Severe mesenteric ischemia with multiple organ failure in a patient previously treated with a humanized monoclonal antibody against programmed death receptor-1 (pembrolizumab), a case of pembrolizumab associated catastrophic antiphospholipid syndrome?

Immune checkpoint inhibitors are used in the treatment of different types of tumors including melanoma and non-small cell lung carcinoma. The use of these inhibitors is associated with a broad spectrum of immune-related adverse effects. Here we report a case of a patient admitted to the intensive care unit with multiple organ failure due to catastrophic antiphospholipid syndrome following treatment with pembrolizumab, an immune checkpoint inhibitor, because of metastatic melanoma. The presented patient had multiple organ failure of lung, gastro-intestinal, renal, and the liver. Vascular thrombosis was confirmed by both imaging (pulmonary embolism on computed tomography-thorax) and histopathological examination of the intestines. In combination with the presence of IgA anti-cardiolipin antibodies and initially IgM anti-cardiolipin antibodies, catastrophic antiphospholipid syndrome was suspected. Despite treatment with plasmapheresis and corticosteroids, the patient died due to multiple organ failure. Catastrophic antiphospholipid syndrome is difficult to recognize and has high mortality rates despite supportive treatment. In this case report, discussion is provided regarding the possible immunological mechanism behind catastrophic antiphospholipid syndrome during or after treatment with immune checkpoint inhibitors. It is important to realize that in modern intensive care unit, more patients with immune-related adverse effects of the treatment with immune checkpoint inhibitors will be admitted, because of an increase in the number of patients treated with these checkpoint inhibitors. When these patients are admitted on the intensive care unit, multi-disciplinary consultation is important because of the difficulty of early recognition and optimal treatment of these possible lethal side effects

Rectification of thermal fluctuations in ideal gases

We calculate the systematic average speed of the adiabatic piston and a thermal Brownian motor, introduced in [Van den Broeck, Kawai and Meurs, \emph{Microscopic analysis of a thermal Brownian motor}, to appear in Phys. Rev. Lett.], by an expansion of the Boltzmann equation and compare with the exact numerical solution.Comment: 18 page

Gender specific effects of the calcium channel TRPV4 on osteoporotic fracture risk and osteoblast-osteoclast coupling

TRPV4 is a member of the transient receptor potential (TRP) superfamily and responds to an array of stimuli, including osmolarity, pH and pressure. Recent findings showing that TRPV4 deficiency leads to reduced sensing of mechanical stimuli led us to explore the role of TRPV4 in bone. TRPV4 mRNA was abundantly expressed in both osteoblasts and osteoclasts as assessed by qPCR. Femoral cortical and trabecular bone mass as assessed by microcomputed tomography was higher in male TRPV4 knockout mice compared to wild type mice. Despite thicker bone structures, cortical porosity was increased in the male TRPV4 knockout mice leading to reduced bone strength as assessed by 3-point bending. Osteoclast and osteoblast differentiation and function was studied, using bone marrow cultures from wildtype and TRPV4 knockout mice. Osteoclast numbers as well as the formation of resorption pits were significantly reduced in cultures of TRPV4 knockout mice compared to wildtype littermates. In contrast, osteoblast differentiation and matrix mineralization was significantly increased in TRPV4 knockout bone marrow cultures. None of these parameters were significantly different in bones and bone marrow cultures of female knock out mice. These data implicate a gender-specific osteoblast–osteoclast uncoupling and support the observed increase in bone mass in male TRPV4 deficient mice. To assess the possible impact of TRPV4 on osteoporotic outcome in humans, we extracted data from the genome-wide association study within the Rotterdam Study. Two single nucleotide polymorphisms (SNPs) in the TRPV4 gene showed strong associations with osteoporotic fracture risk fragility fracture risk and hip fracture risk in men, but not in women. This was not affected after adjusting for height, weight, age and bone mineral density (BMD). In conclusion, TRPV4 plays an important role in male but not female bone biology. Apparently, the increased periosteal bone apposition fails to overcome the increased cortical porosity, leading to reduced bone strength in TRPV4 deficient male mice. In line with the gender-specific findings in mice, variations in the TRPV4 gene are predicting fracture risk in men but not in women

The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats

Background: Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function. Methods: Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis. Results: Hemorrhagic shock significantly decreased renal perfusion (240 +/- 138 to 51 +/- 40, p 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 +/- 3 vs 8 +/- 3 perfused vessels, p < 0.05). Conclusion: Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy

Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution

We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking.</p

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genome-wide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81×10−5). The C allele conferred a reduced risk of 33% to 41% using a case–control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA

Development of a prediction model for future risk of radiographic hip osteoarthritis

Objective: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. Design: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). Results: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. Conclusions: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA

UVES/VLT high resolution spectroscopy of GRB 050730 afterglow: probing the features of the GRB environment

We analyze high resolution spectroscopic observations of the optical afterglow of GRB050730, obtained with UVES@VLT about hours after the GRB trigger. The spectrum shows that the ISM of the GRB host galaxy at z = 3.967 is complex, with at least five components contributing to the main absorption system. We detect strong CII*, SiII*, OI* and FeII* fine structure absorption lines associated to the second and third component. For the first three components we derive information on the relative distance from the site of the GRB explosion. Component 1, which has the highest redshift, does not present any fine structure nor low ionization lines; it only shows very high ionization features, such as CIV and OVI, suggesting that this component is very close to the GRB site. From the analysis of low and high ionization lines and fine structure lines, we find evidences that the distance of component 2 from the site of the GRB explosion is 10-100 times smaller than that of component 3. We evaluated the mean metallicity of the z=3.967 system obtaining values about 0.01 of the solar metallicity or less. However, this should not be taken as representative of the circumburst medium, since the main contribution to the hydrogen column density comes from the outer regions of the galaxy while that of the other elements presumably comes from the ISM closer to the GRB site. Furthermore, difficulties in evaluating dust depletion correction can modify significantly these values. The mean [C/Fe] ratio agrees well with that expected by single star-formation event models. Interestingly the [C/Fe] of component 2 is smaller than that of component 3, in agreement with GRB dust destruction scenarios, if component 2 is closer than component 3 to the GRB site.Comment: 11 pages, 15 postscript figures, accepted for pubblication in A&