a result of block by extracellular magnesium, which has recently been shown to give rise to a complex time dependence, with fast and slow components of responses to changes in membrane potential. Here, we studied the dynamics of block and unblock by measuring voltage step responses in conjunction with fast perfusion of agonist in nucleated patches isolated from rat cortical pyramidal neurons. We found that slow unblock shows a progressive onset during synaptic-like responses to brief pulses of agonist. Repolarizing briefly from +40 to -70 mV revealed that slow unblock is reestablished with a time constant of ∼5 msec at room temperature. Also, the time course of deactivation, in response to a pulse of agonist, slows twofold over the potential range -30 to +40 mV. An asymmetric “trapping block” model in which the voltage-independent closing rate constant of the blocked channel is approximately three times that of the unblocked channel accounts quantitatively for all of these phenomena and for responses to action potential waveform clamp. This model allows much more accurate prediction of NMDAR current in physiological conditions of magnesium concentration and changing membrane potential than previously possible. It suggests a positive allosteric link between occupation of the NMDAR pore by magnesium and closure of the permeation gate.
Cloning of a Novel Apaf-1-Interacting Protein: A Potent Suppressor of Apoptosis and Ischemic Neuronal Cell Death
Authors: Cao Guodong , Xiao Michael , Sun Fengyan , Xiao Xiao , Pei Wei , Li Juan , Graham Steven H. , Simon Roger P. , Chen Jun
Published: July 2004

Cytochromec-initiated activation of apoptotic protease activating factor-1 (Apaf-1) is a key step in the mitochondrial-signaling pathway for the activation of death-executing caspases in apoptosis. This signaling pathway has been implicated in the pathophysiology of various neurological disorders, including ischemic brain injury. In this study, we have cloned a novel rat gene product, designated as Apaf-1-interacting protein (AIP), which functions as a dominant-negative inhibitor of the Apaf-1-caspase-9 pathway. AIP is constitutively expressed in the brain, but at substantially lower levels than Apaf-1 and caspase-9. AIP can directly bind to Apaf-1in vitrothrough its N-terminal caspase-recruiting domain, and this protein interaction was increased in cells undergoing apoptosis. Cytosolic extracts from cells overexpressing AIP were highly resistant to cytochromec- dATP-induced activation of caspase-9 and caspase-3. Gene transfection of AIP into cell lines, including the neuronal-differentiated PC12 cells, potently suppressed apoptosis induced by various pro-apoptotic stimuli. To further investigate the functional role of AIP in primary neurons and in the brain, an adeno-associated virus (AAV) vector carrying the AIP cDNA was constructed. AAV-mediated overexpression of AIP in primary cortical- hippocampal neurons markedly reduced cell death and caspase-3 activation triggered by protein kinase C inhibition, DNA damage, or oxygen- glucose deprivation. Moreover, intracerebral infusion of the AAV vector resulted in robust AIP expression in the hippocampus and significantly promoted CA1 neuronal survival after transient global cerebral ischemia. These results suggest that molecular targeting of the Apaf-1-caspase-9 signaling pathway may be a feasible neuroprotective strategy to enhance the endogenous threshold for caspase activation and prevent neuronal loss in stroke and related disorders.
Correlation between Semaphorin3A-Induced Facilitation of Axonal Transport and Local Activation of a Translation Initiation Factor Eukaryotic Translation Initiation Factor 4E
Authors: Li Chanxia , Sasaki Yukio , Takei Kohtaro , Yamamoto Hiroshi , Shouji Masayuki , Sugiyama Yoshinobu , Kawakami Tadashi , Nakamura Fumio , Yagi Takeshi , Ohshima Toshio , Goshima Yoshio
Published: July 2004

An impressive body of evidence has been accumulated indicating that local protein synthesis is implicated in navigation of neurite extension induced by guidance cues, such as semaphorin3A (Sema3A). We found previously that a Src type tyrosine kinase Fyn and cyclin-dependent kinase 5 (Cdk5) mediate Sema3A-signaling. We also showed that Sema3A elicits axonal transport through neuropilin-1, a receptor for Sema3A, located at the growth cones. Here, we investigate the relationship between Sema3A-induced local signaling, protein synthesis, and axonal transport. Lavendustin A, a tyrosine kinase inhibitor, and olomoucine, a cyclin-dependent kinase inhibitor, suppressed Sema3A-induced facilitation of anterograde and retrograde axonal transport in dorsal root ganglion (DRG) neuron with and without the cell body. Sema3A-induced facilitation of axonal transport was attenuated in DRG neurons offyn- (fyn-/-) and a Cdk5 activator,p35(p35-/-)-deficient mice when compared with those of wild-type or heterozygous mice. Inhibition of protein synthesis suppressed Sema3A-induced facilitation of axonal transport in the DRG neuron with and without the cell body. Sema3A enhanced the level of immunoreactivity of phosphorylated eukaryotic translation initiation factor 4E (eIF-4E) within 5 min in growth cones in a time course similar to that of the facilitated axonal transport. This enhanced signal for phospho-eIF4E was blocked by lavendustin A or olomoucine and was not detected in thefyn-/-andp35-/-neurons. These results provide evidence for a mutual regulatory mechanism between local protein synthesis and axonal transport.
Redistribution of GABAB(1)Protein and Atypical GABABResponses in GABAB(2)-Deficient Mice
Authors: Gassmann Martin , Shaban Hamdy , Vigot Réjan , Sansig Gilles , Haller Corinne , Barbieri Samuel , Humeau Yann , Schuler Valérie , Müller Matthias , Kinzel Bernd , Klebs Klaus , Schmutz Markus , Froestl Wolfgang , Heid Jakob , Kelly Peter H. , Gentry Clive , Jaton Anne-Lise , Van der Putten Herman , Mombereau Cédric , Lecourtier Lucas , Mosbacher Johannes , Cryan John F. , Fritschy Jean-Marc , Lüthi Andreas , Kaupmann Klemens , Bettler Bernhard
Published: July 2004

GABABreceptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABABreceptors are usually only observed after coexpression of GABAB(1)and GABAB(2)subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABAB(1)is responsible for binding of GABA, whereas GABAB(2)is necessary for surface trafficking and G-protein coupling. Consistent with thesein vitroobservations, the GABAB(1)subunit is also essential for all GABABsignalingin vivo. Mice lacking the GABAB(1)subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABABagonists. However, GABAB(1)exhibits a broader cellular expression pattern than GABAB(2), suggesting that GABAB(1)could be functional in the absence of GABAB(2). We now generated GABAB(2)-deficient mice to analyze whether GABAB(1)has the potential to signal without GABAB(2)in neurons. We show that GABAB(2)-/-mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABAB(1)-/-mice. This clearly demonstrates that the lack of heteromeric GABAB(1,2)receptors underlies these phenotypes. To our surprise and in contrast to GABAB(1)-/-mice, we still detect atypical electrophysiological GABABresponses in hippocampal slices of GABAB(2)-/-mice. Furthermore, in the absence of GABAB(2), the GABAB(1)protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABAB(2)with GABAB(1)is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABABreceptors exist in neurons that naturally lack GABAB(2)subunits.
Fluorine Compounds, Inorganic, Ammonium
Authors: Papcun John R.
Published: July 2004

There are two fluoride salts of ammonia: ammonium fluoride, principally a laboratory reagent, and ammonium bifluoride, used primarily as a less hazardous substitute for hydrofluoric acid. In addition to frosting glass, uses of the bifluoride include removing scale from boiler tubes and defouling oil wells. Properties, manufacture, and applications are described.

Lithium fluoride resembles the alkaline‐earth fluorides more closely than the alkali metal fluorides. It is used primarily in the ceramics industry. Properties and manufacture are described.

Magnesium fluoride has a very low chemical reactivity and high optical transparency. It finds application in uv windows. Properties and manufacture are described.

The two stable potassium fluoride salts, potassium fluoride and potassium bifluoride, both have commercial value. The former as a flux, in electroplating, and in synthesis; the latter as a flux and in the manufacture of fluorine. Properties and manufacture are described.
Fluorine Compounds, Inorganic, Antimony
Authors: Mahmood Tariq , Lindahl Charles B.
Published: July 2004

Antimony and arsenic both form a trifluoride and a pentafluoride as well as a very stable hexafluoroantimonate and a hexafluoroarsenate ion, respectively. The chemistry of antimony fluoride compounds is well studied. Antimony trifluoride is used as a mild fluorinating agent for the production of fluorocarbons and for nonmetals and metals for the replacement of other halides. It is also used in the manufacture of fluoride glass. Antimony pentafluoride is a moderate fluorinating agent and a powerful oxidizer. It is used to saturate double bonds and in the production of intercalated compounds of graphite. It is also used to produce superacid systems. Anhydrous metal salts can be used as uv catalysts for the production of polymers.

Arsenic trifluoride is used as a fluorinating agent, in semiconductors, and in the synthesis of hexafluoroarsenates. Arsenic pentafluoride is used as a fluorinating agent, in ion implantation, and to produce conductive polymers. However, environmental and regulatory concerns have severely limited these applications.
Fluorine Compounds, Inorganic, Barium
Authors: Mahmood Tariq , Lindahl Charles B.
Published: July 2004

Barium fluoride is used commercially in combination with other fluorides for arc welding, electrode fluxes, and in the manufacture of fluorophosphate glasses and infrared transmitting windows. Properties and preparation methods are given.

Boron trifluoride is widely used as an acid catalyst, especially for the production of petroleum and polymer products, such as in the manufacture of synthetic lubricants and in the preparation of hydrocarbon resins. Boron trifluoride is also finding increased use as a chemical reagent in the synthesis of boron‐containing materials of various types.

Reactions of boron trifluoride are outlined. The types of complexes formed between boron trifluoride and oxygen‐containing compounds, as well as other complexing agents, are discussed. Methods of handling boron trifluoride are described.
Fluorine Compounds, Inorganic, Boron Trifluoride
Authors: Evans Francis , Mani Ganpat
Published: July 2004

Fluoroboric acid and the fluoroborates are commercially important to a variety of industries. The acid is used in plating circuits, in metal finishing, in the production of aluminum, and as an acid catalyst. Main group metal and ammonium fluoroborates find use as fluxes, as catalysts, and in flame‐retardant manufacture. Transition‐ and other heavy‐metal fluoroborate salts are used in the plating industry and as catalysts. Properties and manufacture are described.
Fluorine Compounds, Inorganic, Copper
Authors: Meshri Dayal T.
Published: July 2004

Copper(II) fluoride forms several stable fluorides, all of which are interconvertible. Several methods of synthesis for CuF
2
have been reported and result in good yields.

Copper(II) fluoride is used as a fluorinating reagent, in superconductors, as a cathode material, for skeletal rearrangements of olefins, for isomerization, as a herbicide and termite repellant, as a catalyst, and for synthesis of heterocyclic tetraaromatics. Physical properties are discussed.