Benralizumab: A novel treatment for the cutaneous features of paediatric eosinophilic granulomatosis with polyangiitis (pEGPA).

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis presenting primarily with pulmonary and cutaneous features. The disease is typically seen in the fifth or sixth decade of life (1, 2). We report a case of EGPA in an adolescent who was successfully treated with the interleukin-5 (IL-5) receptor inhibitor, benralizumab.

Continued Emissions of the Ozone-Depleting Substance Carbon Tetrachloride From Eastern Asia.

Carbon tetrachloride (CCl4) is an ozone-depleting substance, accounting for about 10% of the chlorine in the troposphere. Under the terms of the Montreal Protocol, its production for dispersive uses was banned from 2010. In this work we show that, despite the controls on production being introduced, CCl4 emissions from the eastern part of China did not decline between 2009 and 2016. This finding is in contrast to a recent bottom-up estimate, which predicted a significant decrease in emissions after the introduction of production controls. We find eastern Asian emissions of CCl4 to be 16 (9-24) Gg/year on average between 2009 and 2016, with the primary source regions being in eastern China. The spatial distribution of emissions that we derive suggests that the source distribution of CCl4 in China changed during the 8-year study period, indicating a new source or sources of emissions from China's Shandong province after 2012.

VAEs with structured image covariance applied to compressed sensing MRI.

Objective.This paper investigates how generative models, trained on ground-truth images, can be used as priors for inverse problems, penalizing reconstructions far from images the generator can produce. The aim is that learned regularization will provide complex data-driven priors to inverse problems while still retaining the control and insight of a variational regularization method. Moreover, unsupervised learning, without paired training data, allows the learned regularizer to remain flexible to changes in the forward problem such as noise level, sampling pattern or coil sensitivities in MRI.Approach.We utilize variational autoencoders that generate not only an image but also a covariance uncertainty matrix for each image. The covariance can model changing uncertainty dependencies caused by structure in the image, such as edges or objects, and provides a new distance metric from the manifold of learned images.Main results.We evaluate these novel generative regularizers on retrospectively sub-sampled real-valued MRI measurements from the fastMRI dataset. We compare our proposed learned regularization against other unlearned regularization approaches and unsupervised and supervised deep learning methods.Significance.Our results show that the proposed method is competitive with other state-of-the-art methods and behaves consistently with changing sampling patterns and noise levels.

Anti-glomerular basement membrane disease in Auckland.

BACKGROUND: Anti-glomerular basement membrane (GBM) antibody-mediated disease is rare and classically presents with the syndrome of glomerulonephritis and pulmonary haemorrhage. AIM: This aim of this report was to determine the incidence, clinical features, management and outcomes of anti-GBM disease in Auckland between 1998 and 2008. METHODS: Potential patients were identified by a search for positive anti-GBM antibody serology, diagnostic renal biopsy, or in-hospital admissions using International Classification of Diseases 9 and 10 codes between 1998 and 2008. A retrospective case notes review of all potential cases was performed with data censored at 31 December 2010. RESULTS: Twenty-three cases were identified. The rate of anti-GBM disease was estimated at 1.79 per million person-years. There were 12 men and 11 women. The median age was 45 years, range 12-74 years. Sixteen patients were European, three were Pacific peoples, three were NZ Maori and one was Chinese. Eleven were regular smokers and eight ex-smokers, significantly higher proportions than the population (P ≤ 0.001). Smokers were significantly more likely to have respiratory disease (P= 0.03). The mean creatinine at presentation was 474 µmol/L. All patients had a renal biopsy; 20 had crescentic glomerulonephritis. One patient recovered renal function without treatment. Twenty-two were immunosuppressed with cyclophosphamide and corticosteroids. Seventeen received plasmapheresis. Eighteen were alive, eight with end-stage renal disease, two with chronic kidney disease and eight with normal renal function. CONCLUSIONS: Anti-GBM disease is a rare condition, which is not overrepresented among indigenous people. With aggressive therapy the prognosis has improved; however, the morbidity and mortality of this condition remain significant.

Takotsubo (apical ballooning) syndrome in the recovery period following dobutamine stress echocardiography: a first report.

We report a case of Takotsubo syndrome occurring in the recovery phase after a dobutamine stress echocardiogram. Takotsubo syndrome is a widely acknowledged cause of reversible left ventricular systolic dysfunction. It has garnered much attention from the cardiological community since its presentation frequently mimics that of ST-segment elevation myocardial infarction. The exact aetiology remains incompletely defined, although stress is recognized frequently as a precipitating factor. In recent years it has emerged that stress testing, as part of a patient's investigative assessment, can also induce Takotsubo's syndrome. All prior reports of dobutamine-induced Takotsubo's syndrome have described apical ballooning at peak stress. We describe the case of an 85-year-old lady who developed apical ballooning in the recovery period after a dobutamine stress echocardiogram, despite having normal left ventricular wall motion at rest and at peak stress. We believe this to be the first such case reported in the literature. Dobutamine stress testing can precipitate Takotsubo's syndrome not just at peak stress but also during the recovery period. All those performing dobutamine stress tests should be aware of this rare but potentially important complication.

The peripheral immune response in hyperglycemic stroke.

OBJECTIVES: Hyperglycemia is common in acute ischemic stroke patients and is associated with poor clinical outcome. However, aggressive reduction of post-stroke hyperglycemia did not improve clinical outcome, suggesting that other mechanisms are playing a detrimental role in hyperglycemic stroke. We hypothesize that the acute post-stroke immune response is altered in the hyperglycemic state leading to higher mortality and morbidity. The objective of this study was to characterize temporal changes in circulating immune cells after stroke and their association with clinical outcomes in hyperglycemic compared to euglycemic patients. PATIENTS AND METHODS: This retrospective study included 97 (58 % euglycemic, 42 % hyperglycemic) patients presenting within 12 h of symptom onset of stroke. Blood neutrophil, monocyte and lymphocyte concentrations were measured sequentially for 96 h post stroke. Primary clinical outcome was the difference in the NIH stroke scale at admission compared to discharge. Secondary outcome measures included discharge disposition and the modified Rankin Scale (mRS) at 90 days. RESULTS: Circulating neutrophils were significantly higher in hyperglycemic than in euglycemic patients within the first 48 h post stroke, while lymphocyte counts trended to be lower. Hyperglycemic patients had higher mortality rates, less favorable discharge disposition and worse neurological function at 90 days. In both groups, the neutrophil to lymphocytes ratio ((NLR) remained strongly associated with neurological function at discharge within the first 24 h (p < 0.001), and remained significant in hyperglycemic patients up to 48 h (p < 0.001). Multivariate regression analysis showed no confounding by other factors and a significant correlation with differences in NIHSS score (CI; - 9.287 to -1.46, p = 0.0077**) and NLR (CL; 0.6058-6.901, p = 0.0203*) in hyperglycemic patients. CONCLUSIONS: Our data suggests that circulating immune cells play an important role in mediating poor clinical outcome in hyperglycemic patients following stroke. The NLR is a strong predictor of neurological outcomes in hyperglycemic patients. Thus, the modulation of immune cells may be a viable therapeutic approach to improve outcomes for this high risk group.

Permeability of the cell-to-cell membrane channels in mammalian cell juncton.

The channels in the junctions of various mammalian cell types--primary cultures and lines--were probed with a series of linear fluorescent amino acid and peptide molecules of different size and charge. Permeability is limited by probe size and electronegativity, these two factors apparently being related reciprocally. In respect to both factors, mammalian junctional channels are more restrictive than insect channels; hence the mammalian channels are narrower, more polar, or both. The channels of the various mammalian cell types differed slightly from each other; in some types the serum of the culture medium affected the channel permeability.

Insulin receptor phosphorylation may not be a prerequisite for acute insulin action.

An antiserum to the insulin receptor mimicked insulin's acute actions on glucose transport, phosphorylation of integral membrane proteins, and internalization of the insulin receptor in isolated rat adipose cells. These insulinomimetic actions of the antiserum occurred without the equivalent increase in phosphorylation of the beta subunit of the insulin receptor observed with insulin. Thus, a role of receptor phosphorylation in acute insulin action is now questioned.

Size limit of molecules permeating the junctional membrane channels.

The permeability of the cell-to-cell membrane channels in salivary gland cell junction (Chironomus thummi) was probed with fluorescent-labeled amino acids and synthetic or natural peptides. Molecules up to 1200 daltons pass through the channels with velocities depending on molecular size. Molecules of 1900 daltons or greater do not pass. This passage failure seems to reflect the normal size limit for junctional channel permeation; the channels continue to be permeated by the molecules up to 1200 daltons when these are mixed with the nonpermeant molecules. From this size limit a channel diameter of 10 to 14 angstroms is estimated.

Divergent mechanisms for the insulin resistant and hyperresponsive glucose transport in adipose cells from fasted and refed rats. Alterations in both glucose transporter number and intrinsic activity.

The effects of fasting and refeeding on the glucose transport response to insulin in isolated rat adipose cells have been examined using 3-O-methylglucose transport in intact cells and cytochalasin B binding and Western blotting in subcellular membrane fractions. After a 72-h fast, basal glucose transport activity decreases slightly and insulin-stimulated activity decreases greater than 85%. Following 48 h of fasting, insulin-stimulated glucose transport activity is diminished from 3.9 +/- 0.5 to 1.3 +/- 0.3 fmol/cell per min (mean +/- SEM). Similarly, the concentrations of glucose transporters are reduced with fasting in both the plasma membranes from insulin-stimulated cells from 38 +/- 5 to 18 +/- 3 pmol/mg of membrane protein and the low density microsomes from basal cells from 68 +/- 8 to 34 +/- 9 pmol/mg of membrane protein. Ad lib. refeeding for 6 d after a 48-h fast results in up to twofold greater maximally insulin-stimulated glucose transport activity compared with the control level (7.1 +/- 0.4 vs. 4.5 +/- 0.2 fmol/cell per min), before returning to baseline at 10 d. However, the corresponding concentration of glucose transporters in the plasma membranes is restored only to the control level (45 +/- 5 vs. 50 +/- 5 pmol/mg of membrane protein). Although the concentration of glucose transporters in the low density microsomes of basal cells remains decreased, the total number is restored to the control level due to an increase in low density microsomal protein. Thus, the insulin-resistant glucose transport in adipose cells from fasted rats can be explained by a decreased translocation of glucose transporters to the plasma membrane due to a depleted intracellular pool. In contrast, the insulin hyperresponsive glucose transport observed with refeeding appears to result from (a) a restored translocation of glucose transporters to the plasma membrane from a repleted intracellular pool and (b) enhanced plasma membrane glucose transporter intrinsic activity.

A possible mechanism of insulin resistance in the rat adipose cell in streptozotocin-induced diabetes mellitus. Depletion of intracellular glucose transport systems.

The effects of insulin-dependent diabetes mellitus on glucose transport activity and on the concentrations of glucose transport systems in the plasma and low density microsomal membranes in adipose cells isolated from streptozotocin-induced diabetic rats have been examined. Glucose transport activity was assessed by measuring 3-O-methylglucose transport and the concentration of glucose transport systems estimated by measuring specific D-glucose-inhibitable cytochalasin B-binding. Basal glucose transport activity decreases from 0.19 to 0.12 fmol/cell per min with the induction of diabetes, but remains constant per unit cellular surface area and is accompanied by a constant 6 pmol of glucose transport systems/mg of membrane protein in the plasma membrane fraction. Maximally insulin-stimulated glucose transport activity decreases from 3.16 to 1.05 fmol/cell per min and from 0.26 to 0.12 amol/micrometers 2 per min, and is accompanied by a decrease from 25 to 15 pmol of glucose transport systems/mg of plasma membrane protein. These diminished effects of insulin on glucose transport activity and the concentration of glucose transport systems in the plasma membrane fraction are paralleled by a 45% decrease in the basal number of glucose transport systems per milligram of membrane protein in the low density microsomal membrane fraction, the source of those glucose transport systems appearing in the plasma membrane in response to insulin. Thus, the "insulin resistant" glucose transport of the adipose cell in the streptozotocin-induced diabetic rat appears to be the consequence of a depletion of glucose transport systems in the intracellular pool.

Mechanism of insulin-resistant glucose transport activity in the enlarged adipose cell of the aged, obese rat.

The effects of increasing cell size on glucose transport activity and metabolism and on the concentrations of glucose transport systems in both the plasma and low density microsomal membranes in isolated adipose cells from the aging rat model of obesity have been examined. Glucose transport activity was assessed by measuring l-arabinose transport and the concentration of glucose transport systems estimated by measuring specific d-glucose-inhibitable cytochalasin B-binding. Basal glucose transport activity increases from 0.3 to 1.4 fmol/cell/min with a 10-fold increase in cell size, but remains constant per unit cellular surface area and is accompanied by a constant 5 pmol of glucose transport systems/mg of membrane protein in the plasma membrane fraction. Maximally insulin-stimulated glucose transport activity, on the other hand, remains constant at 2.3 fmol/cell per min with increasing cell size, but markedly decreases per unit cellular surface area and is accompanied by a decrease from 30 pmol of glucose transport systems/mg of plasma membrane protein to the basal level. These diminished effects of insulin on glucose transport activity and the number of glucose transport systems in the plasma membrane fraction in enlarged cells are paralleled by an 80% decrease in the basal number of glucose transport systems/mg of membrane protein in the low density microsomal membrane fraction, the source of those glucose transport systems appearing in the plasma membrane in response to insulin. The effects of cell size on the metabolism of a low concentration of [1-(14)C]glucose (0.56 mM) directly parallel those on glucose transport activity and the concentration of glucose transport systems in the plasma membrane fraction, and are not associated with significant alterations in the cell's sensitivity to insulin. Thus, adipose cellular enlargement is accompanied by the development of a marked "insulin resistance" at the glucose transport level, which may be the consequence of a relative depletion of glucose transport systems in the intracellular pool.

The midcycle increase in ovarian glucose uptake is associated with enhanced expression of glucose transporter 3. Possible role for interleukin-1, a putative intermediary in the ovulatory process.

This study characterizes the rat ovary as a site of hormonally dependent glucose transporter (Glut) expression, and explores the potential role of interleukin (IL)-1, a putative intermediary in the ovulatory process, in this regard. Molecular probing throughout a simulated estrous cycle revealed a significant surge in ovarian Glut3 (but not Glut1) expression at the time of ovulation. Treatment of cultured whole ovarian dispersates from immature rats with IL-1beta resulted in upregulation of the relative abundance of the Glut1 (4.5-fold) and Glut3 (3.5-fold) proteins as determined by Western blot analysis. Other members of the Glut family (i.e., Gluts 2, 4, and 5) remained undetectable. The ability of IL-1 to upregulate Glut1 and Glut3 transcripts proved time-, dose-, nitric oxide-, and protein biosynthesis-dependent but glucose independent. Other ovarian agonists (i.e., TNF alpha, IGF-I, interferon-gamma, and insulin) were without effect. Taken together, our findings establish the mammalian ovary as a site of cyclically determined Glut1 and Glut3 expression, and disclose the ability of IL-1 to induce the ovarian expression as well as translation of Glut1 and Glut3 (but not of Gluts 2, 4, or 5). Our observations also establish IL-1 as the first known regulator of Glut3, the most efficient Glut known to date. In so doing, IL-1, a putative component of the ovulatory process, may be acting to meet the increased metabolic demands imposed on the growing follicle and the ovulated cumulus-enclosed oocyte.

First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India.

In Kerala, south-western India, five patients developed systemic envenoming after bites by hump-nosed pit vipers (Hypnale hypnale), proved by identification of the snakes responsible. Two of the dead snakes had been misidentified as saw-scaled vipers (Echis carinatus), while three had remained unidentified. Symptoms of local envenoming were pain, swelling, haemorrhagic blistering, bruising and regional lymphadenopathy. Systemic symptoms included headache, nausea, vomiting and abdominal and chest pain. There was evidence of haemostatic dysfunction (coagulopathy, fibrinolysis, thrombocytopenia or spontaneous systemic haemorrhage) in all cases and of microangiopathic haemolysis in two. Two patients were haemodialysed for acute renal failure, one of whom developed pulmonary oedema requiring mechanical ventilation. In India, H. hypnale has not previously been regarded as a cause of frequent or potentially dangerous envenoming. Its medical importance has been overlooked throughout its geographical range, probably because of confusion with other small species. No specific antivenom exists, yet most patients are treated with non-specific antivenoms, risking reactions without hope of benefit. An effective antivenom is urgently needed in south India and in Sri Lanka, where this species is also a common cause of bites.

Clinical features in a family with an R460H mutation in transforming growth factor beta receptor 2 gene.

OBJECTIVES: To describe the clinical findings and natural history in 22 carriers of an R460H mutation in the transforming growth factor beta receptor 2 gene (TGFbetaR2) from a five-generation kindred ascertained by familial aortic dissection. METHODS: 13 of the confirmed carriers were interviewed and examined, and information about the remaining carrier was obtained from medical records. Clinical information about deceased individuals was obtained, when possible, from postmortem reports, death certificates and medical records. RESULTS: There have been eight sudden deaths; the cause of death was aortic dissection in all six cases in which a postmortem examination was performed. Three individuals had undergone aortic replacement surgery. Dissection had occurred throughout the aorta, and in one case in the absence of aortic root dilatation. Subarachnoid haemorrhage, due to a ruptured berry aneurysm, had occurred in two individuals. Four gene carriers and one deceased family member who were investigated had tortuous cerebral blood vessels. One had tortuous vertebral arteries, two had tortuous carotid arteries and one a tortuous abdominal aorta. Two individuals were found to have a brachiocephalic artery aneurysm and a subclavian artery aneurysm, respectively. CONCLUSIONS: Despite the predisposition to aortic dilatation and dissection, individuals did not frequently manifest the skeletal features of Marfan syndrome, with the exception of joint hypermobility. No one individual had ocular lens dislocation. Striae and herniae were common. There was some overlap with Ehlers-Danlos syndrome type 4, OMIM 130050, with soft translucent skin, which is easily bruised. Other features were arthralgia, migraine and a tendency to fatigue easily, varicose veins and prominent skin striae. This family provides further evidence that mutations in TGFbetaR2 cause a distinct syndrome that needs to be distinguished from Marfan syndrome to direct investigation and management of patients and shows the natural history, spectrum of clinical features and variable penetrance of this newly recognised condition.

Ghost cell odontogenic carcinoma.

Ghost cell odontogenic carcinoma (GCOC) is the malignant counterpart of calcifying cystic odontogenic tumour and dentinogenic ghost cell tumour. This is the case of a middle-aged male who presented with a slow-growing maxillary tumour. He was asymptomatic until pain symptoms developed prior to initial presentation. The excised tumour was diagnosed as a ghost cell odontogenic carcinoma. More case reports are needed for further understanding of this rare malignant odontogenic tumour.

Evaluation of the effectiveness of air pollution control measures in Hong Kong.

From 2005 to 2013, volatile organic compounds (VOCs) and other trace gases were continuously measured at a suburban site in Hong Kong. The measurement data showed that the concentrations of most air pollutants decreased during these years. However, ozone (O3) and total non-methane hydrocarbon levels increased with the rate of 0.23 ± 0.03 and 0.34 ± 0.02 ppbv/year, respectively, pointing to the increasing severity of photochemical pollution in Hong Kong. The Hong Kong government has ongoing programs to improve air quality in Hong Kong, including a solvent program implemented during 2007-2011, and a diesel commercial vehicle (DCV) program since 2007. From before to after the solvent program, the sum of toluene, ethylbenzene and xylene isomers decreased continuously with an average rate of -99.1 ± 6.9 pptv/year, whereas the sum of ethene and propene increased by 48.2 ± 2.0 pptv/year from before to during the DCV program. Despite this, source apportionment results showed that VOCs emitted from diesel exhaust decreased at a rate of -304.5 ± 17.7 pptv/year, while solvent related VOCs decreased at a rate of -204.7 ± 39.7 pptv/year. The gasoline and liquefied petroleum gas vehicle emissions elevated by 1086 ± 34 pptv/year, and were responsible for the increases of ethene and propene. Overall, the simulated O3 rate of increase was lowered from 0.39 ± 0.03 to 0.16 ± 0.05 ppbv/year by the solvent and DCV programs, because O3 produced by solvent usage and diesel exhaust related VOCs decreased (p < 0.05) by 0.16 ± 0.01 and 0.05 ± 0.01 ppbv/year between 2005 and 2013, respectively. However, enhanced VOC emissions from gasoline and LPG vehicles accounted for most of the O3 increment (0.09 ± 0.01 out of 0.16 ± 0.05 ppbv/year) in these years. To maintain a zero O3 increment in 2020 relative to 2010, the lowest reduction ratio of VOCs/NOx was ∼1.5 under the NOx reduction of 20-30% which was based on the emission reduction plan for Pearl River Delta region in 2020.

Tropospheric volatile organic compounds in China.

Photochemical smog, characterized by high concentrations of ozone (O3) and fine particles (PM2.5) in the atmosphere, has become one of the top environmental concerns in China. Volatile organic compounds (VOCs), one of the key precursors of O3 and secondary organic aerosol (SOA) (an important component of PM2.5), have a critical influence on atmospheric chemistry and subsequently affect regional and global climate. Thus, VOCs have been extensively studied in many cities and regions in China, especially in the North China Plain, the Yangtze River Delta and the Pearl River Delta regions where photochemical smog pollution has become increasingly worse over recent decades. This paper reviews the main studies conducted in China on the characteristics and sources of VOCs, their relationship with O3 and SOA, and their removal technology. This paper also provides an integrated literature review on the formulation and implementation of effective control strategies of VOCs and photochemical smog, as well as suggestions for future directions of VOCs study in China.

The ARKdb: genome databases for farmed and other animals.

The ARKdb genome databases provide comprehensive public repositories for genome mapping data from farmed species and other animals (http://www.thearkdb.org) providing a resource similar in function to that offered by GDB or MGD for human or mouse genome mapping data, respectively. Because we have attempted to build a generic mapping database, the system has wide utility, particularly for those species for which development of a specific resource would be prohibitive. The ARKdb genome database model has been implemented for 10 species to date. These are pig, chicken, sheep, cattle, horse, deer, tilapia, cat, turkey and salmon. Access to the ARKdb databases is effected via the World Wide Web using the ARKdb browser and Anubis map viewer. The information stored includes details of loci, maps, experimental methods and the source references. Links to other information sources such as PubMed and EMBL/GenBank are provided. Responsibility for data entry and curation is shared amongst scientists active in genome research in the species of interest. Mirror sites in the United States are maintained in addition to the central genome server at Roslin.

Internalization of insulin and its receptor in the isolated rat adipose cell. Time-course and insulin concentration dependency.

The time-course and insulin concentration dependency of internalization of insulin and its receptor have been examined in isolated rat adipose cells at 37 degrees C. The internalization of insulin was assessed by examining the subcellular distribution of cell-associated [125I]insulin among plasma membrane, and high-density (endoplasmic reticulum-enriched) and low-density (Golgi-enriched) microsomal membrane fractions prepared by differential ultracentrifugation. The distribution of receptors was measured by the steady-state exchange binding of fresh [125I]insulin to these same membrane fractions. At 37 degrees C, insulin binding to intact cells is accompanied initially by the rapid appearance of intact insulin in the plasma membrane fraction, and subsequently, by its rapid appearance in both the high-density and low-density microsomal membrane fractions. An apparent steady-state distribution of insulin per mg of membrane protein among these subcellular fractions is achieved within 30 min in a ratio of 1:1.54:0.80, respectively. Concomitantly, insulin binding to intact cells is associated with the rapid disappearance of approx. 30% of the insulin receptors initially present in the plasma membrane fraction and appearance of 20-30% of those lost in the low-density microsomal membrane fraction. However, the number of receptors in the high-density microsomal membrane fraction does not change. This redistribution of receptors also appears to reach a steady-state within 30 min. Both processes are insulin concentration-dependent, correlating with receptor occupancy in the intact cell, and are partially inhibited at 16 degrees C. While the steady-state subcellular distributions of insulin and its receptor do not correlate with that of acid phosphatase, chloroquine markedly increases the levels of insulin associated with all three membrane fractions in apparent proportion to the distribution of this lysosomal marker enzyme activity, without more than marginally potentiating insulin's effects on the distribution of receptors. These results demonstrate that insulin, initially bound to the plasma membrane of the isolated rat adipose cell, is rapidly translocated by a receptor-mediated process into at least two intracellular compartments associated with the cell's high- and low-density microsomes. Furthermore, insulin simultaneously induces the translocation of its own receptor from the plasma membrane into the latter compartment. These translocations appear to represent the internalization and partial dissociation of the insulin-receptor complex through insulin-induced receptor cycling.