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Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Human status epilepticus (SE) is associated with a pathological reduction in cerebral blood flow termed the inverse hemodynamic response (IHR). Canonical transient receptor potential 3 (TRPC3) channels are integral to the propagation of seizures in SE, and vascular smooth muscle cell (VSMC) TRPC3 channels participate in vasoconstriction. Therefore, we hypothesize that cerebrovascular TRPC3 channels may contribute to seizure-induced IHR. To examine this possibility, we developed a smooth muscle-specific TRPC3 knockout (TRPC3smcKO) mouse. To quantify changes in neurovascular coupling, we combined laser speckle contrast imaging with simultaneous electroencephalogram recordings. Control mice exhibited multiple IHRs, and a limited increase in cerebral blood flow during SE with a high degree of moment-to-moment variability in which blood flow was not correlated with neuronal activity. In contrast, TRPC3smcKO mice showed a greater increase in blood flow that was less variable and was positively correlated with neuronal activity. Genetic ablation of smooth muscle TRPC3 channels shortened the duration of SE by eliminating a secondary phase of intense seizures, which was evident in littermate controls. Our results are consistent with the idea that TRPC3 channels expressed by cerebral VSMCs contribute to the IHR during SE, which is a critical factor in the progression of SE. Fil: Cozart, Michael A.. University of Arkansas for Medical Sciences; Estados Unidos Fil: Phelan, Kevin D.. University of Arkansas for Medical Sciences; Estados Unidos Fil: Wu, Hong. University of Arkansas for Medical Sciences; Estados Unidos Fil: Mu, Shengyu. University of Arkansas for Medical Sciences; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Rusch, Nancy J.. University of Arkansas for Medical Sciences; Estados Unidos Fil: Zheng, Fang. University of Arkansas for Medical Sciences; Estados Unidos

Background Dilated cardiomyopathy may be heritable but shows extensive genetic heterogeneity. The utility of whole exome sequencing as a first‐line genetic test for patients with dilated cardiomyopathy in a contemporary “real‐world” setting has not been specifically established. Using whole exome sequencing with rigorous, evidence‐based variant interpretation, we aimed to identify the prevalence of a molecular diagnosis in patients with dilated cardiomyopathy in a clinical setting. Methods and Results Whole exome sequencing was performed in eligible patients (n=83) with idiopathic or familial dilated cardiomyopathy. Variants were prioritized for curation in up to 247 genes and classified using American College of Medical Genetics and Genomics–based criteria. Ten (12%) had a pathogenic or likely pathogenic variant. Eight (10%) participants had truncating TTN variants classified as variants of uncertain significance. Five (6%) participants had variants of unknown significance according to strict American College of Medical Genetics and Genomics criteria but classified as either pathogenic or likely pathogenic by other clinical laboratories. Pathogenic or likely pathogenic variants were found in 8 genes (all within tier 1 genes), 2 (20%) of which are not included in a standard commercially available dilated cardiomyopathy panel. Using our bioinformatics pipeline, there was an average of 0.74 variants of uncertain significance per case with ≈0.75 person‐hours needed to interpret each of these variants. Conclusions Whole exome sequencing is an effective diagnostic tool for patients with dilated cardiomyopathy. With stringent classification using American College of Medical Genetics and Genomics criteria, the rate of detection of pathogenic variants is lower than previous reports. Efforts to improve adherence to these guidelines will be important to prevent erroneous misclassification of nonpathogenic variants in dilated cardiomyopathy genetic testing and inappropriate cascade screening.

The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high-fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single-minded family basic helix-loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane-bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1-Cre:Rosa-mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1-Cre:Rosa-mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1-Cre:Rosa-mEGFP male mice, there was decreased alpha-melanocyte-stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506* and p.Glu496* were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

LGR8 was recently identified as a cognate receptor for insulin-like peptide-3 (INSL3), and INSL3-LGR8 signaling is best known for its role in testis descent during development. LGR8 mRNA has been detected in various human tissues including brain, but the regional and cellular distribution of LGR8 expression in the mammalian central nervous system is unknown. Therefore, in this study we investigated the presence and localization of LGR8 mRNA in rat brain using reverse transcription-polymerase chain reaction and in situ hybridization histochemistry. Results revealed a distinct distribution of LGR8 in forebrain, with transcripts principally restricted to the posterior thalamus and highest densities detected in the parafascicular nucleus of both adult and developing rats. Unexpectedly, INSL3 mRNA was not detected in brain by similar methods, but preliminary electrophysiologic studies of parafascicular neurons revealed that INSL3 altered their activity. These findings suggest that LGR8 signaling may be involved in sensorimotor control in the rat and perhaps other species, particularly via actions on parafascicular neurons that project to basal ganglia and are depleted in Parkinson's disease.

Background C225 is an antibody to the epidermal growth factor receptor (EGFR), and inhibits growth of various tumour cells. The antibody is currently being used as a therapeutic agent in several clinical trials of patients with carcinomas. Objectives To determine and investigate the cutaneous side-effects in cancer patients treated with C225. Methods We clinically examined 10 patients treated with C225, and performed immunohistochemical and in situ hybridization studies on skin biopsies. Results The most common cutaneous reaction to C225 therapy was the development of an acneiform follicular eruption, which was most pronounced on the face, chest and upper back and typically manifested a week after the onset of treatment. The consistency of the morphology and timing of the clinical findings in 10 different patients following monotherapy with C225 strongly suggested a direct biological effect of the antibody. Additional dermatological side-effects included focal areas of tender paronychial inflammation of toes and fingers and small aphthous ulcers of the oral mucosa. Serial punch biopsies of chest skin before and after treatment (at 8 days) revealed two main reaction patterns: a superficial dermal inflammatory cell infiltrate surrounding hyperkeratotic and ectatic follicular infundibula, and a suppurative superficial folliculitis. In two biopsies focal intraepidermal acantholysis was found, Microbiological cultures failed to reveal an infectious aetiology. Immunohistochemical and in situ hybridization studies on a subset of the biopsies showed an increase in the expression of p27 Kip1 in epidermal keratinocytes after treatment with C225. Conclusions Our findings support the concept that p27 Kip1 plays a part in the in vivo regulation of follicular and epidermal homeostasis by EGFR.

This study aimed to elucidate the relationship between maternal psychosocial factors related to dietary adherence and growth outcomes in their children with cystic fibrosis (CF). Twenty-five children with CF and mild lung disease, aged 7-12 years, were weighed and measured and completed detailed food records. Mothers completed questionnaires that measured general nutritional knowledge, nutritional knowledge specific to CF, coping strategies, dieting behaviors, self-efficacy about the ability to provide the correct diet, and attitudes and beliefs about CF. Of the cohort, only 16% adhered to the dietary recommendations. Dietary adherence was positively correlated with weight. Maternal nutritional knowledge specific to CF significantly predicted children's dietary adherence score. There was a significant negative correlation between the child's weight and mothers who were dieting successfully. Other psychosocial factors assessed were not related to dietary adherence. Improving the mother's knowledge about nutritional needs in CF appears worthwhile and may have an impact on growth.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related chemicals. Although no endogenous physiological ligand for the AhR has yet been described, persistent expression of hepatic CYP1A1 gene expression (an AhR-dependent response) in congenitally jaundiced Gunn rats indirectly supports the existence of such a ligand(s) in these animals. High plasma levels of the heme degradation product bilirubin (BR) in these animals prompted us to evaluate whether BR is an endogenous AhR agonist. Expression of dioxin responsive element (DRE)-driven luciferase gene expression in stably transfected mouse, guinea pig, rat, and human cells was induced by treatment with physiological concentrations of BR. Biliverdin (BV), the metabolic precursor of bilirubin, also induced luciferase activity in all species. BR and BV not only stimulated AhR transformation and DRE binding in vitro andin cells in culture, but competitive inhibition of [3H]TCDD-specific binding to the cytosolic AhR revealed that these chemicals are AhR ligands. The significantly greater inducing potency of these chemicals in intact cells, compared to their ligand binding and AhR transformation potency in vitro, suggests that BR and BV may also be converted within the cell to a more potent activator(s). Our results demonstrate that the heme degradation products BR and BV are AhR ligands which can regulate the AhR-dependent gene expression pathway.

Objectives: To determine the clinical effects of a change from postural drainage (PD) to positive expiratory pressure chest physiotherapy (PEP) in children with cystic fibrosis (CF) and symptoms of gastro-oesophageal reflux (GOR). To measure the effects of PD on GOR in children with CF. Methods: Study 1: Six adolescents with CF and symptoms of GOR during PD were changed to upright PEP physiotherapy. The effects on lung function, reflux symptom scores and annual hospital days were measured. Study 2: Twenty-four children with CF (mean age 11 years) and symptoms suggestive of GOR underwent 24-h pH monitoring, including periods of chest physiotherapy. Results: Study 1: All six patients reported a reduction in reflux symptoms during PEP therapy (P

This study evaluated adherence to current dietary recommendations of children with cystic fibrosis and mild lung disease and their siblings by comparing energy intake. Fifty children (25with cystic fibrosis) aged between 7 and 12 years completed the study. Energy intake was assessed by weighed dietary intake, resting energy expenditure was used to calculate recommended daily intakes. The children with cystic fibrosis had significant deficits in Z scores for both height and weight compared with their siblings, but there was no difference in percentage of ideal weight for height. The cystic fibrosis group had a significantly higher energy intake per kilogram body weight per day but there was no difference in the percentage of energy derived from fat, protein or carbohydrate. Energy intake (per kg/day) and fat intake (g/kg) were both significant predictors of weight for height in the cystic fibrosis group. Targets for dietary management in cystic fibrosis should perhaps be related to fat intake per kilogram body weight.

OBJECTIVE: To estimate the prevalence of asymptomatic Mycobacterium tuberculosis infection in Melbourne secondary school students. DESIGN: Cross-sectional Mantoux testing of a partly random and partly targeted sample of secondary school students, designed to enable estimation of prevalence by region of birth. SETTING: Fifty-one State and Catholic secondary schools in metropolitan Melbourne during 1995. PARTICIPANTS: Australian and overseas-born students in Years 9 and 10. OUTCOME MEASURES: Proportions of students with positive Mantoux reactions (defined as induration at 48 hours of > or = 5 mm with a history of recent exposure; > or = 10 mm and no prior BCG vaccination; > or = 15 mm and prior BCG vaccination). RESULTS: Of 2586 students potentially eligible for testing, evaluable results were obtained from 1274 (49%). The overall prevalence of infection for Melbourne students in Years 9 and 10 was 2.5% (95% CI, 1.1-3.9%). Main predictors of a positive test were birth overseas and number of years residing overseas. Prevalence varied considerably by region of birth, and was very low in students born in Australia (0.7%), "other developed countries" (0.7%), and Southern Europe (0). The highest rates were observed in students born in Indochina (15.9%), other countries in South East Asia (10.2%), and Eastern Europe (10.2%). CONCLUSIONS: The risk of a young person becoming infected with M. tuberculosis while living in Melbourne is very low. Our results do not indicate a need for the reintroduction of mass screening in Victorian schools. If targeted screening were to be considered, the group most likely to benefit would be recently arrived migrants from Indochina.

AIM—To establish the incidence of pathological gastro-oesophageal reflux (GOR) in newly diagnosed infants with cystic fibrosis and to identify clinical predictors of increased reflux. METHODS—26 infants with cystic fibrosis less than 6 months of age (14 male, 12 female; mean (SEM) age 2.1 (0.21) months, range 0.8to 5.6 months) underwent prolonged oesophageal pH monitoring (mean duration 27.1 (0.49) hours; range 21.3 to 30.2 hours). Reflux symptoms, anthropometric variables, pancreatic status, meconium ileus, genotype, and chest x ray findings were correlated with pH monitoring data. RESULTS—Five infants (19.2%) had an abnormal fractional reflux time of greater than 10%, seven (26.9%) of 5-10%, and 14 (53.8%) of below 5%. Infants who presented with frequent vomiting had a significantly higher fractional reflux time than infants who had infrequent or no vomiting. There was no significant association between abnormal chest x rays and pathological GOR. Sex, genotype, nutritional status, meconium ileus, and pancreatic enzyme supplementation were not significantly associated with pathological GOR. CONCLUSIONS—About one in five newly diagnosed infants with cystic fibrosis had pathological GOR. Pathologically increased reflux was present before radiological lung disease was established. Apart from frequent vomiting, no useful clinical predictors of pathological reflux were found.

Airway inflammation is an important component of cystic fibrosis (CF) lung disease. To determine whether this begins early in the illness, before the onset of infection, we examined bronchoalveolar lavage (BAL) fluid from 46 newly diagnosed infants with CF under the age of 6 mo identified by a neonatal screening program. These infants were divided into three groups: 10 had not experienced respiratory symptoms or received antibiotics and pathogens were absent in their BAL fluid; 18 had clear evidence of lower respiratory viral or bacterial (or = 10(5) CFU/ml) infection; and the remaining 18 had either respiratory symptoms, taken antibiotics, or had10(5) CFU/ml of respiratory pathogens. Their BAL cytology, interleukin-8, and elastolytic activity were compared with those from 13 control subjects. In a longitudinal study to assess if inflammation develops or persists in the absence of infection, the results of 56 paired annual BAL specimens from 44 CF infants were grouped according to whether they showed absence, development, clearance, or persistence of infection. In newly diagnosed infants with CF, those without infection had BAL profiles comparable with control subjects while those with a lower respiratory infection had evidence of airway inflammation. In older children, the development and persistence of infection was accompanied by increased inflammatory markers, whereas these were decreased in the absence, or with the clearance, of infection. We conclude that airway inflammation follows respiratory infection and, in young children, improves when pathogens are eradicated from the airways.

BACKGROUND: Cough is a major symptom in some children with asthma. The relationship between cough and the severity of asthma is ill defined. A study was undertaken to test the hypotheses that, in children with asthma who cough as a major part of their asthma symptoms, cough receptor sensitivity (CRS) is heightened during an acute severe exacerbation of asthma but not in the non-acute phase and airway calibre or its change correlates with CRS. METHODS: Spirometric measurements and the capsaicin CRS test were performed on children admitted to hospital for an acute severe exacerbation of asthma. Nasal secretions were tested for viruses. The children were grouped into those who usually cough with asthma episodes and those who do not. The tests were repeated 7-10 days and 4-6 weeks later. The CRS outcome measure used was the concentration of capsaicin required to stimulate two (Cth) and five coughs (C5). RESULTS: The CRS of the group who coughed (n = 15) was significantly higher than those who did not cough (n = 16) (mean difference log Cth 0.77 mumol (95% CI 0.35 to 1.18), C5 0.72 mumol (95% CI 0.26 to 1.18)) during acute asthma but not after the exacerbation. CRS was not significantly different between groups based on the presence of a viral infection. Neither forced expiratory volume in one second (FEV1) nor its change correlated with CRS nor its change. CONCLUSIONS: In children with asthma CRS is heightened in acute severe asthma in the subgroup of children who have cough as a significant symptom with their asthma episodes. In acute and non-acute asthma CRS does not correlate with FEV1.

In children, recurrent cough is a common presenting symptom that may represent asthma. We tested the hypotheses that children with recurrent cough have increased cough-receptor sensitivity (CRS) or airway hyperresponsiveness (AHR). Skin prick testing, the capsaicin CRS test, and hypertonic saline (HS) challenge were performed in 44 children (median age: 8.9 yr) with recurrent dry cough (> or = 2 episodes of cough, each lasting > or = 2 wk, within a period of 12 mo) and 44 controls. Measures of CRS were the concentration of capsaicin required to stimulate > or = 2 coughs (Cth) and > or = 5 coughs (C5). During the coughing period, Cth (mean log: 0.62 [95% CI: 0.43 to 0.81]) and C5 (mean log: 1.15 [95% CI: 0.86 to 1.44]) of the subjects without AHR were significantly lower (p = 0.0026, 0.027, respectively) than Cth (mean log: 1.27 [95% CI: 0.88 to 1.66]) and C5 (mean log: 1.79 [95% CI: 1.21 to 2.37]) of the subjects with AHR and those of the controls (p = 0.0002 and 0.0001). During the cough-free period, there was no difference in CRS among the groups. In subjects who demonstrated AHR, the provocation dose causing a > or = 15% fall in FEV1 (PD15) during the cough period was significantly lower (p = 0.005) than that during the cough-free period. We conclude that AHR or increased CRS is present during the coughing phase in children with recurrent cough.

Cardiac perforation is a recognised complication of guidewire-introducer techniques. These two new cases of right ventricular perforation implicate the dilator-introducer: one directly and the other due to presumed guidewire buckling.An 85-yr-old man underwent right subclavian cannulation for triple-lumen and pulmonary artery (PA) catheter insertion before coronary artery surgery. Tachycardia (120 bpm) and hypotension (60/30 mmHg) evolved over the next 40 min and resolved with evacuation of 200 ml of clot from the pericardial sac. A ragged 4 mm laceration of the ventricular wall was localised and oversewn without further consequence. A 60-yr-old man with inferior vena caval thrombosis was scheduled for Greenfield filter insertion. The right internal jugular vein was cannulated using the guidewire-introducer technique. Introduction of the introducer-dilator system precipitated cardiovascular collapse. Resuscitation was unsuccessful and post-mortem revealed right ventricular perforation and pericardial tamponade.These cases suggest that shorter introducer-dilators would be safer and probably equally efficacious. The need for a high index of suspicion and rapid therapeutic intervention is also highlighted.

Seizures are the manifestation of highly synchronized burst firing of a large population of cortical neurons. Epileptiform bursts with an underlying plateau potential in neurons are a cellular correlate of seizures. Emerging evidence suggests that the plateau potential is mediated by neuronal canonical transient receptor potential (TRPC) channels composed of members of the TRPC1/4/5 subgroup. We previously showed that TRPC1/4 double-knockout (DKO) mice lack epileptiform bursting in lateral septal neurons and exhibit reduced seizure-induced neuronal cell death, but surprisingly have unaltered pilocarpine-induced seizures. Here, we report that TRPC5 knockout (KO) mice exhibit both significantly reduced seizures and minimal seizure-induced neuronal cell death in the hippocampus. Interestingly, epileptiform bursting induced by agonists for metabotropic glutamate receptors in the hippocampal CA1 area is unaltered in TRPC5 KO mice, but is abolished in TRPC1 KO and TRPC1/4 DKO mice. In contrast, long-term potentiation is greatly reduced in TRPC5 KO mice, but is normal in TRPC1 KO and TRPC1/4 DKO mice. The distinct changes from these knockouts suggest that TRPC5 and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Furthermore, the reduced seizure and excitotoxicity and normal spatial learning exhibited in TRPC5 KO mice suggest that TRPC5 is a promising novel molecular target for new therapy.

Objective: To evaluate the presentation and treatment of infants with acquired subglottic cysts. Design: Case series seen over 12 years. Setting: Academic tertiary referral pediatric medical center. Patients: Eleven patients had subglottic cysts diagnosed. Intervention: Four patients were treated with rupture with the tip of the endoscope. Seven patients underwent endoscopic marsupialization by means of carbon dioxide laser (n=5) and by cup forceps (n=2). Outcome Measures: Intraoperative cyst control. Symptomatic cyst recurrence. Results: Initial cyst management was successful in all cases. There was one symptomatic recurrence in a patient who was managed with cyst rupture. There were no symptomatic recurrences in the group treated by marsupialization. The mean follow-up period was 6 years. Conclusions: Subglottic cysts should be considered in the ex-premature infant with a history of neonatal intubation who presents with stridor or respiratory difficulty. These ductal retention cysts can develop after periods of intubation of less than 24 hours. Endoscopic marsupialization is the recommended form of treatment. (Arch Otolaryngol Head Neck Surg. 1994;120:921-924)

Intracellular injections of Lucifer Yellow were utilized to evaluate the incidence of dye-coupling among dorsolateral septal nucleus (DLSN) neurons recorded from slice preparations of adult rat septal nuclei. Twenty percent of single injections of Lucifer Yellow resulted in pairs of labeled neurons. These dye-coupled cells were morphologically heterogeneous and did not exhibit any morphological characteristics that could be used to distinguish them from non dye-coupled neurons. The spatial separation of cell bodies and close apposition of dendrites within each pair indicated that the dye transfer site(s) were situated at dendrodendritic and/or dendrosomatic rather than somatosomatic junctions. The main axon of some dye-coupled neurons gave rise to intrinsic axon collaterals prior to exiting the nucleus indicating that these coupled neurons function as projection neurons as well as local circuit interneurons. Electrophysiological recordings of the passive membrane properties and spontaneous activity of individual dye-coupled neurons revealed no significant difference from non dye-coupled cells in the DLSN. Some neurons exhibited spontaneously occurring fast potentials which presumably represent electrotonic potentials. These fast potentials were often tightly coupled with action potentials but could be distinguished from synaptic potentials by their shape and their lack of voltage-dependent changes in amplitude. These morphological and supportive electrophysiological data provide the first indirect evidence for electrotonic coupling of dorsolateral septal neurons. The functional significance of this coupling may lie in the potential for synchronization of the output of the DLSN which could play an important role in the septal maintenance and modulation of hippocampal Theta rhythm. © 1993 Wiley-Liss, Inc.

BACKGROUND: Respiratory complications are common after neonatal repair of oesophageal atresia and tracheo-oesophageal fistula. The prevalence of lung function abnormalities and the relation between gastrointestinal complications and lung function has not been studied in a large number of patients. METHODS: Lung volumes and flow-volume loops were measured in 155 patients without spinal curvature aged 6-37 years who had undergone surgery for oesophageal atresia and tracheo-oesophageal fistula. RESULTS: Sixty four of the 155 patients had evidence of mild lower airways disease, with values for FEV1 more than two standardised scores below the predicted value in 39 (25%) and above 2 standardised scores for the residual volume (RV)/total lung capacity (TLC) ratio in 64 (41%). Restrictive lung disease (TLC more than 2 standardised scores below predicted) was present in 28 (18%). Severe lung function abnormalities were present in under 10% of the 155. Half the subjects had some evidence of extra-thoracic tracheal obstruction, with a high ratio of expiratory to inspiratory flow for peak flow in 76 (50%) and at 50% of vital capacity in 59 (38%). Patients with radiological gastro-oesophageal reflux in early childhood had more airways obstruction and smaller lung volumes. Patients with current gastrointestinal symptoms were similar in their lung function to symptom free patients. CONCLUSIONS: Minor lung function abnormalities are common in patients after repair of oesophageal atresia. Early diagnosis and management of gastro-oesophageal reflux may help to minimise these lung function abnormalities.

Membrane potential-dependent changes in the repetitive firing properties of morphologically identified rat dorsolateral septal nucleus neurons were investigated in a submerged slice preparation using intracellular recording techniques and lithium acetate-Lucifer Yellow-filled microelectrodes. The results indicate that the majority of dorsolateral septal nucleus neurons are capable of burst firing and suggest, moreover, the existence of neuronal subtypes with distinct differences in spike waveform and the pattern of spontaneous activity. In the largest proportion of neurons, single spike activity predominated at membrane potentials near rest while burst-like discharges prevailed at more hyperpolarized membrane potentials. Less frequently observed were neurons exhibiting different burst waveforms at various membrane potentials. In a few neurons, hyperpolarization slowed neuronal firing but did not elicit burst-like discharges. Characteristics such as the presence of burst or single spike discharges, spike afterpotentials, and the membrane potential dependence of repetitive firing patterns did not appear to be closely associated with membrane time constant, membrane resistance, or resting membrane potential. A detailed examination of the somatodendritic and axonal morphology of the Lucifer Yellow-filled cells revealed that these electrophysiologically identified neurons in the dorsolateral septal nucleus are morphologically heterogeneous. However, there did not appear to be any correlation between a particular somatodendritic morphology and the expression of a distinct spontaneous firing pattern. The present findings demonstrate that neurons in the rat dorsolateral septal nucleus are morphologically diverse and capable of intrinsically generating rhythmic neuronal activity. Similar patterns of rhythmic neuronal firing in vivo may provide a substrate for the integration of afferent neuronal activity and have a central role in intraseptal circuitry necessary for generation of hippocampal theta rhythm.

The anterograde transport of horseradish peroxidase and tritiated amino acids was used to examine the distribution and morphology of spinal afferent fibers terminating in the rat spinal trigeminal complex. The results confirm the existence of a direct, ipsilateral projection from the spinal cord which is distributed exclusively to the deepest layers of the medullary dorsal horn narrow regions subjacent to the spinal trigeminal tract in trigeminal nucleus interpolaris, trigeminal nucleus oralis and the trigeminal main sensory nucleus. Spinal inputs also terminated in the insular trigeminal-cuneatus lateralis nucleus which is a distinct component of the interstitial system of the spinal trigeminal tract. The spinal afferent fibers which terminated in the dorsolateral parts of the spinal trigeminal complex arose from the dorsal column funiculi, while those that terminated in ventral parts of the complex arose from both the dorsal column and lateral funiculi. The tritiated amino acid experiments indicate that at least part of the spinotrigeminal pathway originates from cells located in the cervical spinal dorsal horn. The present findings also document a complex spatial relationship between the spinotrigeminal and trigeminospinal pathways which includes an extensive overlap between spinotrigeminal fibers and spinal projecting neurons in each of the lateralmost regions of the complex. This spatial overlap supports the existence of anatomical substrates which may underlie functional reciprocal loops between the spinal trigeminal complex and cervical spinal cord. Since these regions are primarily concerned with the processing of sensory information from lateral and posterior parts of the face, it follows that the spinotrigeminal pathway may be primarily concerned with the integration of head and neck functions. In addition, the spatial convergence of spinal inputs and the distribution of other trigeminal efferent neurons suggests that part of the spinotrigeminal pathway may be involved in spino-trigemino-thalamic and spino-trigemino-cerebellar pathways in parallel with other spinobulbar pathways in the medulla.

The retrograde transport of horseradish peroxidase was used to examine and compare the distribution and morphology of thalamic, cerebellar and spinal projecting neurons in rat trigeminal nucleus interpolaris following large injections into their respective targets. The regional distribution of these three populations was evaluated in relation to the six cytoarchitecturally distinct regions which characterize the nucleus. Cerebellar projecting neurons were distributed throughout the rostrocaudal extent of trigeminal nucleus interpolaris, but were infrequently present in its dorsolateral region and in the rostral pole of the nucleus. Thalamic projecting neurons exhibited a distribution pattern that extensively overlapped with that of the trigeminocerebellar neurons; however, they were particularly concentrated in caudal, dorsomedial and rostral, ventrolateral regions of the nucleus. Trigeminospinal projecting neurons exhibited a more restricted distribution within ventral and lateral regions of trigeminal nucleus interpolaris. Although the three populations of projection neurons could not be distinguished solely on the basis of somatic size or shape, distinct regional variations in the distribution and somatodendritic and axonal morphology of these neurons indicated that they arise largely from independent cell populations. However, several regions were identified in which specific cell types were likely to contribute to axonal collateralization among these pathways. In the ventrolateral magnocellular region of the nucleus, for example, more than half of the large multipolar-shaped neurons were retrogradely labeled after injections into each of the three target sites. The results of the present study indicate that the thalamic, cerebellar and spinal projections of trigeminal nucleus interpolaris arise from a morphologically heterogeneous group of neurons. In addition, regional variations in the distribution and morphology of these neurons provide evidence for the existence of functionally distinct regions that parallel the cytoarchitecturally defined regions of the nucleus. This study also provides indirect evidence for and against collateralization among these three projections within specific regions of the nucleus.

1. Conventional intracellular and single-electrode voltage-clamp recordings were obtained from rat brain slices containing dorsolateral septal nucleus (DLSN) neurons in vitro. 2. We observed a slow afterdepolarizing potential (slow-ADP) that lasted up to several seconds (half-decay time was in the range of 0.7-1.4 s) in almost 15% of DLSN neurons; these same neurons could exhibit burst firing activity. The amplitude of this slow-ADP was not affected by hyperpolarization of the membrane potential. 3. The slow-ADP was associated with an increased membrane conductance. Hybrid voltage clamping of the slow-ADP revealed a transient slow inward current (slow-ADC). The current-voltage relationship of the slow-ADC was linear between -40 and -100 mV and generated an extrapolated reversal potential of -30 mV. 4. We investigated the ionic mechanism of the slow-ADP in the rat DLSN. Slow-ADPs were not blocked by 1 microM tetrodotoxin (TTX) but were markedly depressed by 200 microM Cd2+, Ca2(+)-free, low-Na+ solutions, and the intracellular injection of ethylene glycol-bis(B-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). Neither diltiazam (10 microM), an L-type Ca2+ channel blocker nor omega-conatoxin (0.2–2.5 microM), an N-type Ca2+ channel blocker affected the slow-ADP. Similarly, the slow-ADP was not affected in a low-Cl- solution. On the other hand, the slow-ADP was enhanced in a K(+)-free solution. In addition, the slow-ADP was not affected by 1 mM kynurenic acid, a broad-spectrum excitatory amino acid antagonist. 5. We conclude that the slow-ADP in the rat DLSN is mediated by a novel Ca2(+)-dependent, Na(+)-dependent, and nonsynaptic inward current that may be similar to the Ca2(+)-activated nonspecific cation channel currents (i.e., CAN-currents) described in various tissues. This current appears to underlie some forms of spontaneous bursting activity recorded from rat DLSN neurons. It may also be responsible for some types of bursting activity recorded in other CNS neurons

The effects of histamine (HA) on the resting membrane potential and input resistance of rat medial vestibular nucleus (MVN) neurons were investigated using intracellular recording techniques from a submerged brain slice preparation. The exogenous application of HA predominantly produced a concentration-dependent membrane depolarization and induction of action potential firing. The depolarization exhibited a rapid onset, a slow recovery, and usually occurred in the absence of any apparent change in conductance. These effects of HA could be mimicked by the H2-agonist impromidine and were reversibly blocked by the H2-antagonist cimetidine. Tetrodotoxin (TTX) or low calcium/high magnesium-containing media failed to block completely the HA-induced depolarization supporting a direct postsynaptic receptor mediated action of HA. The diminished HA-induced depolarization observed following pretreatment with TTX cannot exclude an additional presynaptic action by HA. The present findings reveal that HA exerts a novel direct excitation of rat MVN neurons through an H2-receptor.

Two hundred twenty-six healthy school children, with a mean age of 8.8 years; 62 girls mean age 8.8, 48 boys mean age 12.6 and 51 girls mean age 12.6 years at the start, were enrolled in a longitudinal study of lung function and tested annually for 5 years. All were free of respiratory symptoms, and none smoked more than five cigarettes per week during the 5 years. Static and dynamic lung volumes (other than residual volume), maximum expiratory and inspiratory flows, and maximum mouth pressures “track,” that is, individuals remain at a constant deviation from the sample mean over time. The data indicate that these measurements of lung function in healthy individuals grow in constant proportion relative to other healthy children and adolescents. Pediatr Pulmonol 1990; 8:172-177.

The transfer of critically ill patients between hospitals carries significant risk. The Mobile Intensive Care Ambulance Service (MICAS) in Ireland was established in 1996 to provide a ground transfer service between hospitals for critically ill patients. The aim of this audit was to determine if a centralised retrieval system for interhospital transport of critically ill patients in Ireland by MICAS is safe and efficient. 484 critically ill patients transported by MICAS between April 1996 and December 2004 were studied retrospectively. There were no patient deaths during transfer. 47% of transfers were between hospitals in the greater Dublin area. 45% were from regional centres to Dublin. 93% of patients required airway intervention before transfer (intubation or tracheostomy) and 32% needed inotropic support during transfer. The MICAS data confirm the demand for interhospital transport of critically ill patients and suggest that transfer using a centralised retrieval system is safe.

Gastro-oesophageal reflux is increased in cystic fibrosis and it is possible that postural drainage techniques may exacerbate reflux, potentially resulting in aspiration and further impairment of pulmonary function. AIM To evaluate the effects of physiotherapy with head down tilt (standard physiotherapy, SPT) on gastro-oesophageal reflux and to compare this with physiotherapy without head down tilt (modified physiotherapy, MPT). METHOD Twenty (mean age 2.1 months) infants with cystic fibrosis underwent 30 hour oesophageal pH monitoring during which SPT and MPT were carried out for two sessions each on consecutive days. RESULTS The number of reflux episodes per hour, but not their duration, was significantly increased during SPT compared with MPT (SPT 2.5 (0.4) v MPT 1.6 (0.3), p = 0.007) and to background (1.1 (0.)1, p = 0.0005). Fractional reflux time was also increased during SPT (11.7 (2.6)%) compared with background (6.9 (1.3)%, p = 0.03) but not compared with MPT (10.7 (2.7)%). There was no significant difference between MPT and background for number of reflux episodes, their duration, or fractional reflux time. CONCLUSION SPT, but not MPT, was associated with a significant increase in gastro-oesophageal reflux in infants with cystic fibrosis.

The first cadaveric transplant at Barnes-Jewish Hospital/Washington University was performed in 1963, the first living related transplant in 1965, and the first living unrelated transplant in 1983. Changes in the renal transplant program initiated in 1993 and 1994 resulted in many improvements over the past decade. Our comparison of 2 modern eras of transplant, 1991-1994 and 1995-2000, showed the following: 1. No significant differences in patient and donor characteristics. 2. Trends toward greater use of living donors (p = 0.07), older cadaveric donors (p = 0.084) and particularly cadaveric donors55 years of age (p = 0.09). 3. Decreasing mean CIT: 19.2 hours vs. 14.2 hours (p0.001). 4. Decreasing use of donors with CIT24 hours: 22% to 3%, (p0.001). 5. Decreased rate of DGF: 13% vs. 8% (p = 0.044). 6. Decreased rate of symptomatic CMV: 35% vs. 14% (p0.001). 7. Decreased rate of PTLD: 3.5% vs. 0.5% (p = 0.004). 8. Decreased one-year rate of acute rejection: 41% vs. 15% (p0.001). 9. Current one-year rate of acute rejection8%. 10. Decreased length of initial hospital stay: 12.7 days to 8.0 days (p0.001). 11. Decreased length of hospital in the first year after transplant: 10.6 days vs. 6.4 days (p0.001). 12. There were no improvements in patient and graft survival at one and 3 years. a. one-year patient survival rates: 95% vs. 96%. b. 3-year patient survival rates: 90% vs. 90%. c. one-year death-censored graft survival rates: 91% vs. 94%. d. 3-year death-censored graft survival rates: 87% vs. 88%.

Objective: To determine whether a defect in energy metabolism exists in infants with cystic fibrosis (CF). Design: Unselected, newly-diagnosed subjects With CF (n = 46) and 24 healthy infants aged

Bronchoalveolar lavage (BAL) performed in specialist centres has improved the understanding of infant cystic fibrosis (CF) lung disease. As most researchers sample from a single lobe, it was determined whether BAL results could be generalized to other lung segments.Thirty-three CF children, aged 1.5–57 months, underwent in random order sequential BAL of their right middle and lingula lobes. Specimens from each lobe had separate quantitative bacteriology, cytology and cytokine analysis.Bacterial counts ≥1×105colony forming units (cfu)·mL−1were observed in nine (27%) subjects, including six involving only the right middle lobe. These six children had similar inflammatory indices in their right middle and lingula lobes, and interleukin (IL)-8 concentrations in the latter were significantly higher than that observed within the lingula lobes of the 24 CF children with bacterial counts 5 cfu·mL−1. Lingula neutrophil and IL-8 levels correlated best with right middle lobe bacteria numbers.This observational study in cystic fibrosis children suggests that while inflammation is detected in both lungs, bacterial distribution may be more inhomogeneous. Bronchoalveolar lavage microbiological findings from a single lobe may therefore, not be generalized to other lung segments. When performing bronchoalveolar lavage in cystic fibrosis children, it is important to sample from multiple sites.

Potential renal transplant recipients with preformed antibodies to HLA resulting from previous transplants, pregnancy, and/or transfusions are unlikely to receive an allograft. The factors contributing to the long-term maintenance of antibody titers in these individuals are still unknown. In the present study, we sought to determine whether chimerism in the blood correlates with maintenance of HLA sensitization in highly sensitized patients.Qualitative analysis of chimerism in blood of sensitized patients was assessed by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) to HLA-DR. PCR single-strand conformation polymorphism (PCR-SSCP) was used to confirm the extra HLA-DR antigens detected by PCR-SSOP.Fourteen of 36 patients (38.9%) were positive for more than two HLA-DR indicative of chimerism. The presence of extra HLA-DR was confirmed by PCR-SSCP. When patients were analyzed on the basis of their panel-reactive antibody (PRA) status, 10 of 15 (66.7%) were positive for chimerism in the sensitized group, compared with only two of eight (25%) in the unsensitized group. Of the five males in the sensitized group who had received a blood transfusion but not a transplant, three were positive for chimerism. An association was observed between chimerism and maintenance of sensitization. None of the eight normal subjects studied demonstrated chimerism.The results obtained with sensitized patients suggest an association between blood chimerism and maintenance of HLA sensitization. We speculate that chimerism may lead to long-term maintenance of anti-HLA antibody titers. This finding implies that abolition of chimerism could result in the eventual elimination of antigenic stimuli for antibody production against HLA antigens.

Malnutrition was once thought to be an inevitable consequence of cystic fibrosis (CF). It is now considered preventable but still contributes considerable morbidity in children. Malnutrition is linked to poorer pulmonary function, reduced survival and quality of life. As the anticipated lifespan of children with CF continues to lengthen, the prevention of malnutrition attains greater importance. This review explores the complex organic and psychosocial factors implicated in the aetiology of malnutrition associated with CF.

Intracellular recording techniques were used in slices of adult rat striatum to compare the sensitivity of presynaptic γ-aminobutyric acid type B (GABA-B) autoreceptor and heteroreceptor-mediated inhibition to the sulfhydryl alkylating agent, N -ethylmaleimide (NEM). NEM (100 μM) alone had no significant effect on resting potential or input resistance and did not consistently effect stimulus-evoked responses. Treatment of slices with NEM for up to 1 h, either in the presence or the absence of the GABA-B receptor-specific agonist, baclofen (BAC; 100 μM), completely blocked the BAC-induced depression of inhibitory, but not excitatory, postsynaptic potentials. This differential sensitivity to NEM alkylation suggests that in the adult rat striatum, the presynaptic GABA-B autoreceptors and heteroreceptors may exhibit distinct receptor–effector coupling mechanisms.

Limited data in children with cystic fibrosis (CF) suggest that respiratory viral infections during infancy result in substantial morbidity. Eighty of 101 (79%) infants with CF diagnosed by neonatal screening during 1991-1996 were recruited into a prospective, multiple-birth cohort study. We aimed to perform an initial, then annual bronchoalveolar lavage (BAL) for bacterial and viral culture, cytology, IL-8, and elastolytic activity over the following 2 years. When possible, BAL was also performed during any hospitalization for a pulmonary exacerbation, and additional specimens for viral culture were collected by nasopharyngeal aspiration. Thirteen infants undergoing bronchoscopy for congenital stridor served as disease controls. During infancy, 31 children (39%) were hospitalized for respiratory disease and 20 (65%) cases had an etiologic agent identified. Respiratory viruses were detected in 16/31 (52%) cases, including four with simultaneous bacterial infection. Another four were infected with Staphylococcus aureus. Respiratory syncytial virus predominated and was found in seven infants. In the absence of bacteria, those with viral infections had acute onset of respiratory distress, were not treated with antibiotics, and had an uncomplicated hospital course. Compared to noninfected CF subjects and controls, infected infants had elevated BAL inflammatory indices (P0.01). Eleven of 31 (35%) hospitalized infants followed for 12-60 months acquired Pseudomonas aeruginosa, compared with only three of 49 (6%) subjects not hospitalized for respiratory symptoms during infancy (risk ratio 5.8, CI 1.9, 24). We conclude that respiratory viruses are important causes of hospitalization in CF infants. While viral infections were self-limited, they were accompanied by airway inflammatory changes, and admission to hospital was associated with early acquisition of Pseudomonas aeruginosa and persistent respiratory symptoms.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of a variety of hydrophobic natural and synthetic chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). Induction of CYP1A1 gene expression is one such response that is known to be regulated by the AhR complex. It was recently reported (Ledirac et al., Toxicol. Appl. Pharmacol. 144, 177-182, 1997) that, although carbaryl, a carbamate insecticide, can induce AhR-dependent expression of CYP1A1, it was not an AhR ligand. Since this apparent ligand-independent activation of the AhR is difficult to reconcile given what is known about the mechanism of AhR action, we have examined the ability of carbaryl to stimulate the AhR signaling pathway. Not only was dioxin responsive element-driven luciferase gene expression induced by carbaryl in stably transfected mouse, rat, guinea pig, and human cells, gel retardation analysis revealed that carbaryl stimulated AhR transformation and DNA binding in vitro and in cells in culture. Dose-response experiments revealed that carbaryl was 300,000-fold less potent that the prototypical inducer, TCDD, in both inducing luciferase gene expression and stimulating AhR transformation and DNA binding in vitro, suggesting that carbaryl itself was the inducing agent. The identification of carbaryl as an AhR ligand was demonstrated by its ability to competitively inhibit [3H]-TCDD to the guinea pig hepatic cytosolic AhR. Our results confirm that carbaryl is both a weak AhR ligand and inducer of AhR-dependent gene expression and argue against its proposed ligand-independent mechanism of AhR activation.

Cough is often used as an outcome measure, although the reporting of cough is unreliable. Using a 24 h ambulatory cough meter to measure cough frequency, the aim of this study was to compare: 1) the correlation of child-completed diary cards to the objective measurement, with that of parent-completed diary cards; and 2) the visual analogue scale (VAS) to the verbal category descriptive (VCD) score. The cough meter consisted of a previously validated Holter monitor and a cough processor. Eighty four children (39 with recurrent cough and 45 controls, aged 6-17 yrs) used a cough meter at least once. Thirty three subjects used the cough meter twice. Parents and children completed separate diary cards using the VAS and VCD scores. The strength of the relationship between the subjective scores and the objective recordings was analysed by spearman's rank correlation coefficient. For daytime cough, child-completed diary cards and the VCD correlated better to the objective measurement than parent-completed diary cards and the VAS, respectively. In subjects that used the cough meter twice, the difference between the cough frequency correlated to the difference in the subjective scores. The confidence intervals for the correlation coefficients were wide. The agreement between the objective and subjective presence of daytime cough was good but that for night-time cough was poor. We conclude that the severity of cough defined on diary cards may not represent cough frequency. Objective readings are first choice but currently not yet practical. The verbal category descriptive diary card completed by children and assisted by parents has the highest correlation to cough frequency measured objectively.

Asthma remains the second most common cause for admissions to a paediatric hospital bed. The aim of this study was to describe the characteristics of children admitted to hospital with an acute asthma attack and to identify factors that may prevent future hospital admissions. Parents of all children aged 3 to 15 years admitted to hospital for acute asthma were interviewed and the child's case record reviewed. Children were recruited consecutively in two groups: 141 summer/autumn and 125 winter/spring 1996. According to the pattern of symptoms in the previous 12 months, 61% of the children had infrequent episodic asthma, 26% had frequent episodic asthma, and 13% persistent asthma. Only 8% of children aged 8years or less had persistent asthma, in contrast to 22% of those aged > 8 years. There was evidence of both inadequate prescription of preventive treatment and poor compliance in the frequent episodic and persistent asthma groups. Of the whole group, 44% had previously been given an acute asthma management plan, but only 9% of them used it before the current hospital admission. There was a delay in seeking medical advice (> 24 hours after the onset of symptoms) in 27% of all admissions. This study has identified potential areas where intervention may reduce the number of future admissions.

In adults, cough sensitivity is influenced by gender and is heightened in those with non-productive cough. This study examined if cough sensitivity is (i) altered in children with asthma, recurrent cough, and cystic fibrosis and (ii) influenced by age, gender, or forced expiratory volume in one second (FEV1). Cough sensitivity to capsaicin and spirometry were performed on 209 children grouped by the diagnosis of asthma, recurrent dry cough, cystic fibrosis, and controls. Cough sensitivity was increased in children with recurrent cough, and lower in children with cystic fibrosis when compared with children with asthma and controls. Age influenced cough sensitivity in the controls. In the asthmatics, FEV1 (% predicted) correlated to cough sensitivity measures. There was no gender difference in cough sensitivity. It is concluded that cough sensitivity is different among children with recurrent dry cough, asthma, and cystic fibrosis. In children, age, but not gender, influences cough sensitivity measures and when cough sensitivity is used in comparative studies, children should be matched for age and FEV1.

Cough is commonly used as an outcome measure in clinical studies, although the subjective reporting of cough is unreliable when compared to objective measures. We describe an inexpensive new ambulatory cough meter that is based on a disused Holter monitor. The cough meter consists of a Holter monitor and a cough processor, designed on a computer to select the most appropriate filters. The cough meter was then validated against the overnight tape recorder on 21 occasions in 18 children (aged 6-15 yrs). The agreement between the cough meter and the tape recorder was good (mean difference of -0.3 coughs x h(-1); limits of agreement -2.2 to 1.7 coughs x h(-1)). We conclude that our newly described ambulatory cough meter provides a valid and inexpensive method of objectively monitoring cough for up to 24 h.

Recurrent cough and asthma are common problems in children. In the evaluation of children with recurrent cough, the sequential measurements of airway responsiveness (AR) and capsaicin cough receptor sensitivity may be useful. However, the effect of capsaicin on AR induced by an indirect stimulus such as hypertonic saline (HS) is not known. Current evidence suggests that a common pathway is involved in both capsaicin and HS challenges. This study was designed to determine whether inhalation of capsaicin for the cough receptor sensitivity test before HS challenge will alter AR of asthmatic and non-asthmatic children to that challenge. Twenty-one children (12 asthmatics, 9 non-asthmatics; mean age, 11.3 years) performed the HS challenge alone or 2 min after capsaicin inhalation on 2 different days in random order. The end point of the capsaicin inhalation was whenor = 5 coughs were stimulated from a single inhalation. The power of the study was90% at a significance level of 0.05. Capsaicin inhalation prior to HS challenge did not alter the AR of normal children. In the asthmatic group, the PD15 (provocation dose causing a fall in forced expiratory volume in 1 s ofor = 15% from the baseline) without prior inhalation of capsaicin (mean, 2.44 +/- SEM 1.21 ml) was not significantly different from that when HS challenge was performed after capsaicin inhalation (mean, 2.19 +/- SEM 0.83 ml). The mean of the difference in log PD15 of the HS challenge with and without capsaicin was -0.02 (95% CI, -0.16, 0.12), i.e. within the equivalence range of the HS challenge in children with asthma. We conclude that in normal and asthmatic children, capsaicin inhalation does not alter AR to HS; consequently the capsaicin cough sensitivity test can be performed validly before an HS challenge.

The longitudinal lung function data in 286 subjects from a 28 year follow-up of childhood asthma is reported. Airway obstruction in mid-adult life was present mainly in those with moderately severe asthma. Subjects who had been wheeze free for at least 3 years, even if asthma had been persistent in childhood, had normal lung function and no increased bronchial reactivity. Only two subjects, both with persistent asthma from childhood, failed to show an improvement in FEV1 of greater than 10% following inhalation of a beta-adrenergic agonist. Subjects with relatively mild asthma who had not taken inhaled steroids did not appear to be disadvantaged with respect to lung function.

MHC antigens, normally expressed as integral membrane proteins, are also present in soluble form in the peripheral circulation. These soluble human leukocyte antigens (sHLA) are found at elevated levels in patients with a variety of infections as well as in organ transplant recipients. In liver transplant recipients, however, most of the circulating sHLA are of donor phenotype, especially during the early posttransplant period. Here we report the purification and characterization of sHLA of both recipient and donor origin from liver transplant recipients. It was observed that sHLA consisted of four major polypeptides having molecular mass of 44, 41, 35-37, and 12 kD complexed with IgM and IgG antibodies. Further analysis revealed that these immunoglobulins contained anti-HLA antibodies. Analysis of the affinity-purified materials by a number of approaches failed to detect any other fragment(s) of HLA class I heavy chain polypeptides smaller than 12 kD. No significant difference was observed in the biochemical nature of the sHLA of donor and recipient origin and they were similar to those found in normal individuals. Affinity-purified HLA-A3 inhibited the cytolytic activity of an HLA-A3-specific CD8+ T cell line, whereas, purified sHLA-A2 failed to inhibit anti-HLA-A3 CTL activity. Further, the proliferation of the T cell line was not inhibited by sHLA-A3. Thus, the inhibitory activity shown by sHLA was antigen-specific and directed against a functional subset of T lymphocytes. These results support the notion that sHLA may play an important regulatory role in the immune response to allograft in humans.

The European Nosocomial Infection Survey enrolled 9127 patients in 14 countries providing epidemiological data on pneumonia in 325 Intensive Care Units (ICU). Ten ICUs took part in Ireland recruiting 205 patients. Using strict diagnostic criteria, the pneumonia rate for the Irish group was 11.7%; European-wide it was of 11.8%. The ICU mortality Ireland was 14.2%, in the overall survey it was 14.3%. The pneumonia mortality rate in the overall survey was 30%.

Projection neurons in the rat dorsolateral septal nucleus (DLSN) were retrogradely labeled following intraseptal injection of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP). Injections of WGA-HRP centered in the medial septum (MS) and parts of the intermediate and ventrolateral subdivisions of the lateral septum retrogradely labeled only a few centrally scattered multipolar-shaped neurons. In contrast, injections placed in the nucleus of the diagonal band of Broca (DBB) consistently resulted in labeling of DLSN neurons of all sizes and shapes. Large injections in rostral DBB appeared to retrogradely label every DLSN neuron, while similar injections in caudal DBB only labeled neurons in restricted regions of the nucleus. A collection of small cells forming the ventricular border of caudal DLSN and a group of larger cells situated in the dorsolateral tip of rostral DLSN were consistently labeled following each DBB injection. The pattern of retrogradely labeled neurons in the DLSN appeared in a complementary fashion to that seen in the other lateral septal nuclei. Our findings support the conclusion that the DLSN is a morphologically heterogeneous nucleus consisting almost entirely of projection neurons. The pattern of retrograde labeling in the lateral septum suggests that these projection neurons may be topographically organized since distinct subpopulations of cells were labeled following different injections in the MS/DBB complex.

Koro is a psychiatric syndrome rare outside certain areas of South East Asia. Most cases described outside of this area are associated with other primary psychiatric syndromes. In this case a primary Koro like syndrome precipitated a brief reactive psychosis in a 32 year old single Irish male.

Twenty-three low risk coronary artery bypass graft patients underwent a controlled study of the effects of prophylactic perioperative dopexamine hydrochloride on haemodynamic indices and peripheral perfusion. The infusion commenced following induction of anaesthesia and continued for 24 h postoperatively. The study demonstrated that dopexamine significantly increased cardiac index compared with the control group (P

The nature and timing of lower respiratory infections in infants with cystic fibrosis is largely unknown1 because infants do not produce sputum and throat cultures may not predict lower respiratory pathogens.2 We performed a prospective cross sectional study of an unselected cohort of infants with cystic fibrosis in which bronchoalveolar lavage was used to determine lower respiratory infection and inflammation during the first three months of life. The state of Victoria, Australia (66000 births per year) has a cystic fibrosis screening programme, all patients being managed by one centre. Between February 1992 and September 1994 we recruited 45 (27 boys) of the 52 infants with newly diagnosed disease; 32 were identified by screening, 12 from meconium ileus, and one by failure to thrive, and all cases were confirmed by sweat testing. Sixteen infants had respiratory symptoms, and seven of them were receiving oral antibiotics when bronchoalveolar lavage was performed at a mean age of 2.6 (SD 1.6) months. Nine otherwise healthy infants (five boys) aged …

Purpose: The changing expectations, therapies and outcomes for young people with cystic fibrosis (CF) necessitate a re-evaluation of the impact of this chronic illness on adolescent development. The aim of this study was to assess the psychological well-being and adjustment of contemporary adolescents with CF. Methods: Forty-nine adolescents with CF (24 males, 25 females) aged 14–18 years were enrolled from the Royal Children's Hospital CF Clinic, Melbourne, Australia. The Offer Self-Image Questionnaire was administered to participating subjects whose growth and pubertal developmental and pulmonary function was assessed. Results: The mean (SD) FEV1% was 82 (21), and mean (SD) National Institute of Health clinical score was 81 (12). There were no significant differences between males and females in pulmonary function or clinical scores, but growth and pubertal development were delayed in both sexes. Females, but not males, with CF were less well-adjusted than their healthy peers. Two-way analysis of variance was performed and showed significant sex differences in sub-scales of the Offer questionnaire numbers I, II, III, VI, VIII, IX, as well as in the total score. Age was significant only for scales II and VIII, and only scale II displayed an interaction between sex and age. Conclusions: This study suggests that adjustment and self-esteem are less than ideal in young people with CF, especially females.