Cochlin in the eye: Functional implications

Aqueous humor is actively produced in the ciliary epithelium of the anterior chamber and has important functions for the eye. Under normal physiological conditions, the inflow and outflow of the aqueous humor are tightly regulated, but in the pathologic state this balance is lost. Aqueous outflow involves structures of the anterior chamber and experiences most resistance at the level of the trabecular meshwork (TM) that acts as a filter. The modulation of the TM structure regulates the filter and its mechanism remains poorly understood. Proteomic analyses have identified cochlin, a protein of poorly understood function, in the glaucomatous TM but not in healthy control TM from human cadaver eyes. The presence of cochlin has subsequently been confirmed by Western and immunohistochemical analyses. Functionally, cochlin undergoes multimerization induced by shear stress and other changes in the microenvironment. Cochlin along with mucopolysaccharide deposits have been found in the TM of glaucoma patients and in the inner ear of subjects affected by the hearing disorder DNFA9, a late onset, progressive disease that also involves alterations in fluid shear regimes. In vitro, cochlin induces aggregation of primary TM cells suggesting a role in cell adhesion, possibly in mechanosensation, and in modulation of the TM filter.

Langerin expressing cells promote skin immune responses under defined conditions.

There are conflicting data in the literature regarding the role of epidermal Langerhans cells (LC) in promoting skin immune responses. On one hand, LC can be extremely potent APCs in vitro, and are thought to be involved in contact hypersensitivity (CHS). On the other hand, it seems counterintuitive that a cell type continually exposed to pathogens at the organism\'s barrier surfaces should readily trigger potent T cell responses. Indeed, LC depletion in one model led to enhanced contact hypersensitivity, suggesting they play a negative regulatory role. However, apparently similar LC depletion models did not show enhanced CHS, and in one case showed reduced CHS. In this study we found that acute depletion of mouse LC reduced CHS, but the timing of toxin administration was critical: toxin administration 3 days before priming did not impair CHS, whereas toxin administration 1 day before priming did. We also show that LC elimination reduced the T cell response to epicutaneous immunization with OVA protein Ag. However, this reduction was only observed when OVA was applied on the flank skin, and not on the ear. Additionally, peptide immunization was not blocked by depletion, regardless of the site. Finally we show that conditions which eliminate epidermal LC but spare other Langerin(+) DC do not impair the epicutaneous immunization response to OVA. Overall, our results reconcile previous conflicting data in the literature, and suggest that Langerin(+) cells do promote T cell responses to skin Ags, but only under defined conditions.

Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol

Background-Asthma, post-nasal drip syndrome (PNDS), and gastrooesophageal reflux (GOR) account for many cases of chronic non-productive cough (CNPC). Each may simultaneously contribute to cough even when clinically silent, and failure to recognise their contribution may lead to unsuccessful treatment.

Methods—Patients (all lifetime non-smokers with normal chest radiographs and spirometric measurements) referred with CNPC persisting for more than three weeks as their sole respiratory symptom underwent histamine challenge, home peak flow measurements, ear, nose and throat (ENT) examination, sinus CT scanning, and 24 hour oesophageal pH monitoring. Treatment was prescribed on the basis of diagnoses informed by investigation results.

RESULTS—Forty three patients (29 women) of mean age 47.5 years (range 18-77) and mean cough duration 67 months (range 2-240) were evaluated. On the basis of a successful response to treatment, a cause for the cough was identified in 35 patients (82%) as follows: cough variant asthma (CVA) (10 cases), PNDS (9 cases), GOR (8cases), and dual aetiologies (8 cases). Histamine challenge correctly predicted CVA in 15 of 17 (88%) positive tests. ENT examination and sinus CT scans each had low positive predictive values for PNDS (10 of 16 (63%) and 12 of 18 (67%) positive cases, respectively), suggesting that upper airways disease frequently co-exists but does not always contribute to cough. When negative, histamine challenge and 24 hour oesophageal pH monitoring effectively ruled out CVA and GOR, respectively, as a cause for cough.

CONCLUSION—This comprehensive approach aids the accurate direction of treatment and, while CVA, PNDS and GOR remain the most important causes of CNPC to consider, a group with no identifiable aetiology remains.

Histamine release from bronchoalveolar lavage cells from asthmatic subjects after allergen challenge and relationship to the late asthmatic response

Background


Metachromatic cells obtained from asthmatic subjects demonstrate increased spontaneous and stimulated histamine release in vitro. Their ability to synthesize and store proinflammatory cytokines has focused renewed interest on their role in asthma.


Objective: The late asthmatic response provides a useful model of clinical asthma. The aim of the study was to examine metachromatic cell derived mediators and histamine releasability in vitro after in vivo allergen exposure in atopic subjects with and without asthma and relate them to the type of physiological response observed.

Methods: Bronchoalveolar lavage (BAL) cells were obtained 4 h after challenge from asthmatics exhibiting a single early response (EAR, n = 5), a dual response (LAR, n = 7), unchallenged (basal, n = 5), atopic non-asthmatic (ANA, n = 6) and non-atopic non-asthmatics (normal, n = 5). BAL histamine and tryptase concentrations and in vitro histamine release (HR) after stimulation with anti-IgE, allergen, A23187, conconavalin A and substance P were compared.

Results:Metachromatic cell numbers were lower in normal controls compared with all asthmatic groups and in LAR compared with EAR. Metachromatic cell derived mediators were higher in asthmatic compared with normal subjects. Spontaneous HR in LAR (20.5 ± 5.0%) was lower than EAR (29.5 ± 3.9%) and ANA (30.2 ± 1.4%) (P < 0.05). No differences were seen in stimulated HR between EAR and LAR. HR in ANA stimulated with anti-IgE was greater than LAR (P < 0.05). HR in ANA stimulated with anti-IgE was greater than LAR (P < 0.05). After stimulation with ionophore A23187 (1 μM), release was greater in LAR compared with basal (P < 0.05) and no different at 5 μM. All subject groups responded to substance P (SP) but was significantly more in the asthmatic subjects compared to normal controls (P < 0.05). Allergen challenge did not modify the response of asthmatic subjects to SP.

Conclusion: Functional differences in metachromatic cell reactivity are present in atopic subjects 4 h after in vivo allergen exposure which relate to the physiological response observed after this time and suggest that there is ongoing metachromatic cell degranulation subjects who subsequently develop LAR.

Factors identifying pigs predisposed to tail biting

Approximately 5% of pigs slaughtered in the UK have been tail-bitten, leading to welfare and production issues. Tail biting is sporadic and not all pigs tail bite. The aim of this study was to identify factors that are common in pigs that perform tail-biting behaviour, and that might be used in a predictive way to identify such animals.

The behaviour of 159 pigs was observed in the post-weaning period. Pigs were weaned at 4 weeks of age. In the week prior to weaning and at 6 weeks of age each pig was individually tested in a tail chew test (tail chew test 1 and 2, respectively). The tail chew test involved recording the pig's behaviour directed towards two ropes, one of which had been soaked in saline solution and the other not. The production performance of the pigs was recorded from birth to 7 weeks of age. Time spent performing tail-biting behaviour correlated positively with time in contact with the rope in tail chew test 2 (r = 0.224, P 1.5% tail biting 8.96 kg, = 1.5% tail biting 15-75 kg, = or = 1.5% tail biting 260 g/day, = 1.5% tail biting 343 g/day, 0.05).

The results suggest that pigs that tail bite have some nutritional deficiency that results in performance of foraging behaviour that is expressed in intensive housing as ear/tail biting.

First record of minimum Irish hare (Lepus timidus hibernicus Bell 1837) longevity in the wild.

Average longevity of the mountain hare (Lepus timidus L., 1758) has been estimated at nine years in the wild (Macdonald D. and Barrett, P. 1993 Mammals of Britain and Europe. Harper Collins Publishers, London) with a maximum recorded age of 18 years for one marked animal (Angerbjörn, A. and Flux, J. E. C. 1995 Lepus timidus. Mammalian Species 495: 1–11). However, the longevity of the Irish hare (L. t. hibernicus Bell 1837) is entirely unknown. A total of 14 Irish hares was trapped and tagged at Belfast International Airport, Co. Antrim from February to April 2005. The sex, age (juvenile or adult) and weight of each animal were recorded. Adults were taken as those individuals >8-10 months old defined by the fusing of the notch between the apophysis and diaphysis of the tibia and humerus (Flux, J. E. C. 1970 Journal of Zoology 161: 75-123). Individual identification was made by a system of colourcoded ear tags (Roxan iD Ltd. Selkirk, Scotland) being inserted in the centre of the pinna of each ear. Each ear tag (6 × 34 mm) and puncture site was disinfected with 70 per cent ethanol prior to insertion. An adult male, #001/002 ‘Blue/Blue’, was tagged on 3 March 2005 weighing 3.8 kg and was sighted during a return site visit on 4 April 2007. An adult female, #026/003 ‘Green/Yellow’, was tagged on 15 April 2005 weighing 4.0 kg and was sighted during return visits on 25 March 2010 and 19 October 2010. The latest possible date of birth for both individuals was spring/summer 2004. Consequently, they were at least 3 years and 6.5 years old, respectively. This is the first record of minimum Irish hare longevity in the wild. These observations suggest that ear tagging does not compromise animal welfare and is an effective means of long-term monitoring. Future research may utilize capture-mark-recapture methods.

Listening – the Cinderella profile component of English

This article investigates the role of listening in English. The importance of ‘reading with the ear’ is discussed, as is research into the views of teachers and pupils on this topic. Practical suggestions are made for according to listening a more meaningful place in English. Originally English was conceived as listening and reading, talking and writing. It would enrich the conception of English as a subject to uncouple listening from talking and instead give it its place as a profile component in its own right.

Trisomy 10p with clinical features of facio-auriculo-vertebral spectrum: a case report

We report a male child born with complete absence of his external ear, hemifacial microsomia of the right side, high arched palate, a down-turned upper lip and slightly upslanting palpebral fissures. The features were suggestive of facio-auriculo-vertebral spectrum. Investigations showed a tandem duplication of the short arm of one chromosome 10 with apparent breakpoints at p14 and p15. This case extends the list of chromosomal abnormalities associated with the facio-auriculo-vertebral phenotype and also adds useful clinical information to possible trisomy 10p phenotypes.

Design and evaluation of tinnitus synthesis methods: From spectral to spatial matching

Purpose
This study was designed to investigate methods to help patients suffering from unilateral tinnitus synthesizing an auditory replica of their tinnitus.

Materials and methods
Two semi-automatic methods (A and B) derived from the auditory threshold of the patient and a method (C) combining a pure tone and a narrow band-pass noise centred on an adjustable frequency were devised and rated on their likeness over two test sessions. A third test evaluated the stability over time of the synthesized tinnitus replica built with method C, and its proneness to merge with the patient's tinnitus. Patients were then asked to try and control the lateralisation of this single percept through the adjustment of the tinnitus replica level.

Results
The first two tests showed that seven out of ten patients chose the tinnitus replica built with method C as their preferred one. The third test, performed on twelve patients, revealed pitch tuning was rather stable over a week interval. It showed that eight patients were able to consistently match the central frequency of the synthesized tinnitus (presented to the contralateral ear) to their own tinnitus, which leaded to a unique tinnitus percept. The lateralisation displacement was consistent across patients and revealed an average range of 29dB to obtain a full lateral shift from the ipsilateral to the contralateral side.

Conclusions
Although spectrally simpler than the semi-automatic methods, method C could replicate patients' tinnitus, to some extent. When a unique percept between synthesized tinnitus and patients' tinnitus arose, lateralisation of this percept was achieved.

Exercise and manual auricular acupuncture:a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) trial)

Evidence supports the use of exercise for chronic low back pain (CLBP); however, adherence is often poor due to ongoing pain. Auricular acupuncture is a form of pain relief involving the stimulation of points on the outer ear corresponding with specific body parts. It may be a useful adjunct to exercise in managing CLBP; however, there is only limited evidence to support its use with this patient group.

Effect of collagen turnover on the accumulation of advanced glycation end products

Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p <0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p <0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p <0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p <0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.

Serine proteases in bone disease

Serine proteases are active in many physiological and pathological processes within bone tissue. Although essential to adequate maintenance of bone and cartilage, their inappropriate expression can lead to exacerbation of tissue destruction and inflammation. Their effects are exerted through multiple pathways, including interaction with signalling molecules such as transforming growth factor ß (TGFß), binding to protease-activated receptors (PARs), and direct proteolysis of extracellular matrix proteins, in some cases working synergistically with matrix metalloproteases in the remodelling of bone tissue. The overall effect of these interactions is not yet clear, but there are strong links between some serine proteases and arthropathies, in addition to metastatic bone invasion. Understanding the contribution of each of these enzymes to the molecular disease process is crucial to developing effective treatment based on inhibitors or agonists. Serine protease inhibitors have shown promise in reducing the severity of arthritis, but greater specificity is required to avoid undesired systemic effects. © 2009 Bentham Science Publishers Ltd.

Soundspace: A Manifesto

The manifesto is a long-standing and powerful tool for challenge within architecture, deployed by those as diverse as Vitruvius and Frank Lloyd Wright (who proposed a Walt Whitman-inspired “Work Song” of 1896) to those publishing in blogs across the designing planet today. Manifestos are locations for dreaming, for the banging of shoes, for passion in words about the environment we invent. Our manifesto follows in that tradition of poetry and critical optimism in calling for a new architecture of soundspace.

Here we wish to act as Markus Miessen’s “uninvited outsider” (Miessen 2010), a transgressive voice that disturbs the status quo beyond comfortable familiarity and brings together different types of thinkers and various modes of critique.[1] In this article we seek to probe “fundamental questions about how and for whom the built environment is produced and … conventional frameworks or oldestablished rules and regulations” through the interdisciplinarity that sound studies demands.[2] The ear to transgression is open.[3]

Bone morphogenetic proteins and their antagonists: current and emerging clinical uses

Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily of secreted cysteine knot proteins that includes TGFβ₁, nodal, activins and inhibins. BMPs were first discovered by Urist in the 1960s when he showed that implantation of demineralized bone into intramuscular tissue of rabbits induced bone and cartilage formation. Since this seminal discovery, BMPs have also been shown to play key roles in several other biological processes, including limb, kidney, skin, hair and neuronal development, as well as maintaining vascular homeostasis. The multifunctional effects of BMPs make them attractive targets for the treatment of several pathologies, including bone disorders, kidney and lung fibrosis, and cancer. This review will summarize current knowledge on the BMP signalling pathway and critically evaluate the potential of recombinant BMPs as pharmacological agents for the treatment of bone repair and tissue fibrosis in patients.