Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease

Pulmonary surfactant is a complex mixture of phospholipids and proteins, which is present in the alveolar lining fluid and is essential for normal lung function. Alterations in surfactant composition have been reported in several interstitial lung diseases (ILDs). Furthermore, a mutation in the surfactant protein C gene that results in complete absence of the protein has been shown to be associated with familial ILD. The role of surfactant in lung disease is therefore drawing increasing attention following the elucidation of the genetic basis underlying its surface expression and the proof of surfactant abnormalities in ILD.     

The SARS-CoV2 envelope differs from host cells,exposes procoagulant lipids,and is disrupted in vivo by oral rinses

The lipid envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of antiviral agents as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Lipidomics revealed that the virus envelope comprised mainly phospholipids (PLs), with some cholesterol and sphingolipids, and with cholesterol/phospholipid ratio similar to lysosomes. Unlike cellular membranes, procoagulant amino-PLs were present on the external side of the viral envelope at levels exceeding those on activated platelets. Accordingly, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, povidone-iodine, or chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-s oral rinse with cetylpyridinium chloride mouthwash eliminated live virus in the oral cavity of patients with coronavirus disease 19 for at least 1 h, whereas povidone-iodine and saline mouthwashes were ineffective. We conclude that the SARS-CoV-2 lipid envelope i) is distinct from the host plasma membrane, which may enable design of selective antiviral approaches; ii) contains exposed phosphatidylethanolamine and phosphatidylserine, which may influence thrombosis, pathogenicity, and inflammation; and iii) can be selectively targeted in vivo by specific oral rinses.     

BioWarehouse: a bioinformatics database warehouse toolkit

Background  

This article addresses the problem of interoperation of heterogeneous bioinformatics databases.     

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA''s mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt''s lymphoma cell lines. Phagocytosis contributed to DARA''s anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.     

Reappraisal of the diagnostic and prognostic value of morning stiffness in arthralgia and early arthritis: results from the Groningen EARC,Leiden EARC,ESPOIR, Leiden EAC and REACH

IntroductionMorning stiffness is assessed daily in the diagnostic process of arthralgia and arthritis, but large-scale studies on the discriminative ability are absent. This study explored the diagnostic value of morning stiffness in 5,202 arthralgia and arthritis patients and the prognostic value in early rheumatoid arthritis (RA).MethodsIn arthralgia patients referred to the Early Arthritis Recognition Clinics (EARC) of Leiden (n = 807) and Groningen (n = 481) or included in the Rotterdam Early Arthritis Cohort (REACH) study (n = 353), the associations (cross-sectional analyses) between morning stiffness and presence of arthritis at physical examination were studied. In early arthritis patients, included in the Leiden Early Arthritis Clinic (EAC) (n = 2,748) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n = 813), associations with fulfilling the 2010-RA criteria after one year were assessed. In 2010-RA patients included in the EAC (n = 1,140) and ESPOIR (n = 677), association with the long-term outcomes of disease-modifying antirheumatic drug (DMARD)-free sustained remission and radiological progression were determined. Morning stiffness was defined as a duration ≥60 minutes; sensitivity analyses were performed for other definitions.ResultsIn arthralgia, morning stiffness (≥60 minutes) associated with the presence of arthritis; Leiden EARC odds ratio (OR) 1.49 (95% CI 1.001 to 2.20), Groningen EARC OR 2.21 (1.33 to 3.69) and REACH OR 1.55 (0.97 to 2.47) but the areas under the receiver operating characteristic curve (AUCs) were low (0.52, 0.57, 0.54). In early arthritis, morning stiffness was associated with 2010-RA independent of other predictors (Leiden EAC OR 1.72 (95% CI 1.31 to 2.25, AUC 0.68), ESPOIR OR 1.68 (1.03 to 2.74, AUC 0.64)). Duration of ≥30 minutes provided optimal discrimination for RA in early arthritis. Morning stiffness was not associated with radiological progression or DMARD-free sustained remission.ConclusionsMorning stiffness in arthralgia and early arthritis is associated with arthritis and RA respectively. This supports the incorporation of morning stiffness in the diagnostic process.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0616-3) contains supplementary material, which is available to authorized users.     

Generating social network data using partially described networks: an example informing avian influenza control in the British poultry industry

Background

The United Kingdom (UK) government has been recording the births, deaths, and movements of cattle for the last decade. Despite reservations about the accuracy of these data, they represent a large and valuable body of information about the demographics of the UK cattle herd and its contact structure. In this article, a range of demographic data about UK cattle, and particularly their movements, are presented, as well as yearly trends in the patterns of movements.

Results

A clear seasonal pattern is evident in the number of movements of cattle, as are the reductions in movement volume due to foot and mouth disease outbreaks in 2001 and 2007. The distribution of ages of cattle at their time of death is multimodal, and the impact of the over thirty months rule is marked. Most movements occur between agricultural holdings, markets, and slaughterhouses, and there is a non-random pattern to the types of holdings movements occur between. Most animals move only a short distance and a few times in their life. Most movements between any given pair of holdings only occurred once in the last 10 years, but about a third occurred between 2 and 10 times in that period. There is no clear trend to movement patterns in the UK since 2002.

Conclusions

Despite a substantial number of regulatory interventions during the last decade, movement patterns show no clear trend since 2002. The observed patterns in the repeatability of movements, the types of holdings involved in movements, the distances and frequencies of cattle movements, and the batch sizes involved give an insight into the structure of the UK cattle industry, and could act as the basis for a predictive model of livestock movements in the UK.     

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis

Introduction

The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9β and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum.

Methods

We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9β, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9β or 9β + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use.

Results

GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease.

Conclusions

Differences in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.     

Predictive Blood Chemistry Parameters for Pansteatitis-Affected Mozambique Tilapia (Oreochromis mossambicus)

One of the largest river systems in South Africa, the Olifants River, has experienced significant changes in water quality due to anthropogenic activities. Since 2005, there have been various “outbreaks” of the inflammatory disease pansteatitis in several vertebrate species. Large-scale pansteatitis-related mortality events have decimated the crocodile population at Lake Loskop and decreased the population at Kruger National Park. Most pansteatitis-related diagnoses within the region are conducted post-mortem by either gross pathology or histology. The application of a non-lethal approach to assess the prevalence and pervasiveness of pansteatitis in the Olifants River region would be of great importance for the development of a management plan for this disease. In this study, several plasma-based biomarkers accurately classified pansteatitis in Mozambique tilapia (Oreochromis mossambicus) collected from Lake Loskop using a commercially available benchtop blood chemistry analyzer combined with data interpretation via artificial neural network analysis. According to the model, four blood chemistry parameters (calcium, sodium, total protein and albumin), in combination with total length, diagnose pansteatitis to a predictive accuracy of 92 percent. In addition, several morphometric traits (total length, age, weight) were also associated with pansteatitis. On-going research will focus on further evaluating the use of blood chemistry to classify pansteatitis across different species, trophic levels, and within different sites along the Olifants River.     

The prognostic value of baseline erosions in undifferentiated arthritis

Introduction  

Undifferentiated arthritis (UA) has a variable disease course; 40 to 50% of UA patients remit spontaneously, while 30% develop rheumatoid arthritis (RA). Identifying the UA patients who will develop RA is essential to initiate early disease-modifying anti-rheumatic drug (DMARD) therapy. Although the presence of bone erosions at baseline is predictive for a severe destructive disease course in RA, the prognostic importance of erosive joints for disease outcome in UA is unknown. This study evaluates the predictive value of erosive joints for the disease outcome in UA as measured by RA development and disease persistency.     

Effects of cycloheximide on a cytoplasmic factor initiating meiotic maturation in Xenopus oocytes

Oocytes induced to undergo meiotic maturation by progesterone possess a cytoplasmic activity that causes germinal vesicle breakdown (GVBD). The cytoplasmic factor postulated to be responsible for this activity is designated as the maturation promoting factor (MPF). The activity of MPF was assayed by injecting cytoplasm into fully-grown oocytes to induce GVBD. It was found that maturing oocyte cytoplasm possesses MPF activity before GVBD begins. Treatment of progesterone stimulated oocytes with cycloheximide, either applied externally or injected, inhibited the appearance of MPF in the cytoplasm as well as GVBD when the inhibitor treatment was initiated before the cytoplasm exhibited MPF activity. In contrast, the same treatment did not inhibit GVBD when it was applied to oocytes after the cytoplasm possessed MPF activity. Furthermore, cycloheximide treatment of recipient oocytes did not inhibit the induction of GVBD by injected cytoplasm containing MPF. Cytoplasm of oocytes injected with MPF subsequently possessed MPF activity as high as that of the original donor cytoplasm in spite of its extensive dilution. This suggests that amplification of MPF took place in the recipient. Cycloheximide treatment did not inhibit the amplification of MPF. It was concluded that cycloheximide inhibits only the initial phase of induction of MPF activity, but neither its amplification nor its action on the nucleus that causes GVBD. From these results, a hypothesis concerning the cytoplasmic mechanism for the induction of GVBD has been proposed.