A PPAR-α agonist protects the non-adrenergic, non-cholinergic inhibitory system of guinea pig trachea from the effect of inhaled ammonium persulphate: a pilot study.

SUMMARY: Aim of the study. Inhaled ammonium persulphate (AP) reduces non adrenergic, non cholinergic (NANC) relaxation in the guinea pig trachea, as a part of its inflammatory effects. Peroxisome Proliferator-Activated Receptor (PPAR) stimulation has shown anti-inflammatory properties. This study aimed at evaluating whether the PPAR-α agonist WY 14643 can prevent the reduction in NANC relaxation caused by inhaled AP in the guinea pig trachea. Materials and Methods. Four groups of ten male guinea pigs were treated for three weeks with inhaled AP (10 mg/m3, 30 min per day, group A), saline (group B), AP and WY 14643 (0.36 µM/die, per os, group C), and AP, WY 14643 and the PPAR-α antagonist GW 6471 (0.36 µM/die, per os, group D). NANC relaxations to electrical field stimulation (EFS) at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Results. The tracheal NANC relaxations were reduced by 90.3% in group A, as compared to group B. In group C, they were reduced by only 22.2%. In group D, they were reduced by 92.6 %. PPAR-α receptors were detected in inhibitory nerve fibers within the trachea as shown by immonohistochemical analysis. Conclusions. The PPAR-α agonist WY 14643 protects the NANC inhibitory system of the guinea pig trachea from the effect of inhaled ammonium persulphate and its protective effect is antagonized by GW 6471. PPAR-α might be exploited.

Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model.

Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting Parkinson's disease (PD) patients. We have previously reported that rats bearing unilateral nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection develop severe constipation together with a region-specific decrease of neuronal nitric oxide synthase (nNOS) in enteric neurons of the lower intestinal tract. Here, we extend these observations on other enteric neuronal subpopulations, investigating also the propulsive activity of isolated colonic specimens. Four weeks post 6-OHDA injection, lesioned rats showed a significant increase of vasoactive intestinal polypeptide (VIP) concomitant with the reduced expression of nNOS in the myenteric plexus of distal ileum and proximal colon; in particular VIP increased in a subpopulation of neurons actively expressing nNOS. On the other hand, choline acetyltransferase (ChAT) was not modified in any of the intestinal segments analyzed. Interestingly, we found a reduced expression of dopamine receptor type 2 (D2R) in proximal (-66.8%) and distal (-54.5%) colon, together with reduced peristalsis efficiency (decrease in intraluminal pressure and frequency of peristaltic events) in the 6-OHDA-lesioned rats. The selective depletion of dopaminergic nigrostriatal neurons is associated with changes in the expression of enteric inhibitory neurotransmitters, as well as of the D2R in intestinal specific regions. Moreover, 6-OHDA-lesioned rats demonstrated altered colon propulsive activity referable to the D2R decrease. Our findings unveil subtle mechanisms underlying the enteric neurochemical plasticity events evoked by disruption of the normal brain-gut cross-talk, giving a peculiar point of view on the pathophysiology of the severe constipation that frequently affects PD patients.

Work-related stress and bullying: gender differences and forensic medicine issues in the diagnostic procedure.

BACKGROUND: The attention of international agencies and scientific community on bullying and work-related stress is increasing. This study describes the gender differences found in victims of bullying and work-related stress in an Italian case series and analyzes the critical issues in the diagnostic workup. METHODS: Between 2001 and 2009 we examined 345 outpatients (148 males, 197 females; mean age: 41 ± 10.49) for suspected psychopathological work-related problems. Diagnosis of bullying was established using international criteria (ICD-10 and DSM-IV). RESULTS: After interdisciplinary diagnostic evaluation (Occupational Medicine Unit, Psychology and Psychiatry Service), the diagnosis of bullying was formulated in 35 subjects, 12 males and 23 females (2 cases of Post-Traumatic Stress Disorder and 33 of Adjustment Disorder). Fifty-four (20 males, 34 females) suffered from work-related anxiety, while work-unrelated Adjustment Disorder and other psychiatric disorders were diagnosed in 7 and 112 subjects, respectively. Women between 34 and 45 years showed a high prevalence (65%) of "mobbing syndrome" or other work-related stress disorders. CONCLUSIONS: At work, women are more subject to harassment (for personal aspects related to emotional and relational factors) than men. The knowledge of the phenomenon is an essential requisite to contrast bullying; prevention can be carried out only through effective information and training of workers and employers, who have the legal obligation to preserve the integrity of the mental and physical status of their employees during work.

Irritant vocal cord dysfunction and occupational bronchial asthma: differential diagnosis in a health care worker.

OBJECTIVES: Vocal cord dysfunction (VCD) is an uncommon respiratory disease characterized by the paradoxical adduction of vocal cords during inspiration, that may mimic bronchial asthma. The pathogenesis of VCD has not been clearly defined but it is possible to recognize non-psychologic and psychologic causes. The majority of patients are female but, interestingly, a high incidence of VCD has been documented in health care workers. A misdiagnosis with asthma leads to hospitalisation, unnecessary use of systemic steroids with related adverse effects, and sometimes tracheostomy and intubation. In a subset of VCD patients, the disease can be attributed to occupational or environmental exposure to inhaled irritants. MATERIALS AND METHODS: We report the case of a 45-year-old woman, working as a nurse, who complained of wheezing, cough, dyspnoea related to inhalation of irritating agents (isopropylic alcohol, formaldehyde, peracetic acid). She underwent chest radiography, pulmonary function assessment both in the presence and in the absence of symptoms, bronchial provocation with methacholine and bronchodilation test with salbutamol to recognize asthma's features, allergy evaluation by skin prick tests and patch tests and video-laryngoscopy. RESULTS: VCD diagnosis was made on the basis of video-laryngoscopy, that visualized the paradoxical motion of the vocal cords during symptoms, in the absence of other pathologic processes. CONCLUSIONS: This case fulfils the proposed criteria for the diagnosis of irritant VCD (IVCD). This is the first report of VCD onset following exposure to several irritants: formaldehyde, glutaraldehyde, sopropylic alcohol, peracetic acid-hydrogen peroxide mixture. These substances are used as cleaning and antiseptic agents in healthcare settings and some ones can also be found in many indoor environments. A correct diagnosis is important both to give the appropriate treatment and for medical legal implications.

Adenosine A1 and A3 receptor agonists inhibit nonadrenergic, noncholinergic relaxations in the guinea pig isolated trachea.

BACKGROUND: Adenosine affects the tone and reactivity of airways by activating specific membrane receptors, named A(1), A(2a), A(2b) and A(3). It affects cellular activities either directly by regulating membrane ion exchanges and polarization, or indirectly by modifying neurotransmitter release. OBJECTIVES: We assessed the effect of A(1) and A(3) receptor activation on electrically induced nonadrenergic, noncholinergic (NANC) relaxations in the guinea pig isolated trachea and the localization of A(1) and A(3) receptors in tracheal inhibitory neurons. METHODS: NANC responses at 3 Hz were evaluated in the presence of 2-chloro-N(6)-cyclopentyladenosine (CCPA), a selective A(1) agonist, and 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), a selective A(3) agonist, before and after the administration of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) antagonist, or 9-chloro-2-(2-furanyl)-5-((phenylacetyl)amino[1,2,4]triazolo[1,5-c])quinazoline (MRS 1220), a selective A(3) antagonist, respectively. For immunohistochemistry, tissues were exposed to antibodies to HuC/D, a general neuronal marker, neuronal nitric oxide synthase (nNOS), and A(1) or A(3) adenosine receptors and processed by indirect immunofluorescence. RESULTS: CCPA (10 nM-3 microM) inhibited NANC relaxations. DPCPX (10 nM) failed to antagonize the effect of CCPA, but inhibited per se NANC relaxations (range 0.1-100 nM). CCPA (10 nM-10 microM) contracted unstimulated tracheal preparations, an effect antagonized by 10 nM DPCPX, with a pK(B) value of 8.43. Cl-IB-MECA (10 nM-3 microM) inhibited NANC relaxations through a mechanism antagonized by MRS 1220 (100 nM). A(1)- and A(3)-positive neurons containing nNOS were detected in tracheal sections. CONCLUSIONS: Enogenous adenosine may induce airway hyperresponsiveness by inhibiting NANC relaxations via A(1) and A(3) receptors.

[Recent insights into the pathogenesis of abdominal symptoms in functional bowel disorders]. / Recenti acquisizioni sulla patogenesi dei sintomi addominali nei disordini funzionali intestinali.

In the gut, 5-HT acts as a paracrine signalling molecule released by enterochromaffin cells and as a transmitter released by some descending serotonergic interneurons. It has a prominent role in the regulation of motility, vascular tone, secretion and perception both in normal and under certain pathophysiological conditions, such as the carcinoid syndrome and the irritable bowel syndrome (IBS). Serotonin is known to markedly influence bowel function by activating at least five receptor types (5-HT(1,2,3,4,7)). Among all 5-HT receptors, those belonging to the 5-HT3 (a ionotropic receptor) and 5-HT4 (a metabotropic receptor) type are the most extensively studied in gastroenterology, resulting in commercially available (although not worldwide) serotonergic agents for the treatment of IBS and functional dyspepsia. Recently, 5-HT7 receptors have been found to participate in the accommodation process of the circular muscle during the preparatory phase of ileal peristalsis. Since an exaggerated accommodation of the gut wall may contribute to abdominal distension and bloating, 5-HT7 receptor ligands may offer innovative opportunities for the pharmacological treatment of functional bowel disorders.

5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum.

BACKGROUND & AIMS: The 5-hydroxytryptamine 7 (5-HT7) receptors mediate intestinal smooth muscle relaxation. In this study, we evaluated the expression of 5-HT7 receptors in the guinea pig ileum and their role in peristalsis and accommodation of the circular muscle. METHODS: We used immunohistochemistry and confocal microscopy with whole tissue and cultured myenteric neurons. Peristalsis was induced by delivering a solution into the oral end of an isolated ileal segment. The effect of the selective 5-HT7 receptor antagonist SB-269970 (100 nmol/L) on peristaltic activity was evaluated at 30, 60, and 90 minutes and compared with control. RESULTS: 5-HT7 receptor immunoreactivity was localized to numerous myenteric neurons, a few submucosal neurons, and a few smooth muscle cells of the ileum. In enteric cultured neurons, 5-HT7 receptor immunoreactivity was observed in subpopulations of after hyperpolarizing neurons and descending neurons as identified by neuron-specific nuclear protein or calbindin and neuronal nitric oxide synthase or vasoactive intestinal peptide antibodies, respectively. SB-269970 significantly increased the threshold pressure by 33.3% +/- 2.2% (P < .001) and by 27.2% +/- 1.6% (P < .05) at 60 and 90 minutes, respectively, without modifying the threshold volume. The accommodation significantly decreased by 27.5% both at 60 and 90 minutes (P < .05). CONCLUSIONS: Our results indicate that endogenous 5-HT is involved in the modulation of circular muscle accommodation during the preparatory phase of peristalsis via the activation of 5-HT7 receptors expressed by neurons in addition to smooth muscle cells. Overstimulation of these receptors leading to an exaggerated accommodation of circular muscle might contribute to abdominal symptoms in functional bowel disorders.