Increased risk of eosinophilic esophagitis with poor environmental quality as measured by the Environmental Quality Index.

Geographic differences in eosinophilic esophagitis (EoE) prevalence suggest the possibility that environmental exposures contribute to EoE pathogenesis. We aimed to examine the association between environmental quality and risk of EoE, using the Environmental Quality Index (EQI), which provides quantification of environmental quality in five domains: air, land, water, built, and sociodemographic for all counties in the United States. To do this, we performed a case-control study in a large pathology database. EoE cases were defined by ≥15 eosinophils per high-power field with other pathologic diagnoses excluded; controls did not have EoE. The pathology data were geocoded and linked with the EQI by county of residence. Logistic regression was used to estimate odds ratio (OR and 95% confidence interval [CI]) of EoE with overall EQI and for each domain, after adjusting for sex, age, and proportion minority race or ethnicity at the county level (higher EQI score indicates worse environmental quality). Of 29,802 EoE cases and 593,329 controls analyzed, odds of EoE were highest in the worst quintile of EQI (OR 1.25; 95% CI: 1.04-1.50), which was largely explained by poor scores in the water domain (OR: 1.33; 1.17-1.50). Conversely, odds of EoE were reduced with higher scores in the air domain (OR: 0.87, 0.74-1.03) and land domain (OR 0.87; 0.76-0.99). Poor EQI, mostly reflected by poor water quality, was associated with increased odds of EoE, while poor air and land quality were inversely associated with EoE. Additional work to identify specific water pollutants that may have an etiologic role in EoE may be warranted.

A visual analogue scale and a Likert scale are simple and responsive tools for assessing dysphagia in eosinophilic oesophagitis.

BACKGROUND: While symptom scores have been developed to evaluate dysphagia in eosinophilic oesophagitis (EoE), their complexity may limit clinical use. AIM: To evaluate a visual analogue scale (VAS) and a 10-point Likert scale (LS) for assessment of dysphagia severity before and after EoE treatment. METHODS: We conducted a prospective cohort study enrolling consecutive adults undergoing out-patient endoscopy. Incident cases of EoE were diagnosed per consensus guidelines. At diagnosis and after 8 weeks of treatment, symptoms were measured using the VAS, LS and the Mayo Dysphagia Questionnaire (MDQ). The percentage change in scores before and after treatment were compared overall, in treatment responders (<15 eos/hpf) and non-responders, and in patients without baseline dilation. RESULTS: In 51 EoE cases, the median VAS decreased from 3.6 at baseline to 1.4 post-treatment (71% decrease), the LS decreased from 6 to 2 (67%) and the MDQ decreased from 20 to 10 (49%). The VAS correlated with both the LS (R = 0.77; P < 0.0001) and MDQ (R = 0.46, P = 0.001). After stratification by histological response, the LS decreased 70% in responders vs. 13% in non-responders (P = 0.02). In patients who did not receive baseline dilation, both the VAS and LS decreased significantly more in the histological responders. CONCLUSIONS: Both the VAS and LS were responsive to successful treatment as measured by histologic improvement. Because the VAS and LS are simple to administer and are responsive to treatment, they can provide an efficient and objective method for assessing dysphagia severity in EoE in clinical practice.

Comparative accuracy of different members of the dental team in detecting malignant and non-malignant oral lesions.

OBJECTIVES: Role substitution between primary care dentists (PCDs) and dental hygienists and therapists is increasingly being used in a number of different countries. Opponents to this development argue that it is unsafe and frequently cite the potential for missing oral malignancy as an inherent danger. The aim of the present study was to determine the comparative diagnostic test accuracy of different members of the dental team when differentiating between standardised photographs of mouth cancer, potentially malignant disorders and benign oral lesions. METHODS: A total of 192 dental professionals, comprising 96 PCDs, 63 DH-Ts, nine hospital-based dental staff and 24 other dental professionals were sampled purposively. Following orientation, participants were asked to score 90 clinical photographs that depicted cases of oral squamous cell carcinoma, potentially malignant disorders and non-malignant lesions of the oral mucosa. For each photograph participants were asked to determine whether they felt the lesion was representative of carcinoma, a potentially malignant disorder (test positive), or whether the lesion was benign (test negative). They were also asked to record their confidence in their decision on a 0-10 scale. Judgement decisions were compared against the known histopathological diagnosis of each lesion. Sensitivity and specificity were calculated for each participant and clinical group. RESULTS: The diagnostic test accuracy of PCDs and DH-Ts was similar. There was a median sensitivity of 81% Interquartile range (IQR) 19%) for PCDs and 77% (IQR 19%) for DH-T, with specificity of 73% (IQR 16%) and 69% (IQR 17%) respectively. DH-Ts missed fewer frank malignant lesions compared to PCDs. CONCLUSION: The performance of PCDs and DH-Ts when differentiating between mouth cancer, potentially malignant disorders and benign lesions is comparable. DH-Ts should be regarded as being as competent as PCDs as front-line healthcare workers with regard to detection of mouth cancer. However, considerable heterogeneity in detection was found within both clinical groups, suggesting that training remains paramount.

Theoretical spectroscopic investigations of HNS(q) and HSN(q) (q = 0, +1, -1) in the gas phase.

We performed accurate ab initio investigations of the geometric parameters and the vibrational structure of neutral HNS/HSN triatomics and their singly charged anions and cations. We used standard and explicitly correlated coupled cluster approaches in connection with large basis sets. At the highest levels of description, we show that results nicely approach those obtained at the complete basis set limit. Moreover, we generated the three-dimensional potential energy surfaces (3D PESs) for these molecular entities at the coupled cluster level with singles and doubles and a perturbative treatment of triple excitations, along with a basis set of augmented quintuple-zeta quality (aug-cc-pV5Z). A full set of spectroscopic constants are deduced from these potentials by applying perturbation theory. In addition, these 3D PESs are incorporated into variational treatment of the nuclear motions. The pattern of the lowest vibrational levels and corresponding wavefunctions, up to around 4000 cm(-1) above the corresponding potential energy minimum, is presented for the first time.

Ab initio structural and spectroscopic study of HPS(x) and HSP(x) (x = 0,+1,-1) in the gas phase.

Accurate ab initio computations of structural and spectroscopic parameters for the HPS/HSP molecules and corresponding cations and anions have been performed. For the electronic structure computations, standard and explicitly correlated coupled cluster techniques in conjunction with large basis sets have been adopted. In particular, we present equilibrium geometries, rotational constants, harmonic vibrational frequencies, adiabatic ionization energies, electron affinities, and, for the neutral species, singlet-triplet relative energies. Besides, the full-dimensional potential energy surfaces (PESs) for HPS(x) and HSP(x) (x = -1,0,1) systems have been generated at the standard coupled cluster level with a basis set of augmented quintuple-zeta quality. By applying perturbation theory to the calculated PESs, an extended set of spectroscopic constants, including τ, first-order centrifugal distortion and anharmonic vibrational constants has been obtained. In addition, the potentials have been used in a variational approach to deduce the whole pattern of vibrational levels up to 4000 cm(-1) above the minima of the corresponding PESs.

Computational study of the linear proton bound ion-molecule complexes of HCNH+ with HCN and HNC.

This work reports the results of a high level ab initio study of the linear proton bound ion-molecule complex of HCNH(+) with HCN and its isomer HNC. The energetics, equilibrium geometries, and predicted equilibrium rotational constants of three strongly interacting ion-molecule complexes are reported from calculations performed at the coupled-cluster calculations including singles, doubles, and perturbative triple excitations (CCSD(T))∕aug-cc-pVnZ (n = 2-5) level of theory. Harmonic vibrational frequencies from calculations performed at the CCSD(T)∕aug-cc-pVnZ (n = 2-4) level of theory are presented. Additional calculations are performed at the CCSD(T)-F12b∕VnZ-F12 level of theory, and the associated energetics, equilibrium geometries, and equilibrium spectroscopic properties are reported. Anharmonicity is treated with the vibrational configuration interaction method, and the predicted anharmonic vibrational frequencies are reported. The results of these calculations show that of the four possible linear interactions of HCNH(+) with HCN and HNC, there are three strongly interacting proton bound complexes. Further, the study presents results that the fourth possible interaction provides the basis for a novel HNC to HCN isomerization pathway in the interstellar medium.

Structural and spectroscopic study of the linear proton-bound complex of PN with HNP+.

This work reports the results of high level ab initio calculations of the PN-HNP(+) complex and the corresponding hydrogen migration transition state. The geometries, rotational constants, harmonic vibrational frequencies, and energetics of each species involved in the complex are reported. A reduced dimensional 2D and 4D potential energy surface is constructed and used to obtain 2D and 4D vibrational states. The results of this study show excellent correlation to available experimental data for PN. The presented results can facilitate both laboratory and interstellar observations of this novel and strongly interacting linear proton-bound complex.

Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection.

The absence or reduction of CFTR function causes CF and results in a pulmonary milieu characterized by bacterial colonization and unresolved inflammation. The ineffectiveness at controlling infection by species such as Pseudomonas aeruginosa suggests defects in innate immunity. Macrophages, neutrophils, and DCs have all been shown to express CFTR mRNA but at low levels, raising the question of whether CFTR has a functional role in these cells. Bone marrow transplants between CF and non-CF mice suggest that these cells are inherently different; we confirm this observation using conditional inactivation of Cftr in myeloid-derived cells. Mice lacking Cftr in myeloid cells overtly appear indistinguishable from non-CF mice until challenged with bacteria instilled into the lungs and airways, at which point, they display survival and inflammatory profiles intermediate in severity as compared with CF mice. These studies demonstrate that Cftr is involved directly in myeloid cell function and imply that these cells contribute to the pathophysiological phenotype of the CF lung.

Structural and spectroscopic study of the van der Waals complex of CO with HCO+ and the isoelectronic complex of CS with HCS+.

This work reports the results of high level ab initio calculations of the OC-HCO(+) complex and the SC-HCS(+) complex and their hydrogen migration transition states. Geometry optimizations are performed at the CCSD(T)/aug-cc-pV5Z level of theory. Subsequent frequency calculations are carried out at the CCSD(T)/aug-cc-pVQZ level of theory. Additional geometry optimizations and harmonic frequency calculations for all the species involved in this study have been done with the explicitly correlated CCSD(T)-F12 method with the aug-cc-pVTZ and VTZ-F12 basis set. The geometries, rotational constants, harmonic vibrational frequencies, and energetics of the species involved in the complex are reported. These methods result in accurate computational predictions that have mean deviations for bond lengths, rotational constants, and vibrational frequencies of 0.001 Å, 163 MHz, and 46 cm(-1), respectively. These results provide essential spectroscopic properties for the complexes that can facilitate both laboratory and interstellar observations, and they also provide a comparison between oxygen and sulfur complex observability based on thermodynamic stability.

Meningitis in preterm neonates: importance of cerebrospinal fluid parameters.

Cerebrospinal fluid parameters are of great importance in diagnosing meningitis, but normal values for preterm neonates are based on small, single-center studies. We sought to determine current values for preterm neonate cerebrospinal fluid parameters and assess the association of cerebrospinal fluid parameters with culture proven meningitis. We performed a cohort study of the first lumbar puncture from 4632 neonates < 34 weeks' gestation performed in the years 1997 to 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical Group. We identified 95 cases of meningitis from the 4632 lumbar punctures. The area under the receiver operating characteristic curves for white blood cell count, glucose, and protein were 0.80, 0.63, and 0.72, respectively, for prediction of culture-proven meningitis. Cerebrospinal fluid parameters used to diagnose meningitis in the absence of dependable cerebrospinal fluid cultures are unreliable. Caution should be employed when interpreting cerebrospinal fluid parameters in the premature neonate.

Airtraq vs standard laryngoscopy by student paramedics and experienced prehospital laryngoscopists managing a model of difficult intubation.

Two consecutive, randomised, cross-over trials compared intubation success rates in third-year paramedic students and experienced prehospital practitioners using the Airtraq or a Macintosh laryngoscope with flexible stylet in a manikin model of a Cormack and Lehane grade III/IV laryngoscopic view. First-time intubation rates for the Macintosh and Airtraq for students were 0/23 (0%) vs 10/23 (44%) (44% difference, 95% CI 26-63%, p < 0.001) and for experienced laryngoscopists were 14/56 (25%) vs 47/56 (84%) (59% difference, 95% CI 42-72%, p < 0.0001), respectively. First-time oesophageal intubation rates for students were 15/23 (65%) vs 3/23 (13%) (-52% difference, 95% CI -25 to -72%, p < 0.001) and for experienced practitioners 9/56 (16%) vs 0/56 (0%) (-16% difference, 95% CI -9 to -28%, p = 0.0014). Student paramedics and experienced prehospital laryngoscopists managing a manikin model of a grade III/IV view had increased first-time intubation rates and had lower rates of oesophageal intubation with the Airtraq compared with a standard laryngoscope.

Use of the Airtraq laryngoscope in a model of difficult intubation by prehospital providers not previously trained in laryngoscopy.

This study evaluated the ability of prehospital providers who had no previous training in intubation, to use an Airtraq laryngoscope to intubate a manikin model of a Cormack and Lehane grade III/IV view. Volunteers attending the Australian College of Ambulance Professionals conference, Adelaide, in November 2006 received approximately 5 min of Airtraq training. First-time intubation success rate was 26/33 (79%) (95% CI 61-91%); oesophageal intubation rate was 0/33 (0%) (95% CI 0-11%); median time to intubation was 17 s (IQR 10-25 s (range 5-30 s)); and median subject-rated difficulty of use score was 21 out of a maximum of 100 (IQR 7.5-35.5 (range 1-65)). Pre-hospital providers without previous laryngoscopy training achieved high first-time intubation success rates when managing a model of a grade III/IV difficult intubation with an Airtraq laryngoscope. Users evaluated it as easy to use and achieved intubation within an acceptable breath-to-breath interval.

A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin.

OBJECTIVES: Very low birth weight (VLBW) infants are vulnerable to nosocomial infections and subsequent morbidity; including infections caused by Staphylococcus aureus: 85% of nosocomial S. aureus infections are caused by capsular polysaccharide (CPS) types 5 and 8. Altastaph is a polyclonal investigational human immunoglobulin G (IgG) with high levels of opsonizing S. aureus CPS types 5 and 8 IgG. METHODS: A Phase 2 clinical trial to assess the safety and kinetics of Altastaph in VLBW infants. Neonates in this multicenter study were randomized to receive two identical 20 ml/kg i.v. infusions of either 0.45% NaCl placebo or 1000 mg Altastaph/kg. Each infant was followed for 28 days after the second infusion or until discharge. Serum S. aureus CPS types 5 and 8 IgG levels were measured preinfusion and at various times after each infusion. RESULTS: Of 206 neonates, 158 received both infusions. Adverse events were similar in the two treatment groups. Six subjects (3% in each group) discontinued owing to an adverse event. Geometric mean anti-type 5 IgG levels were 402 and 642 mcg/ml 1 day following infusion of the first (day 0) and Second (day 14) doses, respectively, in neonates < or =1000 g and slightly higher in neonates 1001 to 1500 g. Trough levels before second infusion were 188 mcg/ml. Type 8 IgG levels were similar. Geometric mean IgG levels among placebo recipients were consistently <2 and <5 mcg/ml for types 5 and 8 in both weight groups. Three episodes of S. aureus bacteremia occurred in each arm. CONCLUSIONS: Infusion of Altastaph in VLBW neonates resulted in high levels of specific S. aureus types 5 and 8 CPS IgG. The administration of this anti-staphylococcal hyperimmune globulin was well tolerated in this population.

Phenotypic analysis of conditionally immortalized cells isolated from the BPK model of ARPKD.

To study the pathophysiology of autosomal recessive polycystic kidney disease (ARPKD), we sought to develop conditionally immortalized control and cystic murine collecting tubule (CT) cell lines. CT cells were isolated from intercross breedings between BPK mice (bpk(+/-)), a murine model of ARPKD, and the Immorto mice (H-2K(b)-ts-A58(+/+)). Second-generation outbred offspring (BPK x Immorto) homozygous for the BPK mutation (bpk(-/-); Im(+/+/-); cystic BPK/H-2K(b)-ts-A58), were phenotypically indistinguishable from inbred cystic BPK animals (bpk(-/-)). Cystic BPK/H-2K(b)-ts-A58 mice developed biliary ductal ectasia and massively enlarged kidneys, leading to renal failure and death by postnatal day 24. Principal cells (PC) were isolated from outbred cystic and noncystic BPK/H-2K(b)-ts-A58 littermates at specific developmental stages. Epithelial monolayers were under nonpermissive conditions for markers of epithelial cell polarity and PC function. Cystic and noncystic cells displayed several properties characteristic of PCs in vivo, including amiloride-sensitive sodium transport and aquaporin 2 expression. Cystic cells exhibited apical epidermal growth factor receptor (EGFR) mislocalization but normal expression of ZO-1 and E-cadherin. Hence, these cell lines retain the requisite characteristics of PCs, and cystic BPK/H-2K(b)-ts-A58 PCs retained the abnormal EGFR membrane expression characteristic of ARPKD. These cell lines represent important new reagents for studying the pathogenesis of ARPKD.

Changes in the exocrine pancreas secondary to altered small intestinal function in the CF mouse.

The exocrine pancreas of the cystic fibrosis (CF) mouse (cftr(m1UNC)) is only mildly affected compared with the human disease, providing a useful model to study alterations in exocrine function. The CF mouse pancreas has approximately 50% of normal amylase levels and approximately 200% normal Muclin levels, the major sulfated glycoprotein of the pancreas. Protein biosynthetic rates and mRNA levels for amylase were not altered in CF compared with normal mice, and increases in Muclin biosynthesis and mRNA paralleled the increased protein content. Stimulated pancreatic amylase secretion in vitro and in vivo tended to be increased in CF mice but was not statistically significant compared with normal mice. We show for the first time that the CF mouse duodenum is abnormally acidic (normal intestinal pH = 6.47 +/- 0.05; CF intestinal pH = 6.15 +/- 0.07) and hypothesize that this may result in increased signaling to the exocrine pancreas. There were significant increases in CF intestinal mRNA levels for secretin (310% of normal, P < 0.001) and vasoactive intestinal peptide (148% of normal, P < 0.05). Furthermore, CF pancreatic cAMP levels were 147% of normal (P < 0.01). These data suggest that the CF pancreas may be chronically stimulated by cAMP-mediated signals, which in turn may exacerbate protein plugging in the acinar/ductal lumen, believed to be the primary cause of destruction of the pancreas in CF.

The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent.

1. The pancreatic variant of the sodium bicarbonate cotransporter, pNBC1, mediates basolateral bicarbonate influx in the exocrine pancreas by coupling the transport of bicarbonate to that of sodium, with a 2 HCO3-:1 Na+ stoichiometry. The kidney variant, kNBC1, mediates basolateral bicarbonate efflux in the proximal tubule by coupling the transport of 3 HCO3- to 1 Na+. The molecular basis underlying the different stoichiometries is not known. 2. pNBC1 and kNBC1 are 93 % identical to each other with 41 N-terminal amino acids of kNBC1 replaced by 85 distinct amino acids in pNBC1. In this study we tested the hypothesis that the differences in stoichiometry are related to the difference between the N-termini of the two proteins. 3. Mouse renal proximal tubule and collecting duct cells, deficient in both pNBC1- and kNBC1-mediated electrogenic sodium bicarbonate cotransport function were transfected with either pNBC1 or kNBC1. Cells were grown on a permeable support to confluence, mounted in an Ussing chamber and permeabilized apically with amphotericin B. Current through the cotransporter was isolated as the difference current due to the reversible inhibitor dinitrostilbene disulfonate. The stoichiometry was calculated from the reversal potential by measuring the current-voltage relationships of the cotransporter at different Na+ concentration gradients. 4. Our data indicate that both kNBC1 and pNBC1 can exhibit either a 2:1 or 3:1 stoichiometry depending on the cell type in which each is expressed. In proximal tubule cells, both pNBC1 and kNBC1 exhibit a 3 HCO3-:1 Na+ stoichiometry, whereas in collecting duct cells, they have a 2:1 stoichiometry. These data argue against the hypothesis that the stoichiometric differences are related to the difference between the N-termini of the two proteins. Moreover, the results suggest that as yet unidentified cellular factor(s) may modify the stoichiometry of these cotransporters.

The stoichiometry of the electrogenic sodium bicarbonate cotransporter pNBC1 in mouse pancreatic duct cells is 2 HCO(3)(-):1 Na(+).

The electrogenic sodium bicarbonate cotransporter pNBC1 is believed to play a major role in the secretion of bicarbonate by pancreatic duct cells, by transporting bicarbonate into the cell across the basolateral membrane. Thermodynamics predict that this function can be achieved only if the reversal potential of the cotransporter is negative to the cell's membrane potential, or equivalently that the HCO3-:Na+ stoichiometry is not larger then 2:However, there are no data available on either the reversal potential or the HCO3-:Na+ stoichiometry of pNBC1 in pancreatic cells. We studied pNBC1 function in mouse pancreatic duct cells. RT-PCR analysis of total RNA revealed that these cells contain the message for pNBC1, but not for kNBC1, NBC2 or NBC3. To measure cotransporter activity, mouse pancreatic duct cells were grown to confluence on a porous substrate, mounted in an Ussing chamber, and the apical plasma membrane permeabilized with amphotericin B. Ion flux through pNBC1 was achieved by applying Na+ concentration gradients across the basolateral plasma membrane. The current through the cotransporter was isolated as the difference current due to the reversible inhibitor dinitrostilbene disulfonate (DNDS). Current-voltage relationships for the cotransporter, measured at three different Na+ concentration gradients, were linear over a range of about 100 mV. The reversal potential data, obtained from these current-voltage relationships, all corresponded to a 2 HCO3-:1 Na+ stoichiometry. The data indicate that pNBC1 is functionally expressed in mouse pancreatic duct cells. The cotransporter operates with a 2 HCO3-:1 Na+ stoichiometry in these cells, and mediates the transport of bicarbonate into the cell across the basolateral membrane.

Sex- and age-of-onset-based locus heterogeneity in asthma.

Asthma is a complex disease with a genetic component. The results of genome-wide linkage studies imply that locus heterogeneity is likely to be an important feature of the genetics of asthma. To attempt to reduce locus heterogeneity, we hypothesized that the following may form the bases for locus heterogeneity at some asthma susceptibility loci: sex of affected individuals, parental origin of alleles shared by affected sib pairs, and age of onset of wheeze. Analysis of such strata may assist in the identification of novel susceptibility loci, or reveal the basis for locus heterogeneity at previously identified loci. Genotype and phenotype data from genome-wide linkage searches for asthma susceptibility loci from three populations were analyzed. Some regions demonstrated evidence for linkage to affected individuals of a particular sex. There was evidence for excess maternal allele sharing at regions on chromosomes 9 and 11. Regions on chromosomes 2 and 6 were linked to late and early age at onset of wheeze in asthma, respectively. These analyses suggest that the bases that we selected for stratification may be appropriate at certain susceptibility loci for asthma, and may therefore assist in the fine mapping of such loci. Differences in such variables between studies may explain apparent nonreplication of linkage results.