The low FODMAP diet in the management of irritable bowel syndrome: an evidence-based review of FODMAP restriction, reintroduction and personalisation in clinical practice.

Dietary restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) is effective in the management of functional gastrointestinal symptoms that occur in irritable bowel syndrome (IBS). Numerous reviews have been published regarding the evidence for their restriction in the low FODMAP diet; however, few reviews discuss the implementation of the low FODMAP diet in practice. The aim of this review is to provide practical guidance on patient assessment and the implementation and monitoring of the low FODMAP diet. Broadly speaking, the low FODMAP diet consists of three stages: FODMAP restriction; FODMAP reintroduction; and FODMAP personalisation. These stages can be covered in at least two dietetic appointments. The first appointment focuses on confirmation of diagnosis, comprehensive symptom and dietary assessment, detailed description of FODMAPs and their association with symptom induction, followed by counselling regarding FODMAP restriction. Dietary counselling should be tailored to individual needs and appropriate resources provided. At the second appointment, symptoms and diet are re-assessed and, if restriction has successfully reduced IBS symptoms, education is provided on FODMAP reintroduction to identify foods triggering symptoms. Following this, the patient can follow FODMAP personalisation for which a less restrictive diet is consumed that excludes their personal FODMAP triggers and enables a more diverse dietary intake. This review provides evidence and practice guidance to assist in delivering high-quality clinical service in relation to the low FODMAP diet.

Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain.

BACKGROUND: Retrospective clinical studies suggest there is a risk for neurodevelopmental impairment following early childhood exposure to anaesthesia. In the developing animal brain, including those of non-human primates (NHPs), anaesthetics induce apoptotic cell death. We previously reported that a 5 h isoflurane (ISO) exposure in infant NHPs increases apoptosis 13-fold compared with control animals. However, the majority of paediatric surgeries requiring anaesthesia are of shorter durations. We examined whether 3 h ISO exposure similarly increases neuroapoptosis in the NHP developing brain. METHODS: Six-day-old NHP infants ( Macaca mulatta ) were exposed to 3 h of a surgical plane of ISO ( n =6) or to room air ( n =5). Following exposure, NHP brains were screened for neuronal and oligodendrocyte apoptosis using activated caspase-3 immunolabelling and unbiased stereology. RESULTS: ISO treatment increased apoptosis (neurones + oligodendrocyte) to greater than four times that in the control group [mean density of apoptotic profiles: 57 (SD 22) mm -3 vs 14 (SD 5.2) mm -3 , respectively]. Oligodendrocyte apoptosis was evenly distributed throughout the white matter whereas neuroapoptosis occurred primarily in the cortex (all regions), caudate, putamen and thalamus. CONCLUSIONS: A 3 h exposure to ISO is sufficient to induce widespread neurotoxicity in the developing primate brain. These results are relevant for clinical medicine, as many surgical and diagnostic procedures in children require anaesthesia durations similar to those modelled here. Further research is necessary to identify long-term neurobehavioural consequences of 3 h ISO exposure.

Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy.

Mutations in receptors, ion channels, and enzymes are frequently recognized by the cellular quality control system as misfolded and retained in the endoplasmic reticulum (ER) or otherwise misrouted. Retention results in loss of function at the normal site of biological activity and disease. Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action. Pharmacoperones of the gonadotropin releasing hormone receptor (GnRHR) have efficacy in cell culture systems, and their cellular and biochemical mechanisms of action are known. Here, we show the efficacy of a pharmacoperone drug in a small animal model, a knock-in mouse, expressing a mutant GnRHR. This recessive mutation (GnRHR E(90)K) causes hypogonadotropic hypogonadism (failed puberty associated with low or apulsatile luteinizing hormone) in both humans and in the mouse model described. We find that pulsatile pharmacoperone therapy restores E(90)K from ER retention to the plasma membrane, concurrently with responsiveness to the endogenous natural ligand, gonadotropin releasing hormone, and an agonist that is specific for the mutant. Spermatogenesis, proteins associated with steroid transport and steroidogenesis, and androgen levels were restored in mutant male mice following pharmacoperone therapy. These results show the efficacy of pharmacoperone therapy in vivo by using physiological, molecular, genetic, endocrine and biochemical markers and optimization of pulsatile administration. We expect that this newly appreciated approach of protein rescue will benefit other disorders sharing pathologies based on misrouting of misfolded protein mutants.

Enhancement of the pulmonary arteries and thoracic aorta: comparison of a biphasic contrast injection and fixed delay protocol with a monophasic injection and a timing bolus protocol.

The definitive diagnosis of pulmonary embolism, a significant cause of morbidity and mortality, relies on imaging. In this study, we compare the conventional computed tomography pulmonary angiogram (CTPA) protocol to a double-rule out CT angiogram (DRO CTA) protocol in terms of vascular enhancement, radiation dose, and contrast volume delivered. The CTPA protocol involves injection of a timing bolus for localization of the pulmonary artery, whereas the DRO CTA protocol involves a biphasic contrast. We analyzed 248 consecutive CTPA studies and 242 consecutive DRO CTA studies. Vessel enhancement using region of interest (ROI) measurements, radiation dose delivered, and total contrast volume administered was recorded. The enhancement of all vessels measured was statistically significantly higher with the biphasic DRO CTA protocol than the CTPA protocol. The difference in mean vascular enhancement for the two protocols was greatest in the descending aorta (DA, P < 0.001) and least in the main pulmonary artery (MPA, P = 0.001). The percent of studies with vascular enhancement ≥250 Hounsfield units (HU) was significantly greater in all vascular beds except the MPA when the DRO CTA protocol was used. Studies performed with the DRO CTA protocol led to less radiation exposure and used less contrast than those performed with the CTPA protocol (P < 0.001 for both). According to the final radiology report, 35.08 % of studies in the CTPA group and 22.31 % of studies in the DRO CTA group were considered indeterminate (P = 0.001). In conclusion, the biphasic DRO CTA protocol leads to statistically significantly higher opacification of all pulmonary arterial and aortic vessels studied, with no greater delivery of radiation or contrast, than the monophasic CTPA protocol.

Minimal aortic injury of the thoracic aorta: imaging appearances and outcome.

The aim of this study is to describe the frequency, computed tomographic angiography (CTA) imaging appearance, management, and outcome of patients who present with minimal thoracic aortic injury. This retrospective study was Institutional Review Board-approved. Eighty-one patients with blunt traumatic aortic injuries (BTAI) were identified between 2004 and 2008, comprising 23 patients with minimal aortic injury (MAI) (mean age, 43.2 years ±18.2 years; 12 males and 11 females) and 58 patients with non-minimal aortic injury (mean age, 42.6 years ±22.7 years). CTA imaging was reviewed for each patient to differentiate those with MAI from those with non-MAI BTAI. Inclusion criteria for MAI on CTA were: post-traumatic abnormality of the internal contour of the aorta wall projecting into the lumen, intimal flap, intraluminal filling defect, intramural hematoma, and no evidence of an abnormality to the external contour of the aorta. Relevant follow-up imaging for MAI patients was also reviewed for resolution, stability, or progression of the vascular injury. The electronic medical record of each patient was reviewed and mechanism of injury, injury severity score, associated injuries, type and date of management, outcome, and days from injury to last medical consultation. Minimal aortic injury represented 28.4 % of all BTAI over the study period. Mean injury severity score (37.1), age (43.2 years), and gender did not differ significantly between MAI and non-MAI types of BTAI. Most MAI occurred in the descending thoracic aorta (16/23, 69 %). Without operative or endovascular repair, there was no death or complication due to MAI. One death occurred secondary to MAI (4.4 %) in a patient who underwent endovascular repair and surgical bypass, compared with an overall mortality rate of 8.6 % in the non-MAI BTAI group (p = 0.508). The most common CT appearance of MAI was a rounded or triangular intra-luminal aortic filling detect (18/23 patients, 78 %). In a mean of 466 days of clinical follow-up, no complications were observed in survivors treated without endovascular repair or operation. Minimal aortic injury is identified by multi-detector row CT in more than a quarter of cases of BTAI and has a low mortality. Conservative management is associated with an excellent outcome.

Adaptations for marine habitat and the effect of Triassic and Jurassic predator pressure on development of decompression syndrome in ichthyosaurs.

Decompression syndrome (caisson disease or the "the bends") resulting in avascular necrosis has been documented in mosasaurs, sauropterygians, ichthyosaurs, and turtles from the Middle Jurassic to Late Cretaceous, but it was unclear that this disease occurred as far back as the Triassic. We have examined a large Triassic sample of ichthyosaurs and compared it with an equally large post-Triassic sample. Avascular necrosis was observed in over 15% of Late Middle Jurassic to Cretaceous ichthyosaurs with the highest occurrence (18%) in the Early Cretaceous, but was rare or absent in geologically older specimens. Triassic reptiles that dive were either physiologically protected, or rapid changes of their position in the water column rare and insignificant enough to prevent being recorded in the skeleton. Emergency surfacing due to a threat from an underwater predator may be the most important cause of avascular necrosis for air-breathing divers, with relative frequency of such events documented in the skeleton. Diving in the Triassic appears to have been a "leisurely" behavior until the evolution of large predators in the Late Jurassic that forced sudden depth alterations contributed to a higher occurrence of bends.

State of the art: technologies for computed tomography dose reduction.

The utilization of computed tomography (CT) in the emergency department has grown rapidly in the last decade, driven by strong evidence supporting its effectiveness in the rapid diagnosis of an increasing range of diseases. Concerns have been raised about potential cancer induction caused by the increased use of CT and the high radiation dose associated with some multidetector row CT examinations. Recent research into protocol design and new CT scanner technologies enable high-quality examinations to be performed with a significant reduction in radiation dose. These advances are discussed, with emphasis on their application to emergency radiology.

Uterine diverticulum.

BACKGROUND: Uterine diverticula complicating pregnancy rarely are reported and should be differentiated from sacculation of pregnancy and other pelvic masses. CASE: A primigravida presented for a routine second-trimester anatomical survey ultrasound examination at 22 weeks of gestation. She initially was thought to have a bicornuate, bicolic uterus with bulging membranes. However, on examination, one normal-appearing cervix was found, and no membranes were visible. Magnetic resonance imaging demonstrated a posterolateral uterine diverticulum. At 31 weeks of gestation, she had premature rupture of membranes and onset of labor. Delivery by cesarean was performed, and the presence of a uterine diverticulum was confirmed. CONCLUSION: Uterine diverticula are rare anomalies in the pregnant uterus and should be considered in the differential diagnosis of a fluid-filled pelvic mass. With close observation, successful pregnancy outcome can be achieved.

Avascular necrosis: occurrence in diving cretaceous mosasaurs.

A study of vertebrae of extinct giant marine lizards showed the presence of avascular necrosis in two of the three most common genera of these mosasaurs, Platecarpus and Tylosaurus. This bone disease was invariably present (involving 5 to 66% of vertebrae) in these genera, but absent in a third genus Clidastes. Differential occurrence of avascular necrosis may be related to decompression syndrome, suggesting different habitat and diving habits of the respective genera.

Teeth in ichthyornis (class: aves).

Both Hesperornis and Ichthyornis are toothed birds; they and Archaeopteryx share broad flattened teeth with highly expanded roots. The teeth of Ichthyornis have been reported to have been set in sockets as were those of Archaeopteryx, but new specimens of Ichthyornis show the teeth set in a groove as in Hesperornis. These new fossils are from an adult but not old bird; thus, the presence or absence of tooth sockets in birds may be dependent on age.

A cheetah-like cat in the north american pleistocene.

The discovery of abundant skeletal remains of Felis trumani from a late Pleistocene deposit in Wyoming shows that it was as highly modified for cursorial locomotion as the cheetah (Acinonyx). Several other Pleistocene felids that have been regarded as pumas seem to be related forms. The late Pleistocene fauna of the Big Horn Basin in Wyoming is dominated by cursorial taxa.

Nonavian feathers in a late Triassic archosaur.

Longisquama insignis was an unusual archosaur from the Late Triassic of central Asia. Along its dorsal axis Longisquama bore a series of paired integumentary appendages that resembled avian feathers in many details, especially in the anatomy of the basal region. The latter is sufficiently similar to the calamus of modern feathers that each probably represents the culmination of virtually identical morphogenetic processes. The exact relationship of Longisquama to birds is uncertain. Nevertheless, we interpret Longisquama's elongate integumentary appendages as nonavian feathers and suggest that they are probably homologous with avian feathers. If so, they antedate the feathers of Archaeopteryx, the first known bird from the Late Jurassic.

Multidetector computed tomography pulmonary angiography: does arm position affect pulmonary artery enhancement?

OBJECTIVE: To evaluate whether arm position affects pulmonary artery enhancement in computed tomographic pulmonary angiography (CTPA). METHODS: Study protocol had local ethics committee approval. Eighty-six patients who received 16 detector row CTPA for suspected pulmonary embolism were scanned with their contrast-injected arm resting at their side and compared with 94 patients who were scanned with both arms resting above their head. Two radiologists assessed pulmonary artery enhancement with a region-of-interest measurement of the main pulmonary artery density, scored the degree of beam-hardening artifact arising from the superior vena cava (SVC) and from the dependent arm that crossed the pulmonary arteries (1 = no artifact, 5 = artery obscured), and measured the degree of central venous compression of the injected veins at the thoracic inlet. A 2-tailed t test was performed to compare pulmonary artery density and central venous compression. RESULTS: There was no difference in pulmonary artery enhancement between the 2 arm positions. Mean density of contrast in the main pulmonary artery was 329 Hounsfield units (HU) (95% confidence interval (CI), 310-350) in the arm-down group, compared with 325 HU (95% CI, 306-346) in the arm-up group (P = 0.65). Greater compression of the central veins occurred in the arm-up group (48.5%; 95% CI, 42.3%-54.8%) than in the arm-down group (22.3%; 95% CI, 16.8%-27.8%) (P < 0.05). There was also more beam hardening arising from contrast in the SVC in the arm-up group (P < 0.0001). CONCLUSIONS: Arm position does not affect pulmonary arterial enhancement during CTPA. There was greater central venous compression and more beam-hardening artifact arising from the SVC when the arm was held above the head.

Computed tomographic and magnetic resonance features of gynecologic abnormalities in women presenting with acute or chronic abdominal pain.

Advances in technology and improved availability have led to increased use of computed tomography (CT) and magnetic resonance imaging (MRI) to evaluate women presenting to the emergency department or to their primary care provider with abdominal and/or pelvic pain. Computed tomographic examinations are often performed to evaluate the presence of appendicitis or renal stone disease. However, gynecologic abnormalities are frequently identified on these examinations. Although ultrasound remains the primary modality by which complaints specific to the pelvis are evaluated, in many instances, CT and MRI imaging occurs before sonographic evaluation.Historically, because of cost, radiation exposure, and relative ease of use, ultrasound examinations have preceded all other imaging modalities when evaluating pelvic disorders. However, as CT and MRI technology have improved, their use in diagnosing causes of pelvic pain has become equal to that of ultrasound. In some cases, primarily because of historic comfort with sonographic evaluation, gynecologic abnormalities originally diagnosed on CT or MRI may be immediately and unnecessarily reevaluated by ultrasound. For a woman in her reproductive years, the most common adnexal masses are physiological cysts, endometriomas, and cystic teratomas. Although lesions are often asymptomatic and incidentally detected, they can present with pain, and they increase the risk of ovarian torsion. Common causes of chronic pelvic pain in this population include leiomyomata and adenomyosis. In postmenopausal women, ovarian carcinoma, which often does not present clinically until a late stage, has to be included in the differential diagnosis of adnexal masses. If a gynecologic pathology is discovered on CT or MRI, an immediate follow-up ultrasound need not be pursued if the lesion can be characterized as benign, needing immediate surgical intervention, or a variant of normal anatomy. If, on the other hand, findings demonstrate a mass that either is uncharacteristic of a benign lesion, has an indeterminate risk for malignancy, or demonstrates suspicious characteristics for malignancy (such as enhancing mural nodules), further evaluation by serial ultrasound, biochemical marker, and/or CT or MRI is warranted. The purpose of this review is to present a series of commonly encountered gynecologic abnormalities with either CT or MR to make radiologists more familiar with gynecologic pathology on CT and MRI.

Permanent rescue of a non-Mendelian mutation of Paramecium by microinjection of specific DNA sequences.

The mutant Paramecium tetraurelia cell line d48 is unable to express the serotype A protein on its surface. Although the A gene is intact in the micronuclei of d48, the A gene copies in the macronucleus contain a large deletion eliminating virtually the entire coding sequence. Previous studies showed that microinjection of a plasmid containing the entire A gene into the macronucleus of d48 permanently restored A expression after autogamy. Together with other data, this result suggests that in wild type cells the A gene in the old macronucleus ensures the presence of a cytoplasmic factor that prevents A gene deletions at autogamy. In d48, where there are few, if any copies of the intact A gene in the old macronucleus, deletions occur during macronuclear formation. To elucidate the specific molecular mechanisms involved in this unusual phenomenon, we attempted to define the region(s) of the A gene necessary for rescuing d48. We show that microinjection of a 4.5-kb internal A gene fragment is sufficient for proper processing at autogamy and leads to permanent rescue of d48; i.e., the rescued strain is indistinguishable from wild type. Thus, rescue of d48 does not require upstream transcriptional control sequences, intact A mRNA or A serotype protein. We also show that various fragments of the A gene have the ability to rescue d48 to different extents, some being more efficient than others. We find no evidence to suggest that the A gene gives rise to a small stable RNA that might act as or encode a cytoplasmic factor. Molecular mechanisms that may be involved in the rescue of d48 are discussed.

(E)-3-[6-[[(2,6-dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid: a high-affinity leukotriene B4 receptor antagonist with oral antiinflammatory activity.

An extensive structure-activity study based around the high-affinity leukotriene B4 (LTB4) receptor antagonist SB 201146 (1) led to the identification of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid (3). This compound displays high affinity for the human neutrophil LTB4 receptor (Ki = 0.78 nM), blocks LTB4-induced Ca2+ mobilization with an IC50 of 6.6 +/- 1.5 nM, and demonstrates potent oral and topical antiinflammatory activity in a murine model of dermal inflammation.

(E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]-methyl]thio]methyl]benzoic acid and related compounds: high affinity leukotriene B4 receptor antagonists.

(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocytes with a Ki of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.

In vitro and in vivo characterization of NK3 receptors in the rabbit eye by use of selective non-peptide NK3 receptor antagonists.

1. Inhibition of NK3 receptor agonist-induced contraction in the rabbit isolated iris sphincter muscle was used to assess the in vitro functional activity of three 2-phenyl-4-quinolinecarboxamides, members of a novel class of potent and selective non-peptide NK3 receptor antagonists. In addition, an in vivo correlate of this in vitro response, namely NK3 receptor agonist-induced miosis in conscious rabbits, was characterized with some of these antagonists. 2. In vitro senktide (succinyl-[Asp9,MePhe8]-substance P (6-11) and [MePhe7]-neurokinin B ([MePhe7]-NKB) were potent contractile agents in the rabbit iris sphincter muscle but exhibited quite different profiles. Senktide produced monophasic log concentration-effect curves with a mean pD2=9.03+/-0.06 and mean nH=1.2+/-0.02 (n=14). In contrast, [MePhe7]-NKB produced shallow log concentration-effect curves which often appeared biphasic (nH=0.54+/-0.04, n=8), preventing the accurate determination of pD2 values. 3. The contractile responses to the NK3 receptor agonist senktide were antagonized in a surmountable and concentration-dependent manner by SB 223412 ((-)-(S)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-ca rboxamide; 3-30 nM, pA2=8.4, slope=1.8+/-0.3, n=4). SB 222200 ((-)-(S)-N-(alpha-ethylbenzyl)-3-methyl-2-phenylquinoline-4-car box amide; 30-300 nM, pA2=7.9, slope=1.4+/-0.06, n=4) and SB 218795 ((-)-(R)-N-(alpha-methoxycarbonylbenzyl)-2-phenylquinoline-4-carboxamide; 0.3 and 3 microM apparent pKB=7.4+/-0.06, n=6). 4. Contractile responses to the NK3 receptor agonist [MePhe7]-NKB in the rabbit iris sphincter muscle were unaffected by SB 218795 (0.3 and 3 microM, n=8). In contrast, SB 223412 (30 and 300 microM n=4) and SB 222200 (0.3 and 3 microM, n=4) inhibited responses to low concentrations (< or = 1 nM), to a greater extent than higher concentrations (> 1 nM) of [MePhe7]-NKB. Furthermore, log concentration-effect curves to [MePhe7]-NKB became steeper and monophasic in the presence of each antagonist. 5. SB 218795 (3 microM, n=4) had no effect on contractions induced by transmural nerve stimulation (2 Hz) or substance P, exemplifying the selectivity of this class of antagonist for functional NK3 receptors over NK1 receptors in the rabbit. 6. In vivo, senktide (1, 10 and 25 microg i.v., i.e. 1.2, 11.9 and 29.7 nmol, respectively) induced concentration-dependent bilateral miosis in conscious rabbits (maximum pupillary constriction=4.25+/-0.25 mm; basal pupillary diameter 7.75+/-0.48 mm; n=4). The onset of miosis was within 2-5 min of application of senktide and responses lasted up to 30 min. Responses to two i.v. administrations of 25 microg senktide given 30 min apart revealed no evidence of tachyphylaxis. Topical administration of atropine (1%) to the eye enhanced pupillary responses to 25 microg senktide. This was probably due to the mydriatic effect of atropine since it significantly increased baseline pupillary diameter from 7.0+/-0.4 mm to 9.0+/-0.7 mm (n=4), thereby increasing the maximum capacity for miosis. Senktide-induced miosis was inhibited by SB 222200 (1 and 2 mg kg[-1], i.v., i.e. 2.63 and 5.26 micromol kg[-1]; maximum inhibition 100%; n=3-4), SB 223412 (0.5 and 1 mg kg[-1], i.v., i.e. 1.31 and 2.61 micromol kg[-1]; maximum inhibition 100%; n=3), SB 218795 (0.5 and 1 mg kg[-1] i.v., i.e. 1.26 and 2.52 micromol kg-1; maximum inhibition 78%; n=3), and the structurally distinct NK3 receptor antagonist SR 142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylepipiperidin-4-yl)-N-methylacetamide; 1.5mg kg-1, i.v., i.e. 2.47micromol kg-1, maximum inhibition 92%; n=3). 7. Topical administration of senktide (25microg; 29.7nmol) to the eye induced unilateral miosis in the treated eye only. At this dose there was no significant difference (P<0.05) between pupillary constriction obtained by topical or i.v. senktide, and topically administered atropine had no significant effect on responses to topical senktide (n=4). 8. [MePhe7]-NKB (125, 250 and 500microg, i.v., i.e. 98.31, 196.62 and 393.24nmol, respectively) also induced bilateral miosis in conscious rabbits (maximum pupillary constriction=4.13+/-0.30mm; n=4), but in contrast to in vitro studies this agonist was approximately 100 fold less potent than senktide. [MePhe7]-NKB-induced miosis was inhibited by SB 222200 (5mg kg-1, i.v., i.e. 13.14micromol kg-1; maximum inhibition 69%; n=3). 9. In summary, SB 223412, SB 222200 and SB 218795 are potent and selective antagonists of NK3 receptor-mediated contraction in the rabbit isolated iris sphincter muscle. In addition, NK3 receptor agonist-induced miosis in conscious rabbits is a good in vivo correlate of the in vitro rabbit iris sphincter muscle preparation and appears to be a useful model for characterizing the pharmacodynamic profile and efficacy of structurally distinct NK3 receptor antagonists, such as SB 222200, SB 223412, SB 218795 and SR 142801.

The role of reactive oxygen and nitrogen species in airway epithelial gene expression.

The body first encounters deleterious inhaled substances, such as allergens, industrial particles, pollutants, and infectious agents, at the airway epithelium. When this occurs, the epithelium and its resident inflammatory cells respond defensively by increasing production of cytokines, mucus, and reactive oxygen and nitrogen species (ROS/RNS). As inflammation in the airway increases, additional infiltrating cells increase the level of these products. Recent interest has focused on ROS/RNS as potential modulators of the expression of inflammation-associated genes important to the pathogenesis of various respiratory diseases. ROS/RNS appear to play a variety of roles that lead to changes in expression of genes such as interleukin-6 and intercellular adhesion molecule 1. By controlling this regulation, the reactive species can serve as exogenous stimuli, as intercellular signaling molecules, and as modulators of the redox state in epithelial cells. Unraveling the molecular mechanisms affected by ROS/RNS acting in these capacities should aid in the understanding of how stimulated defense mechanisms within the airway can lead to disease.

The role of reactive oxygen and nitrogen species in the response of airway epithelium to particulates.

Epidemiologic and occupational studies indicate adverse health effects due to inhalation of particulate air pollutants, but precise biologic mechanisms responsible have yet to be fully established. The tracheobronchial epithelium forms the body's first physiologic barrier to such airborne pollutants, where ciliary movement functions to remove the offending substances caught in the overlying mucus layer. Resident and infiltrating phagocytic cells also function in this removal process. In this paper, we examine the role of reactive oxygen and nitrogen species (ROS/RNS) in the response of airway epithelium to particulates. Some particulates themselves can generate ROS, as can the epithelial cells, in response to appropriate stimulation. In addition, resident macrophages in the airways and the alveolar spaces can release ROS/RNS after phagocytosis of inhaled particles. These macrophages also release large amounts of tumor necrosis factor alpha (TNF-alpha), a cytokine that can generate responses within the airway epithelium dependent upon intracellular generation of ROS/RNS. As a result, signal transduction pathways are set in motion that may contribute to inflammation and other pathobiology in the airway. Such effects include increased expression of intercellular adhesion molecule 1, interleukin-6, cytosolic and inducible nitric oxide synthase, manganese superoxide dismutase, cytosolic phospholipase A2, and hypersecretion of mucus. Ultimately, ROS/RNS may play a role in the global response of the airway epithelium to particulate pollutants via activation of kinases and transcription factors common to many response genes. Thus, defense mechanisms involved in responding to offending particulates may result in a complex cascade of events that can contribute to airway pathology.