Regeneration and Sprouting of Chronically Injured Corticospinal Tract Fibers in Adult Rats Promoted by NT-3 and the mAb IN-1, Which Neutralizes Myelin-Associated Neurite Growth Inhibitors

Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5–6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2–11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery.     

Performance of OCT segmentation procedures to assess morphology and extension in geographic atrophy

Purpose: Investigating segmentation procedures and morphological findings in time domain (TD) and current spectral domain (SD) optical coherence tomography (OCT) devices in patients with geographic atrophy (GA). Methods: Fifty eyes of 46 patients with GA secondary to AMD and 15 control eyes were examined in this prospective noninterventional comparative case series. All patients underwent Stratus (model 3000), Cirrus (Carl Zeiss Meditec), Spectralis (Spectralis HRA+OCT; Heidelberg Engineering) and 3D‐OCT‐1000 (Topcon). Automated segmentation analyses were compared. An overlay of scanning laser ophthalmoscope (SLO) and three‐dimensional retinal thickness (RT) maps were used to investigate whether areas of retinal thinning correspond to areas of retinal pigment epithelium (RPE) atrophy. Results: Geographic atrophy areas identified in SLO scans were significantly larger than areas of retinal thinning in RT maps. No convincing topographic correlation could be found between areas of retinal thinning and actual GA size as identified in SLO and fundus photography. Spectralis OCT showed significantly more mild and severe segmentation errors than 3D and Cirrus OCT. Conclusion: This study showed substantial limitations in identifying zones of GA reliably when using automatic segmentation procedures in current SD‐OCT devices. This limitation should be addressed to visualize and document RPE loss realistically in a frequent disease like GA.     

Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors

Axial spondyloarthritis (axSpA), which encompasses ankylosing spondylitis, is a complex genetic disease. Aberrant bone formation is a key feature of pathogenesis that can lead to ankylosis of the spine. Our objective is to determine, whether genes whose variants confer susceptibility to AS are expressed in bone progenitors like mesenchymal stem cells (MSCs). Since MSCs from bone marrow is difficult to obtain, we first examined, whether MSCs can be derived from induced pluripotent stem cells (iPSCs). Dermal fibroblasts of two axSpA patients and one healthy control were reprogrammed into iPSCs using a Sendai virus vector encoding pluripotency genes. Pluripotency of iPSCs was examined by embryoid body formation and by testing for stem cell specific gene and protein expression using RT-PCR and immuno fluorescence. iPSCs were differentiated into MSCs by a TGFß inhibitor. MSCs were characterized by flow cytometry using lineage specific antibodies and by their capacity to develop into chondrocytes, adipocytes, and osteoblasts in lineage-specific medium. RNA-seq was applied to determine genome-wide gene expression patterns in MSCs, iPSCs, and blood. We show for the first time, that expression levels of several AS susceptibility genes (EDIL3, ANO6, HAPLN1, ANTXR2) involved in bone formation are significantly elevated in MSCs (2–15-fold; p ≤ 0.05) compared to blood or iPSCs and demonstrate that iPSC-derived MSCs can be differentiated into osteoblasts, chondrocytes, and adipocytes. We conclude, MSCs generated from patient fibroblast-derived iPSC lines are useful tools for studying functional genomics of risk genes associated with bone formation in AS pathogenesis.     

Head-to-head comparison between <Superscript>18</Superscript>F-FDOPA PET/CT and MR/CT angiography in clinically recurrent head and neck paragangliomas

Purpose

Head and neck paragangliomas (HNPGLs) can relapse after primary treatment. Optimal imaging protocols have not yet been established for posttreatment evaluation. The aim of the present study was to assess the diagnostic value of ¹⁸F-FDOPA PET/CT and MR/CT angiography (MRA/CTA) in HNPGL patients with clinical relapse during their follow-up.

Methods

Sixteen consecutive patients presenting with local pain, tinnitus, dysphagia, hoarse voice, cranial nerve involvement, deafness, or retrotympanic mass appearing during follow-up after the initial treatment of HNPGLs were retrospectively evaluated. Patients underwent both ¹⁸F-FDOPA PET/CT and MRA (15 patents) or CTA (1 patent). Both methods were first assessed under blinded conditions and afterwards correlated. Head and neck imaging abnormalities without histological confirmation were considered true-positive results based on a consensus between radiologists and nuclear physicians and on further ¹⁸F-FDOPA PET/CT and/or MRA.

Results

¹⁸F-FDOPA PET/CT and MRA/CTA were concordant in 14 patients and in disagreement in 2 patients. ¹⁸F-FDOPA PET/CT and MRA/CTA identified, respectively, 12 and 10 presumed recurrent HNPGLs in 12 patients. The two lesions diagnosed by PET/CT only were confirmed during follow-up by otoscopic examination and MRA performed 29 and 17 months later. ¹⁸F-FDOPA PET/CT images were only slightly influenced by the posttreatment sequelae, showing a better interobserver reproducibility than MRA/CTA. Finally, in 2 of the 16 studied patients, ¹⁸F-FDOPA PET/CT detected two additional synchronous primary HNPGLs.

Conclusion

¹⁸F-FDOPA PET/CT is highly sensitive in posttreatment evaluation of patients with HNPGLs, and also offers better interobserver reproducibility than MRA/CTA and whole-body examination. We therefore suggest that ¹⁸F-FDOPA PET/CT is performed as the first diagnostic imaging modality in symptomatic patients with suspicion of HNPGL relapse after primary treatment when ⁶⁸Ga-labeled somatostatin analogues are not available.

     

Quality of Online Information on Multiple Myeloma Available for Laypersons

Online information can increase patients’ competence and engagement. However, there are concerns regarding invalid information. Overall, 300 websites and 50 YouTube videos on multiple myeloma (MM) were evaluated. The websites did not differ between the search engines or search ranks. The median time since the last update was 9 months. The 63 unique websites showed a poor general quality (median JAMA score 2 of 4, only 18% with a valid HON certificate). The patient- (user-) focused quality was medium to poor (median sum DISCERN score 41 out of 80 points). The overall reading level was difficult requiring at least a 12th US school grade. The content level was low (median 24 out of 73 points). Sixteen percent contained misleading/wrong facts. Websites provided by foundation/advocacies showed a significantly higher general and patient- (user-) focused quality. For videos, the median time since upload was 18 months. Judged by the HON foundation score ~80% of videos showed a medium general quality. The patient- (user-) focused quality was medium to poor (median sum DISCERN score 43 points). The content level was very low (median 8 points). MM relevant websites and videos showed a medium to low general, patient- (user-) focused and content quality. Therefore, incorporation of quality indices and regular review is warranted.     

The serum D-xylose test as a useful tool to identify malabsorption in rats with antigen specific gut inflammatory reaction

The inappropriate immune response to foods, such as peanut, wheat and milk may be the basis in the pathogenesis of enteropathies like coeliac and Crohn disease, which present small intestinal malabsorption. A number of recent studies have utilized d -xylose absorption as an investigative tool to study small intestinal function in a variety of clinical settings. Thus, the aim of this experimental study was to evaluate the intestinal absorption of d -xylose in an antigen-specific gut inflammatory reaction rat model. Animals of the experimental group were inoculated with peanut protein extract before their exposure to a challenge diet containing exclusively peanut seeds to induce the gut inflammatory reaction caused by peanut allergy. Our results show that systemic inoculation with peanut protein extract renders significantly higher antibody titres (5.085 ± 0.126 units) ( P  < 0.0001) than control rats (0.905 ± 0.053 units) and that the antibody titres correlate positively to an inflammatory alteration of the gut morphology ( P  < 0.0001). Animals pertaining to the experimental group showed an intestinal absorption of d -xylose lower than control rats ( P  < 0.0001). We also observed that d -xylose absorption correlates negatively with IgG titres and positively with morphometric parameters (Pearson correlation). In conclusion, the use of serum d -xylose test was useful to identify the presence of small intestinal malabsorption in our antigen specific gut inflammatory reaction rat model.     

Plasma concentrations of interleukin-6, organ failure, vasopressor support, and successful coronary revascularization in predicting 30-day mortality of patients with cardiogenic shock complicating acute myocardial infarction

OBJECTIVE: Inflammation may play an important role in the pathogenesis, persistence, and prognosis of cardiogenic shock. We analyzed whether elevated plasma concentrations of inflammatory markers are independently associated with an adverse prognosis (increased 30-day mortality rate) in patients with cardiogenic shock. DESIGN: Retrospective study. SETTING: Single-center study, eight-bed intensive care unit at a university hospital. PATIENTS: Retrospective study on stored plasma samples from 38 patients with cardiogenic shock complicating acute myocardial infarction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-day nonsurvivors (n = 23, 61%) had been less frequently successfully revascularized, exhibited more frequently renal failure, needed higher vasopressor doses, and presented with significantly higher interleukin-6 plasma concentrations on intensive care unit admission than 30-day survivors. Univariate hazard ratios (95% confidence interval) for 30-day mortality were 1.49 (1.24-1.80) for every 50 pg/mL increase in the interleukin-6 plasma concentration (p = .00003), 1.06 (1.02-1.10) for every 0.1 microg x kg x min increase in the total vasopressor dose (p = .007), 1.14 (1.04-1.25) for every mmol/L increase in serum lactate (p = .006), 2.47 (1.06-5.73) for acute renal failure (p = .036), and 0.34 (0.14-0.82) for successful revascularization (p = .016). However, interleukin-6 plasma concentrations were correlated with vasopressor need and were significantly higher in patients with acute renal failure and in patients without or unsuccessful revascularization. In a multivariate Cox-proportional hazard model, interleukin-6 was the only significant predictor of 30-day mortality with a hazard ratio of 1.42 (1.12-1.80, p = .004). Accordingly, interleukin-6 concentrations > or =200 pg/mL (the point of maximum interest by receiver operating characteristic analysis with a specificity of 87% and a sensitivity of 74%) were associated with a significantly increased 30-day mortality rate in both patients with and patients without successful revascularization. CONCLUSIONS: Interleukin-6 concentrations are an independent predictor of 30-day mortality in patients with acute myocardial infarction complicated by cardiogenic shock.