Tuberculosis in migrant populations. A systematic review of the qualitative literature.

BACKGROUND The re-emergence of tuberculosis (TB) in low-incidence countries and its disproportionate burden on immigrants is a public health concern posing specific social and ethical challenges. This review explores perceptions, knowledge, attitudes and treatment adherence behaviour relating to TB and their social implications as reported in the qualitative literature. METHODS Systematic review in four electronic databases. Findings from thirty selected studies extracted, tabulated, compared and synthesized. FINDINGS TB was attributed to many non-exclusive causes including air-born transmission of bacteria, genetics, malnutrition, excessive work, irresponsible lifestyles, casual contact with infected persons or objects; and exposure to low temperatures, dirt, stress and witchcraft. Perceived as curable but potentially lethal and highly contagious, there was confusion around a condition surrounded by fears. A range of economic, legislative, cultural, social and health system barriers could delay treatment seeking. Fears of deportation and having contacts traced could prevent individuals from seeking medical assistance. Once on treatment, family support and "the personal touch" of health providers emerged as key factors facilitating adherence. The concept of latent infection was difficult to comprehend and while TB screening was often seen as a socially responsible act, it could be perceived as discriminatory. Immigration and the infectiousness of TB mutually reinforced each another exacerbating stigma. This was further aggravated by indirect costs such as losing a job, being evicted by a landlord or not being able to attend school. CONCLUSIONS Understanding immigrants' views of TB and the obstacles that they face when accessing the health system and adhering to a treatment programme-taking into consideration their previous experiences at countries of origin as well as the social, economic and legislative context in which they live at host countries- has an important role and should be considered in the design, evaluation and adaptation of programmes.

Pore-forming pyocin S5 utilizes the FptA ferripyochelin receptor to kill Pseudomonas aeruginosa.

Pyocins are toxic proteins produced by some strains of Pseudomonas aeruginosa that are lethal for related strains of the same species. Some soluble pyocins (S2, S3 and S4) were previously shown to use the pyoverdine siderophore receptors to enter the cell. The P. aeruginosa PAO1 pore-forming pyocin S5 encoding gene (PAO985) was cloned into the expression vector pET15b, and the affinity-purified protein product tested for its killing activity against different P. aeruginosa strains. The results, however, did not show any correlation with a specific ferripyoverdine receptor. To further identify the S5 receptor, transposon mutants were generated. Pooled mutants were exposed to pyocin S5 and the resistant colonies growing in the killing zone were selected. The majority of S5-resistant mutants had an insertion in the fptA gene encoding the receptor for the siderophore pyochelin. Complementation of an fptA transposon mutant with the P. aeruginosa fptA gene in trans restored the sensitivity to S5. In order to define the receptor-binding domain of pyocin S5, two hybrid pyocins were constructed containing different regions from pyocin S5 fused to the C-terminal translocation and DNase killing domains of pyocin S2. Only the protein containing amino acid residues 151 to 300 from S5 showed toxicity, indicating that the pyocin S5 receptor-binding domain is not at the N-terminus of the protein as in other S-type pyocins. Pyocin S5 was, however, unable to kill Burkholderia cenocepacia strains producing a ferripyochelin FptA receptor, nor was the B. cenocepacia fptA gene able to restore the sensitivity of the resistant fptA mutant P. aeruginosa strain.

Neuronal in vitro models for the estimation of acute systemic toxicity.

The objective of the EU funded integrated project "ACuteTox" is to develop a strategy in which general cytotoxicity, together with organ-specific endpoints and biokinetic features, are taken into consideration in the in vitro prediction of oral acute systemic toxicity. With regard to the nervous system, the effects of 23 reference chemicals were tested with approximately 50 endpoints, using a neuronal cell line, primary neuronal cell cultures, brain slices and aggregated brain cell cultures. Comparison of the in vitro neurotoxicity data with general cytotoxicity data generated in a non-neuronal cell line and with in vivo data such as acute human lethal blood concentration, revealed that GABA(A) receptor function, acetylcholine esterase activity, cell membrane potential, glucose uptake, total RNA expression and altered gene expression of NF-H, GFAP, MBP, HSP32 and caspase-3 were the best endpoints to use for further testing with 36 additional chemicals. The results of the second analysis showed that no single neuronal endpoint could give a perfect improvement in the in vitro-in vivo correlation, indicating that several specific endpoints need to be analysed and combined with biokinetic data to obtain the best correlation with in vivo acute toxicity.

Enhanced heat shock protein 70 expression alters proteasomal degradation of IkappaB kinase in experimental acute respiratory distress syndrome.

OBJECTIVES: Acute respiratory distress syndrome is a common and highly lethal inflammatory lung syndrome. We previously have shown that an adenoviral vector expressing the heat shock protein (Hsp)70 (AdHSP) protects against experimental sepsis-induced acute respiratory distress syndrome in part by limiting neutrophil accumulation in the lung. Neutrophil accumulation and activation is modulated, in part, by the nuclear factor-kappaB (NF-kappaB) signal transduction pathway. NF-kappaB activation requires dissociation/degradation of a bound inhibitor, IkappaBalpha. IkappaBalpha degradation requires phosphorylation by IkappaB kinase, ubiquitination by the SCFbeta-TrCP (Skp1/Cullin1/Fbox beta-transducing repeat-containing protein) ubiquitin ligase, and degradation by the 26S proteasome. We tested the hypothesis that Hsp70 attenuates NF-kappaB activation at multiple points in the IkappaBalpha degradative pathway. DESIGN: Laboratory investigation. SETTING: University medical center research laboratory. SUBJECTS: Adolescent (200 g) Sprague-Dawley rats and murine lung epithelial-12 cells in culture. INTERVENTIONS: Lung injury was induced in rats via cecal ligation and double puncture. Thereafter, animals were treated with intratracheal injection of 1) phosphate buffer saline, 2) AdHSP, or 3) an adenovirus expressing green fluorescent protein. Murine lung epithelial-12 cells were stimulated with tumor necrosis factor-alpha and transfected. NF-kappaB was examined using molecular biological tools. MEASUREMENTS AND MAIN RESULTS: Intratracheal administration of AdHSP to rats with cecal ligation and double puncture limited nuclear translocation of NF-kappaB and attenuated phosphorylation of IkappaBalpha. AdHSP treatment reduced, but did not eliminate, phosphorylation of the beta-subunit of IkappaB kinase. In vitro kinase activity assays and gel filtration chromatography revealed that treatment of sepsis-induced lung injury with AdHSP induced fragmentation of the IkappaB kinase signalosome. This stabilized intermediary complexes containing IkappaB kinase components, IkappaBalpha, and NF-kappaB. Cellular studies indicate that although ubiquitination of IkappaBalpha was maintained, proteasomal degradation was impaired by an indirect mechanism. CONCLUSIONS: Treatment of sepsis-induced lung injury with AdHSP limits NF-kappaB activation. This results from stabilization of intermediary NF-kappaB/IkappaBalpha/IkappaB kinase complexes in a way that impairs proteasomal degradation of IkappaBalpha. This novel mechanism by which Hsp70 attenuates an intracellular process may be of therapeutic value.

Genetic and environmental effects on early life-history traits in salmonids

Les changements environnementaux, tels la température ou les maladies infectieuses, peuvent influencer l'évolution en induisant de la sélection, mais ceci à la seule condition qu'il y ait assez de diversité génétique pour les traits en question ou pour l'expression plastique de ces traits. Au cours cette thèse, nous avons étudié l'effet de potentielles pressions environnementales sur différents phénotypes de trois représentants des sous familles des salmonidés: l'ombre commun (Thymallus thymallus; Thymallinae), la truite de rivière {Salmo trutta; Salmoninae) et le corégone Coregonus palaea (Coregoninae). Les salmonidés se prêtent particulièrement bien à ce type d'expériences car étant hautement sensibles aux conditions environnementales, ils montrent une large variabilité dans leurs traits morphologiques, comportementaux ainsi que d'histoire de vie, tout en bénéficiant d'un large intérêt général. Nous avons testé si le sexe de l'ombre commun pouvait être modifié par la température, ce qui pourrait ainsi expliquer un changement abrupte de sex ratio observé dans l'une des plus grandes populations de Suisse. Nous n'avons trouvé aucun indice permettant de conclure que la température puisse induire ce changement chez l'ombre commun ou chez la truite de rivière. De plus nous avons étudié la plasticité de développement ainsi que d'éclosion, et avons observé des différences entre familles ainsi qu'entre populations. Alors que ces différences comportementales entre populations suggéraient une adaptation aux conditions environnementales locales, cette prédiction n'a pas été confirmée par une expérience de transplantation réciproque d'embryons entre cinq rivières de la même région. Cette étude a montré que les embryons ne survivaient pas mieux dans leur rivière d'origine, indiquant donc une absence d'adaptation locale. Nous avons aussi montré que la mortalité embryonnaire était influencée autant par des "bons gènes" que par des "gènes compatibles", que la qualité des mâles pouvait être signalée par leur coloration, et que le fait d'élever des poissons dans une pisciculture pouvait aboutir a des relations contre-intuitives entre la coloration des mâles et la qualité de leur jeunes. Nos résultats contribuent ainsi à une meilleure compréhension de l'effet de diverses pressions environnementales sur la morphologie, le comportement ou les traits d'histoire de vie chez les salmonidés. - Environmental changes, such as changes in temperatures or infection levels, can induce selection and drive evolution if there is sufficient genetic variation for the traits or the plasticity in trait expression. In this thesis, we investigated the influence of potential environmental stressors on various phenotypes in representatives of the three salmonid subfamilies: the European grayling (Thymallus thymallus; Thymallinae), the brown trout (,Salmo trutta; Salmoninae), and the whitefish Coregonus palaea (Coregoninae). Salmonids are ideal study species, as they seem sensitive to changing environmental conditions, show considerable variability in morphological, behavioral, and life history traits, and are of broad public interest. We investigated whether temperature-induced sex reversal could explain the sex-ratio distortion found in one of Switzerland's largest grayling populations. We found no evidence of temperature-induced sex reversal in either graylings or brown trout. We also examined plasticity in embryo development and the timing of hatching. We found variation at the level of family and population. Although behavioral differences between populations suggested adaptation to local environmental conditions, no indications of local adaptation could be found in reciprocal transplant experiments carried out over five rivers in the same region. We also demonstrate that embryo development and viability is influenced by 'good genes' and 'compatible genes', that the genetic quality of sires can be signaled by their grey coloration, and that raising larvae in a hatchery environment can produce counter-intuitive relationships between male phenotypes and offspring viability. Our results contribute to the understanding of how changing environmental conditions affect the phenotypes and the heritability of early life-history traits in salmonids.

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review.

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.

Modelling short-term ultraviolet exposure as an alternative to individual dosimetry

Background: Excessive exposure to solar Ultra-Violet (UV) light is the main cause of most skin cancers in humans. Factors such as the increase of solar irradiation at ground level (anthropic pollution), the rise in standard of living (vacation in sunny areas), and (mostly) the development of outdoor activities have contributed to increase exposure. Thus, unsurprisingly, incidence of skin cancers has increased over the last decades more than that of any other cancer. Melanoma is the most lethal cutaneous cancer, while cutaneous carcinomas are the most common cancer type worldwide. UV exposure depends on environmental as well as individual factors related to activity. The influence of individual factors on exposure among building workers was investigated in a previous study. Posture and orientation were found to account for at least 38% of the total variance of relative individual exposure. A high variance of short-term exposure was observed between different body locations, indicating the occurrence of intense, subacute exposures. It was also found that effective short-term exposure ranged between 0 and 200% of ambient irradiation, suggesting that ambient irradiation is a poor predictor of effective exposure. Various dosimetric techniques enable to assess individual effective exposure, but dosimetric measurements remain tedious and tend to be situation-specific. As a matter of facts, individual factors (exposure time, body posture and orientation in the sun) often limit the extrapolation of exposure results to similar activities conducted in other conditions. Objective: The research presented in this paper aims at developing and validating a predictive tool of effective individual exposure to solar UV. Methods: Existing computer graphic techniques (3D rendering) were adapted to reflect solar exposure conditions and calculate short-term anatomical doses. A numerical model, represented as a 3D triangular mesh, is used to represent the exposed body. The amount of solar energy received by each "triangle is calculated, taking into account irradiation intensity, incidence angle and possible shadowing from other body parts. The model take into account the three components of the solar irradiation (direct, diffuse and albedo) as well as the orientation and posture of the body. Field measurements were carried out using a forensic mannequin at the Payerne MeteoSwiss station. Short-term dosimetric measurements were performed in 7 anatomical locations for 5 body postures. Field results were compared to the model prediction obtained from the numerical model. Results: The best match between prediction and measurements was obtained for upper body parts such as shoulders (Ratio Modelled/Measured; Mean = 1.21, SD = 0.34) and neck (Mean = 0.81, SD = 0.32). Small curved body parts such as forehead (Mean = 6.48, SD = 9.61) exhibited a lower matching. The prediction is less accurate for complex postures such as kneeling (Mean = 4.13, SD = 8.38) compared to standing up (Mean = 0.85, SD = 0.48). The values obtained from the dosimeters and the ones computed from the model are globally consistent. Conclusion: Although further development and validation are required, these results suggest that effective exposure could be predicted for a given activity (work or leisure) in various ambient irradiation conditions. Using a generic modelling approach is of high interest in terms of implementation costs as well as predictive and retrospective capabilities.

Confirmation of natural gas explosion from methane quantification by headspace gas chromatography-mass spectrometry (HS-GC-MS) in postmortem samples: a case report.

A new analytical approach for measuring methane in tissues is presented. For the first time, the use of in situ-produced, stably labelled CDH(3) provides a reliable and precise methane quantification. This method was applied to postmortem samples obtained from two victims to help determine the explosion origin. There was evidence of methane in the adipose tissue (82 nmol/g) and cardiac blood (1.3 nmol/g) of one victim, which corresponded to a lethal methane outburst. These results are discussed in the context of the available literature to define an analysis protocol for application in the event of a gas explosion.

A case of suicide by ingestion of caffeine

Summary Intentional or unintentional caffeine abuse due to excessive intake of beverages or energy drinks containing caffeine is relatively frequent. However, death due to caffeine intoxication is rare and case reports of fatalities from caffeine toxicity are relatively infrequent. In this report, we describe an autopsy case involving a 31 year-old man who intentionally took a large amount of caffeine tablets in the form of a weight loss supplement as part of a suicide plan. Caffeine femoral blood concentration (170 mg/l) was within the toxic and potentially lethal ranges reported in the literature in similar cases. Postmortem biochemistry results suggested depressed glomerular filtration rate and prerenal failure at the time of death and failed to reveal myoglobinuria, glycosuria, ketonuria or ketonemia. Based on the absence of pathological findings at autopsy and the high blood caffeine level, death was attributed to acute caffeine toxicity. The case emphasizes the usefulness of performing exhaustive toxicology and searching for all potentially relevant information in order to formulate appropriate hypotheses concerning the cause and manner of death.

Palliative care and prehospital emergency medicine: analysis of a case series.

Palliative care, which is intended to keep patients at home as long as possible, is increasingly proposed for patients who live at home, with their family, or in retirement homes. Although their condition is expected to have a lethal evolution, the patients-or more often their families or entourages-are sometimes confronted with sudden situations of respiratory distress, convulsions, hemorrhage, coma, anxiety, or pain. Prehospital emergency services are therefore often confronted with palliative care situations, situations in which medical teams are not skilled and therefore frequently feel awkward.We conducted a retrospective study about cases of palliative care situations that were managed by prehospital emergency physicians (EPs) over a period of 8 months in 2012, in the urban region of Lausanne in the State of Vaud, Switzerland.The prehospital EPs managed 1586 prehospital emergencies during the study period. We report 4 situations of respiratory distress or neurological disorders in advanced cancer patients, highlighting end-of-life and palliative care situations that may be encountered by prehospital emergency services.The similarity of the cases, the reasons leading to the involvement of prehospital EPs, and the ethical dilemma illustrated by these situations are discussed. These situations highlight the need for more formal education in palliative care for EPs and prehospital emergency teams, and the need to fully communicate the planning and implementation of palliative care with patients and patients' family members.

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls.

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

TRPV4-associated skeletal dysplasias.

Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis. © 2012 Wiley Periodicals, Inc.

Gastrointestinal complications of post-diarrheal hemolytic uremic syndrome.

PURPOSE: Whereas gastrointestinal symptoms such as vomiting, diarrhea and abdominal pain are common in children suffering from the so-called post-diarrheal form (D+) of hemolytic uremic syndrome (HUS), more serious gastrointestinal complications are rare. We tried to define factors predictive of the severity of gastrointestinal complications post D+ HUS. METHODS: We reviewed the files of all children admitted to our hospital for D+ HUS between 1988 and 2000. We retained those cases with gastrointestinal complications and analyzed the consequences of these complications on the evolution of the children's conditions. RESULTS: Sixty-five children with D+ HUS were admitted to our hospital during this period. Sixteen children developed gastrointestinal complications involving one or more digestive organs: necrosis of the colon or ileum, hemorrhagic colitis, pancreatitis, transient diabetes, hepatic cytolysis and cholestasis, peritonitis and prolapse of the rectum. One child died. CONCLUSION: Gastrointestinal complications of D+ HUS are rare, but they can be lethal, and early surgery may sometimes prove necessary. However, we were not able to demonstrate a correlation between the severity of the gastrointestinal manifestations and the clinical or biological signs accompanying D+ HUS.

Contrast enhanced breast ultrasound to differentiate papillomas from intraductal secretion : initial experience : P22

Purpose: To describe low mechanical index grey scale contrast enhanced breast ultrasound in patients with intraductal echogenic material in the differentiation of papillomas from intraductal secretions. Methods and materials: In five patients with echographically detected ductal dilatation containing echogenic material low mechanical index grey scale contrast enhanced ultrasonography was performed. No patient had nipple discharge. The examination was performed with a 9 MHz linear transducer after injection of 4 ml of Sonovue. It was assessed if contrast enhancement was present or not. The results were correlated with histologic results after surgical resection or percutaneous biopsy when performed. Results: In 3 patients contrast enhancement was observed. These patients were operated and the papillomas confirmed by histology. In two patients no contrast enhancement was observed. In one of these two patients percutaneous biopsy was performed without evidence of a papillary lesion. The second patient presented with multiple dilated ducts containing echogenic material. No biopsy was performed but breast MRI showed no intraductal enhancement supporting the non papillary nature of the intraductal material. Conclusion: This pilot study shows that contrast enhanced ultrasound is able to detect the vascularisation of papillomas and that it may differentiate intraductal papillomas from secretions.