Early diagnosis of adult-onset immunodeficiency associated with neutralizing anti-interferon-gamma autoantibodies (anti-IFNγ Abs) remains difficult given the lack of a distinctive phenotype and a ...routine test. This study aimed to investigate the determinants of incorrect tentative diagnoses and useful clues for early disease recognition.
This study enrolled adult patients who had unexplained opportunistic infections diagnosed at six hospitals and identified those having neutralizing anti-IFNγ Abs (cases). Demographics, medical history, initial presentations and laboratory data, causative pathogens, tentative diagnoses, and treatment were analysed and compared among individuals having neutralizing anti-IFNγ Abs (cases) and those without (controls).
Among the 154 patients enrolled, neutralizing anti-IFN-γ Abs were detected in 50 (71%) of 70 patients with disseminated non-tuberculous mycobacterial infection (dNTM) but not in 84 patients without dNTM. The median time from disease onset to the recognition of dNTM associated with neutralizing anti-IFNγ Abs was 1.6 years (range, 0.25–19 years). Incorrect tentative diagnoses resulted in the administration of anti-tuberculosis regimens (60%, 30/50), immunosuppressants (48%, 24/50), and systemic chemotherapy (2%, 10/50) to the 50 cases. Multivariate analysis revealed that case patients were more likely than controls to present with multiple bone lesions (adjusted odds ratio (OR), 27.16; 95% confidence interval (CI), 1.21–609.59) and leukocytosis (adjusted OR, 1.48; 95% CI, 1.12–1.95); however, the controls had a higher rate of mycobacterial bloodstream infection (adjusted OR, 0.05; 95% CI 0.00–0.66).
The high rate of incorrect tentative diagnoses led to frequent inappropriate management in patients with neutralizing anti-IFNγ Abs, and highlighted the need for increased awareness among clinicians.
Tiller number per plant (TN) and plant height (PH) are important agronomic traits related to grain yield (GY) in rice (
Oryza sativa
L.). A total of 30 additive quantitative trait loci (A-QTL) and 9 ...significant additive × environment interaction QTLs (AE-QTL) were detected, while the phenotypic and QTL correlations confirmed the intrinsic relationship of the three traits. These QTLs were integrated with 986 QTLs from previous studies by metaanalysis. Consensus maps contained 7156 markers for a total map length of 1112.71 cM, onto which 863 QTLs were projected; 78 meta-QTLs (MQTLs) covering 11 of the 30 QTLs were detected from the cross between Dongnong422 and Kongyu131 in this study. A total of 705 predicted genes were distributed over the 21 MQTL intervals with physical length <0.3 Mb; 13 of the 21 MQTLs, and 34 candidate genes related to grain yield and plant development, were screened. Five major QTLs, viz.
qGY6
-
2
,
qPH7
-
2
,
qPH6
-
3
,
qTN6
-
1
, and
qTN7
-
1
, were not detected in the MQTL intervals and could be used as newly discovered QTLs. Candidate genes within these QTL intervals will play a meaningful role in molecular marker-assisted selection and map-based cloning of rice TN, PH, and GY.
Strontium ranelate is a relatively new medication with good safety profile for the treatment of postmenopausal osteoporosis. However, severe cutaneous adverse drug reactions have been reported, such ...as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We report the case of a 70-year-old woman who developed multiple itching erythematous macules and plaques about 1 month after beginning strontium ranelate medication. The cutaneous lesions progressed over the entire body with severe oral and ocular mucosa involvement. Probable mild SJS was diagnosed, compatible with the pathology findings, and strontium ranelate was discontinued immediately. Systemic methylprednisolone was administered to suppress the overactive immune system and ameliorate cutaneous symptoms. With early recognition and prompt treatment, the patient’s prognosis was good.
Abstract
An axion insulator is a three-dimensional (3D) topological insulator (TI), in which the bulk maintains the time-reversal symmetry or inversion symmetry but the surface states are gapped by ...surface magnetization. The axion insulator state has been observed in molecular beam epitaxy (MBE)-grown magnetically doped TI sandwiches and exfoliated intrinsic magnetic TI MnBi
2
Te
4
flakes with an even number layer. All these samples have a thickness of ~ 10 nm, near the 2D-to-3D boundary. The coupling between the top and bottom surface states in thin samples may hinder the observation of quantized topological magnetoelectric response. Here, we employ MBE to synthesize magnetic TI sandwich heterostructures and find that the axion insulator state persists in a 3D sample with a thickness of ~ 106 nm. Our transport results show that the axion insulator state starts to emerge when the thickness of the middle undoped TI layer is greater than ~ 3 nm. The 3D hundred-nanometer-thick axion insulator provides a promising platform for the exploration of the topological magnetoelectric effect and other emergent magnetic topological states, such as the high-order TI phase.
To determine whether fruit bats in Singapore have been exposed to filoviruses, we screened 409 serum samples from bats of 3 species by using a multiplex assay that detects antibodies against ...filoviruses. Positive samples reacted with glycoproteins from Bundibugyo, Ebola, and Sudan viruses, indicating filovirus circulation among bats in Southeast Asia.
Microcontact printing (μCP) is widely used to create patterns of biomolecules essential for studies of cell mechanics, migration, and tissue engineering. However, different types of μCPs may create ...micropatterns with varied protein–substrate adhesion, which may change cell behaviors and pose uncertainty in result interpretation. Here, we characterize two μCP methods for coating extracellular matrix (ECM) proteins (stamp-off and covalent bond) and demonstrate for the first time the important role of protein–substrate adhesion in determining cell behavior. We found that, as compared to cells with weaker traction force (e.g., endothelial cells), cells with strong traction force (e.g., vascular smooth muscle cells) may delaminate the ECM patterns, which reduced cell viability as a result. Importantly, such ECM delamination was observed on patterns by stamp-off but not on the patterns by covalent bonds. Further comparisons of the displacement of the ECM patterns between the normal VSMCs and the force-reduced VSMCs suggested that the cell traction force plays an essential role in this ECM delamination. Together, our results indicated that μCPs with insufficient adhesion may lead to ECM delamination and cause cell death, providing new insight for micropatterning in cell–biomaterial interaction on biointerfaces.
Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as ...choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown.
We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05).
Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.
Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the ...Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin-RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
The air pollution index (API) sequences in 10 cities in northern China and the synoptic pressure patterns during autumn and winter from 2002 to 2006 were analyzed with diagnostic and statistical ...methods. The results showed that the air qualities in northern China had a prominent correlation with the pressure systems. It revealed that (a) the increasing phase of API was associated with high pressure and the successive low pressure, (b) the preceding part of front (i.e. the retral part of low pressure) was associated with the maximum of API values during a cycle of air pollution process, (c) the pressure systems with high gradient led to the decrease of API, and (d) the synoptic pressure patterns and their evolvements were the main causes of regional air pollution processes. These relations can be used to analyze the variation characteristics and mechanism of regional atmosphere pollution process, and provide important basis for the qualitative prediction, control, and management of regional air pollution problems.
Starting from the nanoscale structural heterogeneities intrinsic to metallic glasses (MGs), here we show that there are two concurrent contributions to their microscale quasi-static shear modulus GI: ...one (μ) is related to the atomic bonding strength of solid-like regions and the other (GII) to the change in the possible configurations of liquid-like regions (dynamic relaxation). Through carefully designed high-rate nanoscale indentation tests, a simple constitutive relation (μ=GI+GII) is experimentally verified. On a fundamental level, our current work provides a structure–property correlation that may be applicable to a wide range of glassy materials.
PDF
