The antioxidant, tert-butylhydroquinone: a new cause of asthma.

The antioxidant, tert-butylhydroquinone (TBHQ), a common additive in food and cosmetics can cause allergic contact dermatitis. A 49-year-old non-atopic male factory worker developed asthma in connection with cleaning mixing drums containing TBHQ. Due to the suspicion that TBHQ might be the cause of asthma, a specific inhalation challenge was carried out. Lactose was used as a control agent. The following day he developed asthma symptoms with a 41% drop in FEV1 after 30-min exposure to small amounts of TBHQ and water. Methacholine reactivity increased 5-fold after TBHQ exposure compared to pre-exposure reactivity. This suggests that TBHQ may be the cause of asthma in this case. Due to this case respirators were introduced in the factory to reduce TBHQ exposure. TBHQ has not previously been shown to cause asthma.

Molecular imaging of neuroinflammation in patients after mild traumatic brain injury: a longitudinal 123 I-CLINDE single photon emission computed tomography study.

BACKGROUND AND PURPOSE: Neuroinflammation has been proposed as part of the pathogenesis of post-concussion symptoms (PCS), but the inflammatory response of the human brain to mild traumatic brain injury (mTBI) remains unknown. We hypothesized that a neuroinflammatory response is present in mTBI at 1-2 weeks post-injury and persists in patients with PCS. METHODS: We scanned 14 patients with mTBI without signs of structural damage at 1-2 weeks and 3-4 months post-injury and 22 healthy controls once using the single photon emission computed tomography tracer 123 I-CLINDE, which visualizes translocator protein (TSPO), a protein upregulated in active immune cells. PCS was defined as three or more persisting symptoms from the Rivermead Post Concussion Symptoms Questionnaire at 3 months post-injury. RESULTS: Across brain regions, patients had significantly higher 123 I-CLINDE binding to TSPO than healthy controls, both at 1-2 weeks after the injury in all patients (P = 0.011) and at 3-4 months in the seven patients with PCS (P = 0.006) and in the six patients with good recovery (P = 0.018). When the nine brain regions were tested separately and results were corrected for multiple comparisons, no individual region differed significantly, but all estimated parameters indicated increased 123 I-CLINDE binding to TSPO, ranging from 2% to 19% in all patients at 1-2 weeks, 13% to 27% in patients with PCS at 3-4 months and -9% to 17% in patients with good recovery at 3-4 months. CONCLUSIONS: Neuroinflammation was present in mTBI at 1-2 weeks post-injury and persisted at 3-4 months post-injury with a tendency to be most pronounced in patients with PCS.

Systemic injection of AAV9-GDNF provides modest functional improvements in the SOD1G93A ALS rat but has adverse side effects.

Injecting proteins into the central nervous system that stimulate neuronal growth can lead to beneficial effects in animal models of disease. In particular, glial cell line-derived neurotrophic factor (GDNF) has shown promise in animal and cell models of Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS). Here, systemic AAV9-GDNF was delivered via tail vein injections to young rats to determine whether this could be a safe and functional strategy to treat the SOD1G93A rat model of ALS and, therefore, translated to a therapy for ALS patients. We found that GDNF administration in this manner resulted in modest functional improvement, whereby grip strength was maintained for longer and the onset of forelimb paralysis was delayed compared to non-treated rats. This did not, however, translate into an extension in survival. In addition, ALS rats receiving GDNF exhibited slower weight gain, reduced activity levels and decreased working memory. Collectively, these results confirm that caution should be applied when applying growth factors such as GDNF systemically to multiple tissues.

First detection of TR46/Y121F/T289A and TR34/L98H alterations in Aspergillus fumigatus isolates from azole-naive patients in Denmark despite negative findings in the environment.

Azole-resistant Aspergillus fumigatus harboring the TR34/L98H or TR46/Y121F/T289A alterations is increasingly found in Europe and Asia. Here, we present the first clinical cases of TR46/Y121/T289A and three cases of TR34/L98H outside the cystic fibrosis (CF) population in Denmark and the results of environmental surveys. Four patients (2012 to 2014) with 11 A. fumigatus and 4 Rhizomucor pusillus isolates and 239 soil samples (spring 2010 and autumn 2013, respectively) with a total of 113 A. fumigatus isolates were examined. Aspergillus isolates were screened for azole resistance using azole-containing agar. Confirmatory susceptibility testing was done using the EUCAST microbroth dilution EDEF 9.1 reference method. For relevant A. fumigatus isolates, CYP51A sequencing and microsatellite genotyping were performed. Three patients harbored TR34/L98H isolates. Two were azole naive at the time of acquisition and two were coinfected with wild-type A. fumigatus or R. pusillus isolates, complicating and delaying diagnosis. The TR46/Y121F/T289A strain was isolated in 2014 from a lung transplant patient. Genotyping indicated that susceptible and resistant Aspergillus isolates were unrelated and that no transmission between patients occurred. Azole resistance was not detected in any of the 113 soil isolates. TR34/L98H and TR46/Y121F/T289A alterations appear to be emerging in the clinical setting in Denmark and now involve azole-naive patients. Two recent soil-sampling surveys in Denmark were unable to indicate any increased prevalence of azole-resistant A. fumigatus in the environment. These findings further support the demand for real-time susceptibility testing of all clinically relevant isolates and for studies investigating the seasonal variation and ecological niches for azole-resistant environmental A. fumigatus.

Gamete interactions in Xenopus laevis: identification of sperm binding glycoproteins in the egg vitelline envelope.

A quantitative assay was developed to study the interaction of Xenopus laevis sperm and eggs. Using this assay it was found that sperm bound in approximately equal numbers to the surface of both hemispheres of the unfertilized egg, but not to the surface of the fertilized egg. To understand the molecular basis of sperm binding to the egg vitelline envelope (VE), a competition assay was used and it was found that solubilized total VE proteins inhibited sperm-egg binding in a concentration-dependent manner. Individual VE proteins were then isolated and tested for their ability to inhibit sperm binding. Of the seven proteins in the VE, two related glycoproteins, gp69 and gp64, inhibited sperm-egg binding. Polyclonal antibody was prepared that specifically recognized gp69 and gp64. This gp69/64 specific antibody bound to the VE surface and blocked sperm binding, as well as fertilization. Moreover, agarose beads coated with gp69/64 showed high sperm binding activity, while beads coated with other VE proteins bound few sperm. Treatment of unfertilized eggs with crude collagenase resulted in proteolytic modification of only the gp69/64 components of the VE, and this modification abolished sperm-egg binding. Small glycopeptides generated by Pronase digestion of gp69/64 also inhibited sperm-egg binding and this inhibition was abolished by treatment of the glycopeptides with periodate. Based on these observations, we conclude that the gp69/64 glycoproteins in the egg vitelline envelope mediate sperm-egg binding, an initial step in Xenopus fertilization, and that the oligosaccharide chains of these glycoproteins may play a critical role in this process.

The relation between paracetamol use and asthma: a GA2LEN European case-control study.

Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.

A case-control study of the relation between plasma selenium and asthma in European populations: a GAL2EN project.

BACKGROUND: There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. METHODS: The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. RESULTS: All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). CONCLUSION: This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.

Vg1 and regional specification in vertebrates: a new role for an old molecule.

The Vg1 protein was discovered some ten years ago in a screen for localized maternal RNA molecules involved in early embryonic patterning in the frog Xenopus laevis. The localization of this molecule to the vegetal pole suggested that Vg1 might function as a determinant of embryonic cell fate, and its DNA sequence revealed that it is related to factors involved in induction of the mesoderm. However, it is only in the past year that evidence hinting at the role of Vg1 in early development has emerged. It now seems that although the key component for specifying a vertebrate dorsal axis has been known to us for a decade, cryptic processing pathways have kept its role in this important process hidden from view.

Genomic organization and nucleotide sequence of two distinct histone gene clusters from Xenopus laevis. Identification of novel conserved upstream sequence elements.

We have performed a detailed analysis of the genomic organization and the nucleotide sequence of two distinct Xenopus laevis histone gene clusters totaling approximately 23.5 X 10(3) base-pairs. Each cluster contains at least one copy of each of the five histone genes. However, these genes are present in different arrangements within each cluster and different H1A, H2A and H2B proteins (variants) are encoded by the respective genes of each cluster. Southern blot analysis of genomic X. laevis DNA indicates that each cluster is a member of a distinct family of tandemly repeated histone gene clusters. A comparative analysis of the nucleotide sequences flanking the histone genes within these two clusters has revealed the presence of multiple conserved sequence elements that are specific for each histone gene class and located at preferred upstream positions. Several of these elements correspond to sequences that are known to be required for maximal transcription of the corresponding genes. Most of these sequence elements have not been identified previously, although we find that many of them are present at corresponding locations upstream of histone genes from other organisms. We suggest that the conserved upstream sequence elements may play an important role in the expression of histone genes in vivo.

Ventral mesoderm induction and patterning by bone morphogenetic protein heterodimers in Xenopus embryos.

Bone morphogenetic proteins (BMPs) perform diverse functions in vertebrate development. Here we demonstrate that the heterodimeric BMP-4/7 protein directly induces ventral mesoderm and blood in Xenopus animal caps, and BMP-2/7 heterodimers may function similarly. We also provide indirect evidence that BMP heterodimers function in embryos, using assays with dominant-negative BMP ligands. Homodimeric BMP-2 and BMP-4 proteins do not induce mesoderm, but they ventralize mesoderm induction by activin. In contrast, BMP-7 protein interferes with mesoderm induction by activin, but BMP-7 stimulates ventral mesoderm induction by the heterodimer, BMP-4/7. This novel property of BMP-7 distinguishes it from other BMPs. BMP-7 may therefore function in early embryogenesis to antagonize activin signals and potentiate BMP signals. We propose that BMP heterodimers convey signals for ventral mesoderm induction and patterning in Xenopus development.

Cerebral blood flow in patients with chronic heart failure before and after heart transplantation.

BACKGROUND AND PURPOSE: Arterial blood pressure and cardiac output are often reduced in patients with chronic heart failure (CHF). Counterregulatory mechanisms with increased neurohormonal activation and changes in the distribution of cardiac output are assumed to secure vital organ perfusion. However, clinical examination of patients with CHF frequently reveals neurological symptoms with dizziness and memory problems, suggesting altered brain perfusion. In this study we determined whether cerebral blood flow (CBF) is reduced in patients with New York Heart Association (NYHA) functional class III and IV (n=12) compared with healthy control subjects (n=12). Furthermore, we examined whether heart transplantation (n=5) could restore CBF. METHODS: CBF was estimated by single-photon emission computed tomography and (133)Xe as tracer, and middle cerebral artery velocity was measured by transcranial Doppler ultrasound. RESULTS: In the CHF patients, CBF was 36+/-1 mL/min per 100 g, corresponding to a 31% reduction compared with the control group (52+/-5 mL/min per 100 g) (P<0.05). After heart transplantation, CBF increased from 35+/-3 mL/min per 100 g before transplantation to 50+/-3 mL/min per 100 g within the first postoperative month (P<0.05). CONCLUSIONS: We conclude that CBF is substantially, but reversibly, reduced in patients with NYHA class III/IV heart failure. This phenomenon suggests that redistribution of cardiac output inadequately secures brain perfusion in patients with severe CHF.

Hepatocellular carcinoma presenting as a tumour of the hilar and extrahepatic bile ducts.

A case of hepatocellular carcinoma extending within the large extra- and intrahepatic bile ducts is reported. No primary tumour was found in the liver parenchyma by abdominal ultrasound, spiral computed tomography or magnetic resonance, but transduodenal cholangioscopy showed tumour in the common hepatic ducts and the two main branches. Endoscopic biopsy showed highly differentiated hepatocellular carcinoma. The patient was treated with endoscopic biliary drainage and died at home 7 months after admittance.

The design and implementation of a ventilator-management advisor.

VentPlan is an implementation of the architecture developed by the qualitative-quantitative (QQ) research group for combining qualitative and quantitative computation in a ventilator-management advisor (VMA). VentPlan calculates recommended settings for four controls of a ventilator by evaluating the predicted effects of alternative ventilator settings. A belief network converts clinical diagnoses to distributions on physiologic parameters. A mathematical-modeling module applies a patient-specific mathematical model of cardiopulmonary physiology to predict the effects of alternative ventilator settings. A decision-theoretic plan evaluator ranks the predicted effects of alternative ventilator settings according to a multiattribute-value model that specifies physician preferences for ventilator treatments. Our architecture allows VentPlan to interpret quantitative observations in light of the clinical context (such as the clinical diagnosis). We report a retrospective study of the ventilator-setting changes encountered in postoperative patients in a surgical intensive-care unit (ICU). We conclude that the QQ architecture allows VentPlan to apply a patient-specific physiologic model to calculate ventilator settings that are optimal with respect to a decision-theoretic value model describing physician preferences for setting the ventilator.

[Occupational asthma induced by cyanoacrylate glue]. / Arbejdsbetinget astma udløst af cyanoakrylatlim.

A case of asthma due to a short period of work with ethyl-cyanoacrylate glue is reported. The diagnostic method is serial peak flow measurement. The need for preventive precautions in work with cyanoacrylates is proposed.

[Spontaneous rupture of the kidney with perirenal hemorrhage in undiagnosed polyarteritis nodosa]. / Spontan nyreruptur med perirenal blødning ved ikkeerkendt polyarteritis nodosa.

Spontaneous rupture of the kidney with perirenal haemorrhage is a rare and serious complication of polyarteritis nodosa (PAN), usually requiring urgent surgery. The present case was a 28-year old male, who had been ill for 14 days, with abdominal pain, loss of appetite, nausea and vomiting. The patient was in shock on hospital admission. Explorative laparotomy revealed a massive haemorrhage from the right kidney. The kidney was removed and histological examination of the specimen revealed polyarteritis nodosa. The clinical history of the presented case is similar to previously described cases of kidney rupture in PAN. In the case presented, however, the diagnosis was first established histologically, while the diagnosis in most of the former cases was established on renal angiography, with findings of spindle-formed renal aneurysms.

No correlation between body mass index and striatal dopamine transporter availability in healthy volunteers using SPECT and [123I]PE2I.

OBJECTIVE: Dopamine plays an important role in both the rewarding and conditioning effects of food. These effects involve mesolimbic, mesocortical, and nigrostriatal pathways. In humans, the most consistent finding has been reduced striatal dopamine D2/3 receptor availability. In striatum, dopamine is inactivated by reuptake via the dopamine transporter (DAT). The aim of the study was to test the hypothesis of lower DAT availability in obese healthy subjects using a selective DAT radiotracer in a sample of subjects with a wide range of BMI values. DESIGN AND METHODS: Thirty-three healthy subjects with a mean age of 48.4 ± 13.3 (range, 21-71) years and a mean BMI of 29.6 ± 7.8 kg/m2 (range, 21.0-49.5) were included in the study. We used [123I]PE2I and SPECT to measure DAT availability. RESULTS: Using multiple linear regression analyses with striatal DAT as the dependent variable and BMI, age and gender as predictors was performed. We found no correlation between BMI and striatal DAT availability in striatum (P = 0.99), caudate nucleus (P = 0.61), and putamen (P = 0.30). Furthermore, we found no group difference between obese/severely obese (BMI > 30 kg/m2) and normal weight controls (BMI ≤ 25 kg/m2). CONCLUSIONS: We did not find any correlation between BMI and DAT availability in healthy volunteers.