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.

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.

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.

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.

Gossypiboma: tales of lost sponges and lessons learned.

OBJECTIVE: To review the details surrounding cases of patients found to have retained laparotomy sponges after surgical procedures and share policy changes that have led to process improvements at one academic medical center. DESIGN: Retrospective medical record review as part of a quality improvement process. SETTING: Single academic medical center. PATIENTS: Patients identified through the quality improvement process as having had retained foreign bodies after surgery. CONCLUSIONS: Sentinel events such as retained foreign bodies after surgery require intensive review to identify systems problems. This can lead to protocol changes to improve the process. After a series of incidents, protocol changes at our institution have led to no further incidents of retained foreign bodies.

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.

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.

High-resolution CT findings of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

PURPOSE: To describe the high-resolution computed tomography (CT) findings occurring in bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) and to determine the relationship between pulmonary function tests (PFTs) and air trapping detected on expiratory CT. MATERIALS AND METHODS: The high-resolution CT scans of 33 patients who underwent HSCT and subsequently developed BOS were evaluated by 2 observers blinded to PFT results. Scans were ranked for degree of air trapping and scored for findings of bronchial wall thickening, bronchiectasis, and centrilobular opacities. Air-trapping rank was correlated with the degree of airflow obstruction as determined by PFTs. RESULTS: The ranking of air trapping correlated significantly with 1-second forced expiratory volume (P=0.001), 1-second forced expiratory volume/forced vital capacity (P<0.001), residual volume (P<0.001), carbon monoxide diffusion capacity (P=0.023), but not forced vital capacity (P=0.14) or total lung capacity (P=0.07). Bronchial wall thickening occurred in 73.0%, predominantly in lower lobes (P=0.007), but was mild. Bronchiectasis occurred in 42.4% and centrilobular opacities in 39.4%. CONCLUSIONS: In BOS developing after HSCT, air trapping is the principal finding on CT, and its severity correlates with PFTs. Bronchial wall thickening is common, but almost always mild; bronchiectasis and centrilobular opacities occur in less than half of cases and are also mild.

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.

Extinction may not be forever.

Here we review the phenomenon of ecomorph evolution and the hypothesis of iterative climatic cycles. Although a widely known phenomenon, convergent evolution has been underappreciated in both its scope and commonality. The power of natural selection to override genealogy to create similar morphologies (even among distantly related organisms) supports classical Darwinian evolution. That this occurs repeatedly in stratigraphically closely spaced intervals is one of the most striking features of Earth history. Periodic extinctions followed by re-evolution of adaptive types (ecomorphs) are not isolated occurrences but are embedded within complex ecological systems that evolve, become extinct, and repeat themselves in temporal synchrony. These complexes of radiation and extinction bundle the biostratigraphic record and provide the basis for a global stratigraphy. At this scale, climatic change is the only mechanism adequate to explain the observed record of repeating faunas and floras. Understanding of the underlying causes may lead to predictive theories of global biostratigraphy, evolutionary processes, and climatic change.

Epidemiologic study of tumors in dinosaurs.

Occasional reports in isolated fragments of dinosaur bones have suggested that tumors might represent a population phenomenon. Previous study of humans has demonstrated that vertebral radiology is a powerful diagnostic tool for population screening. The epidemiology of tumors in dinosaurs was here investigated by fluoroscopically screening dinosaur vertebrae for evidence of tumors. Computerized tomography (CT) and cross-sections were obtained where appropriate. Among more than 10,000 specimens x-rayed, tumors were only found in Cretaceous hadrosaurs (duck-billed dinosaurs). These included hemangiomas and metastatic cancer (previously identified in dinosaurs), desmoplastic fibroma, and osteoblastoma. The epidemiology of tumors in dinosaurs seems to reflect a familial pattern. A genetic propensity or environmental mutagens are suspected.

Frequency of pathology in a large natural sample from Natural Trap Cave with special remarks on erosive disease in the Pleistocene.

Population data are presented for erosive arthritis, osteoarthritis, diffuse idiopathic skeletal hyperostosis (DISH), joint eburnation and dental injury in a fauna from Natural Trap Cave, Wyoming, represented by over thirty thousand bones from twenty-four different species. Erosive arthritis is limited to the bovids, Bison, Ovis and Bootherium. Erosive arthritis is also present in bison from the late Pleistocene Twelve Mile Creek site in Kansas and from an early Holocene site in Wisconsin. The restriction of the known Pleistocene occurrences to bovids indicate the presence of a pathogen that predisposes bovids to erosive arthritis. The pathogen was identified as Mvcobacterium tuberculosis. Osteoarthritis and DISH are rare in the Natural Trap Cave, although Bison shows a relatively high occurrence of the former. Tooth breakage due to errors in bone manipulation was a problem for carnivores and one lion, Pantera atrox, was apparently reduced by joint disease to a scavenging lifestyle.

Extinction and re-evolution of similar adaptive types (ecomorphs) in Cenozoic North American ungulates and carnivores reflect van der Hammen's cycles.

Numerous patterns in periodicity (e.g., climate, extinction, and sedimentary cycles) and evolutionary change (e.g., chronofaunas and coordinated stasis) have been described based on aspects of the geologic record. Recently, convergent occurrences of faunal types or "repeating faunas" have received attention, but a highly specific, iterative pattern was first reported over 40 years ago. In the late 1950s, van der Hammen described climatic/floral cycles on the order of six million years based on a succession of A, B, and C pollen community types in South America. These A-B-C cycles are also seen in the replacement pattern of particular carnivore and ungulate adaptive types in Cenozoic North America as reported by Martin in the 1980s. For example, in the last 36 million years, there were four iterations of a sabertooth cat ecomorph independently evolving, dominating the niche through an A-B-C cycle, and then going extinct. Here we show further support for the existence of these cycles in the dominance turnover in hippo and dog ecomorphs in the North American Cenozoic. Shared patterns of extinction and re-evolution of adaptive types among plants and mammals across two continents suggest a global mechanism, which appears to be climatic change. Iterative climatic cycles of various scales may form a predictive framework for understanding fundamental patterns in the geologic record, such as radiations, extinction, rates of change, convergence, and sedimentary cycles.

A new fossil mustelid from the Miocene of South Dakota, USA.

A skull from the Barstovian of South Dakota has typical leptarctine characteristics, including robust zygomatic arches, double sagittal crests, grooves on the lingual side of the lower canines, and bony projections from the tympanic bullae. The robust mandibles and expanded masseteric fossa of this specimen indicate that it had large jaw muscles. Dental morphology and other characters lead us to agree with earlier suggestions that Hypsoparia is a valid genus. The morphology of Hypsoparia suggests that leptarctines were more herbivorous than most other Carnivora. Mustelids vary greatly in size and include 67 extant species in 25 genera. These species occupy many habitats, including fresh and salt water, and all land areas of the world except the West Indies, Madagascar, Sulawesi, Antarctica, and most oceanic islands (Nowak 1999). Qiu and Schmidt-Kittler (1982) considered Leptarctinae to be a subfamily of mustelids including Craterogale (North America, Middle Miocene), Trocharion (Europe, Middle Miocene), Hypsoparia (North America, Upper Miocene), and Leptarctus (North America and Asia, Lower to Upper Miocene). Leptarctus ranges from basal Hemingfordian strata to the Early Hemphillian (Lim 1999). The characters diagnosing Leptarctus as a mustelid include absence of M2, absence of a notch between the paracone and the metacone of the upper carnassial, and a reduced dentition with loss of P1 and p1. Among mustelids, Leptarctus also has many unique characters, including prominent double sagittal crests, a well-developed hypocone on P4, grooved lower canines, heavy zygomatic arches, and bony projections on the tympanic bullae (Lim 1999). Dorr (1954) erected a new genus and species of leptarctine mustelid from the Late Miocene of Montana, USA: Hypsoparia bozemanensis. Qiu and Schmidt-Kittler (1982) confirmed it as a taxon separate from Leptarctus. However, McKenna and Bell (1997) and Baskin (1998) synonymized H. bozemanensis with Leptarctus primus. The new specimen from the Miocene of South Dakota, USA, provides evidence that Hypsoparia is a separate genus from Leptarctus. We can describe this animal as follows: Systematic paleontology: class, Mammalia; order, Carnivora; family, Mustelidae (Fischer von Waldheim 1817); subfamily, Leptarctinae (Gazin 1936); genus Hypsoparia (Dorr 1954). Emended diagnosis: the muzzle short, deep, and wide compared with that of Leptarctus; small, round infraorbital foramen; relatively greater height of zygomatic arch; upper canine with anterior wear; P2 and P3 unicuspid with complete cingula; P4 and M1 longer than wide; labial side longer than lingual side on P4; anterior margin of M1 curving inward; mandibles larger and more robust than in L. primus; mandible deep with two mental foramina located below p2 and p3; masseteric fossa enlarged; m2 longer than wide; m1 with a broadly basined talonid; p3 and p4 with prominent cingula.

Personal computer-based PACS display system: comparison with a dedicated PACS workstation for review of computed radiographic images in rheumatoid arthritis.

RATIONALE AND OBJECTIVES: The authors' purpose was to investigate the reliability of a personal computer (PC)-based display system compared with a workstation in the evaluation of rheumatoid arthritis on computed radiographs of the hands. MATERIALS AND METHODS: Two radiologists on two occasions independently scored randomized computed radiographs of individual joints of the hands from 23 patients with rheumatoid arthritis and 14 control subjects. Each joint was scored from 0 (definitely normal) to 30 (severe disease) for each of four variables: soft-tissue swelling, osteopenia, erosions, and joint space narrowing. The observations were replicated on a picture archiving and communication system workstation and a PC. Intraobserver and interobserver reliability were calculated, as was the difference in scores between the two systems. The null hypothesis was that there was no difference between the workstation and the PC. RESULTS: The intraobserver reliability for normal versus abnormal joints was 73% with the workstation and 79% with the PC. The intraobserver reliability for workstation versus PC was 83%. There was moderate interreader reliability for both platforms (average kappa statistic, 0.46 [workstation] vs 0.45 [PC]). Small differences in scores between platforms are probably due mostly to the ordinal nature of the scoring system. CONCLUSION: For evaluating computed radiographs of the hands in early rheumatoid arthritis, a PC-based system provides results similar to those obtained with a workstation, at considerably reduced cost.

Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha.

Remodeling of the airways, as occurs in asthmatic patients, is associated with the continual presence of inflammatory mediators and Th2 cytokines, especially interleukin (IL)-13, during cycles of epithelial injury and repair. In this study, we examined the effect of IL-13 on well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air-liquid interface culture. IL-13 induced proliferation of NHBE cells after 24 h exposure, as reflected by [(3)H]thymidine uptake and cell counts. The effects of IL-13 were mediated through the epidermal growth factor receptor (EGFR), as proliferation was attenuated by AG1478, an EGFR tyrosine kinase inhibitor. Proliferation appeared to be mediated by transforming growth factor (TGF)-alpha, a potent ligand for EGFR, which was released rapidly from NHBE cells in response to IL-13. Neutralizing antibody to TGF-alpha, but not antibodies against other potentially important growth factors (EGF, heparin binding epidermal growth factor-like growth factor [HB-EGF], platelet-derived growth factor [PDGF]), inhibited the mitogenic response to IL-13. This study provides the first experimental evidence that IL-13 can initiate a proliferative response of human airway epithelium in the absence of inflammatory cells or other cell types. The results are consistent with a mechanism whereby IL-13 induces release of TGF-alpha from the epithelial cells, which in turn binds via an autocrine/paracrine-type action to the EGFR, initiating proliferation. IL-13-induced airway remodeling in vivo may involve this epithelium-driven response.

Enhanced expression of mucin genes in a guinea pig model of allergic asthma.

The ovalbumin (OVA)-sensitized guinea pig is often used as an animal model of asthma and airway hyperreactivity. A characteristic lesion of asthma is excessive production of mucin in the airways. Mechanistic studies of this lesion in guinea pigs have been limited due to lack of mucin gene probes for this species. The aim of the present study was to clone the cDNAs encoding two major airway mucins (Muc2 and Muc5ac) from the guinea pig, and investigate mucin gene expression in lungs of sensitized animals in response to antigen challenge. We isolated and sequenced two cDNA fragments coding for the sequences located within the carboxyl-terminal cysteine-rich region of guinea pig Muc2 and Muc5ac mucins. Comparison of cloned cDNAs with those from other species revealed high degrees of sequence identity and conservation of all cysteine residues in deduced primary sequences. Based on the resultant sequence information, we also designed oligonucleotide primers for specific detection of guinea-pig Muc2 and Muc5ac steady-state mRNA levels via reverse transcriptase/ polymerase chain reaction (RT-PCR). Levels of both Muc2 and Muc5ac mRNA in lungs of OVA-sensitized guinea pigs increased significantly by 30 min after an acute exposure to 0.3% OVA. In addition, levels of eotaxin mRNA also increased in these tissues, but the increases were not significant until 2 h after challenge. Correspondingly, the number of eosinophils in bronchoalveolar lavage fluid did not increase until 4 h postchallenge. Results of these studies suggest that the OVA-sensitized guinea pig responds to allergic challenge with enhanced expression of genes (e.g., eotaxin, Muc2, and Muc5ac) that likely play a role in increased airway inflammation and mucin overproduction, and enhanced mucin gene expression appears to occur before eosinophil infiltration.