The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat.

Allergen challenges induce airway hyperresponsiveness (AHR) and increased airway smooth muscle (ASM) mass in the sensitized rat. Whether the remodeled ASM changes its phenotype is uncertain. We examined, in sensitized Brown Norway rats, the effects of multiple ovalbumin (Ova) challenges on ASM remodeling and phenotype and the role of the epidermal growth factor receptor (EGFR) in these processes. Rats were sensitized with Ova and challenged three times at 5-day intervals with phosphate-buffered saline or Ova and pretreated with the EGFR inhibitor AG-1478 (5 mg/kg) or its vehicle dimethyl sulfoxide. Ova challenges increased ASM mass in all-sized airways and in large airway mRNA expression of smooth muscle myosin heavy chain (sm-MHC), assessed by laser capture. Myosin light chain kinase and the fast myosin isoform SM-B mRNA expressions were not affected. Ova induced AHR to methacholine, and, based on the constant-phase model, this was largely attributable to the small airways and lung derecruitment at 48 h that recovered by 1 wk. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor (HB-EGF) were increased in bronchoalveolar lavage fluid at 48 h after Ova exposure. AG-1478 inhibited AHR and prevented ASM growth. Epithelial gene expression of EGFR, HB-EGF, matrix metalloproteinase (MMP)-9, Gro-α, and transforming growth factor-ß was unaffected by Ova challenges. We conclude that EGFR drives remodeling of ASM, which results from repeated Ova challenge. Furthermore, the latter results in excessive small airway and, to a lesser degree, large airway narrowing to methacholine, and large airway gene expression of contractile protein is conserved.

European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full supplement publication.

Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010.  They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.

Enhanced imaging of developed fingerprints using mass spectrometry imaging.

Latent fingermarks are invisible to the naked eye and normally require the application of a chemical developer followed by an optical imaging step in order to visualize the ridge detail. If the finger deposition is poor, or the fingermark is aged, it can sometimes be difficult to produce an image of sufficient quality for identification. In this work, we show for the first time how mass spectrometry imaging (in this case time-of-flight secondary ion mass spectrometry, ToF-SIMS) can be used to enhance the quality of partially recovered fingermarks. We show three examples of how chemical imaging can be used to obtain enhanced images of fingermarks deposited on aluminium foil, glass and the handle of a hand grenade compared with conventional development techniques.

Microarray and allergenic activity assessment of milk allergens.

BACKGROUND: Cow's milk is one of the most common causes of food allergy affecting approximately 2.5% of infants in the first years of their life. However, only limited information regarding the allergenic activity of individual cow's milk allergens is available. OBJECTIVE: To analyse the frequency of IgE reactivity and to determine the allergenic activity of individual cow's milk allergens. METHODS: A nitrocellulose-based microarray, based on purified natural and recombinant cow's milk allergens was used to determine IgE reactivity profiles using sera from 78 cow's milk-sensitized individuals of varying ages. The allergenic activity of the individual allergens was tested using patients' sera for loading rat basophil leukaemia cells (RBL) expressing the α-chain of the human receptor FcεRI. RESULTS: Using the microarray and the RBL assay, cow's milk allergens were assessed for frequency of IgE recognition and allergenic activity. Moreover, the RBL assay allowed distinguishing individuals without or with mild clinical reactions from those with severe systemic or gastrointestinal symptoms as well as persons who grew out cow's milk allergy from those who did not. CONCLUSIONS: Component-resolved testing using milk allergen microarrays and RBL assays seems to provide useful additional diagnostic information and may represent a basis for future forms of prophylactic and therapeutic strategies for cow's milk allergy.

The amino terminus of the yeast F1-ATPase beta-subunit precursor functions as a mitochondrial import signal.

The ATP2 gene of Saccharomyces cerevisiae codes for the cytoplasmically synthesized beta-subunit protein of the mitochondrial F1-ATPase. To define the amino acid sequence determinants necessary for the in vivo targeting and import of this protein into mitochondria, we have constructed gene fusions between the ATP2 gene and either the Escherichia coli lacZ gene or the S. cerevisiae SUC2 gene (which codes for invertase). The ATP2-lacZ and ATP2-SUC2 gene fusions code for hybrid proteins that are efficiently targeted to yeast mitochondria in vivo. The mitochondrially associated hybrid proteins fractionate with the inner mitochondrial membrane and are resistant to proteinase digestion in the isolated organelle. Results obtained with the gene fusions and with targeting-defective ATP2 deletion mutants provide evidence that the amino-terminal 27 amino acids of the beta-subunit protein precursor are sufficient to direct both specific sorting of this protein to yeast mitochondria and its import into the organelle. Also, we have observed that certain of the mitochondrially associated Atp2-LacZ and Atp2-Suc2 hybrid proteins confer a novel respiration-defective phenotype to yeast cells.

Is sonographic surveillance of polytetrafluoroethylene-covered transjugular intrahepatic portosystemic shunts (TIPS) necessary? A single centre experience comparing both types of stents.

AIM: To investigate whether sonographic (US) surveillance of polytetrafluoroethylene covered transjugular intrahepatic portosystemic shunts (TIPS) is necessary. MATERIALS AND METHODS: We identified 128 patients who underwent TIPS for complications of portal hypertension between January 2001 and December 2005 at a large tertiary centre. Procedural data were retrospectively analysed. US surveillance of the TIPS was performed at baseline with scheduled follow-up or whenever shunt dysfunction was suspected. Clinical and radiology reports were compared to assess US surveillance of the TIPS. RESULTS: Four hundred and twenty-six US studies were performed, with a median of three per patient (range 1-5). The median follow-up period was 378 days (range 1-1749 days). Twenty-three patients (18%) had baseline US studies performed only whereas 105 (82%) also had follow-up studies. Forty-one (32%) of 128 patients [32 (78%) Wallstent, nine (22%) Viatorr] had Doppler ultrasound abnormalities noted. Venography was performed in all 41 patients. Abnormal venography and elevated hepatic venous pressure gradient (HVPG) was seen in 34 (82.9%) of the 41 patients [29 (85.3%) Wallstent, five (14.7%) Viatorr]. Among the 34 patients, 17 (50%) [13 (76.5%) Wallstent, four (23.5%) Viatorr] had venographic abnormalities noted at the hepatic venous end accompanied by increased HVPG. All four of the Viatorr patients had minor narrowing at the hepatic venous end and HVPG measurements that ranged 3-4 mm Hg above 12 mm Hg. CONCLUSION: Considering the improved patency of covered stents in TIPS, US surveillance may be superfluous after the baseline study.

Mammographic features and histopathological findings of interval breast cancers.

BACKGROUND: Interval cancers are considered a shortcoming in screening mammography due to less favorable prognostic tumor characteristics compared to screening-detected cancers and consequently a lower chance of survival from the disease. PURPOSE: To describe the mammographic features and prognostic histopathological tumor characteristics of interval breast cancers. MATERIAL AND METHODS: A total of 231 interval breast cancer cases diagnosed in prevalently screened women aged 50-69 years old were examined. Thirty-five percent of the cases were retrospectively classified as missed cancers, 23% as minimal sign, and 42% as true negative (including occult cancers) in a definitive classification performed by six experienced breast radiologists. The retrospective classification described the mammographic features of the baseline screening mammograms in missed and minimal-sign interval cancers, while histopathological reports were used to describe the tumor characteristics in all the subgroups of interval cancers. RESULTS: Fifty percent of the missed and minimal-sign interval cancers combined presented poorly defined mass or asymmetric density, and 26% calcifications with or without associated density or mass at baseline screening. Twenty-seven percent of invasive tumors were <15 mm for missed and 47% for true interval cancers (P<0.001). Lymph node involvement was more common in missed (49%) compared with the true cases (33%, P<0.05). CONCLUSION: Missed interval cancers have less prognostically favorable histopathological tumor characteristics compared with true interval cancers. Improving the radiologist's perception and interpretation by establishing systematic collection of features and implementation of organized reviews may decrease the number of interval cancers in a screening program.

Audit feedback on reading performance of screening mammograms: An international comparison.

OBJECTIVE: Providing feedback to mammography radiologists and facilities may improve interpretive performance. We conducted a web-based survey to investigate how and why such feedback is undertaken and used in mammographic screening programmes. METHODS: The survey was sent to representatives in 30 International Cancer Screening Network member countries where mammographic screening is offered. RESULTS: Seventeen programmes in 14 countries responded to the survey. Audit feedback was aimed at readers in 14 programmes, and facilities in 12 programmes. Monitoring quality assurance was the most common purpose of audit feedback. Screening volume, recall rate, and rate of screen-detected cancers were typically reported performance measures. Audit reports were commonly provided annually, but more frequently when target guidelines were not reached. CONCLUSION: The purpose, target audience, performance measures included, form and frequency of the audit feedback varied amongst mammographic screening programmes. These variations may provide a basis for those developing and improving such programmes.

Ultradian rapid cycling in prepubertal and early adolescent bipolarity is not in transmission disequilibrium with val/met COMT alleles.

BACKGROUND: Prepubertal children and early adolescents with bipolar disorders (PEA-BP) who participate in the ongoing study "Phenomenology and Course of Pediatric Bipolar Disorders" have a high prevalence of ultradian (within 24-hour periods) rapid cycling. Based on a case-control finding reported in bipolar (BP) adults of an association between rapid and ultradian rapid cycling with the low-activity allele of catechol-O-methyltransferase (l-COMT), study of linkage and linkage disequilibrium of l-COMT in the PEA-BP population seemed warranted. METHODS: Genotypes on a subset of the larger PEA-BP sample, for whom trio blood collection was complete (i. e., probands and both of their biological parents), were used to perform transmission disequilibrium tests (TDTs). Diagnoses were established from a comprehensive battery that included WASH-U-KSADS (Washington University Kiddie Schedule for Affective Disorders and Schizophrenia) given to both mothers and children and from consensus conferences. Probands with PEA-BP (N = 52) were 10.9 +/- 2.8 years old at index episode; had a mean age of BP onset at 8.0 +/- 3.8 years; were severely impaired, with a mean Children's Global Assessment Scale score of 44.5 +/- 8.9; and manifested the cardinal features of BP (84.6% had euphoric mood, 76.9% had grandiosity, and 57.7% had psychosis). Ultradian rapid cycling occurred in 75%. Genotyping of the single nucleotide polymorphism at COMT was performed using automated capillary electrophoresis single-strand conformational polymorphism with detection by laser-induced fluorescence. RESULTS: Transmission disequilibrium tests were not significant for preferential transmission of l-COMT for the ultradian rapid-cycling subgroup or for the entire PEA-BP sample. CONCLUSIONS: The lack of linkage disequilibrium between l-COMT and ultradian rapid cycling in the PEA-BP sample compared to reported findings of an association in case-control studies of adults is discussed in terms of age-specific developmentally relevant phenotypes, anticipatory mechanisms, and heterogeneity. Repeat TDT analyses after these PEA-BP probands reach their adult phenotypes will be informative.

Serotonin transporter gene (HTTLPR) is not in linkage disequilibrium with prepubertal and early adolescent bipolarity.

BACKGROUND: As part of an ongoing, larger study, "Phenomenology and Course of Pediatric Bipolarity", a subset of prepubertal and early adolescent onset bipolar (PEA-BP) probands, on whom trio blood collection was complete, were used to study genetic transmission of the serotonin transporter linked promoter region (HTTLPR) short and long alleles using the transmission disequilibrium test(TDT). The HTTLPR alleles were selected based on postulated serotonergic mechanisms for PEA-BP and on the burgeoning number of HTTLPR allele studies in bipolar (BP) adults. METHODS: There were 46 complete trios of PEA-BP probands and both biological parents. Probands had a mean age of 11.1 +/- 3.0 years and a mean age of onset of PEA-BP of 8.1 +/- 4.0 years. Comprehensive diagnostic assessments included a semi-structured research interview, the WASH-U-KSADS, administered separately to mothers and to children by blind raters. Probands manifested severe impairment (CGAS 43.9 +/- 8.9), elated mood (84.8%), grandiosity (78.3%), rapid cycling (78.3%) and psychosis (63.0%). The HTTLPR length variant was genotyped using fluorescently labeled primers and automated capillary electrophoresis using laser-induced fluorescence. RESULTS: The TDT was not significant (TDT chi square = .020, df = 1, p = .89). CONCLUSIONS: This negative result is consistent with the one negative TDT and two negative linkage studies of HTTLPR alleles in bipolar adults in the literature.

Preliminary data on the dexamethasone suppression test in children with major depressive disorder.

The authors administered the dexamethasone suppression test to 14 children aged 5-12 years who met the Research Diagnostic Criteria and DSM-III criteria for major depressive disorder. The dexamethasone dose used was 20 micrograms/kg; 2 subjects were nonsuppressors.

Dose and plasma levels of nortriptyline and chlorpromazine in delusionally depressed adolescents and of nortriptyline in nondelusionally depressed adolescents.

Eight adolescents with major depressive disorder were treated with nortriptyline and six adolescents with delusional depression were treated with combined nortriptyline and chlorpromazine. Dose and plasma levels of nortriptyline for the two groups were compared. The delusional group receiving combined drug treatment needed significantly less nortriptyline than did the nondelusional group receiving only nortriptyline to obtain similar mean steady state plasma levels of the drug. The mean plasma chlorpromazine levels were quite low.

Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder.

OBJECTIVE: The authors' goal was to conduct an adult follow-up of subjects who had participated in a study of nortriptyline for childhood depression. METHOD: The study group represented 100 (90. 9%) of the original 110 subjects and included 72 subjects who had a prepubertal diagnosis of major depressive disorder and 28 normal comparison subjects. Subjects were assessed with semistructured research interviews given by research nurses who were blind to the subjects' original diagnoses. RESULTS: In the original study, the mean age of the children with prepubertal major depressive disorder was 10.3 years (SD=1.5); at adult follow-up the mean age of these subjects was 20.7 years (SD=2.0). At follow-up, significantly more of the subjects who had prepubertal diagnoses of major depressive disorder (N=24 [33.3%]) than normal comparison subjects (none) had bipolar I disorder. Subjects who had prepubertal diagnoses of major depressive disorder also had significantly higher rates of any bipolar disorder than normal subjects (48.6% [N=35] versus 7.1% [N=2]), major depressive disorder (36.1% [N=26] versus 14.3% [N=4]), substance use disorders (30.6% [N=22] versus 10.7% [N=3]), and suicidality (22.2% [N=16] versus 3.6% [N=1]). Parental and grandparental mania predicted bipolar I disorder outcomes. CONCLUSIONS: High rates of switching to mania have implications for the treatment of depressed children. The authors discuss the reasons for their finding a higher rate of bipolar disorder in this outcome study than was found in the one other adult outcome study of prepubertal major depressive disorder.

Preliminary data on DSM-III associated features of major depressive disorder in children and adolescents.

Fifty-nine subjects 5-16 years old with major depressive disorder were assessed for the presence of separation anxiety and antisocial behavior, mentioned in DSM-III as associated features of the disorder in children and adolescents. The findings of the study support the existence of these associated features.

Serial ECG measurements at controlled plasma levels of nortriptyline in depressed children.

The authors investigated ECG measurements in 21 children with major depressive disorder treated with nortriptyline at plasma levels of 50-100 ng/ml. P-R and QRS intervals and heart rate measured at baseline and once a week during treatment remained within guidelines.

Preliminary data on the relationship between nortriptyline plasma level and response in depressed children.

Twenty-two subjects 6-12 years old who met Research Diagnostic Criteria and DSM-III criteria for major depressive disorder received a fixed daily dose of nortriptyline during an 8-week protocol. Weekly plasma levels were measured; the raters performing behavioral assessments were blind to these levels. There was a highly significant difference between the mean steady-state plasma levels and the milligram-per-kilogram doses of the responders and nonresponders. The data suggest that the lower limit of the therapeutic range of nortriptyline in children (over 60 ng/ml) is similar to that reported for adults. The disadvantages of the use of a milligram-per-kilogram dose rather than a pharmacokinetic approach are discussed.

One-year recovery and relapse rates of children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: The study examined 1-year recovery and relapse rates for mania in subjects who met criteria for a prepubertal and early adolescent bipolar disorder phenotype. METHOD: Outpatients identified by consecutive new-case ascertainment were assessed by means of separate child and parent interviews, consensus conferences, and blind best estimates. The definition of the prepubertal and early adolescent bipolar disorder phenotype was DSM-IV mania with elation and/or grandiosity as one criterion. RESULTS: Of 93 subjects seen at baseline, 89 were seen at 1 year (95.7% retention). The rate of recovery from mania was 37.1%, and the rate of relapse after recovery was 38.3%. No covariates were significantly associated with recovery or relapse. CONCLUSIONS: The low recovery and high relapse rates supported the study hypothesis of poor outcomes, which was made on the basis of similarity between the characteristics of the prepubertal and early adolescent bipolar disorder phenotype (long episode duration and high prevalence of mixed mania, psychosis, and rapid cycling) and those of severe bipolar disorder in adults.

Minor physical anomalies in young psychotic children.

The authors examined three groups of children for minor physical anomalies: 52 autistic children, 34 nonautistic siblings of these patients, and 29 normal controls. The total number of anomalies and the weighted score were significantly higher in the autistic children. The formation of these anomalies in the first three months of fetal life may concur with the developmental deviation of the central nervous system in some of these individuals.

Psychological management of acute paraplegia in adolescence.

Important management principles regarding emotional needs of the teenager with acute paraplegia during early hospitalization are discussed. One illustrative case is presented. Mourning reaction of the patient and family to this severe loss of bodily function is reviewed. Reaction of medical caretakers to this catastrophe is also discussed. It is emphasized that these concepts be applied by pediatricians in managing adolescent paraplegics.

Haloperidol-induced comatose state with hyperthermia and rigidity in adolescence: two case reports with a literature review.

Two adolescents who developed severe extrapyramidal and hypothalamic reactions due to haloperidol therapy are describe. This is a rarely reported result of utilizing this medication in children and youth, and caution is urged in its use. Prolonged reactions have occurred.