sCR1sLeX reduces lung allograft ischemia-reperfusion injury but does not ameliorate acute rejection

Background: Combined inhibition of complement and leukocyte adhesion by sCR1sLeX reduces lung allograft dysfunction up to 24 h. In the present study its effect on graft function and acute rejection was evaluated up to 5 days after experimental transplantation. Methods: Orthotopic single left lung transplantation was performed in 35 male rats (Brown Norway to Fischer 344) after a total ischemic time of 20 h. Two groups were assessed after 1, 3, and 5 days post-transplant, respectively (n=5 per group and time point): controls vs. recipients which received 10 mg/kg sCR1sLeX 15 min prior to reperfusion. In addition, five animals received 10 mg/kg per day sCR1sLeX for 5 days. For blood gas analysis of the graft, the contralateral lung was occluded for 5 min to assess graft function. Lung grafts were flushed, and histological grading was performed in blinded fashion according to the International Society for Heart and Lung Transplantation criteria. Results: Graft PaO2 in recipients treated with sCR1sLeX was superior on day 1 (383±118 vs. 56±15 mmHg; P≪0.0001) and day 3 (446±48 vs. 231±108 mmHg; P≪0.0001). Five days after transplantation, no difference in PaO2 was found (61±28 vs. 83±31 mmHg; P=0.59). Repeated treatment with sCR1sLeX for 5 days did not improve PaO2 (64±5 mmHg; P=0.65 vs. control; P=0.93 vs. sCR1sLeX). At any time point, there was no difference in the degree of rejection between groups. Conclusions: In this model sCR1sLeX provided marked improvement of graft function up to 3 days, but inhibition of both complement system and selectin dependent leukocyte adhesion failed to protect against acute rejectio

Insufficient treatment of severe depression in neuromyelitis optica spectrum disorder

OBJECTIVE: To investigate depression frequency, severity, current treatment, and interactions with somatic symptoms among patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this dual-center observational study, we included 71 patients diagnosed with NMOSD according to the International Panel for NMO Diagnosis 2015 criteria. The Beck Depression Inventory (BDI) was classified into severe, moderate, or minimal/no depressive state category. We used the Fatigue Severity Scale to evaluate fatigue. Scores from the Brief Pain Inventory and the PainDETECT Questionnaire were normalized to estimate neuropathic pain. Psychotropic, pain, and immunosuppressant medications were tabulated by established classes. RESULTS: Twenty-eight percent of patients with NMOSD (n = 20) had BDI scores indicative of moderate or severe depression; 48% of patients (n = 34) endorsed significant levels of neuropathic pain. Severity of depression was moderately associated with neuropathic pain (r = 0.341, p < 0.004) but this relationship was confounded by levels of fatigue. Furthermore, only 40% of patients with moderate or severe depressive symptoms received antidepressant medical treatment. Fifty percent of those treated reported persistent moderate to severe depressive symptoms under treatment. CONCLUSIONS: Moderate and severe depression in patients with NMOSD is associated with neuropathic pain and fatigue and is insufficiently treated. These results are consistent across 2 research centers and continents. Future research needs to address how depression can be effectively managed and treated in NMOSD

Risk prediction of developing venous thrombosis in combined oral contraceptive users.

Venous thromboembolism (VTE) is a complex multifactorial disease influenced by genetic and environmental risk factors. An example for the latter is the regular use of combined oral contraceptives (CC), which increases the risk to develop VTE by 3 to 7 fold, depending on estrogen dosage and the type of progestin present in the pill. One out of 1'000 women using CC develops thrombosis, often with life-long consequences; a risk assessment is therefore necessary prior to such treatment. Currently known clinical risk factors associated with VTE development in general are routinely checked by medical doctors, however they are far from being sufficient for risk prediction, even when combined with genetic tests for Factor V Leiden and Factor II G20210A variants. Thus, clinical and notably genetic risk factors specific to the development of thrombosis associated with the use of CC in particular should be identified. Step-wise (logistic) model selection was applied to a population of 1622 women using CC, half of whom (794) had developed a thromboembolic event while using contraceptives. 46 polymorphisms and clinical parameters were tested in the model selection and a specific combination of 4 clinical risk factors and 9 polymorphisms were identified. Among the 9 polymorphisms, there are two novel genetic polymorphisms (rs1799853 and rs4379368) that had not been previously associated with the development of thromboembolic event. This new prediction model outperforms (AUC 0.71, 95% CI 0.69-0.74) previously published models for general thromboembolic events in a cross-validation setting. Further validation in independent populations should be envisaged. We identified two new genetic variants associated to VTE development, as well as a robust prediction model to assess the risk of thrombosis for women using combined oral contraceptives. This model outperforms current medical practice as well as previously published models and is the first model specific to CC use

MyD88‐dependent production of IL‐17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway

The interleukin‐17 (IL‐17) family of cytokines plays important roles in innate immune defenses against bacterial and fungal pathogens. While much is known about IL‐17A, much less information is available about the IL‐17F isoform. Here, we investigated gene expression and release of IL‐17F and its regulation by the complement system. IL‐17F was produced in mouse peritoneal elicited macrophages after TLR4 activation by LPS, peaking after 12 h. This effect was completely dependent on the presence of the adaptor protein MyD88. The copresence of the complement activation product, C5a (EC50=10 nM), amplified IL‐17F production via the receptor C5aR. In vitro signaling studies indicated that LPS or C5a, or the combination, caused phosphorylation of Akt occurring at threonine 308 but not at serine 473. Treatment of macrophages with pharmacologic inhibitors of PI3K‐Akt greatly reduced production of IL‐17F as well as mRNA for IL‐17F. In endotoxemia, C5a levels peaked at 6 h, while IL‐17F levels peaked between 6‐12 h. Full in vivo production of IL‐17F during endotoxemia required C5a. A similar result was found in the cecal ligation and puncture sepsis model. These data suggest that maximal production of IL‐17F requires complement activation and presence of C5a.—Bosmann, M., Patel, V. R., Russkamp, N. F., Pache, F., Zetoune, F. S., Sarma, J. V., Ward, P. A. MyD88‐dependent production of IL‐17F is modulated by the anaphylatoxin C5a via the Akt signaling pathway. FASEB J. 25, 4222–4232 (2011). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154335/1/fsb2fj11191205.pd

Coherent transfer functions and extended depth of field

To preserve the speed advantage of Fourier Domain detection in Optical Coherence Microscopy (OCM), extended depth of field is needed. With a narrow probing volume that extends over a long axial range, tissue could be measured in vivo and at cellular resolution. To assess and improve the DOF and the lateral resolution, we analyzed the coherent transfer function (CTF) of OCM. Both the illumination and detection optics contribute equally to the overall imaging performance. In the Fourier domain detection, each pixel of the spectrometer has its specific CTF, sampling a different region of the object’s spatial frequency spectrum. For classical optics and increasing numerical apertures these regions start to overlap and bend, which limits the depth of field. Annular apertures, created with Bessel-like beams produced by axicon lenses or phase filters, circumvent these detrimental effects, but introduce strong side lobes. Decoupling the detection and the illumination apertures is needed to provide the flexibility in engineering a CTF that optimizes the lateral resolution and the DOF at the same time all while reducing these side lobes. We evaluated different combinations of Gaussian and Bessel-like illumination and detection optics, both theoretically and experimentally. Using Bessel-like beams as well in the illumination as in the detection paths, but with annular apertures of different lobe radii, we obtained a lateral resolution of 1.3 μm and an extended depth of field of more than 300 μm, which was completely decoupled from the numerical aperture and scalable to high lateral resolution

Feasibility of a prehabilitation program before major abdominal surgery: a pilot prospective study.

To assess the feasibility of a prehabilitation program and its effects on physical performance and outcomes after major abdominal surgery. In this prospective pilot study, patients underwent prehabilitation involving three training sessions per week for 3 weeks preoperatively. The feasibility of delivering the intervention was assessed based on recruitment and adherence to the program. Its impacts on fitness (oxygen uptake (VO &lt;sub&gt;2&lt;/sub&gt; )) and physical performance (Timed Up and Go Test, 6-Minute Walk Test) were evaluated. From May 2017 to January 2020, 980 patients were identified and 44 (4.5%) were invited to participate. The main obstacles to patient recruitment were insufficient time (&lt;3 weeks) prior to scheduled surgery (n = 276, 28%) and screening failure (n = 312, 32%). Of the 44 patients, 24 (55%) declined to participate, and 20 (23%) were included. Of these, six (30%) were not adherent to the program. Among the remaining 14 patients, VO &lt;sub&gt;2&lt;/sub&gt; at ventilatory threshold significantly increased from 9.7 to 10.9 mL/min/kg. No significant difference in physical performance was observed before and after prehabilitation. Although prehabilitation seemed to have positive effects on exercise capacity, logistic and patient-related difficulties were encountered. The program is not feasible in its current form for all-comers

Normal volumes and microstructural integrity of deep gray matter structures in AQP4+ NMOSD

OBJECTIVE: To assess volumes and microstructural integrity of deep gray matter structures in a homogeneous cohort of patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: This was a cross-sectional study including 36 aquaporin-4 antibody-positive (AQP4 Ab-positive) Caucasian patients with NMOSD and healthy controls matched for age, sex, and education. Volumetry of deep gray matter structures (DGM; thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) was performed using 2 independent automated methods. Microstructural integrity was assessed based on diffusion tensor imaging. RESULTS: Both volumetric analysis methods consistently revealed similar volumes of DGM structures in patients and controls without significant group differences. Moreover, no differences in DGM microstructural integrity were observed between groups. CONCLUSIONS: Deep gray matter structures are not affected in AQP4 Ab-positive Caucasian patients with NMOSD. NMOSD imaging studies should be interpreted with respect to Ab status, educational background, and ethnicity of included patients

Tyrosine kinase 2 promotes sepsis‐associated lethality by facilitating production of interleukin‐27

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141056/1/jlb0123-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141056/2/jlb0123.pd