Familial hypocalciuric hypercalcaemia as a differential diagnosis of hyperparathyroidism:studies in a large kindred and a review of surgical experience in the condition

We have studied 46 members of a large kindred with familial hypocalciuric hypercalcaemia (FHH) after a neck exploration failed to cure hypercalcaemia in an asymptomatic patient. Serum calcium, serum phosphate, plasma parathormone and vitamin D metabolites do not distinguish affected members from patients with hyperparathyroidism. Because of the continuing debate as to whether or not FHH is a variant of, or distinct from, hyperparathyroidism, we have carried out a review of surgical experience with subtotal parathyroidectomy in hyperparathyroidism secondary to parathyroid hyperplasia and in FHH. Whereas the procedure is successful in 90 per cent of the former cases only one case of FHH has been cured by it. This provides evidence for the two conditions being aetiologically distinct. Before patients with asymptomatic hypercalcaemia are referred for parathyroid surgery the calcium:creatinine clearance ratio should be measured using a 2 h urine sample collected after an overnight fast and a fasting blood sample. If this ratio is less than 0.01 then screening of first degree relations should be undertaken before any parathyroid surgery is performed. Unnecessary surgery can therefore be avoided.

Constitutive expression of human keratin 14 gene in mouse lung induces premalignant lesions and squamous differentiation

Squamous cell carcinoma accounts for 20% of all human lung cancers and is strongly linked to cigarette smoking. It develops through premalignant changes that are characterized by high levels of keratin 14 (K14) expression in the airway epithelium and evolve through basal cell hyperplasia, squamous metaplasia and dysplasia to carcinoma in situ and invasive carcinoma. In order to explore the impact of K14 in the pulmonary epithelium that normally lacks both squamous differentiation and K14 expression, human keratin 14 gene hK14 was constitutively expressed in mouse airway progenitor cells using a mouse Clara cell specific 10 kDa protein (CC10) promoter. While the lungs of CC10-hK14 transgenic mice developed normally, we detected increased expression of K14 and the molecular markers of squamous differentiation program such as involucrin, loricrin, small proline-rich protein 1A, transglutaminase 1 and cholesterol sulfotransferase 2B1. In contrast, wild-type lungs were negative. Aging CC10-hK14 mice revealed multifocal airway cell hyperplasia, occasional squamous metaplasia and their lung tumors displayed evidence for multidirectional differentiation. We conclude that constitutive expression of hK14 initiates squamous differentiation program in the mouse lung, but fails to promote squamous maturation. Our study provides a novel model for assessing the mechanisms of premalignant lesions in vivo by modifying differentiation and proliferation of airway progenitor cells. © The Author 2008. Published by Oxford University Press. All rights reserved.

Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium

The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas. © 2007 USCAP, Inc All rights reserved.

alpha(1A)-adrenoceptors mediate sympathetically evoked pupillary dilation in rats

Evidence suggests that in some species (cats, rabbits, and possibly humans) alpha-adrenoceptors in the iris dilator muscle are "atypical" in that they cannot be readily classified by conventional criteria. This study was undertaken in an attempt to characterize the alpha-adrenoceptor subtype(s) mediating sympathetically elicited mydriasis in rats. Frequency-response pupillary dilator curves were generated by stimulation of the preganglionic cervical sympathetic nerve (1-32 Hz) in pentobarbital-anesthetized rats. Evoked responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-1 mg/kg). The selective alpha(1)-adrenergic antagonist, prazosin (0.01-1 mg/kg), also was effective, although alpha(2)-adrenergic antagonism with rauwolscine (0.1-1 mg/kg) was not. alpha(1A)-Adrenoceptor-selective antagonists, 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101; 0.1-1 mg/kg) and 5-methylurapidil (0.1-1 mg/kg), as well as the alpha(1D)-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY-7378; 1-3 mg/kg), were used to determine the subtype(s) involved. Evoked mydriasis was significantly antagonized by both WB-4101 and 5-methylurapidil but not by BMY-7378. These results suggest that, unlike some other species, adrenoceptors in the rat iris dilator mediating neurogenic mydriasis are "typical" and, in addition, can be characterized as being primarily of the alpha(1A)-adrenoceptor subtype.

PS1-12sk is a Peculiar Supernova From a He-rich Progenitor System in a Brightest Cluster Galaxy Environment

We report on our discovery and observations of the Pan-STARRS1 supernova (SN) PS1-12sk, a transient with properties that indicate atypical star formation in its host galaxy cluster or pose a challenge to popular progenitor system models for this class of explosion. The optical spectra of PS1-12sk classify it as a Type Ibn SN (c.f. SN 2006jc), dominated by intermediate-width (3x10^3 km/s) and time variable He I emission. Our multi-wavelength monitoring establishes the rise time dt = 9-23 days and shows an NUV-NIR SED with temperature > 17x10^3 K and a peak rise magnitude of Mz = -18.9 mag. SN Ibn spectroscopic properties are commonly interpreted as the signature of a massive star (17 - 100 M_sun) explosion within a He-enriched circumstellar medium. However, unlike previous Type Ibn supernovae, PS1-12sk is associated with an elliptical brightest cluster galaxy, CGCG 208-042 (z = 0.054) in cluster RXC J0844.9+4258. The expected probability of an event like PS1-12sk in such environments is low given the measured infrequency of core-collapse SNe in red sequence galaxies compounded by the low volumetric rate of SN Ibn. Furthermore, we find no evidence of star formation at the explosion site to sensitive limits (Sigma Halpha

PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na/H exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial

Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease.

A Novel Investigation of a Blister-Like Syndrome in Aquarium Echinopora lamellosa

This study investigates potential causes of a novel blister-like syndrome in the plating coral Echinopora lamellosa. Visual inspections of this novel coral syndrome showed no obvious signs of macroparasites and the blisters themselves manifested as fluid-filled sacs on the surface of the coral, which rose from the coenosarc between the coral polyps. Histological analysis of the blisters showed that there was no associated necrosis with the epidermal or gastrodermal tissues. The only difference between blistered areas and apparently healthy tissues was the presence of proliferated growth (possible mucosal cell hyperplasia) directly at the blister interface (area between where the edge of the blister joined apparently healthy tissue). No bacterial aggregates were identified in any histological samples, nor any sign of tissue necrosis identified. We conclude, that the blister formations are not apparently caused by a specific microbial infection, but instead may be the result of irritation following growth anomalies of the epidermis. However, future work should be conducted to search for other potential casual agents, including viruses. © 2014 Smith et al.

Acute respiratory distress syndrome caused by Mycoplasma pneumoniae diagnosed by polymerase chain reaction

Mycoplasma pneumoniae (M. pneumoniae) is a common pathogen in cases of atypical pneumonia. Most individuals with Mycoplasma pneumonia run a benign course, with non-specific symptoms of malaise, fever and non-productive cough that usually resolve with no long-term sequelae. Acute lung injury is not commonly seen in Mycoplasma pneumonia. We report a case of acute respiratory distress syndrome cause by M. pneumoniae diagnosed by quantitative real-time polymerase chain reaction (RT-PCR).

Echoes of the future: Adults with disabilities living at home with their parents

Almost 90% of all adult sons and daughters with disabilities live at home with their parents. Consequently, they have life experiences that are atypical for most of their adult peers and their aging caregivers are under stress due to failing health, financial pressures, bereavement, and worry about the future.

Adults with intellectual disabilities and aging parents took part in focus groups and interviews. results show a loving and caring home environment but evidence a lack of effective life skills development and futures planning. the paper draws attention to the inevitable crisis that occurs when aging caregivers are no longer able to care. The urgent need for skill development and timely futures planning is outlined.

The Limits of Local Accommodation: Why Contentious Events Remain Prone to Conflict in Northern Ireland

This article examines the difficulties of finding local solutions to the problem of contentious events in contemporary Northern Ireland. In so doing, it offers a sociological perspective on fundamental divisions in Northern Ireland: between classes and between communities. It shows how its chosen case study—parades and associated protests in north Belfast—exemplifies the most fundamental problem that endures in post-Agreement Northern Ireland, namely that political authority is not derived from a common civic culture (as is the norm in Western liberal democracy) but rather that legitimacy is still founded on the basis of the culture of either one or the other community. Haugaard’s reflections on authority and legitimacy are used to explore Northern Ireland’s atypical experience of political conflict vis-`a-vis the Western liberal democratic model. The Bourdieusian concepts of field illusio and doxa help to explain why it is that parading remains such an important political and symbolic touchstone in this society.

Low rates of Pseudomonas aeruginosa misidentification in isolates from cystic fibrosis patients

Pseudomonas aeruginosa is an important cause of pulmonary infection in cystic fibrosis (CF). Its correct identification ensures effective patient management and infection control strategies. However, little is known about how often CF sputum isolates are falsely identified as P. aeruginosa. We used P. aeruginosa-specific duplex real-time PCR assays to determine if 2,267 P. aeruginosa sputum isolates from 561 CF patients were correctly identified by 17 Australian clinical microbiology laboratories. Misidentified isolates underwent further phenotypic tests, amplified rRNA gene restriction analysis, and partial 16S rRNA gene sequence analysis. Participating laboratories were surveyed on how they identified P. aeruginosa from CF sputum. Overall, 2,214 (97.7%) isolates from 531 (94.7%) CF patients were correctly identified as P. aeruginosa. Further testing with the API 20NE kit correctly identified only 34 (59%) of the misidentified isolates. Twelve (40%) patients had previously grown the misidentified species in their sputum. Achromobacter xylosoxidans (n = 21), Stenotrophomonas maltophilia (n = 15), and Inquilinus limosus (n = 4) were the species most commonly misidentified as P. aeruginosa. Overall, there were very low rates of P. aeruginosa misidentification among isolates from a broad cross section of Australian CF patients. Additional improvements are possible by undertaking a culture history review, noting colonial morphology, and performing stringent oxidase, DNase, and colistin susceptibility testing for all presumptive P. aeruginosa isolates. Isolates exhibiting atypical phenotypic features should be evaluated further by additional phenotypic or genotypic identification techniques.

The main-belt comets: The Pan-STARRS1 perspective

We analyze a set of 760 475 observations of 333 026 unique main-belt objects obtained by the Pan-STARRS1(PS1) survey telescope between 2012 May 20 and 2013 November 9, a period during which PS1 discoveredtwo main-belt comets, P/2012 T1 (PANSTARRS) and P/2013 R3 (Catalina-PANSTARRS). PS1 cometdetection procedures currently consist of the comparison of the point spread functions (PSFs) of movingobjects to those of reference stars, and the flagging of objects that show anomalously large radial PSFwidths for human evaluation and possible observational follow-up. Based on the number of missed discoveryopportunities among comets discovered by other observers, we estimate an upper limit comet discoveryefficiency rate of 70% for PS1. Additional analyses that could improve comet discovery yields infuture surveys include linear PSF analysis, modeling of trailed stellar PSFs for comparison to trailed movingobject PSFs, searches for azimuthally localized activity, comparison of point-source-optimized photometryto extended-source-optimized photometry, searches for photometric excesses in objects withknown absolute magnitudes, and crowd-sourcing. Analysis of the discovery statistics of the PS1 surveyindicates an expected fraction of 59 MBCs per 106 outer main-belt asteroids (corresponding to a totalexpected population of 140 MBCs among the outer main-belt asteroid population with absolute magnitudesof 12 < HV < 19:5), and a 95% confidence upper limit of 96 MBCs per 106 outer main-belt asteroids(corresponding to a total of 230 MBCs), assuming a detection efficiency of 50%. We note howeverthat significantly more sensitive future surveys (particularly those utilizing larger aperture telescopes)could detect many more MBCs than estimated here. Examination of the orbital element distribution ofall known MBCs reveals an excess of high eccentricities (0:1 < e < 0:3) relative to the background asteroidpopulation. Theoretical calculations show that, given these eccentricities, the sublimation rate for atypical MBC is orders of magnitude larger at perihelion than at aphelion, providing a plausible physicalexplanation for the observed behavior of MBCs peaking in observed activity strength near perihelion.These results indicate that the overall rate of mantle growth should be slow, consistent with observationalevidence that MBC activity can be sustained over multiple orbit passages.

Pre-Main-Sequence Accretion in the Low Metallicity Galactic Star-forming Region Sh 2-284

We present optical spectra of pre-main-sequence (PMS) candidates around the Ha region taken with the Southern African Large Telescope in the low metallicity (Z) Galactic region Sh 2-284, which includes the open cluster Dolidze 25 with an atypical low metallicity of Z similar to 1/5 Z(circle dot). It has been suggested on the basis of both theory and observations that PMS mass-accretion rates, (M) over dot(acc), are a function of Z. We present the first sample of spectroscopic estimates of mass-accretion rates for PMS stars in any low-Z star-forming region. Our data set was enlarged with literature data of H alpha emission in intermediate-resolution R-band spectroscopy. Our total sample includes 24 objects spanning a mass range between 1 and 2 M-circle dot and with a median age of approximately 3.5 Myr. The vast majority (21 out of 24) show evidence for a circumstellar disk on the basis of Two Micron All Sky Survey and Spitzer infrared photometry. We find (M) over dot(acc) in the 1-2 M-circle dot interval to depend quasi-quadratically on stellarmass, with (M) over dot(acc) proportional to M-*(2.4 +/- 0.35), and inversely with stellar age, with (M) over dot(acc) proportional to t(*)(-0.7 +/- 0.4). Furthermore, we compare our spectroscopic (M) over dot(acc) measurements with solar Z Galactic PMS stars in the same mass range, but, surprisingly find no evidence for a systematic change in (M) over dot(acc) with Z. We show that literature accretion-rate studies are influenced by detection limits, and we suggest that (M) over dot(acc) may be controlled by factors other than Z(*), M-*, and age.

Epidermal Growth Factor Removal or Tyrphostin AG1478 Treatment Reduces Goblet Cells & Mucus Secretion of Epithelial Cells from Asthmatic Children Using the Air-Liquid Interface Model

RATIONALE: Epithelial remodelling in asthma is characterised by goblet cell hyperplasia and mucus hypersecretion for which no therapies exist. Differentiated bronchial air-liquid interface cultures from asthmatic children display high goblet cell numbers. Epidermal growth factor and its receptor have been implicated in goblet cell hyperplasia.

OBJECTIVES: We hypothesised that EGF removal or tyrphostin AG1478 treatment of differentiating air-liquid interface cultures from asthmatic children would result in a reduction of epithelial goblet cells and mucus secretion.

METHODS: In Aim 1 primary bronchial epithelial cells from non-asthmatic (n = 5) and asthmatic (n = 5) children were differentiated under EGF-positive (10ng/ml EGF) and EGF-negative culture conditions for 28 days. In Aim 2, cultures from a further group of asthmatic children (n = 5) were grown under tyrphostin AG1478, a tyrosine kinase inhibitor, conditions. All cultures were analysed for epithelial resistance, markers of differentiation using immunocytochemistry, ELISA for MUC5AC mucin secretion and qPCR for MUC5AC mRNA.

RESULTS: In cultures from asthmatic children the goblet cell number was reduced in the EGF negative group (p = 0.01). Tyrphostin AG1478 treatment of cultures from asthmatic children had significant reductions in goblet cells at 0.2μg/ml (p = 0.03) and 2μg/ml (p = 0.003) as well as mucus secretion at 2μg/ml (p = 0.04).

CONCLUSIONS: We have shown in this preliminary study that through EGF removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced. This further highlights the epidermal growth factor receptor as a potential therapeutic target to inhibit goblet cell hyperplasia and mucus hypersecretion in asthma.