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In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.
Selective BRAF inhibitors such as vemurafenib have become a treatment option in patients with Langerhans cell Histiocytosis (LCH). To date, only 14 patients receiving vemurafenib for LCH have been reported. Although vemurafenib can stabilize the clinical condition of these patients, it does not seem to cure the patients, and it is unknown, when and how to stop vemurafenib treatment. We present a girl with severe multisystem LCH who responded only to vemurafenib. After 8 months of treatment, vemurafenib was tapered and replaced by prednisone and vinblastine, a strategy which has not been described to date. Despite chemotherapy, early relapse occurred, but remission was achieved by re-institution of vemurafenib. Further investigation needs to address the optimal duration of vemurafenib therapy in LCH and whether and which chemotherapeutic regimen may prevent disease relapse after cessation of vemurafenib.
Ventriculoperitoneal shunts equipped with a reservoir and a valve to manually switch off the shunt function can be used for intraventricular injections of therapeutics in patients suffering from a communicating hydrocephalus caused by leptomeningeal metastases. These shunt devices avoid the risk of injecting therapeutics through the distal leg of the shunt system into the intraperitoneal space, which may cause toxicity. Furthermore, regular intraventricular injections of chemotherapeutics help to maintain sufficient concentrations in the ventricular space. Therefore, ventriculoperitoneal shunts equipped with an on-off valve are a useful tool to reliably inject chemotherapeutics into the ventricles. In order to systematically assess feasibility, safety, and efficacy of this procedure, we performed a retrospective analysis of all patients with leptomeningeal metastases who had received a shunt system at our institution. In total, six adult patients had a ventriculoperitoneal shunt equipped with an on-off valve implanted. Out of these six patients, two patients subsequently received intraventricular injections of chemotherapeutics. The configuration of the valve setting and the intraventricular injections were easily feasible in the setting of a neuro-oncology department. The complication of a shunt leakage occurred in one patient following the first intraventricular injection. No extra-central nervous system (CNS) toxicities were observed. In summary, ventriculoperitoneal shunts with on-off valves are useful tools for reliable intraventricular administration of therapeutics.
The longevity of the population in the Okinawa Islands of Japan has been ascribed to genetic factors and the traditional Okinawa cuisine, which is low in calories and high in plant content. This diet includes shell ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) of the ginger family (Zingiberaceae). Due to its local popularity, Alpinia zerumbet has become the subject of a good deal of study at the University of the Ryukyus in Okinawa. Personal local experience and review of the literature now suggest that culinary shell ginger may contribute to longevity among the population in Okinawa. This is supported by its abundant phytochemical content, with antioxidant and anti-obesity properties. The major bioactive phytochemicals are dihydro-5,6-dehydrokawain (DDK; 80–410 mg g−1 fresh weight), 5,6-dehydrokawain (DK; ≤100 mg g−1), and essential oils, phenols, phenolic acids, and fatty acids (≤150 mg g−1 each). Further, Alpinia zerumbet extends the lifespan in animals by 22.6%. In conclusion, culinary shell ginger may significantly contribute to human longevity in Okinawa.
Background: Vitamin D is required to maintain the integrity of the intestinal barrier and inhibits inflammatory signaling pathways.
Objective: Vitamin D deficiency might be involved in cirrhosis-associated systemic inflammation and risk of hepatic decompensation in patients with liver cirrhosis.
Methods: Outpatients of the Hepatology Unit of the University Hospital Frankfurt with advanced liver fibrosis and cirrhosis were prospectively enrolled. 25-hydroxyvitamin D (25(OH)D3) serum concentrations were quantified and associated with markers of systemic inflammation / intestinal bacterial translocation and hepatic decompensation.
Results: A total of 338 patients with advanced liver fibrosis or cirrhosis were included. Of those, 51 patients (15%) were hospitalized due to hepatic decompensation during follow-up. Overall, 72 patients (21%) had severe vitamin D deficiency. However, patients receiving vitamin D supplements had significantly higher 25(OH)D3 serum levels compared to patients without supplements (37 ng/mL vs. 16 ng/ml, P<0.0001). Uni- and multivariate analyses revealed an independent association of severe vitamin D deficiency with the risk of hepatic decompensation during follow-up (multivariate P = 0.012; OR = 3.25, 95% CI = 1.30–8.2), together with MELD score, low hemoglobin concentration, low coffee consumption, and presence of diabetes. Of note, serum levels of C-reactive protein, IL-6 and soluble CD14 were significantly higher in patients with versus without severe vitamin D deficiency, and serum levels of soluble CD14 levels declined in patients with de novo supplementation of vitamin D (median 2.15 vs. 1.87 ng/mL, P = 0.002).
Conclusions: In this prospective cohort study, baseline vitamin D levels were inversely associated with liver-cirrhosis related systemic inflammation and the risk of hepatic decompensation.
Background: Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in FOXO3a gene in respect to thyroid diseases, as well as to evaluate the hypothesis of Sirtuin1-FOXO3a interaction being a mediator of anti-proliferative vitamin D effects.
Methods: The SNP's FOXO3a rs4946936/rs4945816/rs9400239 were genotyped in 257 patients with differentiated thyroid carcinoma (DTC), 139 patients with Hashimoto thyroiditis (HT) and 463 healthy controls (HC). Moreover, T-helper cells of HC and papillary thyroid cancer cell line BCPAP were incubated with 1,25(OH)2D3 and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro.
Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (pcorrected = pc = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (pc = 0.02 and pc = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)2D3 showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05).
Conclusions: FOXO3a rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects.
The identification of pathological atrophy in MRI scans requires specialized training, which is scarce outside dedicated centers. We sought to investigate the clinical usefulness of computer-generated representations of local grey matter (GM) loss or increased volume of cerebral fluids (CSF) as normalized deviations (z-scores) from healthy aging to either aid human visual readings or directly detect pathological atrophy.
Two experienced neuroradiologists rated atrophy in 30 patients with Alzheimer's disease (AD), 30 patients with frontotemporal dementia (FTD), 30 with dementia due to Lewy-body disease (LBD) and 30 healthy controls (HC) on a three-point scale in 10 anatomical regions as reference gold standard. Seven raters, varying in their experience with MRI diagnostics rated all cases on the same scale once with and once without computer-generated volume deviation maps that were overlaid on anatomical slices. In addition, we investigated the predictive value of the computer generated deviation maps on their own for the detection of atrophy as identified by the gold standard raters.
Inter and intra-rater agreements of the two gold standard raters were substantial (Cohen's kappa κ > 0.62). The intra-rater agreement of the other raters ranged from fair (κ = 0.37) to substantial (κ = 0.72) and improved on average by 0.13 (0.57 < κ < 0.87) when volume deviation maps were displayed. The seven other raters showed good agreement with the gold standard in regions including the hippocampus but agreement was substantially lower in e.g. the parietal cortex and did not improve with the display of atrophy scores. Rating speed increased over the course of the study and irrespective of the presentation of voxel-wise deviations.
Automatically detected large deviations of local volume were consistently associated with gold standard atrophy reading as shown by an area under the receiver operator characteristic of up to 0.95 for the hippocampus region. When applying these test characteristics to prevalences typically found in a memory clinic, we observed a positive or negative predictive value close to or above 0.9 in the hippocampus for almost all of the expected cases. The volume deviation maps derived from CSF volume increase were generally better in detecting atrophy.
Our study demonstrates an agreement of visual ratings among non-experts not further increased by displaying, region-specific deviations of volume. The high predictive value of computer generated local deviations independent from human interaction and the consistent advantages of CSF-over GM-based estimations should be considered in the development of diagnostic tools and indicate clinical utility well beyond aiding visual assessments.
White matter microstructural changes and episodic memory disturbances in late-onset bipolar disorder
(2018)
Background: Bipolar disorder (BD) has been associated with distributed network disruption, but little is known on how different clinical subtypes, particularly those with an earlier and later onset of disease, are related to connectivity changes in white matter (WM) tracts.
Methods: Diffusion tensor imaging (DTI) and volumetric measures were carried out in early-onset bipolar patients [(EOD) (n = 16)], late-onset bipolar disorder [(LOD)(n = 14)] and healthy controls (n = 32). We also computed ROI analysis of gray matter (GM) and white matter (WM) volumes using the regions with significant group differences in the DTI parameters. Cognitive and behavior measurements were analyzed between groups.
Results: Lower fraction of anisotropy (FA) in the right hemisphere comprising anterior thalamic radiation, fornix, posterior cingulate, internal capsule, splenium of corpus callosum was observed in the LOD in comparison with EOD; additionally, lower FA was also found in the LOD in comparison with healthy controls, mostly in the right hemisphere and comprising fibers of the splenium of the corpus callosum, cingulum, superior frontal gyrus and posterior thalamic radiation; LOD also showed worse episodic memory performance than EOD; no statistical significant differences between mood symptoms, WM and GM volumes were found between BD groups.
Conclusion: Even after correcting for age differences, LOD was associated with more extensive WM microstructural changes and worse episodic memory performance than EOD; these findings suggest that changes in the WM fiber integrity may be associated with a later presentation of BD, possibly due to mechanisms other than neuroprogression. However, these findings deserve replication in larger, prospective, studies.
One of the crucial steps during trials for Zika and other vaccines is to recruit participants and to understand how participants’ attitudes and sociodemographic characteristics affect willingness to participate (WTP). This study was conducted to assess WTP, its explanatory variables, and the impact of financial compensation on WTP in Indonesia. A health facility-based cross-sectional study was conducted in eleven regencies in the Aceh and West Sumatra provinces of Indonesia. Participants were recruited via a convenience sampling method and were interviewed. The associations between explanatory variables and WTP were assessed using a two-step logistic regression analysis. A total of 1,102 parents were approached, and of these 956 (86.8%) completed the interview and were included in analysis. Of those, 144 (15.1%) were willing to participate in a Zika vaccine trial without a financial compensation. In the multivariate analysis, WTP was tied to an age of more than 50 years old, compared to 20–29 years (odds ratio (OR): 5.0; 95% confidence interval (CI): 2.37–10.53), to being female (OR: 2.20; 95% CI: 1.11–4.37), and to having heard about Zika (OR: 2.41; 95% CI: 1.59–3.65). Participants’ WTP increased gradually with higher financial compensation. The rate of WTP increased to 62.3% at the highest offer (US$ 350.4), and those who were still unwilling to participate (37.7%) had a poorer attitude towards childhood vaccination. This study highlights that pre-existing knowledge about Zika and attitudes towards childhood vaccination are important in determining community members being willing to participate in a vaccine trial. Financial incentives are still an important factor to enhance participant recruitment during a vaccine trial.