Challenges of circulatory unstable pelvic fracture in Greenland.

Management of circulatory unstable pelvic fracture in Greenland - from a remote village to Level 1 Trauma center. This case report depicts the transportation of an unstable patient in a rural area, where transportation of the critically ill patient is inherently difficult due to infrastructure. The case report brings knowledge to the reader of logistic conditions in Greenland, which differ greatly from those in Denmark. Furthermore, it highlights the importance of knowledge of damage control surgery and of great intercollegiate cooperation.

N-Map: High-resolution groundwater N-retention mapping and modelling by integration of geophysical, geological, geochemical, and hydrological data.

A key aspect of protecting aquatic ecosystems from agricultural nitrogen (N) is to locate (i) farmlands where nitrate leaches from the bottom of the root zone and (ii) denitrifying zones in the aquifers where nitrate is removed before entering the surface water (N-retention). N-retention affects the choice of field mitigation measures to reduce delivered N to surface water. Farmland parcels associated with high N-retention gives the lowest impact of the targeted field measures and vice versa. In Denmark, a targeted N-regulation approach is currently implemented on small catchment scale (approx. 15 km2). Although this regulatory scale is much more detailed than what has been used previously, it is still so large that regulation for most individual fields will be either over- or under-regulated due to large spatial variation in the N-retention. The potential cost reduction for farmers is of up to 20-30% from detailed retention mapping at the field scale compared to the current small catchment scale. In this study, we present a mapping framework (N-Map) for differentiating farmland according to their N-retention, which can be used for improving the effectiveness of targeted N-regulation. The framework currently only includes N-retention in the groundwater. The framework benefits from the incorporation of innovative geophysics in hydrogeological and geochemical mapping and modelling. To capture and describe relevant uncertainties a large number of equally probable realizations are created through Multiple Point Statistical (MPS) methods. This allows relevant descriptions of uncertainties of parts of the model structure and includes other relevant uncertainty measures that affects the obtained N-retention. The output is data-driven high-resolution groundwater N-retention maps, to be used by the individual farmers to manage their cropping systems due to the given regulatory boundary conditions. The detailed mapping allows farmers to use this information in the farm planning in order to optimize the use of field measures to reduce delivered agricultural N to the surface water and thereby lower the costs of the field measures. From farmer interviews, however, it is clear that not all farms will have an economic gain from the detailed mapping as the mapping costs will exceed the potential economic gains for the farmers. The costs of N-Map is here estimated to 5-7 €/ha/year plus implementation costs at the farm. At the society level, the N-retention maps allow authorities to point out opportunities for a more targeted implementation of field measures to efficiently reduce the delivered N-load to surface waters.

Gene Transfer Agents in Symbiotic Microbes.

Prokaryotes commonly undergo genome reduction, particularly in the case of symbiotic bacteria. Genome reductions tend toward the energetically favorable removal of unnecessary, redundant, or nonfunctional genes. However, without mechanisms to compensate for these losses, deleterious mutation and genetic drift might otherwise overwhelm a population. Among the mechanisms employed to counter gene loss and share evolutionary success within a population, gene transfer agents (GTAs) are increasingly becoming recognized as important contributors. Although viral in origin, GTA particles package fragments of their "host" genome for distribution within a population of cells, often in a synchronized manner, rather than selfishly packaging genes necessary for their spread. Microbes as diverse as archaea and alpha-proteobacteria have been known to produce GTA particles, which are capable of transferring selective advantages such as virulence factors and antibiotic resistance. In this review, we discuss the various types of GTAs identified thus far, focusing on a defined set of symbiotic alpha-proteobacteria known to carry them. Drawing attention to the predicted presence of these genes, we discuss their potential within the selective marine and terrestrial environments occupied by mutualistic, parasitic, and endosymbiotic microbes.

A Role for Maternal Factors in Suppressing Cytoplasmic Incompatibility.

Wolbachia are maternally transmitted bacterial endosymbionts, carried by approximately half of all insect species. Wolbachia prevalence in nature stems from manipulation of host reproduction to favor the success of infected females. The best known reproductive modification induced by Wolbachia is referred to as sperm-egg Cytoplasmic Incompatibility (CI). In CI, the sperm of Wolbachia-infected males cause embryonic lethality, attributed to paternal chromatin segregation defects during early mitotic divisions. Remarkably, the embryos of Wolbachia-infected females "rescue" CI lethality, yielding egg hatch rates equivalent to uninfected female crosses. Several models have been discussed as the basis for Rescue, and functional evidence indicates a major contribution by Wolbachia CI factors. A role for host contributions to Rescue remains largely untested. In this study, we used a chemical feeding approach to test for CI suppression capabilities by Drosophila simulans. We found that uninfected females exhibited significantly higher CI egg hatch rates in response to seven chemical treatments that affect DNA integrity, cell cycle control, and protein turnover. Three of these treatments suppressed CI induced by endogenous wRi Wolbachia, as well as an ectopic wMel Wolbachia infection. The results implicate DNA integrity as a focal aspect of CI suppression for different Wolbachia strains. The framework presented here, applied to diverse CI models, will further enrich our understanding of host reproductive manipulation by insect endosymbionts.

[Trochlearis palsy due to chronic sinusitis].

Chronic rhinosinusitis and nasal polyposis are common rhinological diagnoses. Left untreated both diseases can result in visual dysfunctions because of their close proximity to orbita. We report a rare case of an isolated trochlear nerve palsy caused by chronic sinusitis and nasal polyposis. The patient was a healthy 54-year-old woman. She was successfully managed with sinus surgery and recovered fully. Despite the rare aetiology, diseases in the sinuses should be considered in the differential diagnosis of trochlear nerve palsy.

Quantitative methods for assessing local and bodywide contributions to Wolbachia titer in maternal germline cells of Drosophila.

BACKGROUND: Little is known about how bacterial endosymbionts colonize host tissues. Because many insect endosymbionts are maternally transmitted, egg colonization is critical for endosymbiont success. Wolbachia bacteria, carried by approximately half of all insect species, provide an excellent model for characterizing endosymbiont infection dynamics. To date, technical limitations have precluded stepwise analysis of germline colonization by Wolbachia. It is not clear to what extent titer-altering effects are primarily mediated by growth rates of Wolbachia within cell lineages or migration of Wolbachia between cells. RESULTS: The objective of this work is to inform mechanisms of germline colonization through use of optimized methodology. The approaches are framed in terms of nutritional impacts on Wolbachia. Yeast-rich diets in particular have been shown to suppress Wolbachia titer in the Drosophila melanogaster germline. To determine the extent of Wolbachia sensitivity to diet, we optimized 3-dimensional, multi-stage quantification of Wolbachia titer in maternal germline cells. Technical and statistical validation confirmed the identity of Wolbachia in vivo, the reproducibility of Wolbachia quantification and the statistical power to detect these effects. The data from adult feeding experiments demonstrated that germline Wolbachia titer is distinctly sensitive to yeast-rich host diets in late oogenesis. To investigate the physiological basis for these nutritional impacts, we optimized methodology for absolute Wolbachia quantification by real-time qPCR. We found that yeast-rich diets exerted no significant effect on bodywide Wolbachia titer, although ovarian titers were significantly reduced. This suggests that host diets affects Wolbachia distribution between the soma and late stage germline cells. Notably, relative qPCR methods distorted apparent wsp abundance, due to altered host DNA copy number in yeast-rich conditions. This highlights the importance of absolute quantification data for testing mechanistic hypotheses. CONCLUSIONS: We demonstrate that absolute quantification of Wolbachia, using well-controlled cytological and qPCR-based methods, creates new opportunities to determine how bacterial abundance within the germline relates to bacterial distribution within the body. This methodology can be applied to further test germline infection dynamics in response to chemical treatments, genetic conditions, new host/endosymbiont combinations, or potentially adapted to analyze other cell and tissue types.

Proteomics reveals a set of highly enriched proteins in epiretinal membrane compared with inner limiting membrane.

Few data exist regarding the protein composition of idiopathic epiretinal membrane (iERM). In the present study we compared the proteome of epiretinal membrane of iERM with the proteome of the inner limiting membrane (ILM) of idiopathic macular hole (iMH). Twelve epiretinal membrane samples were obtained from patients with iERM undergoing therapeutic vitrectomy. Twelve ILM samples from patients with iMH were used as controls. Proteomic analysis was conducted with discovery-based label-free quantitative nano-liquid chromatography - tandem mass spectrometry (LFQ nLC-MS/MS). Verification of results was performed with targeted MS using selected reaction monitoring on a different set of samples. Discovery data were searched against the Uniprot Homo sapiens protein database using MaxQuant Software. Identified proteins were filtered with Perseus software. Bioinformatic analysis of the differences in protein expression between epiretinal membrane from iERM and ILM from iMH was performed using STRING. A total of 2,183 different proteins were identified. 357 proteins were found to be present in all samples. The protein profile of iERM was highly different from iMH with 62 proteins found at significantly higher levels in iERM. The proteins upregulated more than 10-fold in iERM were: fibrillin-1, tenascin, prolargin, biglycan, opticin, collagen alpha-1(II) chain, protein-glutamine gamma-glutamyltransferase 2, fibronectin, filamin-A, collagen alpha-2(IX) chain, spectrin alpha chain, transforming growth factor beta induced protein ig-h3, dihydropyrimidinase - related protein 3, endoplasmin and glutamate dehydrogenase 1. Proteins with high level in iERM consisted of proteins that especially localized to the actin cytoskeleton, the extracellular matrix and the mitochondrion. Analysis of all proteins indicated that the disease process in iERM at least in part can be characterized as skin formation with perturbation of nucleotide metabolism. Our study identified proteins that have not earlier been associated with iERM. Fifteen proteins are found at very high concentration, 10-fold or more, and amongst these four proteins, fibrillin-1, tenascin, prolargin and biglycan were found at more than a 100-fold higher content compared to ILM of iMH. These proteins may be potential therapeutic targets. Data are available via ProteomeXchange with identifier PXD014286.

CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.

A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c.G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.

Predictive Genomic Analyses Inform the Basis for Vitamin Metabolism and Provisioning in Bacteria-Arthropod Endosymbioses.

The requirement of vitamins for core metabolic processes creates a unique set of pressures for arthropods subsisting on nutrient-limited diets. While endosymbiotic bacteria carried by arthropods have been widely implicated in vitamin provisioning, the underlying molecular mechanisms are not well understood. To address this issue, standardized predictive assessment of vitamin metabolism was performed in 50 endosymbionts of insects and arachnids. The results predicted that arthropod endosymbionts overall have little capacity for complete de novo biosynthesis of conventional or active vitamin forms. Partial biosynthesis pathways were commonly predicted, suggesting a substantial role in vitamin provisioning. Neither taxonomic relationships between host and symbiont, nor the mode of host-symbiont interaction were clear predictors of endosymbiont vitamin pathway capacity. Endosymbiont genome size and the synthetic capacity of nonsymbiont taxonomic relatives were more reliable predictors. We developed a new software application that also predicted that last-step conversion of intermediates into active vitamin forms may contribute further to vitamin biosynthesis by endosymbionts. Most instances of predicted vitamin conversion were paralleled by predictions of vitamin use. This is consistent with achievement of provisioning in some cases through upregulation of pathways that were retained for endosymbiont benefit. The predicted absence of other enzyme classes further suggests a baseline of vitamin requirement by the majority of endosymbionts, as well as some instances of putative mutualism. Adaptation of this workflow to analysis of other organisms and metabolic pathways will provide new routes for considering the molecular basis for symbiosis on a comprehensive scale.

Incidence of cancer in adolescent idiopathic scoliosis patients treated 25 years previously.

PURPOSE: To report the incidence of cancer in a cohort of adolescent idiopathic scoliosis (AIS) patients treated 25 years previously. METHODS: 215 consecutive AIS patients treated between 1983 and 1990 were identified and requested to return for clinical and radiographic examination. The incidence of cancer was determined through chart review and follow-up interviews. Using the original radiographic log file that included patient position, mAs, kV and the total number of X-rays taken, a radiation physicist calculated the total radiation dose during treatment and follow-up adjusted for BMI and sex. RESULTS: From the original cohort of 215 consecutive AIS patients, radiation information was available in 211 of the patients, and medical charts were available in 209 AIS patients. 170 (83 %) of the 205 AIS patients participated in the follow-up study with questionnaires. The calculated mean total radiation exposure was 0.8-1.4 mSV per examination and 2.4-5.6 mSv/year. An average of 16 radiographs were taken during the treatment period. Nine AIS patients developed cancer, mostly breast (3) and endometrial (4). The AIS patients had a relative risk of 4.8 (CI 2.3-5.8, p < 0.000) for developing cancer compared to the normal Danish population. CONCLUSIONS: The overall cancer rate in this AIS cohort was 4.3 % which is five times higher than compared to the age-matched Danish population, and endometrial and breast cancer was most frequent. The radiation dose applied to the patients in this study, is comparable to modern equipment. This is to our knowledge the first study to report increased rates of endometrial cancers in a cohort of AIS patients, and future attention is needed to reduce the radiation dose distributed to the AIS patients both pre-operatively and during surgery.

Wolbachia Endosymbionts Modify Drosophila Ovary Protein Levels in a Context-Dependent Manner.

UNLABELLED: Endosymbiosis is a unique form of interaction between organisms, with one organism dwelling inside the other. One of the most widespread endosymbionts is Wolbachia pipientis, a maternally transmitted bacterium carried by insects, crustaceans, mites, and filarial nematodes. Although candidate proteins that contribute to maternal transmission have been identified, the molecular basis for maternal Wolbachia transmission remains largely unknown. To investigate transmission-related processes in response to Wolbachia infection, ovarian proteomes were analyzed from Wolbachia-infected Drosophila melanogaster and D. simulans. Endogenous and variant host-strain combinations were investigated. Significant and differentially abundant ovarian proteins were detected, indicating substantial regulatory changes in response to Wolbachia Variant Wolbachia strains were associated with a broader impact on the ovary proteome than endogenous Wolbachia strains. The D. melanogaster ovarian environment also exhibited a higher level of diversity of proteomic responses to Wolbachia than D. simulans. Overall, many Wolbachia-responsive ovarian proteins detected in this study were consistent with expectations from the experimental literature. This suggests that context-specific changes in protein abundance contribute to Wolbachia manipulation of transmission-related mechanisms in oogenesis. IMPORTANCE: Millions of insect species naturally carry bacterial endosymbionts called Wolbachia. Wolbachia bacteria are transmitted by females to their offspring through a robust egg-loading mechanism. The molecular basis for Wolbachia transmission remains poorly understood at this time, however. This proteomic study identified specific fruit fly ovarian proteins as being upregulated or downregulated in response to Wolbachia infection. The majority of these protein responses correlated specifically with the type of host and Wolbachia strain involved. This work corroborates previously identified factors and mechanisms while also framing the broader context of ovarian manipulation by Wolbachia.

[Ectopic tooth as a rare cause of foreign body reaction of the nose].

This is a case report of a 71-year-old male with three months of gradually increasing irritation, secretion and right-sided nasal stenosis. The patient had not experienced any facial trauma nor had he had any previous surgical intervention to the nasal or oral cavity. An examination of the nasal cavity raised the suspicion of a foreign body in the right nasal floor. A computed tomography was performed and a high-density, foreign body was identified. The patient was referred to the local department of otorhinolaryngology, where an ectopic tooth was successfully removed in local anaesthesia.

Health-related quality-of-life in adolescent idiopathic scoliosis patients 25 years after treatment.

BACKGROUND: Since 1962 to the mid eighties the Harrington Rod instrumentation was the Golden standard for surgical treatment of Adolescent Idiopathic Scoliosis (AIS). The Boston braces were introduced in the 1970´s and are still used as a conservative treatment, for curves less than 40°. Very few long-term studies exists, focusing on the health related quality of life. The purpose of this study was to evaluate the long-term health related outcome, in a cohort of AIS patients, treated 25 years ago. METHOD: 219 consecutive patients treated with Boston brace (Brace) or posterior spinal fusion (PSF) using Harrington- DDT instrumentation between 1983 and 1990 at Rigshospitalet Copenhagen, were invited to participate in a long-term evaluation study. A validated Danish version of the Scoliosis Research Society 22R (SRS22R) and Short Form-36 (SF36v1) were administrated to the patients two weeks before the clinical and radiological examination. RESULTS: 159 (72,6 %) patients participated in the clinical follow up and questionnaires, 11 patients participated only in the questionnaires, 8 emigrated, 4 were excluded due to progressive neurological disease and 2 were deceased. The total follow up was 170 patients (83 %), and the average follow up was 24.5 years (22-30 years). SRS22R domain scores were within the range described as normal for the general population with no statistical difference between the groups except in the Satisfaction domain, where the PSF group had better scores than the braced group. The SF36 PCS and MCS scores in both AIS cohorts were similar to the scores for the general population. CONCLUSION: HRQOLs, as measured by the SRS22R and SF-36, of adult AIS patients treated with Boston brace or PSF during adolescence were similar to the general population. No clinical progression of the deformity has been detected during the 25-year follow up period. The PSF group had a small but statistically significant higher score in the Satisfaction domain compared to the braced group. TRIAL REGISTRATION: S-20110025 Regional Committees on Health Research Ethics for Southern Denmark.

Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.

BACKGROUND CONTEXT: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. PURPOSE: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. STUDY DESIGN: This was a case control study. PATIENT SAMPLE: A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. OUTCOME MEASURE: The outcome measure was idiopathic scoliosis. METHODS: The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5'UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. RESULTS: Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10(-18)). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5'UTR, noncoding exon and promoter regions of LBX1. CONCLUSIONS: Here, we confirm LBX1 as a susceptibility gene for idiopathic scoliosis in a Scandinavian population and report that we are unable to find evidence of other genes of similar or stronger effect.

Comparative analysis of wolbachia genomes reveals streamlining and divergence of minimalist two-component systems.

Two-component regulatory systems are commonly used by bacteria to coordinate intracellular responses with environmental cues. These systems are composed of functional protein pairs consisting of a sensor histidine kinase and cognate response regulator. In contrast to the well-studied Caulobacter crescentus system, which carries dozens of these pairs, the streamlined bacterial endosymbiont Wolbachia pipientis encodes only two pairs: CckA/CtrA and PleC/PleD. Here, we used bioinformatic tools to compare characterized two-component system relays from C. crescentus, the related Anaplasmataceae species Anaplasma phagocytophilum and Ehrlichia chaffeensis, and 12 sequenced Wolbachia strains. We found the core protein pairs and a subset of interacting partners to be highly conserved within Wolbachia and these other Anaplasmataceae. Genes involved in two-component signaling were positioned differently within the various Wolbachia genomes, whereas the local context of each gene was conserved. Unlike Anaplasma and Ehrlichia, Wolbachia two-component genes were more consistently found clustered with metabolic genes. The domain architecture and key functional residues standard for two-component system proteins were well-conserved in Wolbachia, although residues that specify cognate pairing diverged substantially from other Anaplasmataceae. These findings indicate that Wolbachia two-component signaling pairs share considerable functional overlap with other α-proteobacterial systems, whereas their divergence suggests the potential for regulatory differences and cross-talk.

Radiological Outcomes in Adolescent Idiopathic Scoliosis Patients More Than 22 Years After Treatment.

STUDY DESIGN: Longitudinal cohort. OBJECTIVES: To evaluate the long-term radiologic outcomes in adolescent idiopathic scoliosis (AIS) patients more than 22 years after treatment. SUMMARY OF BACKGROUND DATA: Although treatment for AIS is prophylactic and is aimed at preventing curve progression, very few studies report long-term outcomes of treatment. METHODS: AIS patients treated with Boston brace or posterior spinal fusion (PSF) with Harrington-dorso-transverse traction (DTT) instrumentation from 1983 to 1990 were requested to return to clinic. Subsequently, 36-inch standing radiographs were obtained after patient consent. Cobb angles were compared with pretreatment and immediate posttreatment radiographs. Any evidence of adjacent-level disease or local kyphosis was also noted. RESULTS: One hundred fifty-nine (78%) of 219 patients were available for follow-up, 66 braced and 93 surgical. There were 85 females with an average age at surgery of 14.3 years and an average age at follow-up of 37.6 years. The mean length of follow-up was 24.5 years (range, 22-30 years). There was a statistically significant curve progression of 2.9° in the PSF group. There was a greater degree of curve progression in the braced group (5.5°), but this was not statistically significant. Proximal segment degeneration was seen in 8 (5%), 2 in the brace cohort and 6 in the PSF cohort. Distal segment degeneration was seen in 26 (16%) patients, 4 treated with brace and 22 treated with PSF. No patient developed proximal junction kyphosis. Three patients in the PSF cohort required additional surgery for distal adding-on. Four patients had a noncontiguous L5-S1 fusion, three from the PSF cohort and one from the braced cohort. CONCLUSION: In this cohort with an average follow-up of 24.5 years, with 78% available for follow-up, both the braced and surgically treated patients had a very small degree of curve progression, with a small incidence of distal segment degeneration and reoperation. LEVEL OF EVIDENCE: III.

A MODFLOW Infiltration Device Package for Simulating Storm Water Infiltration.

This article describes a MODFLOW Infiltration Device (INFD) Package that can simulate infiltration devices and their two-way interaction with groundwater. The INFD Package relies on a water balance including inflow of storm water, leakage-like seepage through the device faces, overflow, and change in storage. The water balance for the device can be simulated in multiple INFD time steps within a single MODFLOW time step, and infiltration from the device can be routed through the unsaturated zone to the groundwater table. A benchmark test shows that the INFD Package's analytical solution for stage computes exact results for transient behavior. To achieve similar accuracy by the numerical solution of the MODFLOW Surface-Water Routing (SWR1) Process requires many small time steps. Furthermore, the INFD Package includes an improved representation of flow through the INFD sides that results in lower infiltration rates than simulated by SWR1. The INFD Package is also demonstrated in a transient simulation of a hypothetical catchment where two devices interact differently with groundwater. This simulation demonstrates that device and groundwater interaction depends on the thickness of the unsaturated zone because a shallow groundwater table (a likely result from storm water infiltration itself) may occupy retention volume, whereas a thick unsaturated zone may cause a phase shift and a change of amplitude in groundwater table response to a change of infiltration. We thus find that the INFD Package accommodates the simulation of infiltration devices and groundwater in an integrated manner on small as well as large spatial and temporal scales.

[The sweet Christmas rash]. / Den søde julekløe

Christmas tree hypersensitivity is a rare condition, which has so far obtained scarce attention in the medical literature. We present two clinical cases of hypersensitivity associated with Christmas tree exposure, a 51-year-old woman with allergic contact dermatitis and a 41-year-old man with allergic rhinitis. The female patient had a positive patch test reaction to colophony, and the male patient had a positive skin prick test reaction to alternaria mould. Both were successfully advised to avoid prolonged exposure to Christmas trees and buy artificial trees for Christmas.

Local pulmonary administration of factor VIIa (rFVIIa) in diffuse alveolar hemorrhage (DAH) - a review of a new treatment paradigm.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a clinical syndrome with typical symptoms dyspnea and hemoptysis. DAH is a complication of specific diseases, in some cases with acute catastrophic hemoptysis, while other patients present low grade alveolar bleeding with a need of chronic transfusion as in pulmonary hemosiderosis. METHODS: Current literature in the PubMed database and other sources was reviewed in order to evaluate the current treatment recommendations, efficacy of this treatment, and finally the risk of complications after off-label use of rFVIIa in respect to DAH. OBJECTIVES: (i) To elucidate the clinical aspects of alveolar hemorrhage, (ii) to develop a simple diagnostic algorithm in order to separate DAH from other important pulmonary diseases with similar clinical picture and comparably high mortality. Such an algorithm has important therapeutic consequences because these diseases: acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) have different therapies, (iii) to evaluate and discuss whether local pulmonary administration may improve outcome and reduce mortality in DAH, and (iv) to suggest a treatment schedule. RESULTS: Hitherto the diagnosis and treatment of DAH has been based on anecdotal reports. The treatment has relied on different unspecific treatment modalities based on a mixture of treatment of the underlying disease and treatment without evidence targeted to stop the alveolar bleeding. However, recently a number of publications have advocated the use of intrapulmonary rFVIIa. Even in severe bleeding DAH has been shown to respond promptly without thromboembolic complication when FVIIa was administered locally via the air side, because the FVIIa does not penetrate the alveolo-capillary membrane to the blood-side. The incidence of DAH (in the US and Europe is 100,000-150,000, and 50,000 patients annually are at risk of developing DAH following hematopoietic stem cell transplant (HSCT) and autoimmune diseases. Finally 50,000-100,000 patients may be falsely categorized as having acute respiratory distress syndrome/acute lung injury (ARDS/ALI) because DAH and ARDS cannot be separated clinically. A new treatment paradigm of DAH is proposed as no other intervention has been able to ensure pulmonary hemostasis in DAH. The diagnosis of DAH is simple, a series of broncho-alveolar washes which become increasingly bloody. This test should be performed in all patients with pulmonary opacities in order to separate ARDS/ALI from DAH. FVIIa administrated via pulmonary route is "drug of choice", because it stops bleeding in the life-threatening syndrome DAH. Hemostasis is obtained after only one to two small doses of FVIIa (50 µg/kg body weight per dose) and after hemostasis the oxygen transport quickly improves. CONCLUSION: Intrapulmonary administration of rFVIIa is recommended as the treatment of choice for DAH and blast lung injury (BLI) because the treatment has been shown to be successful and uncomplicated in spite of the fact that only a small series of DAH has been documented.

The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm.

BACKGROUND: Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (T(H)2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the T(H)2 into the more favorable T-helper 1 (T(H)1) response. METHODS: Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF. RESULTS: It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the T(H)2 response may be transformed into an active T(H)1 state with a normal pulmonary host defense. The shift of the T(H)2 to the T(H)1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called T(H)2 subset into the more acute T(H)1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane. CONCLUSIONS: Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.