Severe combined immunodeficiency: otolaryngological presentation and management

In order to increase the awareness of otolaryngologists of severe combined immunodeficiency syndrome (SCIDS) so they may contribute to an earlier diagnosis of this disorder, we performed a retrospective chart review of a multicenter series from 2 children's hospital medical centers. Eighteen cases were identified, and 14 had an otolaryngological presentation. The average age of presentation was 3.3 months, and 72% were males. Most cases were inherited in an X-linked fashion. Five patients had thrush; 4 had recurrent otitis media. Other otolaryngological presentations included cough, mouth ulcers, pharyngitis, mastoiditis, and bilateral neck abscess. The most severe form of immunodeficiency, SCIDS is a rare condition that involves a disorder in both T and B cell functions. The manifestations involving the head and neck include recurrent upper respiratory tract infections, otitis media, thrush, oral ulcers, and abscesses. It is important that SCIDS be considered in any infant with recurrences of these common infections.     

A key role for transmembrane prolines in calcitonin receptor-like receptor agonist binding and signalling: implications for family B G-protein-coupled receptors

Calcitonin receptor like-receptor is a family B G-protein coupled receptor (GPCR). It requires receptor activity modifying protein (RAMP) 1 to give a calcitonin gene-related peptide (CGRP) receptor. Little is known of how members of this receptor family function. Proline residues often form important kinks in alpha-helices. Therefore, all proline residues within the transmembrane helices of the receptor (Pro241, Pro244 in helix 4, Pro275 in helix 5, Pro321 and Pro331 in helix 6) were mutated to alanine. Pro241, Pro275, and Pro321 are highly conserved throughout all family B GPCRs. The binding of CGRP and its ability to stimulate cAMP production were investigated in mutant and wild-type receptors after transient transfection into COS-7 cells with RAMP1. The P321A mutation significantly decreased the pEC(50) for CGRP and reduced its affinity but did not change cell-surface expression. Antagonist binding [CGRP(8-37) and 1-piperidinecarboxamide, N-[2-[[5amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS)] was little altered by the mutation. Adrenomedullin-mediated signaling was disrupted when P321A was coexpressed with RAMP1, RAMP2, or RAMP3. The P331A mutant produced a moderate reduction in CGRP binding and receptor activation. Mutation of the other residues had no effect on receptor function. Thus, Pro321 and Pro331 are required for agonist binding and receptor activation. Modeling suggested that Pro321 induces a bend in helix 6, bringing its C terminus near that of helix 3, as seen in many family A GPCRs. This is abolished in P321A. P321A-I325P, predicted to restore this conformation, showed wild-type activation. Modeling can also rationalize the effects of transmembrane proline mutants previously reported for another family B GPCR, the VPAC(1) receptor.     

Well leg compartment syndrome after pelvic and perineal surgery in the lithotomy position

Objective: Lower limb compartment syndrome after prolonged surgical procedures performed in the lithotomy position is a rare but potentially devastating complication. It is recognised after urological, colorectal, and gynaecological procedures. Sixteen cases of compartment syndrome after urological surgery have been reported. The objective of this study was to estimate the incidence of this complication in urological practice and identify risk factors for its development. Design: A postal survey of UK consultant urologists was conducted. Results: Replies were received from 261 consultants. In total there were 65 cases of compartment syndrome. Compartment syndrome occurred after radical cystectomy and urinary diversion in 51 cases and was rare in procedures lasting less than four hours. The incidence of compartment syndrome after cystectomy was estimated at around 1 in 500 cases. Risk factors for its development included perioperative blood loss, peripheral vascular disease, and obesity. Conclusions: Compartment syndrome after use of the lithotomy position may be more common than is generally appreciated and has been underreported in the past. All staff should be aware of this serious complication and adopt strategies for its avoidance.     

The test-retest reliability of a standardized neurocognitive and neurophysiological test battery: "neuromarker"

NeuroMarker combines EEG and ERP measures with neurocognitive tests in a fully computerized and standardized testing system. It is designed for use across the lifespan and has a large normative database of over 1,000 subjects. This study was a preliminary evaluation of "NeuroMarker" in subjects spanning four decades. Twenty-one healthy subjects (12-57 years) were tested at baseline and four weeks later. From the "Neuromarker" battery, the authors analyzed EEG data (eyes open and closed) and ERPs elicited during auditory oddball (N100, P200, N200, P300) and working memory (P150, P300) tasks. Concomitant neuropsychological data, acquired using a touch-screen system, comprised measures of sensori-motor, attention, verbal, executive, and memory function. Test-retest data were examined using analyses of variance and correlational procedures (corrected for multiple comparisons), with parallel analyses of age. EEG data did not differ across sessions, and showed high test-retest reliability (.71-.95), particularly for theta and delta (>.85). ERP components also showed sound reliability, particularly for sites where components are maximal: fronto-central N100 (.76-.77), centro-parietal P300 (.78-.81) to oddball targets, N100 and P200 (.74-.86) to oddball non-targets, and P150 amplitude and latency (.84-.93) to working memory stimuli. Neuropsychological tests showed a similarly sound level of consistency (on average, .70), with the most consistent tests tapping simple motor function, estimated intelligence, switching of attention (Part 2), verbal interference response time and memory intrusions (.71-.89). Age and sex did not have a differential impact on reliability for EEG, ERP, or neuropsychology measures. These findings provide preliminary evidence that the "NeuroMarker" battery is reliable for test-retest assessments. The results suggest that the standardized approach has utility for providing sensitive clinical and treatment evaluations across age groups.     

Transmigration across a lung epithelial monolayer delays apoptosis of polymorphonuclear leukocytes

BACKGROUND: Suppression of polymorphonuclear leukocyte (PMNL) apoptosis may cause or exaggerate acute lung injury that is associated with the acute respiratory distress syndrome. We hypothesized that transepithelial migration would modulate PMNL apoptosis. METHOD: PMNLs that were freshly purified from normal volunteers were allowed to migrate across transwell membranes alone or coated with monolayers of human lung epithelial cells in response to chemoattractants (interleukin-8, formyl-methionylleucylphenylalanine and leukotriene B(4)). We assessed for migration efficiency, apoptosis, and functional activity of the PMNLs. Changes in the expression of genes modulating PMNL apoptosis were examined with messenger RNA and protein analyses. RESULTS: Transepithelial migration caused a significant decrease in the percentage of apoptotic PMNLs (interleukin-8; from 31% to 16% at 8 hours; P<.01). This apoptotic delay was sustained to at least 20 hours that was associated with prolongation of PMNL functional activity and independent of chemoattractant-type. Gene and protein expression levels of the antiapoptotic proteins Mcl-1 and 14-3-3 zeta were either augmented or preserved by interleukin-8 treatment alone and after transepithelial migration. CONCLUSION: Our data reveal, for the first time, the important role of transepithelial migration in the modulation of PMNL apoptosis and may provide insights into possible novel targets for the regulation of PMNL apoptosis during lung inflammation and injury.