Agreement Between Computed Tomography and Pathologic Nodule Counts in Colorectal Lung Metastases.

BACKGROUND: Computed tomography is the most common technique used to estimate the number of pulmonary metastases and their resectability. A lack of agreement between radiologic and surgical pathologic findings could potentially lead to incomplete resection or to rejection of patients for potentially curative treatments. The objective of this study was to estimate the disagreement between the number of radiologic lesions and the number of histologically confirmed malignant lesions excised from patients with pulmonary metastases from colorectal cancer. METHODS: This was a multicenter longitudinal study using a national registry. All patients underwent open surgery for pulmonary metastasectomy. RESULTS: Radiologic unilateral involvement was documented in 345 of 404 patients (85%); 253 (73%) presented with single nodules. The radiologic and malignant pathologic findings were concordant in 316 (78%) patients. The two independent predictors of discordance between computed tomography and the number of pathologic metastases were the bilateral involvement and the number of radiologic nodules. This model explained 28% of the variability in the disagreement frequency and discriminated between agreement and disagreement in 85% of the patients. Discrepancies increased with the nodule count with an odds ratio of 6.17 (95% confidence interval, 4.08 to 9.33) per additional nodule. For similar nodule counts, a lower disagreement frequency was observed among bilateral cases (odds ratio, 0.2; 95% confidence interval, 0.07 to 0.55). CONCLUSIONS: Differences between the radiologic and pathologic findings were documented in 1 of every 5 patients. The correlation was very accurate in patients with single radiologic nodules. However, half of the patients with more nodules showed discrepancies.

[Toxicological evaluation in the childhood]. / Evaluación toxicológica del menor.

Intoxications in infancy require urgent medical treatment within national health systems. In our country they represent 0.3% of paediatric urgencies. Most of them are accidental intoxications but is not infrequent to find some related to child abuse or to suicidal intentions, especially in adolescence. The objectives of the study are to evaluate both clinical health care and medical legal aspects in intoxications in infancy. Medical assistance is described and it includes clinical diagnosis, typology of the more common toxics, percentages and referral to social work and emergency care equipment units of the Ministry of Social Welfare and the Department of Health or, where appropriate, directly to prosecutors and courts for their intervention. In cases of detection of alcohol, drugs or medication in infants, the importance of the correct interpretation of the results of toxicological findings is discussed. Several studies for the interpretation of results concerning the detection of these toxics are reported. Both legal aspects and the forensic medical opinion are assessed. The findings will be analysed by the judicial authority in order to circumscribe responsibilities or to take appropriate decisions concerning the protection of infants' interests. In conclusion intoxication in infancy can lead to legal proceedings requiring specific actions for their protection. Both physicians and hospitals must comply with the legal requirement of the submission to the court of judicial parties. On the other hand, this information is an interesting step toward reinforcing public health surveillance.

Evaluación toxicológica del menor / Toxicological evaluation in the childhood

Las intoxicaciones en la infancia requieren la atención médica urgente dentro del sistema sanitario. En nuestro país supone el 0,3% de las urgencias pediátricas. La mayoría son intoxicaciones accidentales, pero no son infrecuentes las relacionadas con el maltrato infantil o las intencionales con finalidad autolítica, especialmente en la adolescencia. Los objetivos del estudio son valorar la intoxicación en el menor en los aspectos clínicos asistenciales y medicolegales. Se valora la asistencia médica que comprende el diagnóstico clínico, el tipo de tóxicos más comunes, su frecuencia y la derivación a las unidades de trabajo social y equipos de asistencia urgente, dependientes de la Consejería de Bienestar Social y Consejería de Salud o, en su caso, la intervención directa de fiscalías y juzgados. Se discute la importancia de la correcta interpretación de los resultados toxicológicos en los casos de la detección en los menores de alcohol, drogas o medicamentos y se describen varios estudios de interpretación de resultados relativos a la detección de estos tóxicos Se valoran los aspectos legales y el dictamen médico forense. Las conclusiones se analizarán por la autoridad judicial a fin de delimitar responsabilidades o tomar decisiones que protejan los intereses del menor. En conclusión, la intoxicación de los menores puede derivar en procedimientos legales que requieran actuaciones concretas para su protección. El envío al juzgado de los partes judiciales es un requisito legal que deben cumplir los facultativos y centros sanitarios. Al mismo tiempo, esta información supone una vía de vigilancia epidemiológica de interés en salud pública (AU)

Intoxications in infancy require urgent medical treatment within national health systems. In our country they represent 0.3% of paediatric urgencies. Most of them are accidental intoxications but is not infrequent to find some related to child abuse or to suicidal intentions, especially in adolescence. The objectives of the study are to evaluate both clinical health care and medical legal aspects in intoxications in infancy. Medical assistance is described and it includes clinical diagnosis, typology of the more common toxics, percentages and referral to social work and emergency care equipment units of the Ministry of Social Welfare and the Department of Health or, where appropriate, directly to prosecutors and courts for their intervention. In cases of detection of alcohol, drugs or medication in infants, the importance of the correct interpretation of the results of toxicological findings is discussed. Several studies for the interpretation of results concerning the detection of these toxics are reported. Both legal aspects and the forensic medical opinion are assessed. The findings will be analysed by the judicial authority in order to circumscribe responsibilities or to take appropriate decisions concerning the protection of infants’ interests. In conclusion intoxication in infancy can lead to legal proceedings requiring specific actions for their protection. Both physicians and hospitals must comply with the legal requirement of the submission to the court of judicial parties. On the other hand, this information is an interesting step toward reinforcing public health surveillance (AU)

Drivers under the influence of drugs of abuse: quantification of cocaine and impaired driving.

In recent years, the interest in oral fluid as a biological matrix has significantly increased, particularly for detecting driving under the influence of drugs. In this study, the concentration of cocaine and its relationship with clinical symptoms in drivers suspected of driving under the influence of drugs was evaluated. A total of 154 samples of oral fluid, which tested positive for cocaine in previous immunoassay screening, Cozart Drug Detector System, were confirmed using gas chromatography/mass spectrometry method. In Catalonia, during 2007-2010, there were 1791 samples positive for cocaine among a total of 3468 samples taken from drivers who tested positive for any drug of abuse. The evaluation of clinical symptoms was through a questionnaire that was filled in by the police officers who collected the samples. The mean concentration of cocaine was 4.11 mg/l and median concentration was 0.38 mg/l (range 0.01-345.64 mg/l). Clinical impairment symptoms such as motor coordination, walking, speech, mood and state of pupils were not significant. The testing of oral fluids presents fewer ethical problems than blood or urine.

Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study.

BACKGROUND: The study aimed to investigate the role of medical history (skin warts, Candida albicans, herpetic lesions, heartburn, regurgitation) and medication use (for heartburn; for regurgitation; aspirin) in the aetiology of upper aerodigestive tract (UADT) cancer. METHODS: A multicentre (10 European countries) case-control study [Alcohol-Related CAncers and GEnetic susceptibility (ARCAGE) project]. RESULTS: There were 1779 cases of UADT cancer and 1993 controls. History of warts or C. albicans infection was associated with a reduced risk [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.68-0.94 and OR 0.73, 95% CI 0.60-0.89, respectively] but there was no association with herpetic lesions, heartburn, regurgitation or medication for related symptoms. Regurgitation was associated with an increased risk for cancer of the oesophagus (OR 1.47, 95% CI 0.98-2.21). Regular aspirin use was not associated with risk of UADT cancer overall but was associated with a reduced risk for cancer of oesophagus (OR 0.51, 95% CI 0.28-0.96), hypopharynx (OR 0.53, 95% CI 0.28-1.02) and larynx (OR 0.74, 95% CI 0.54-1.01). CONCLUSIONS: A history of some infections appears to be a marker for decreased risk of UADT cancer. The role of medical history and medication use varied by UADT subsites with aspirin use associated with a decreased risk of oesophageal cancer and suggestive of a decreased risk of hypopharyngeal and laryngeal cancers.

Applicability of an on-site test for its use in post-mortem blood.

The number of deaths related to drugs of abuse makes necessary the use of an on-site test for those cases in which a rapid detection of the consumed drug is required. Cozart® DDS test provides a simple, fast and reliable tool for the qualitative on-site analysis in post-mortem blood. Owing that this test is prepared for oral fluid samples, a validation becomes essential in order to use it for a different matrix than the established one. According to that, results obtained by Cozart® DDS test used in post-mortem blood samples have been compared with a qualitative gas chromatography-mass spectrometry (GC/MS/MS). Positive results for cocaine family compounds (COC-F) were 43.75%, for opiates family compounds (OPI-F) 25.78%, and for cannabis family compounds (THC-F) 2.34%. Negative results were 28.13%. No amphetamines (AMP) or methamphetamines (MA) were found. Sensitivity and specificity was available for cocaine and opiates but not for cannabis because only five cases were detected. Sensitivity, specificity, predictive positive value and predictive negative value for cocaine were 98%, 91%, 88% and 99%, respectively. Sensivilty, specificity, predictive positive value (PPV) and predictive negative value (NPV) for opiates were 93%, 92%, 76% and 98%, respectively. Likelihood positive ratios for cocaine and opiates have been 10.92 and 11.69, respectively, while likelihood negative ratios have been 0.02 and 0.08, respectively. Results show the suitability of Cozart® DDS test for the qualitative detection of cocaine and opiates in post-mortem blood.

No association between educational level and pancreatic cancer incidence in the European Prospective Investigation into Cancer and Nutrition.

INTRODUCTION: Until now, studies examining the relationship between socioeconomic status and pancreatic cancer incidence have been inconclusive. AIM: To prospectively investigate to what extent pancreatic cancer incidence varies according to educational level within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: In the EPIC study, socioeconomic status at baseline was measured using the highest level of education attained. Hazard ratios by educational level and a summary index, the relative indices of inequality (RII), were estimated using Cox regression models stratified by age, gender, and center and adjusted for known risk factors. In addition, we conducted separate analyses by age, gender and geographical region. RESULTS: Within the source population of 407, 944 individuals at baseline, 490 first incident primary pancreatic adenocarcinoma cases were identified in 9 European countries. The crude difference in risk of pancreatic cancer according to level of education was small and not statistically significant (RII=1.14, 95% CI 0.80-1.62). Adjustment for known risk factors reduced the inequality estimates to only a small extent. In addition, no statistically significant associations were observed for age groups (adjusted RII(≤ 60 years)=0.85, 95% CI 0.44-1.64, adjusted RII(>60 years)=1.18, 95% CI 0.73-1.90), gender (adjusted RII(male)=1.20, 95% CI 0.68-2.10, adjusted RII(female)=0.96, 95% CI 0.56-1.62) or geographical region (adjusted RII(Northern Europe)=1.14, 95% CI 0.81-1.61, adjusted RII(Middle Europe)=1.72, 95% CI 0.93-3.19, adjusted RII(Southern Europe)=0.75, 95% CI 0.32-1.80). CONCLUSION: Despite large educational inequalities in many risk factors within the EPIC study, we found no evidence for an association between educational level and the risk of developing pancreatic cancer in this European cohort.

Life course social mobility and risk of upper aerodigestive tract cancer in men.

The aim of this study was to explore associations between social mobility and tumours of the upper aero-digestive tract (UADT), focussing on life-course transitions in social prestige (SP) based on occupational history. 1,796 cases diagnosed between 1993 and 2005 in ten European countries were compared with 1585 controls. SP was classified by the Standard International Occupational Prestige Scale (SIOPS) based on job histories. SIOPS was categorised in high (H), medium (M) and low (L). Time weighted average achieved and transitions between SP with nine trajectories: H --> H, H --> M, H --> L, M --> H, M --> M, M --> L, L --> H, L --> M and L --> L were analysed. Odds ratios (ORs) and 95%-confidence intervals [95%-CIs] were estimated with logistic regression models including age, consumption of fruits/vegetables, study centre, smoking and alcohol consumption. The adjusted OR for the lowest versus the highest of three categories (time weighted average of SP) was 1.28 [1.04-1.56]. The distance of SP widened between cases and controls during working life. The downward trajectory H --> L gave an OR of 1.71 [0.75-3.87] as compared to H --> H. Subjects with M --> M and L --> L trajectories ORs were also elevated relative to subjects with H --> H trajectories. The association between SP and UADT is not fully explained by confounding factors. Downward social trajectory during the life course may be an independent risk factor for UADT cancers.

Socioeconomic factors associated with risk of upper aerodigestive tract cancer in Europe.

INTRODUCTION: In the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year--more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet. PATIENTS AND METHODS: A multicentre case-control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression. RESULTS: When controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR=1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators--comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR=1.60 (1.28, 2.00); and for unemployment OR=1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR=1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community). CONCLUSION: Socioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.

Drogas de abuso en detenidos en el juzgado de guardia: repercusión en el ámbito penal / Drugs of abuse in detainees at the Court: Criminal justice repercussion

Objetivos. El consumo de drogas no institucionalizadas tiene una importante dimensión epidemiológica. En la actualidad, aumenta el consumo de cocaína y de cannabis, y se estabiliza o disminuye el de opiáceos. En la mayoría de los países hay una relación entre la drogadicción y el delito. Los objetivos del estudio son: a) obtener datos sociodemográficos en una población detenida que pasa a disposición judicial; b) recoger datos sanitarios referentes a infección por el virus de la inmunodeficiencia humana (VIH) y el virus de la hepatitis B (VHB) y C (VHC); c) obtener datos de consumo de cocaína, hachís, heroína, benzodiacepinas y drogas de síntesis y d) valorar la relación de la adicción a drogas con la delictología. Material y métodos. Estudio realizado en una población de 150 sujetos consumidores de drogas ilegales en los juzgados de guardia de la ciudad de Barcelona, durante un año y medio. Se ha administrado un cuestionario con datos sociodemográficos, sanitarios y de consumo de tóxicos. Obtención de una muestra de orina que se analizó por enzimoinmuno ensayo en el analizador AsXym (Abbott). Los resultados se interpretaron como positivos o negativos según el punto de corte establecido para el método. Resultados. El perfil de la muestra es un varón soltero, con estudios primarios y sin profesión tipificada. La droga ilegal más consumida es la cocaína(77,5 %), seguida de los opiáceos (62,9 %), de las benzodiacepinas en el 61,6 % (automedicadas40,9 %) y del cannabis (60,3 %). La prevalencia clínica del VIH fue del 16,7 %, del VHB del 19,1 % y del VHC del 37,9 %. El delito más relacionado con el consumo de drogas fue el hurto. Conclusiones. Se detecta un alto consumo de cocaína y una disminución del de heroína. El consumo (..) (AU)

Objective. The consumption of illicit drugs has an important epidemiological significance. Actually cocaine and cannabis use are increasing and opiates consumption is declining. Every where relation between drug abuse and delinquency is established. The aims of the study were: a) to determine sociodemographic data related to drug consumption in a jail detents sample at court department; b) to obtain healthy data referring to VIH, VHB and VHC infections; c) to obtain cocaine, hachis, heroine, benzodiazepines and synthesis drugs consume data and d) to evaluate the relation between the addiction to drugs with the delictology. Matherial and methods. Study realized in a population of 150 subject consumers of illegal drugs in the courts of policeman of the city of Barcelona, during a year and half (AU)

Influencia de los polimorfismos en genes de metabolización de carcinógenos y riesgo de cáncer de pulmón / Metabolic gene polymorphisms and lung cancer risk

Objetivo: Comprobar que polimorfismos implicados en genes del metabolismo de carcinógenos pueden contribuir a la susceptibilidad individual a desarrollar cáncer de pulmón. Hemos estudiado la relación entre dos polimorfismos en estos genes (CYP1A1 MspI y GSTP1 Ile105Val) y el riesgo de desarrollar cáncer de pulmón.Diseño: Estudio caso control de base hospitalaria que incluye 406 casos incidentes de cáncer de pulmón y 436 controles apareados por edad, género y área geográfica. Los genotipos fueron determinados por PCR-RFLP y los resultados fueron analizados usando un método de regresión logística.Resultados: Encontramos asociación entre el polimorfismoCYP1A1MspI y el riesgo de desarrollar cáncer de pulmón mientras que no encontramos asociación al estudiar el polimorfismo GSTP1 Ile105Val. El valor de la OR ajustada obtenida en el caso del CYP1A1MspI es de 1,47; 95% CI = 0,35-6,14, lo cual indica que aumenta el riesgo a desarrollar cáncer de pulmón aunque nuestros datos no son estadísticamente significativos. Por otra parte, parece que el genotipo heterocigoto para el polimorfismoGSTP1 Ile105Val tiene un papel protector frente aldesarrollo del cáncer de pulmón en mujeres (OR ajustada=0,22; CI = 0,09-0,56).Conclusión: Nuestros resultados apoyan la hipótesis de que polimorfismos en genes implicados en el metabolismo de carcinógenos y sus combinaciones pueden influir en la etiología del cáncer de pulmón

Purpose: Polymorphisms in genes involved in carcinogens metabolism might contribute to the individual susceptibility to develop different types of cancer. We have investigated the relationship between polymorphisms in two of these genes, CYP1A1 (MspI) and GSTP (Ile105Val) and the risk of developing lung cancer.Experimental Design: A hospital-based case-control studywas designed including 406 lung cancer patients and 436control subjects matched on age, gender, and geographicalarea. Genotypes were determined by PCR-RFLP and the results were analyzed using unconditional logistic regression, adjusting for relevant confounding variables.Results: A slight association was found for CYP1A1 MspI polymorphism, while no association was observed for GSTP1Ile105Val polymorphism. In this regard, the CYP1A1MspI genotype was associated with an increased risk of lung cancer(adjusted OR=1,47; 95% CI = 0,35-6,14) but there was no statistical significance. It seems that heterozygous GSTP1 variant protects to develop lung cancer in women (adjusted OR= 0,22; CI = 0,09-0,56). Furthermore, an interaction between CYP1A1 MspI and GSTP1 Ile105Val was observed, resulting in a further increase in the risk of developing lung cancer.Conclusions: These results support the hypothesis that polymorphisms and their combined effects in metabolic genes might play a role in lung cancer etiology (AU)

Effects of starvation and desiccation on energy metabolism in desert and mesic Drosophila.

Energy availability can limit the ability of organisms to survive under stressful conditions. In Drosophila, laboratory experiments have revealed that energy storage patterns differ between populations selected for desiccation and starvation. This suggests that flies may use different sources of energy when exposed to these stresses, but the actual substrates used have not been examined. We measured lipid, carbohydrate, and protein content in 16 Drosophila species from arid and mesic habitats. In five species, we measured the rate at which each substrate was metabolized under starvation or desiccation stress. Rates of lipid and protein metabolism were similar during starvation and desiccation, but carbohydrate metabolism was several-fold higher during desiccation. Thus, total energy consumption was lower in starved flies than desiccated ones. Cactophilic Drosophila did not have greater initial amounts of reserves than mesic species, but may have lower metabolic rates that contribute to stress resistance.

Transgenic rescue implicates beta2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice.

Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from T-cell-mediated autoimmune destruction of insulin-producing pancreatic beta cells. Linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosomal susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proven problematic because of the limitations of linkage analysis. In this paper, we provide evidence implicating a single diabetes susceptibility gene, which lies outside the major histocompatibility complex region. Using allelic reconstitution by transgenic rescue, we show that NOD mice expressing the beta(2) microglobulin (beta(2)M)(a) allele develop diabetes, whereas NOD mice expressing a murine beta(2)M(b) or human allele are protected. The murine beta(2)M(a) allele differs from the beta(2)M(b) allele only at a single amino acid. Mechanistic studies indicate that the absence of the NOD beta(2)M(a) isoform on nonhematopoietic cells inhibits the development or activation of diabetogenic T cells.

Autoreactive diabetogenic T-cells in NOD mice can efficiently expand from a greatly reduced precursor pool.

A broad repertoire of pancreatic beta-cell autoreactive T-cells normally contributes to the development of type 1 diabetes in NOD mice. However, it has been unknown if a large reduction in the precursor pool from which autoreactive T-cells are drawn would inhibit the development of type 1 diabetes. To address this issue, we reduced the precursor frequency of autoreactive T-cells in NOD mice through allelic exclusion induced by transgenic expression of an H2-Db class I-restricted T-cell receptor (TCR) specific for a pathologically irrelevant lymphocytic choriomeningitis virus (LCMV) peptide. TCR allelic exclusion greatly reduced the pool of T-cells from which diabetogenic effectors could be derived in these NODxLCMV TCR Tg mice. Surprisingly, this did not impair their type 1 diabetes susceptibility. Furthermore, a diabetogenic CD8 T-cell population that is prevalent in standard NOD mice was present at essentially equivalent levels in pancreatic islets of NODxLCMV TCR Tg mice. Other data indicated that the antigenic specificity of these CD8 T-cells is primarily the function of a shared TCR-alpha chain. Although the percentage of TCR transgenic T-cells decreased in NOD versus B6,D2 control mice, much higher total numbers of both the TCR transgenic and the nontransgenic T-cells accumulated in the NOD strain. This transgenic T-cell accumulation in the absence of the cognate peptide indicated that the NOD genetic background preferentially promotes a highly efficient antigen-independent T-cell expansion. This might allow diabetogenic T-cells in NOD mice to undergo an efficient expansion before encountering antigen, which would represent an important and previously unconsidered aspect of pathogenesis.

Axonemal beta heavy chain dynein DNAH9: cDNA sequence, genomic structure, and investigation of its role in primary ciliary dyskinesia.

Dyneins are multisubunit protein complexes that couple ATPase activity with conformational changes. They are involved in the cytoplasmatic movement of organelles (cytoplasmic dyneins) and the bending of cilia and flagella (axonemal dyneins). Here we present the first complete cDNA and genomic sequences of a human axonemal dynein beta heavy chain gene, DNAH9, which maps to 17p12. The 14-kb-long cDNA is divided into 69 exons spread over 390 kb. The cDNA sequence of DNAH9 was determined using a combination of methods including 5' rapid amplification of cDNA ends, RT-PCR, and cDNA library screening. RT-PCR using nasal epithelium and testis RNA revealed several alternatively spliced transcripts. The genomic structure was determined using three overlapping BACs sequenced by the Whitehead Institute/MIT Center for Genome Research. The predicted protein, of 4486 amino acids, is highly homologous to sea urchin axonemal beta heavy chain dyneins (67% identity). It consists of an N-terminal stem and a globular C-terminus containing the four P-loops that constitute the motor domain. Lack of proper ciliary and flagellar movement characterizes primary ciliary dyskinesia (PCD), a genetically heterogeneous autosomal recessive disorder with respiratory tract infections, bronchiectasis, male subfertility, and, in 50% of cases, situs inversus (Kartagener syndrome, KS). Dyneins are excellent candidate genes for PCD and KS because in over 50% of cases the ultrastructural defects of cilia are related to the dynein complex. Genotype analysis was performed in 31 PCD families with two or more affected siblings using a highly informative dinucleotide polymorphism located in intron 26 of DNAH9. Two families with concordant inheritance of DNAH9 alleles in affected individuals were observed. A mutation search was performed in these two "candidate families," but only polymorphic variants were found. In the absence of pathogenic mutations, the DNAH9 gene has been excluded as being responsible for autosomal recessive PCD in these families.

Pressure area care in infants and children: Nimbus Paediatric System.

Survival rates in both critically and chronically ill infants and children have improved dramatically in recent years and new challenges exist in the nursing care given to these patients. Among these is the increased risk of pressure ulcer development. Children in intensive care environments are especially at risk. Prevention and management of pressure ulceration in the paediatric population requires clinical judgement and skill. The use of pressure ulcer risk assessment tools can assist in this process; however, to date, there is a lack of research evidence and further studies are needed. The pressure relief requirements of the paediatric patient are significantly different to those of the adult patient. In children under the age of 36 months, the ears and occiput are the areas most at risk of pressure injury as a result of the fact that this area is proportionately the largest and heaviest bony prominence. Despite the abundance of specialist pressure redistributing devices for adults, there is little available specifically for the paediatric patient. This article describes a review of the literature on these subject areas and follows with a short report of the evaluation of the new Paediatric Nimbus System undertaken at the Royal Hospital for Sick Children in Edinburgh.

Evidence for heterotypic interaction between the receptor tyrosine kinases TIE-1 and TIE-2.

The orphan receptor tyrosine kinase Tie-1 is expressed in endothelial cells and is essential for vascular development. Nothing is known about the signaling pathways utilized by this receptor. In this study we have used chimeric receptors composed of the TrkA ectodomain fused to the transmembrane and intracellular domains of Tie-1, or the related receptor Tie-2, to examine Tie-1 signaling capacity. In contrast to TrkA/Tie-2, the Tie-1 chimera was unable to phosphorylate cellular proteins or undergo autophosphorylation. Consistent with this Tie-1 exhibited negligible kinase activity. Co-immunoprecipitation analysis revealed Tie-1 was present in endothelial cells bound to Tie-2. Full-length Tie-1 and truncated receptor, formed by regulated endoproteolytic cleavage, were found to complex with Tie-2. Association was mediated by the intracellular domains of the receptors and did not require Tie-1 to be membrane-localized. Tie-1 bound to Tie-2 was not tyrosine-phosphorylated under basal conditions or following Tie-2 stimulation. This study provides the first evidence for the existence of a pre-formed complex of Tie-1 and Tie-2 in endothelial cells. The data suggest Tie-1 does not signal via ligand-induced kinase activation involving homo-oligomerization. The physical association between Tie-1 and Tie-2 is consistent with Tie-1 having a role in modulating Tie-2 signaling.

Fine-mapping of the type 1 diabetes locus (IDDM4) on chromosome 11q and evaluation of two candidate genes (FADD and GALN) by affected sibpair and linkage-disequilibrium analyses.

Previous studies have identified a susceptibility region for insulin-dependent (type 1) diabetes mellitus on chromosome 11q13 (IDDM4). In this study, 15 polymorphic markers were analyzed for 382 affected sibpair (ASP) families with type 1 diabetes. Our analyses provided additional evidence for linkage for IDDM4 (a peak LOD score of 3.4 at D11S913). The markers with strong linkage evidence are located within an interval of approximately 6 cM between D11S4205 and GALN. We also identified polymorphisms in two candidate genes, Fas-associated death domain protein (FADD) and galanin (GALN). Analyses of the data by transmission/disequilibrium test (TDT) and extended TDT (ETDT) did not provide any evidence for association/linkage with these candidate genes. However, ETDT did reveal significant association/linkage with the marker D11S987 (P=0.0004) within the IDDM4 interval defined by ASP analyses, suggesting that IDDM4 may be in the close proximity of D11S987.

Tie-1 receptor tyrosine kinase endodomain interaction with SHP2: potential signalling mechanisms and roles in angiogenesis.

The endothelial receptor tyrosine kinase plays an essential role in vascular development where it is thought to be required for vessel maturation and stabilization. The ligands responsible for activating Tie-1, its signalling pathways and specific cellular functions are however not known. As with some other receptor tyrosine kinases, Tie-1 is subject to extracellular proteolytic cleavage generating a membrane bound receptor fragment comprising the intracellular and transmembrane domains. Here we examine the signalling potential of this Tie-1 endodomain. We show that the Tie-1 endodomain has poor ability to induce tyrosine phosphorylation. However, on formation the endodomain physically associates with a number of tyrosine phosphorylated signalling intermediates including the tyrosine phosphatase and adaptor protein SHP2. The assembly of this multimolecular complex is consistent with the endodomain having a ligand-independent signalling role in the endothelial cell. The potential roles of ectodomain cleavage and cleavage activated signalling in regulating microvessel stability in angiogenesis, vessel remodelling and regression are considered.