Background
Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase‐4 (DPP‐4) is a ...cell surface serine protease expressed in a variety of tissues. DPP‐4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose‐lowering action, for example, renoprotective and anti‐inflammatory properties, but the exact mechanisms remain unknown. We hypothesised that DPP‐4 inhibitors block adverse complement activation by inhibiting complement‐activating serine proteases.
Materials and methods
We analysed the effects of 7 different DPP‐4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan‐binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg (n = 34) or placebo (n = 37) for 12 weeks.
Results
All the 7 DPP‐4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose‐dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow‐up in both groups without significant effect of sitagliptin.
Conclusions
We demonstrated an inhibitory effect of DPP‐4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP‐4 inhibitors remains to be fully elucidated.
Filter samples of fine and coarse air particulate matter (PM) collected over a period of one year in central Europe (Mainz, Germany) were analyzed for water-soluble organic compounds (WSOCs), ...including the α- and β-pinene oxidation products pinic acid, pinonic acid and 3-methyl-1,2,3-butanetricarboxylic acid (3-MBTCA), as well as a variety of dicarboxylic acids and nitrophenols. Seasonal variations and other characteristic features in fine, coarse, and total PM (TSP) are discussed with regard to aerosol sources and sinks in comparison to data from other studies and regions. The ratios of adipic acid and phthalic acid to azelaic acid indicate that the investigated aerosol samples were mainly influenced by biogenic sources. A strong Arrhenius-type correlation was found between the 3-MBTCA concentration and inverse temperature (R2 = 0.79, n = 52, Ea = 126 ± 10 kJ mol−1, temperature range 275–300 K). Model calculations suggest that the temperature dependence observed for 3-MBTCA can be explained by enhanced photochemical production due to an increase of hydroxyl radical (OH) concentration with increasing temperature, whereas the influence of gas-particle partitioning appears to play a minor role. The results indicate that the OH-initiated oxidation of pinonic acid is the rate-limiting step in the formation of 3-MBTCA, and that 3-MBTCA may be a suitable tracer for the chemical aging of biogenic secondary organic aerosol (SOA) by OH radicals. An Arrhenius-type temperature dependence was also observed for the concentration of pinic acid (R2 = 0.60, n = 56, Ea = 84 ± 9 kJ mol−1); it can be tentatively explained by the temperature dependence of biogenic pinene emission as the rate-limiting step of pinic acid formation.
Background
When a child is diagnosed with autism, parents are faced with the task of choosing from many different intervention options. To find information about the options available, parents turn ...to a number of different sources. This study explores parents' (n = 23) intervention decision‐making processes and information preferences following the diagnosis of ASD for their child.
Methods
Qualitative thematic analysis of verbatim transcripts from interviews and focus groups involving parents of children with an autism diagnosis was undertaken.
Results
Analysis of the results revealed that there are concurrent emotional and pragmatic intervention ‘journeys’ undertaken by parents post diagnosis, which encompass the primary themes of: (1) information sources used, (2) parents' information preferences and (3) factors influencing intervention decision making. Parents described a journey from the point of diagnosis that involved seeking information on ASD interventions from multiple sources, with the Internet being the primary source. They were overwhelmed by the sheer volume of information available, and their preferences for information varied according to their stage in the journey post diagnosis. Parents had a ‘trial and error’ approach to choosing ASD interventions, with confidence increasing as they became more familiar with their child's condition, and had opportunities to explore numerous information sources about their child's diagnosis. While confidence increased over time, consideration of the effectiveness or evidence supporting interventions remained largely absent throughout the journey.
Conclusion
This study highlights the need for parents of children with ASD to be supported to make informed intervention decisions, particularly with consideration for research evidence.
Despite great efforts, transoral robotic laser surgery has not been established clinically. Patient benefits are yet to be proven to accept shortcomings of robotic systems. In particular, laryngeal ...reachability and transition from microscope to accurate endoscopic laser ablation have not been achieved. We have addressed those challenges with a highly integrated robotic endoscope for non-contact endolaryngeal laser surgery. The current performance status has been assessed in multi-level user studies. In addition, the system was deployed to an
ex vivo
porcine larynx. The robotic design comprises an extensible continuum manipulator with multifunctional tip. The latter features laser optics, stereo vision, and illumination. Vision-based performance assessment is derived from depth estimation and scene tracking. Novices and experts (
n
= 20) conducted teleoperated delineation tasks to mimic laser ablation of delicate anatomy. Delineation with motion-compensated and raw endoscopic visualisation was carried out on planar and non-planar nominal patterns. Root mean square tracing errors of less than 0.75 mm were feasible with task completion times below 45 s. Relevant anatomy in the porcine larynx was exposed successfully. Accuracy and usability of the integrated platform bear potential for dexterous laser manipulation in clinical settings. Cadaver and
in vivo
animal studies may translate
ex vivo
findings.
Microvascular procedures require visual magnification of the surgical field, e.g. by a microscope. This can be accompanied by an unergonomic posture with musculoskeletal pain or long-term ...degenerative changes as the eye is bound to the ocular throughout the whole procedure. The presented study describes the advantages and drawbacks of a 3D exoscope camera system. The RoboticScope
®
-system (BHS Technologies
®
, Innsbruck, Austria) features a high-resolution 3D-camera that is placed over the surgical field and a head-mounted-display (HMD) that the camera pictures are transferred to. A motion sensor in the HMD allows for hands-free change of the exoscope position via head movements. For general evaluation of the system functions coronary artery anastomoses of ex-vivo pig hearts were performed. Second, the system was evaluated for anastomosis of a radial-forearm-free-flap in a clinical setting/in vivo. The system positioning was possible entirely hands-free using head movements. Camera control was intuitive; visualization of the operation site was adequate and independent from head or body position. Besides technical instructions of the providing company, there was no special surgical training of the surgeons or involved staff upfront performing the procedures necessary. An ergonomic assessment questionnaire showed a favorable ergonomic position in comparison to surgery with a microscope. The outcome of the operated patient was good. There were no intra- or postoperative complications. The exoscope facilitates a change of head and body position without losing focus of the operation site and an ergonomic working position. Repeated applications have to clarify if the system benefits in clinical routine.
During the last years, two new cardiovascular drug classes, namely inhibitors of DPP IV or neprilysin, have been developed. In both cases, there is clinical evidence for their potential to induce ...angioedema as known already from blockers of the renin–angiotensin–aldosterone system (RAAS). The majority of angioedema induced by DPP IV inhibitors occurs during concomitant treatment with ACEi and is therefore likely mediated by overactivation of bradykinin type 2 receptors (B2). In striking contrast, the molecular pathways causing angioedema induced by neprilysin inhibitors, that is, sacubitril, are unclear, although a contribution of bradykinin appears likely. Nevertheless, there is no clinical evidence suggesting that inhibition of B2 might relieve the symptoms and/or prevent invasive treatment including coniotomy or tracheotomy in angioedema caused by these drugs. Therefore, the risk of angioedema should always be considered, especially in ambulatory care situations where patients have no rapid access to intensive care.
The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, ...tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well.
The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers (
= 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood:
= 13; TIL:
= 17) and elderly cancer patients (70-90 yrs.; blood:
= 20; TIL:
= 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4
and CD8
T cells as well as regulatory T cells (T
) were assessed by flow cytometry.
We observed lower frequencies of CD8
cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients.
Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.
Purpose
In recent years Magnetic Resonance Elastography (MRE) emerged into a clinically applicable imaging technique. It has been shown that MRE is capable of measuring global changes of the ...viscoelastic properties of cerebral tissue. The purpose of our study was to evaluate a spatially resolved three-dimensional multi-frequent MRE (3DMMRE) for assessment of the viscoelastic properties of intracranial tumours.
Methods
A total of 27 patients (63±13 years) were included. All examinations were performed on a 3.0 T scanner, using a modified phase-contrast echo planar imaging sequence. We used 7 vibration frequencies in the low acoustic range with a temporal resolution of 8 dynamics per wave cycle. Post-processing included multi-frequency dual elasto-visco (MDEV) inversion to generate high-resolution maps of the magnitude |
G
*| and the phase angle φ of the complex valued shear modulus.
Results
The tumour entities included in this study were: glioblastoma (
n
= 11), anaplastic astrocytoma (
n
= 3), meningioma (
n
= 7), cerebral metastasis (
n
= 5) and intracerebral abscess formation (
n
= 1). Primary brain tumours and cerebral metastases were not distinguishable in terms of |
G
*| and φ. Glioblastoma presented the largest range of |
G
*| values and a trend was delineable that glioblastoma were slightly softer than WHO grade III tumours. In terms of φ, meningiomas were clearly distinguishable from all other entities.
Conclusions
In this pilot study, while analysing the viscoelastic constants of various intracranial tumour entities with an improved spatial resolution, it was possible to characterize intracranial tumours by their mechanical properties. We were able to clearly delineate meningiomas from intraaxial tumours, while for the latter group an overlap remains in viscoelastic terms.
Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we ...evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy.
Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry.
TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival.
Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.
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