Break on through: The role of innate immunity and barrier defence in atopic dermatitis and psoriasis.

The human skin can be affected by a multitude of diseases including inflammatory conditions such as atopic dermatitis and psoriasis. Here, we describe how skin barrier integrity and immunity become dysregulated during these two most common inflammatory skin conditions. We summarise recent advances made in the field of the skin innate immune system and its interaction with adaptive immunity. We review gene variants associated with atopic dermatitis and psoriasis that affect innate immune mechanisms and skin barrier integrity. Finally, we discuss how current and future therapies may affect innate immune responses and skin barrier integrity in a generalized or more targeted approach in order to ameliorate disease in patients.

Anaesthesia-related haemodynamic complications in Williams syndrome patients: a review of one institution's experience.

Williams syndrome is a genetic disorder associated with cardiac pathology, including supravalvular aortic stenosis and coronary artery stenosis. Sudden cardiac death has been reported in the perioperative period and attributed to cardiovascular pathology. In this retrospective audit, case note and anaesthetic records were reviewed for all confirmed Williams syndrome patients who had received an anaesthetic in our institution between July 1974 and November 2009. There were a total of 108 anaesthetics administered in 29 patients. Twelve of the anaesthetics (11.1%) were associated with cardiac complications including cardiac arrest in two cases (1.85%). Of the two cardiac arrests, one patient died within the first 24 hours postanaesthetic and the other patient survived, giving an overall mortality of 0.9% (3.4%). We conclude that Williams syndrome confers a significant anaesthetic risk, which should be recognised and considered by clinicians planning procedures requiring general anaesthesia.

Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukaemia: transmission from an allogeneic donor.

We report on a patient who developed donor-derived cutaneous T-cell lymphoma (CTCL) 4 years after successful treatment of chronic myeloid leukaemia with an allogeneic bone marrow transplant. The patient developed an eczematous rash unresponsive to topical therapy and immunosuppression. When CTCL was diagnosed in the recipient, his sibling donor had been attending his local dermatology unit with a maculosquamous rash, which proved subsequently to be mycosis fungoides. An identical pattern of donor and recipient clonality assessment and T-cell receptor gene sequencing indicated that the CTCL was probably transmitted in the bone marrow harvest. This suggests that CTCL cells circulate in the marrow at an early subclinical stage in this disease. This is the second case of donor-derived CTCL reported to date.

A survey of aseptic precautions and needle type for paediatric caudal block in Australia and New Zealand.

This cross-sectional survey was designed to evaluate the current practice of anaesthetists in Australia and New Zealand with regard to aseptic technique and needle type during the performance of single-shot caudal blocks. Professional bodies suggest that full aseptic precautions be taken during the administration of caudal or epidural blocks. It has been suggested that using an intravenous cannula or a styletted needle may obviate the occurrence of epidermoid tumours. A total of 202 members of the Society for Paediatric Anaesthesia in New Zealand and Australia were invited to participate in this internet-based survey. Eighty-four responses were received. Most respondents used some form of antiseptic handwash (81%), wore sterile gloves (85.7%), used antiseptic skin preparation (100%) and draped the site (57.1%). When performing caudal blocks, 43.1% used unstyletted needles, 27.2% used styletted spinal needles and 29.6% used intravenous cannulas. However, 11.9% did not wash hands, 10.7% did not wear gloves and 42.9% did not drape the site. Three respondents reported neither handwashing, wearing gloves or draping, instead only using an alcohol swab for skin preparation. The majority of respondents in our region appear to use some level of aseptic precautions, albeit to a variable degree. Published recommendations may either be perceived as overly cautious or as ambiguous in that they do not specify caudal practice as distinct from other epidural blocks. There is a need for clearer professional guidance to support a minimum level of aseptic precaution for single-shot caudal epidural blocks.

Anaesthetists' risk assessment of placebo nerve block studies using the SHAM (Serious Harm and Morbidity) scale.

The SHAM (Serious Harm and Morbidity) scale was developed to categorise the severity of potential complications of placebo control interventions in the context of local anaesthesia research. A convenience sample of 43 anaesthetists used the SHAM scale to grade ten published randomised controlled trials investigating local anaesthesia nerve blocks. The Fleiss κ statistic assessed agreement between these anaesthetists and probability of random agreement (Pr(e)) when using the SHAM scale; a κ > 0 shows concordance between assessors above random agreement. Overall κ was 0.50 (95% CI 0.49-0.51, p < 0.001), Pr(e) = 0.21. There was moderate agreement between assessors in determining whether studies were low-risk (SHAM score 0-2) or high-risk (SHAM score 3-4) (κ 0.60 (95% CI 0.58-0.62), Pr(e) = 0.51). Compared with anaesthetists given clinical examples of interventions when applying the SHAM score, anaesthetists who were not given examples showed significantly less inter-individual agreement (κ 0.76 (95% CI 0.72-0.81), Pr(e) = 0.5 vs 0.45 (95% CI 0.41-0.49), Pr(e) = 0.52, p < 0.0001). These results suggest that the SHAM score can be successfully used to grade the severity of potential complications of placebo-controlled interventions in local anaesthesia research and represent a first step towards the score's validation.

Use of invasive placebos in research on local anaesthetic interventions.

Placebos play a vital role in clinical research, but their invasive use in the context of local anaesthetic blocks is controversial. We assessed whether recently published randomised controlled trials of local anaesthetic blocks risked harming control group patients in contravention of the Declaration of Helsinki. We developed the 'SHAM' (Serious Harm and Morbidity) scale to assess risk: grade 0 = no risk (no intervention); grade 1 = minimal risk (for example, skin allergy to dressing); grade 2 = minor risk (for example, subcutaneous haematoma, infection); grade 3 = moderate risk (with or without placebo injection) (for example, neuropraxia); and grade 4 = major risk (such as blindness, pneumothorax, or liver laceration). Placebo interventions of the 59 included trials were given a SHAM grade. Nine hundred and nineteen patients in 31 studies, including six studies with 183 children, received an invasive placebo assessed as SHAM grade ≥ 3. A high level of agreement (78%, κ = 0.80, p < 0.001) for SHAM grades 0-4 increased to 100% following discussion between assessors. More than half of the randomised controlled study designs subjected patients in control groups to risks of serious or irreversible harm. A debate on whether it is justifiable to expose control group patients to risks of serious harm is overdue.

Anaesthesia for excision of an intraoral mass in a neonate: use of a laryngeal mask during removal of congenital epulis.

Congenital epulis is a rare intraoral tumour of the newborn arising from gingival mucosa, most commonly from the alveolar ridge. It may interfere with normal feeding or potentially compromise respiration. We describe the anaesthetic management of one such case of a female infant born with a single epulis, approximately 3 cm in diameter, protruding from her mouth. The lesion was removed one day after delivery, under general anaesthesia using a laryngeal mask airway to control the infant's airway. The rationale for this management plan and alternatives to this strategy are discussed.

Descending necrotising mediastinitis: a safe treatment algorithm.

Descending necrotising mediastinitis can complicate oropharyngeal infection and has a high associated mortality. We present three cases treated in our department and propose a treatment algorithm based on our experience and literature review. The primary oropharyngeal infection was peritonsillar abscess in two cases and odontogenic abscess in one. Two patients underwent cervicotomy and later thoracotomy. The third underwent cervicotomy with transcervical mediastinal drainage and later required pericardial drainage via a subxiphoid incision. All recovered fully and were discharged within 6 weeks. To enable successful treatment, diagnosis needs to be prompt and surgical drainage adequate. Thoracic management of the chest is essential.

Sedation for paediatric stereotactic radiosurgery: the dexmedetomidine experience.

Dexmedetomidine is a potent alpha2 adrenergic agonist, with sedative and analgesic properties which may make it a suitable sedative agent for procedures on paediatric patients. A six-year-old boy required sedation for stereotactic radiosurgical ablation of an arteriovenous malformation on two occasions. Sedation with dexmedetomidine was planned, with increased dosage used on the second occasion. On both occasions dexmedetomidine was inadequate as a sole agent and required supplementation with other agents.

Cochlear implantation in children with large vestibular aqueduct syndrome and a review of the syndrome.

OBJECTIVE: Children with Large Vestibular Aqueduct Syndrome (LVAS) frequently develop speech and language skills prior to deterioration of their hearing. Operations designed to halt the progression of hearing loss have largely failed so the question of Cochlear Implantation in these children has arisen. It had been suggested that there would be technical difficulties in implanting these patients and, therefore, there had been an initial reluctance to proceed to implantation. The aim of the present paper is to assess surgical and functional outcomes in implanted children with LVAS and review the related literature. MATERIAL AND METHODS: From the 170 children assessed by MRI in the Nottingham Paediatric Cochlear Implant Programme, seven (4%) were identified as having LVAS. Four of these children were implanted and had at least 12 months follow up. Two of the children are on the waiting list for implantation and one child was not implanted because of absence of the cochlear nerve. Operative findings, complications and outcome measures were recorded. The auditory skills of the children were assessed before implantation and 1 year following implantation. A literature search was done to identify other series with experience in implanting children with LVAS. RESULTS: Full insertion of the electrode array was achieved in all our cases. After cochleostomy two patients experienced a mild CSF leak that was easily controlled by the muscle graft. On the first day post-operation two patients were nauseous and one had an episode of vomiting, however, all were discharged within 24 h of surgery. Initial outcome measures at 12 months post-implantation were encouraging showing significant progress in children's auditory skills. CONCLUSIONS: The results of the present study and the review of the literature suggest that LVAS is not a contraindication to implantation as initial concerns about severe perilymph leaks and surgical complications have proved to be unfounded. The post-operative progress of these children in listening skills also suggest that these children are suitable for cochlear implantation

Facial paralysis in Wegener's granulomatosis of the middle ear.

A case of Wegener's granulomatosis, which presented as chronic otitis media with facial nerve palsy, is described. Early diagnosis is vital if unnecessary surgical exploration is to be avoided. A false negative cANCA may delay the diagnosis, especially in cases of locoregional disease, and a policy of repeated titres should be adopted, if clinical suspicion is high.

Nasal polyposis and facial pain.

A cohort of 973 patients with symptoms of rhinosinusitis and/or facial pain was followed up for a mean of 2 years 2 months and, within this, was a group of 220 with nasal polyps. Only 39 (18%) had pain or pressure as a symptom. Out of the 220 with nasal polyps, 190 had polyps without any purulent secretions and, of these, only 5 (2.6%) had pain attributable to their paranasal sinus disease. Ten out of the 15 with pain and polyps without pus were found to have pain as a result of neurological or medical cause after endoscopic sinus surgery and a trial of medical nasal treatment and, where necessary, drugs to treat neurological conditions. Thirty patients (13.6%) had nasal polyposis and purulent secretions, and, within this subgroup, 24 (79%) had pain as well. Of the 24 with pain and purulent secretions, 19 (80%) responded to treatment for their paranasal sinus disease, a far higher proportion than with nasal polyps without pus. In conclusion, in patients who have nasal polyps without purulent secretions, be cautious about attributing any symptoms of facial pain or pressure as being due to their paranasal sinuses as it is more probable that it is coincidental and the result of a neurological cause.

Role of amino acid sequences flanking dibasic cleavage sites in precursor proteolytic processing. The importance of the first residue C-terminal of the cleavage site.

The amino acid sequences flanking 352 dibasic moieties contained in 83 prohormones and pro-proteins listed in a database were examined. Frequency calculations on the occurrence of given residues at positions P6 to P'4 allowed us to delineate a number of features which might be in part responsible for the in vivo discrimination between cleaved and uncleaved dibasic sites. These include the following: amino acids at these positions were characterized by a large variability in composition and properties; no major contribution of a given precursor subsite to endoprotease specificity was observed; some amino acid residues appeared to occupy preferentially certain precursor subsites (for instance, Met in P6 and P3, Asp and Ala in P'1, Pro in P6, Gly in P3 and P'2 etc.) whereas some others appeared to be excluded. Most amino acid residues occupying the P'1 position in these precursor cleavage sites were tolerated. But the beta-carbon branched side chain residues (Thr, Val, Leu, Ile) and Pro, Cys, Met and Trp were either totally excluded or poorly represented, suggesting that they might be unfavourable to cleavage. The biological relevance of these observations to the efficacy of dibasic cleavage by model propeptide convertases was in vitro tested using both pro-ocytocin convertase and Kex2 protease action on a series of pro-ocytocin related synthetic substrates reproducing the Pro7-->Leu15 sequence of the precursor in which the Ala13 residue (P'1 in the LysArg-Ala motif) was replaced by various amino acid residues. A good correlation was obtained on this model system indicating that P'1 residue of precursor dibasic processing sites is an important feature and may play the role of anchoring motif to S'1 convertase subsite. We tentatively propose that the present database, and the corresponding model, may be used for further investigation of dibasic endoproteolytic processing of propeptides and pro-proteins.

Lighting a lamp for persons who are visually challenged.

This paper is an outgrowth of an investigation to (1) identify persons with diabetes mellitus who manifest varying degrees of self-destructive behavior, (2) compile a list of dangerously negative self-management practices observed in the person who is visually challenged, (3) outline a comprehensive diabetes skills update designed to restore self-esteem, and (4) suggest to the rehabilitation worker and the diabetes educator ways to enhance instruction. The paper lists behaviors that may cause deadly harm to persons visually challenged by diabetes mellitus, requiring careful observation by the diabetes educator. A case report shows that numerous teaching opportunities arise from analyzing self-care skills that are lost due to vision pathology.

Somatostatin-28 and pro-ocytocin/neurophysin convertases: basic pair selective endoproteases involved in pro-hormone processing in the rat brain cortex and bovine corpus luteum.

Two neuropeptide precursor processing enzyme systems were characterized in the rat brain cortex and bovine neurohypophysis and corpus luteum. The first one combines the action of a 90 kDa endoprotease which cleaves somatostatin-28 before the Arg-Lys doublet and that of an aminopeptidase B-like enzyme. The second system associates the action of a 58 kDa endoprotease cleaving pro-ocytocin/neurophysin (1-20) after the Lys-Arg dibasic moiety and a carboxypeptidase B-like activity. Both systems appear to be located in membrane-limited secretory vesicles of the producing organs, and to exhibit the properties of metallo-enzymes sensitive to divalent cation chelators. In contrast, they do not show the characteristics of serine-proteases and of trypsin-like enzymes. Studies with substrate analogs selectively modified at the basic doublet indicated that the integrity of both basic amino acids is essential but that conformational parameters, probably governed by the amino acid sequences flanking the basic doublet, play an important role. These data will be discussed in relation to a hypothesis on the predicted preferred secondary structure of these restriction loci.

Partial purification and functional properties of an endoprotease from bovine neurosecretory granules cleaving proocytocin/neurophysin peptides at the basic amino acid doublet.

An enriched preparation of neurosecretory granules from bovine pituitary neural lobes was used as a source of processing enzymes possibly involved in the cleavage of the proocytocin/neurophysin precursor. A synthetic eicosapeptide reproducing the entire (1-20) sequence of the NH2-terminal domain of the bovine ocytocin/neurophysin precursor was used as a substrate to monitor an endoprotease activity cleaving at the Lys11-Arg12 doublet. The 58-kDa endoprotease detected in the lysate of neurohypophyseal granules produced a single cleavage, after the doublet, at the Arg12-Ala13 peptide bond. This endoprotease with pHi 6.9 and 7.2 exhibits maximal activity at pH around neutrality (7.0) and was strongly inhibited by divalent cation chelating agents [ethylenediaminetetraacetic acid and ethylene glycol bis(beta-aminoethyl ether)-N,N,N',-N'-tetraacetic acid] and to some extent by p-(chloromercuri)benzoate and p-(chloromercuri)benzenesulfonic acid, while phenylmethanesulfonyl fluoride and pepstatin were not active. This endoprotease action was sensitive to any modification of the substrate at either basic amino acid of the doublet since replacement of either L-Lys11 or L-Arg12 by D-Lys or D-Arg and by L-Nle abolished the cleavage reaction. In contrast, reversal of the polarity of the doublet in [Arg11,Lys12]proocytocin/neurophysin(1-20) had no effect on the mode of endoproteolytic cleavage as well as modifications of Gly10 (replaced by Ala10). It is concluded that the selectivity of this endoprotease, which may be involved in the primary event occurring in proocytocin/neurophysin processing, is strictly dependent upon the integrity of the basic doublet but that other parameters determined by the amino acid sequence around this doublet may play an important role.