Norepinephrine transporter (NET) promoter and 5'-UTR polymorphisms: association analysis in panic disorder

Several biochemical and pharmacological studies suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is relevant for the pathogenesis of panic disorder. Three single nucleotide polymorphisms in the promoter or untranslated 5' region of the NET gene were investigated by means of RFLP analysis in a sample of 115 German patients with panic disorder and 115 matched controls. Statistical analysis failed to show association with the overall diagnosis of panic disorder. In the subgroup of patients with panic disorder without agoraphobia, however, two polymorphisms were found to be associated with the disease (G/C (rs2397771): p < 0.05; T/C (rs2242446): p < 0.01). While our data do not support a major function of the NET gene in the development of panic disorder, it may play a role in the subgroup of panic disorder without agoraphobia.     

Test of the dual‐belief system in women with and without phobic fear of spiders: a pilot study

This study tests the so‐called dual‐belief systems. According to this concept, patients with phobia foster two conflicting peripheral beliefs (situational dependent) about the fear‐inducing stimulus. The existence of such conflicting beliefs can only be explained by so‐called bridging core beliefs. These bridging core beliefs are situation independent and integrate the contradictions of the peripheral beliefs. To test the existence of bridging core beliefs, 60 women with and without spider phobia were interviewed during exposition to phobic and neutral stimuli. Women with phobic anxiety reported more phobic emotions, thoughts, and peripheral beliefs during exposure to a phobic stimulus than during exposure to a neutral stimulus. In core beliefs no differences between the two conditions were found. In the non‐phobic control group, no differences were found for the conditions in any of the dependent variables. All together, these data provide support for the existence of dual‐belief systems as well as bridging core beliefs. Copyright © 2006 John Wiley & Sons, Ltd.     

Endotoxins prevent murine IgE production,T(H)2 immune responses,and development of airway eosinophilia but not airway hyperreactivity

BACKGROUND: Contact with immunomodulatory factors, such as LPS, in early infancy is associated with decreased allergen sensitization. OBJECTIVE: We sought to study the effects of systemic or airway exposure with LPS on the development of allergen sensitization, eosinophilic airway inflammation, and increased in vivo airway reactivity (AR) in a mouse model. METHODS: BALB/c mice were systemically sensitized with ovalbumin (OVA) plus adjuvant on days 1 and 14 and challenged through the airways with allergen on days 34 to 36. We performed measurement of OVA-specific IgE serum levels, in vitro T(H)2 cytokine production, differential cell counts in bronchoalveolar lavage fluids, and assessment of in vivo AR to inhaled methacholine by means of barometric whole-body plethysmography. RESULTS: Systemic LPS administration before OVA sensitization reduced OVA-specific IgE serum levels (426 +/- 76 vs 880 +/- 104 U/mL, P <.01), T(H)2 cytokine production by splenic mononuclear cells (IL-4: 0.08 +/- 0.01 vs 0.17 +/- 0.01 ng/mL; IL-5: 1.98 +/- 0.52 vs 4.11 +/- 0.54 ng/mL; P <.01), and extent of airway eosinophilia (total cell counts: 93 vs 376 x 10(3)/mL; eosinophils: 23% vs 51%; P <.01) compared with that in OVA-sensitized mice. Local LPS administration to sensitized mice before airway allergen challenges particularly induced IFN-gamma production by peribronchial lymph node cells in vitro (1718 +/- 315 vs 483 +/- 103 ng/mL, P <.01) associated with reduced airway eosinophilia compared with that seen in OVA-sensitized mice. Development of increased AR was not affected by systemic or local LPS exposure. Inhibitory effects of LPS on allergen sensitization and eosinophilic airway inflammation were inhibited by administration of anti-IL-12 antibodies before LPS exposure. CONCLUSION: These data indicate that local and systemic application of LPS modulates systemic and local T(H)1/T(H)2 immune responses in a distinct but similarly IL-12-dependent mode.     

A role for the basal ganglia in nicotinic modulation of the blink reflex

Summary In humans and rats we found that nicotine transiently modifies the blink reflex. For blinks elicited by stimulation of the supraorbital branch of the trigeminal nerve, nicotine decreased the magnitude of the orbicularis oculi electromyogram (OOemg) and increased the latency of only the long-latency (R2) component. For blinks elicited by electrical stimulation of the cornea, nicotine decreased the magnitude and increased the latency of the single component of OOemg response. Since nicotine modified only one component of the supraorbitally elicited blink reflex, nicotine must act primarily on the central nervous system rather than at the muscle. The effects of nicotine could be caused by direct action on lower brainstem interneurons or indirectly by modulating descending systems impinging on blink interneurons. Since precollicular decerebration eliminated nicotine's effects on the blink reflex, nicotine must act through descending systems. Three lines of evidence suggest that nicotine affects the blink reflex through the basal ganglia by causing dopamine release in the striatum. First, stimulation of the substantia nigra mimicked the effects of nicotine on the blink reflex. Second, haloperidol, a dopamine (D₂) receptor antagonist, blocked the effect of nicotine on the blink reflex. Third, apomorphine, a D₂ receptor agonist, mimicked the effects of nicotine on the blink reflex.     

Bacterial persistence within erythrocytes: a unique pathogenic strategy of Bartonella spp

The genus Bartonella comprises human-specific and zoonotic pathogens responsible for a wide range of clinical manifestations, including Carrion's disease, trench fever, cat scratch disease, bacillary angiomatosis and peliosis, endocarditis and bacteremia. These arthropod-borne pathogens typically parasitise erythrocytes in their mammalian reservoir host(s), resulting in a long-lasting haemotropic infection. We have studied the process of Bartonella erythrocyte parasitism by tracking green fluorescent protein-expressing bacteria in the blood of experimentally infected animals. Following intravenous infection, bacteria colonise a yet enigmatic primary niche, from where they are seeded into the blood stream in regular intervals of approximately five days. Bacteria invade mature erythrocytes, replicate temporarily and persist in this unique intracellular niche for the remaining life span of the infected erythrocytes. A triggered antibody response typically results in an abrogation of bacteremia within 3 months of infection, likely by blocking new waves of bacterial invasion into erythrocytes. The recent establishment of genetic tools for Bartonella spp. permitted us to identify several putative pathogenicity determinants. Application of differential fluorescence induction technology resulted in the isolation of bacterial genes differentially expressed during infection in vitro and in vivo, including an unknown family of autotransporter proteins as well as a novel type IV secretion system homologous to the conjugation system of E. coli plasmid R388. Mutational analysis of a previously described type IV secretion system displaying homology to the virB locus of Agrobacterium tumefaciens provided the first example of an essential pathogenicity locus in Bartonella. Though required for establishing haemotropic infection, it remains to be demonstrated if this type IV secretion system is necessary for colonisation of the primary niche or for the subsequent colonisation of erythrocytes.     

Rewarding effects of the optical isomers of 3,4-methylenedioxy-methylamphetamine ('Ecstasy') and 3,4-methylenedioxy-ethylamphetamine ('Eve') measured by conditioned place preference in rats

3,4-methylenedioxy-methylamphetamine (MDMA) (‘Ecstasy’) and its analogue 3,4-methylenedioxy-methylamphetamine (MDE) (‘Eve’) are well known illicit street drugs mainly abused by young people. In spite of the actual research going on, the classification of their abuse potential remains unclear. Since secondary reinforcers are the main factors responsible for craving and relapse, the aim of our study was to assess the potency of MDMA and MDE in a second order reinforcement paradigm, i.e. conditioned place preference (CPP). For the general assessment of our study conditions, we compared MDMA with amphetamine. Unexpectedly, no significant CPP for MDMA was found in contrast to amphetamine. Detailed analysis of current literature led us to the working hypothesis that social environment is crucial for the development of CPP. In a subsequent experiment we tested the influence of housing conditions on CPP using MDMA and demonstrated that isolated animals show significant CPP compared to group-housed ones. In order to better understand the rewarding mechanisms of Ecstasy-derivatives, we tested both the racemic drugs and the pure isomers in the CPP paradigm. Both MDMA's optical isomers and racemic MDMA showed significant CPP without notable differences, while MDE and its isomers completely failed to show any significant CPP. In conclusion, the mechanism by which MDMA induces addiction is much more complicated than assumed so far and more pronounced in isolated animals. The fact that both optical isomers of MDMA led to CPP implies that at least two pathways by which MDMA induces craving behaviour exist.     

Role of gamma delta T cells in inflammatory bowel disease.

gammadelta T cells have previously been shown to play a protective role in various animal models of chronic inflammation (e.g., experimental autoimmune encephalomyelitis, collagen-induced arthritis, and non-obese diabetes). This immunoregulatory potential is exerted by synthesizing various anti-inflammatory cytokines and growth factors (e.g., transforming growth factor-beta). As the normal balance between inflammatory and regulatory cytokines is perturbed in inflammatory bowel disease (IBD) a protective effect of gammadelta T cells seems likely. This notion is supported by our finding of increased mortality of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis following gammadelta T cell depletion. In contrast, no effect was observed after depletion of gammadelta T cells in a Crohn's disease animal model with terminal ileitis (TNF(DeltaARE) mice). Therefore, future studies must further define where in the intestinal immune system gammadelta T cells exert their protective function and how this can be used in the treatment of IBD.     

Impaired sodium excretion, decreased glomerular filtration rate and elevated blood pressure in endothelin receptor type B deficient rats

The renal endothelin (ET) system, particularly the ET type B receptor, has been implicated in the regulation of sodium excretion and glomerular filtration rate (GFR). We analyzed kidney morphology and function in a rat strain characterized by complete absence of a functional ETB receptor. Due to Hirschsprung's disease limiting lifetime in these rats, studies were performed in 23-day-old rats. Kidney size and morphology (glomerular and interstitial matrix content, glomerular size and cell density and intrarenal vascular morphology) were normal in ETB-deficient rats. There were also no evidence of altered kidney cell cycle regulation in these rats. GFR was significantly lower, by 72% (P<0.001), in homozygous ETB-deficient rats than in wild-type rats. Fractional sodium excretion was likewise markedly reduced by 84% in homozygous ETB-deficient rats (P<0.001 versus wild-type rats). Treatment with the specific epithelial sodium channel blocker amiloride led to a much higher increase in fractional sodium excretion in ETB-deficient rats (934.2+/-73% in ETB-deficient rats versus 297+/-20% in wild-type rats, expressed as percentage of corresponding placebo treated control; P<0.001). Mean arterial blood pressure was elevated by 7.9 mmHg in homozygous ETB-deficient rats (P<0.05 versus wild-type rats). Our study demonstrates that ETB-deficiency causes early onset kidney dysfunction characterized by a markedly reduced sodium excretion, decreased GFR, and slightly elevated blood pressure. The complete absence of the ETB receptor causes in the kidney--in contrast to the colon--a functional rather than a developmental, neural crest cell dependent disease, since kidney morphology was normal in ETB-deficient rats. The much higher increase in the fractional sodium excretion in ETB-deficient rats after pharmacological blockade of the epithelial sodium channel indicates that the decreased fractional sodium excretion in ETB-deficient rats is most probably due to a lack of the inhibitory property of the ETB receptor on the epithelial sodium channel activity.     

Ontogeny, differentiation and growth of the endocrine pancreas

The pancreas develops from the primitive foregut endoderm, which differentiates into ductal, acinar and endocrine cells. This complex process is probably replicated in the adult pancreas when endocrine cell renewal is required, as may be the case in diabetes mellitus. This review describes what is known about the morphogenesis of the endocrine pancreas during ontogeny and the mechanisms regulating its differentiation and growth. Received: 23 December 1999 / Accepted: 15 February 2000