Acute endometriosis-related sigmoid perforation in pregnancy- case report.

BACKGROUND: An acute abdomen is an emergency that requires accurate diagnosis and prompt treatment. In pregnancy, the process is even more challenging and sometimes the radiological findings are unclear. Moreover, endometriosis- related complications are rare, especially in previously unknown endometriosis. CASE PRESENTATION: We report on a case of acute endometriosis-related sigmoid perforation during pregnancy (34 weeks of gestation) due to a previously unknown deep intestinal infiltrating endometriosis with focal ulceration of the affected colonic mucosa. CONCLUSIONS: Despite the low relative risk, clinicians should be aware of possible endometriosis-associated complications in pregnancy with potentially life-threatening events, even in previously unknown endometriosis. Further studies should evaluate intestinal complications during pregnancy in relation to previous treatment of intestinal endometriosis (conservative vs. surgical).

Baseline characteristics and comorbidities in the CAnadian REgistry for Pulmonary Fibrosis.

BACKGROUND: The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic interstitial lung disease (ILD) in adults. The aim of this cross-sectional sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF to date. METHODS: Patients completed study questionnaires and clinical measurements at enrollment and each follow-up visit. Environmental exposures were assessed by patient self-report and comorbidities by the Charlson Comorbidity Index (CCI). Baseline characteristics, exposures, and comorbidities were described for the overall study population and for incident cases, and were compared across ILD subtypes. RESULTS: The full cohort included 1285 patients with ILD (961 incident cases (74.8%)). Diagnoses included connective tissue disease-associated ILD (33.3%), idiopathic pulmonary fibrosis (IPF) (24.7%), unclassifiable ILD (22.3%), chronic hypersensitivity pneumonitis (HP) (7.5%), sarcoidosis (3.2%), non-IPF idiopathic interstitial pneumonias (3.0%, including idiopathic nonspecific interstitial pneumonia (NSIP) in 0.9%), and other ILDs (6.0%). Patient-reported exposures were most frequent amongst chronic HP, but common across all ILD subtypes. The CCI was ≤2 in 81% of patients, with a narrow distribution and range of values. CONCLUSIONS: CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to recommended diagnostic criteria. CCI had a very narrow distribution across our cohort suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD.

A molecular rheostat adjusts auxin flux to promote root protophloem differentiation.

Auxin influences plant development through several distinct concentration-dependent effects 1 . In the Arabidopsis root tip, polar auxin transport by PIN-FORMED (PIN) proteins creates a local auxin accumulation that is required for the maintenance of the stem-cell niche2-4. Proximally, stem-cell daughter cells divide repeatedly before they eventually differentiate. This developmental gradient is accompanied by a gradual decrease in auxin levels as cells divide, and subsequently by a gradual increase as the cells differentiate5,6. However, the timing of differentiation is not uniform across cell files. For instance, developing protophloem sieve elements (PPSEs) differentiate as neighbouring cells still divide. Here we show that PPSE differentiation involves local steepening of the post-meristematic auxin gradient. BREVIS RADIX (BRX) and PROTEIN KINASE ASSOCIATED WITH BRX (PAX) are interacting plasma-membrane-associated, polarly localized proteins that co-localize with PIN proteins at the rootward end of developing PPSEs. Both brx and pax mutants display impaired PPSE differentiation. Similar to other AGC-family kinases, PAX activates PIN-mediated auxin efflux, whereas BRX strongly dampens this stimulation. Efficient BRX plasma-membrane localization depends on PAX, but auxin negatively regulates BRX plasma-membrane association and promotes PAX activity. Thus, our data support a model in which BRX and PAX are elements of a molecular rheostat that modulates auxin flux through developing PPSEs, thereby timing PPSE differentiation.

[DGP Interstitial Lung Disease Patient Questionnaire]. / Patientenfragebogen zur Erfassung der Ursachen interstitieller und seltener Lungenerkrankungen ­ klinische Sektion der DGP.

BACKGROUND: Interstitial lung diseases (ILD) encompass different heterogeneous, mainly chronic diseases of the pulmonary interstitium and/or alveoli with known and unknown reasons. The diagnostic of ILD is challenging and should be performed interdisciplinary. The medical history is of major importance and therefore, in German-speaking countries the Frankfurter Bogen (published in 1985) was utilised to scrutinise the medical history of the patient. This by now more than 30-years-old questionnaire requires a revision with regard to content and language. METHOD: Under the auspices of the clinical section of the DGP the new Interstitial Lung Disease Patient Questionnaire was developed in collaboration amongst pulmonologist, occupational medicine physicians and psychologists and supported by patient support groups. The questionnaire was finally optimised linguistically with the help of patients. RESULTS: The newly developed patient questionnaire for interstitial and rare lung diseases encompasses different domains: initial and current symptoms, medical history questions including prior drug treatments, previous pulmonary and extrapulmonary diseases, potential exposition at home, work and leisure time as well as family history and travelling. CONCLUSION: The newly developed questionnaire can facilitate the diagnosis in patients with suspicion on interstitial lung disease in clinical routine.

Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients.

OBJECTIVES: Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity. METHODS: We performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German out-patient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat. We also evaluated factors associated with dolutegravir discontinuation. RESULTS: A total of 1950 INSTI-based therapies were initiated in 1704 patients eligible for analysis within the observation period. The estimated rates of any AE and of neuropsychiatric AEs leading to discontinuation within 12 months were 7.6% and 5.6%, respectively, for dolutegravir (n = 985), 7.6% and 0.7%, respectively, for elvitegravir (n = 287), and 3.3% and 1.9%, respectively, for raltegravir (n = 678). Neuropsychiatric AEs leading to dolutegravir discontinuation were observed more frequently in women [hazard ratio (HR) 2.64; 95% confidence interval (CI) 1.23-5.65; P = 0.012], in patients older than 60 years (HR: 2.86; 95% CI: 1.42-5.77; P = 0.003) and in human leucocyte antigen (HLA)-B*5701-negative patients who initiated abacavir at the same time (HR: 2.42; 95% CI: 1.38-4.24; P = 0.002). CONCLUSIONS: In this large cohort, the rate of discontinuation of dolutegravir because of neuropsychiatric adverse events was significantly higher than for other INSTIs, at almost 6% within 12 months. Despite the limitations of this retrospective study, the almost three-fold higher discontinuation rates observed amongst women and older patients underscore the need for further investigation, especially in patient populations usually underrepresented in clinical trials.

Inflammation and dysregulated fibroblast proliferation--new mechanisms?

Idiopathic pulmonary fibrosis (IPF) is a devastating, age-related lung disease of unknown cause that has few treatment options. Once thought to be a chronic inflammatory process, current evidence indicates that the fibrotic response may primarily be driven by abnormally activated alveolar epithelial cells and the underlying mesenchyme. The mediators produced and present in this microenvironment induce the formation of fibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The detailed mechanisms that link IPF with ageing and aberrant epithelial activation are unknown, but some evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes may play a role. This review provides a brief synopsis of highlights in the current understanding of the pathophysiology of IPF, as well as novel therapeutics being explored in clinical trials for the treatment of this devastating disease.

Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis.

Altered transforming growth factor (TGF)-ß expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-ß in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-ß1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-ß1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-ß1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-ß1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-ß1 overexpression was no longer evident. Therefore, overexpression of TGF-ß1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.

Bleomycin induces pleural and subpleural fibrosis in the presence of carbon particles.

The pathological changes in idiopathic pulmonary fibrosis (IPF) typically start in subpleural lung regions, a feature that is currently not explained. IPF, as well as bleomycin-induced lung fibrosis, are more common in smokers. We hypothesised that carbon particles, which are major components of cigarette smoke that are transported to alveoli and pleural surface, might be involved in the development of subpleural fibrosis through interaction with pleural mesothelial cells. Carbon particles were administered to mice in combination with bleomycin through intratracheal and/or intrapleural injection and fibrosis was assessed using histomorphometry. Carbon administered to the chest cavity caused severe pleural fibrosis in the presence of bleomycin, whereas bleomycin alone had no fibrogenic effect. The pleural response was associated with progressive fibrosis in subpleural regions, similar to IPF in humans. Matrix accumulation within this area evolved through mesothelial-fibroblastoid transformation, where mesothelial cells acquire myofibroblast characteristics. In contrast, carbon did not exaggerate bleomycin-induced pulmonary fibrosis after combined intratracheal administration. This represents a novel approach to induce a robust experimental model of pleural fibrosis. It also suggests that carbon particles might be involved as a cofactor in the initiation and/or progression of (subpleural) pulmonary and pleural fibrosis. Mesothelial cells appear to be critical contributors to this fibrotic process.

An exploratory study measuring verbal order content and context.

BACKGROUND: The use of verbal orders, while essential in some healthcare settings, has been identified as a potential contributor to poor quality and less safe care. Despite the widespread use of verbal orders, little research attention has been paid to understanding and measuring the content of verbal orders or variables related to the context in which verbal orders are made. AIM: This paper first identifies variables related to verbal order content and context, and then provides detailed analyses from two exploratory studies conducted in one community hospital. METHODS: The data presented were collected using both a paper-based manual audit, and an analysis of data generated from a computerised order entry system. DISCUSSION: Selected analyses focus of variations in types and timing of verbal orders hospital-wide as well as for specific inpatient units, changes in verbal order utilisation following implementation of a computerised provider order entry system, and an analysis of the presence of sound-alike and high-alert medications in verbal orders.

Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study.

BACKGROUND: Asthma is a disease characterized by variable and reversible airway obstruction and is associated with airway inflammation, airway remodelling (including goblet cell hyperplasia, increased collagen deposition and increased smooth muscle mass) and increased airway responsiveness. It is believed that airway inflammation plays a critical role in the development of airway remodelling, with IL-13 and TGF-beta1 pathways being strongly associated with the disease progression. Mouse models of asthma are capable of recapitulating some components of asthma and have been used to look at both IL-13 and TGF-beta1 pathways, which use STAT6 and SMAD2 signalling molecules, respectively. OBJECTIVES: Using brief and chronic models of allergen exposure, we utilized BALB/c and C57Bl/6 to explore the hypothesis that observed differences in responses to allergen between these mouse strains will involve fundamental differences in IL-13 and TGF-beta1 responses. METHODS: The following outcome measurements were performed: airway physiology, bronchoalveolar lavage cell counts/cytokine analysis, histology, immunoblots and gene expression assays. RESULTS: We demonstrate in BALB/c mice an IL-13-dependent phosphorylation of STAT6, nuclear localized in inflammatory cells, which is associated with indices of airway remodelling and development of airway dysfunction. In BALB/c mice, phosphorylation of SMAD2 is delayed relative to STAT6 activation and also involves an IL-13-dependent mechanism. In contrast, despite an allergen-induced increase in IL-4, IL-13 and eosinophils, C57Bl/6 demonstrates a reduced and distinct pattern of phosphorylated STAT6, no SMAD2 phosphorylation changes and fail to develop indices of remodelling or changes in airway function. CONCLUSION: The activation of signalling pathways and nuclear translocation of signalling molecules downstream of IL-13 and TGF-beta1 further support the central role of these molecules in the pathology and dysfunction in animal models of asthma. Activation of signalling pathways downstream from IL-13 and TGF-beta1 may be more relevant in disease progression than elevations in airway inflammation alone.

TGF-beta receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung.

Transforming growth factor (TGF)-beta signalling plays important roles in regulating lung development. However, the specific regulatory functions of TGF-beta signalling in developing lung epithelial versus mesenchymal cells are still unknown. By immunostaining, the expression pattern of the TGF-beta type II receptor (TbetaRII) was first determined in the developing mouse lung. The functions of TbetaRII in developing lung were then determined by conditionally knocking out TbetaRII in the lung epithelium of floxed-TbetaRII/surfactant protein C-reverse tetracycline transactivator/TetO-Cre mice versus mesenchyme of floxed-TbetaRII/Dermo1-Cre mice. TbetaRII was expressed only in distal airway epithelium at early gestation (embryonic day (E)11.5), but in both airway epithelium and mesenchyme from mid-gestation (E14.5) to post-natal day 14. Abrogation of TbetaRII in mouse lung epithelium resulted in retardation of post-natal lung alveolarisation, with markedly decreased type I alveolar epithelial cells, while no abnormality in prenatal lung development was observed. In contrast, blockade of TbetaRII in mesoderm-derived tissues, including lung mesenchyme, resulted in mildly abnormal lung branching and reduced cell proliferation after mid-gestation, accompanied by multiple defects in other organs, including diaphragmatic hernia. The primary lung branching defect was verified in embryonic lung explant culture. The novel findings of the present study suggest that transforming growth factor-beta type II receptor-mediated transforming growth factor-beta signalling plays distinct roles in lung epithelium versus mesenchyme to differentially control specific stages of lung development.

Three-dimensional computed tomography imaging in an animal model of emphysema.

Emphysema is a major health problem and novel drugs are needed. Animal disease models are pivotal in their development, but the validity and sensitivity of current tools for the evaluation of drug efficacy is limited. The usefulness of micro computed tomography (CT) as an innovative tool to assess emphysema in a mouse model was investigated. Serial CT scans were performed in bi-weekly intervals in Smad3 knockout (KO) mice, which spontaneously develop airspace enlargement. Lung density was quantified in two- and three-dimensional images and correlated to mean linear intercept and lung compliance. CT scans of Smad3 KO lungs revealed a significant decrease in lung density at age 8 weeks and a further progression at age 14 weeks with respect to age-matched wild-type (WT) animals. Emphysema could be reliably assessed with both the two- and three-dimensional approach, but the three-dimensional approach was superior, due to normalisation to lung volumes and less variability. Lung compliance by week 14 was 0.053+/-0.005 and 0.034+/-0.002% of maximum volume.cmH(2)O(-1) for KO and WT mice, respectively, reflecting significant physiologically relevant emphysema. Small animal computed tomography imaging and density quantification in a reconstructed three-dimensional image is a useful tool for quantifying emphysematous changes in an animal disease model. It adds significant information to conventional assessment.

TGF-beta, Smad3 and the process of progressive fibrosis.

Transient adenovirus-mediated gene transfer of active TGF-beta1 (transforming growth factor-beta1) induces severe and progressive fibrosis in rodent lung without apparent inflammation. Alternatively, transfer of IL-1beta (interleukin 1beta) induces marked tissue injury and inflammation, which develops into progressive fibrosis, associated with an increase in TGF-beta1 concentrations in lung fluid and tissue. Both vector treatments induce a fibrotic response involving myofibroblasts and progressive matrix deposition starting at the peri-bronchial site of expression and extending over days to involve the entire lung and pleural surface. Administration of the TGF-beta1 vector to the pleural space induces progressive pleural fibrosis, which minimally extends into the lung parenchyma. The mechanisms involved in progressive fibrosis need to account for the limitation of fibrosis to specific organs (lung fibrosis and not liver fibrosis or vice versa) and the lack of effect of anti-inflammatory treatments in regulating progressive fibrosis. TGF-beta1 is a key cytokine in the process of fibrogenesis, using intracellular signalling pathways involving the ALK5 receptor and signalling molecules Smad2 and Smad3. Transient gene transfer of either TGF-beta1 or IL-1beta to Smad3-null mouse lung provides little evidence of progressive fibrosis and no fibrogenesis-associated genes are induced. These results suggest that mechanisms of progressive fibrosis involve factors presented within the context of the matrix that define the microenvironment for progressive matrix deposition.

Assessment of the environmental impact of landfill sites with open combustion located in arid regions by combined chemical and ecotoxicological studies.

Two different waste disposal sites in Jordan were investigated in order to determine the environmental situation in context with waste disposal techniques. One landfill, located at Marka/Amman, had been closed about 25 years ago and covered with soil. Here, the waste had been actively open combusted and openings in the cover, still emitting smoke, indicated that waste was still smoldering inside the landfill's body. The second disposal site close to Ekeeder/Irbid is still operated. On this ground, the solid waste is not intentionally burned, although spontaneous fires frequently come up. Samples of waste, soil, and entrained dust were collected and analyzed. From the solid samples, respectively, their eluates, sum parameters, ecotoxicological effects as well as contents of elements/heavy metals and organic pollutants (PAH, PCDD/F) were determined. In general, the Ekeeder-samples were low-contaminated. The investigation of the Marka-samples showed higher contamination of the site's center, clearly being influenced by combustion processes. A significant contamination of the landfill's vicinity by its emissions could not be derived from the analytical data. Ecotoxicological investigations, applying a bio-test battery, revealed correlations with the sum parameters but not with the trace pollutants. Thus, the Marka-samples with the highest measured values of sum parameters caused adverse effects on three different test species, whereas other samples from Marka and Ekeeder had small or no effects. The results of these investigations depict the influence of different disposal techniques on the contamination situation of a landfill and they shall contribute to assess the conditions of other disposal sites in (semi)arid regions.

[The role of cytokines and growth factors in fibroproliferative lung disease]. / Die Bedeutung von Zytokinen und Wachstumsfaktoren bei fibrosierenden Lungenerkrankungen.

A new hypothesis of the pathogenesis of fibroproliferative lung disease suggests that fibrosis is caused by abnormal and excessive wound healing and pathologic tissue remodelling. Inflammation is possibly an epiphenomenon. Cytokines are critical players in the pathologic process and attractive targets for pharmacological intervention. TGF beta is a key profibrotic growth factor, a variety of approaches are known to modify and inhibit its activity. This article reviews the basic pathological concepts of pulmonary fibrogenesis and outlines its potential clinical benefit.

Budesonide enhances repeated gene transfer and expression in the lung with adenoviral vectors.

The immune response with generation of neutralizing antiviral antibodies is an obstacle to effective repeated adenoviral gene transfer. Different immunosuppressive drugs facilitate repeat administration of adenovectors, but the clinical utility is uncertain because of systemic side effects. We investigated the use of topical corticosteroid in improving gene expression after repeated injection of adenovectors into mouse lungs. Using a vector expressing murine interleukin-6 (mIL-6) as a marker cytokine for gene expression, we show that budesonide given around exposure to adenovirus to the lung significantly maintained high levels of expressed transgene protein in bronchoalveolar lavage fluid (BALF) after as many as four consecutive injections of virus at two weekly intervals (p = 0.02 versus saline). Differences between treatment groups were most obvious 4 and 6 wk after the initial exposure to adenovirus (equivalent to three and four total exposures). In Week 4, transgene mIL-6 concentration was 2,327 +/- 955 pg/ml in budesonide compared with 336 +/- 246 pg/ml in saline-treated mice (p = 0.001). However, budesonide did not significantly protect transgene expression beyond Week 8 (four prior exposures). The improved transgene expression in budesonide-treated compared with saline-treated animals was associated with a reduction, but not prevention of neutralizing antiviral antibodies (BALF p < 0.001, serum p = 0.04). We conclude that budesonide can be valuable in gene therapy of the lung where repeated transient gene transfer is necessary.