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The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3’UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3’UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism. In a cohort of 515 healthy stem cell donors we attempted to reproduce the correlation of the CXCL12 3’UTR SNP and mobilization responses and tested the role of miR941 in this context. The SNP was distributed with the expected frequency. Mobilization efficiency for CD34+ cells in WT, heterozygous and homozygous SNP individuals was indistinguishable, even after controlling for gender. miR941 expression in non-hematopoietic bone marrow cells was undetectable and miR941 did not interact with the 3’ UTR of CXCL12. Proposed effects of the SNP rs1801157 on G-CSF responsiveness cannot be confirmed in a larger cohort.
Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples.
Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss–Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied.
Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder.
Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.
Background: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.
Methods: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.
Results: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78).
Conclusions: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
Background: Standardization in clinical practice may lead to improved outcomes. Unfortunately, little is known about the variability of non-pharmacological anti-infective measures in children with cancer.
Design and Methods: A web-based survey assessed institutional recommendations regarding restrictions of social contacts, pets and food and instructions on wearing face masks in public for children with standard- risk acute lymphoblastic leuk emia and acute myeloid leukemia during intensive chemotherapy.
Results: A total of 336 institutions in 27 countries responded to the survey (range, 1-76 institutions per country; overall response rate 61%). Most institutions recommend that patients with acute myeloid leukemia avoid indoor public places and daycare, kindergarten and school, whereas recommendations for patients with acute lymphoblastic leukemia differ considerably by institution. In terms of restrictions related to pets, there was a wide variability between institutions for both acute lymphoblastic and acute myeloid leukemia patients. Most, but not all institutions do not allow children with either acute lymphoblastic or acute myeloid leukemia to eat raw meat, raw seafood or unpasteurized milk. Whereas most institutions do not routinely recommend that patients with acute lymphoblastic leukemia wear face masks in public, advice on this matter varies for patients with acute myeloid leukemia.
Conclusions: The survey demonstrates that there is a wide variation in recommendations on non-pharmacological anti-infective measures between different institutions, countries and continents. This information may be used to encourage harmonization of supportive care practices and future clinical trials.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases
(2021)
Background and Purpose: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.
Experimental Approach: As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates.
Key Results: Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response.
Conclusions and Implications: Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.
Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.
Background Vasoplegic syndrome is frequently observed during cardiac surgery and resembles a complication of high mortality and morbidity. There is a clinical need for therapy and prevention of vasoplegic syndrome during complex cardiac surgical procedures. Therefore, we investigated different strategies in a porcine model of vasoplegia.
Methods We evaluated new medical therapies and prophylaxis to avoid vasoplegic syndrome in a porcine model. After induction of anesthesia, cardiopulmonary bypass was established through median sternotomy and central cannulation. Prolonged aortic cross-clamping (120 min) simulated a complex surgical procedure. The influence of sevoflurane-guided anesthesia (sevoflurane group) and the administration of glibenclamide (glibenclamide group) were compared to a control group, which received standard anesthesia using propofol. Online hemodynamic assessment was performed using PiCCO® measurements. In addition, blood and tissue samples were taken to evaluate hemodynamic effects and the degree of inflammatory response.
Results Glibenclamide was able to break through early vasoplegic syndrome by raising the blood pressure and systemic vascular resistance as well as less need of norepinephrine doses. Sevoflurane reduced the occurrence of the vasoplegic syndrome in the mean of stable blood pressure and less need of norepinephrine doses.
Conclusion Glibenclamide could serve as a potent drug to reduce effects of vasoplegic syndrome. Sevoflurane anesthesia during cardiopulmonary bypass shows less occurrence of vasoplegic syndrome and therefore could be used to prevent it in high-risk patients.
Clinical Perspective; what is new?
* to our knowledge, this is the first randomized in vivo study evaluating the hemodynamic effects of glibenclamide after the onset of vasoplegic syndrome
* furthermore according to literature research, there is no study showing the effect of sevoflurane-guided anesthesia on the occurrence of a vasoplegic syndrome
Clinical Perspective; clinical implications?
to achieve better outcomes after complex cardiac surgery there is a need for optimized drug therapy and prevention of the vasoplegic syndrome
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.
Protein turnover and quality control by the proteasome is of paramount importance for cell homeostasis. Dysfunction of the proteasome is associated with aging processes and human diseases such as neurodegeneration, cardiomyopathy, and cancer. The regulation, i.e. activation and inhibition of this fundamentally important protein degradation system, is still widely unexplored. We demonstrate here that the evolutionarily highly conserved type II triple-A ATPase VCP and the proteasome inhibitor PSMF1/PI31 interact directly, and antagonistically regulate proteasomal activity. Our data provide novel insights into the regulation of proteasomal activity.
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.
Venomous secretions from marine snails of the Terebridae family target acetylcholine receptors
(2013)
Venoms from cone snails (Conidae) have been extensively studied during the last decades, but those from other members of the suborder Toxoglossa, such as of Terebridae and Turridae superfamilies attracted less interest so far. Here, we report the effects of venom and gland extracts from three species of the superfamily Terebridae. By 2-electrode voltage-clamp technique the gland extracts were tested on Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) of rat neuronal (α3β2, α3β4, α4β2, α4β4, α7) and muscle subtypes (α1β1γδ), and expressing potassium (Kv1.2 and Kv1.3) and sodium channels (Nav1.2, 1.3, 1.4, 1.6). The extracts were shown to exhibit remarkably high inhibitory activities on almost all nAChRs tested, in particular on the α7 subtype suggesting the presence of peptides of the A-superfamily from the venom of Conus species. In contrast, no effects on the potassium and sodium channels tested were observed. The venoms of terebrid snails may offer an additional source of novel biologically active peptides.
Adolescence has been linked to an enhanced tolerance of uncertainty and risky behavior and is possibly connected to an increased response toward rewards. However, previous research has produced inconsistent findings. To investigate whether these findings are due to different reward probabilities used in the experimental design, we extended a monetary incentive delay (MID) task by including three different reward probabilities. Using functional magnetic resonance imaging, 25 healthy adolescents and 22 adults were studied during anticipation of rewards in the VS. Differently colored cue stimuli indicated either a monetary or verbal trial and symbolized different reward probabilities, to which the participants were blinded. Results demonstrated faster reaction times for lower reward probabilities (33%) in both age groups. Adolescents were slower through all conditions and had less activation on a neural level. Imaging results showed a three-way interaction between age group x condition x reward probability with differences in percent signal change between adolescents and adults for the high reward probabilities (66%, 88%) while adolescents demonstrated differences for the lowest (33%). Therefore, previous inconsistent findings could be due to different reward probabilities, which makes examining these crucial for a better understanding of adolescent and adult behavior.
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.
Beyond well-established difficulties with working memory in individuals with attention deficit hyperactivity disorder (ADHD), evidence is emerging that other memory processes may also be affected. We investigated, first, which memory processes show differences in adults and adolescents with ADHD in comparison to control participants, focusing on working and short-term memory, initial learning, interference, delayed and recognition memory. Second, we investigated whether ADHD severity, co-occurring depressive symptoms, IQ and physical fitness are associated with the memory performance in the individuals with ADHD.
We assessed 205 participants with ADHD (mean age 25.8 years, SD 7.99) and 50 control participants (mean age 21.1 years, SD 5.07) on cognitive tasks including the digit span forward (DSF) and backward (DSB), the Rey Auditory Verbal Learning Test (RAVLT), and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Participants with ADHD were additionally assessed on ADHD severity, depression symptoms and cardiorespiratory fitness. A series of regressions were run, with sensitivity analyses performed when variables were skewed.
ADHD-control comparisons were significant for DSF, DSB, delayed and recognition memory, with people with ADHD performing less well than the control participants. The result for recognition memory was no longer significant in sensitivity analysis. Memory performance was not associated with greater ADHD or depression symptoms severity. IQ was positively associated with all memory variables except DSF. Cardiorespiratory fitness was negatively associated with the majority of RAVLT variables.
Individuals with ADHD showed difficulties with working memory, short-term memory and delayed memory, as well as a potential difficulty with recognition memory, despite preserved initial learning.
Objective: Vertigo is a common side effect of cochlear implant (CI) treatment. This prospective study examines the incidence of postoperative vertigo over time and aims to analyze influencing factors such as electrode design and insertion angle (IA).
Study Design and Setting: This is a prospective study which has been conducted at a tertiary referral center (academic hospital).
Patients: A total of 29 adults were enrolled and received a unilateral CI using one of six different electrode carriers, which were categorized into “structure-preserving” (I), “potentially structure-preserving” (II), and “not structure-preserving” (III).
Intervention: Subjective vertigo was assessed by questionnaires at five different time-points before up to 6 months after surgery. The participants were divided into four groups depending on the time of the presence of vertigo before and after surgery. Preoperatively and at 6 months postoperatively, a comprehensive vertigo diagnosis consisting of Romberg test, Unterberger test, subjective visual vertical, optokinetic test, video head impulse test, and caloric irrigation test was performed. In addition, the IA was determined, and the patients were divided in two groups (<430°; ≥430°).
Main Outcome Measures: The incidence of vertigo after CI surgery (group 1) was reported, as well as the correlation of subjective vertigo with electrode array categories (I–III) and IA.
Results: Among the participants, 45.8% experienced new vertigo after implantation. Based on the questionnaire data, a vestibular origin was suspected in 72.7%. The results did not show a significant correlation with subjective vertigo for any of the performed tests. In group 1 with postoperative vertigo, 18% of patients showed conspicuous results in a quantitative analysis of caloric irrigation test despite the fact that the category I or II electrodes were implanted, which are suitable for structure preservation. Average IA was 404° for the overall group and 409° for group 1. There was no statistically significant correlation between IA and perceived vertigo.
Conclusions: Though vertigo after CI surgery seems to be a common complication, the test battery used here could not objectify the symptoms. Further studies should clarify whether this is due to the multifactorial cause of vertigo or to the lack of sensitivity of the tests currently in use. The proof of reduced probability for vertigo when using atraumatic electrode carrier was not successful, nor was the proof of a negative influence of the insertion depth.
Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.
Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.
Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.
Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.
Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.
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.
Vimentin is currently used to differentiate between malignant renal carcinomas and benign oncocytomas. Recent reports showing Vimentin positive oncocytomas seriously question the validity of this present diagnostic approach. Vimentin 3 is a spliced variant and ends with a unique C-terminal ending after exon 7 which differentiates it from the full length version that has 9 exons. Therefore, the protein size is different; the full length Vimentin version has a protein size of ~57 kDa and the truncated version of ~47 kDa. We designed an antibody, called Vim3, against the unique C-terminal ending of the Vimentin 3 variant. Using immune histology, immune fluorescence, Western blot, and qRT-PCR analysis, a Vim3 overexpression was detectable exclusively in oncocytoma, making the detection of Vim3 a potential specific marker for benign kidney tumors. This antibody is the first to clearly differentiate benign oncocytoma and the mimicking eosinophilic variants of the RCCs. This differentiation between malignant and benign RCCs is essential for operative planning, follow-up therapy, and patients' survival. In the future the usage of Vimentin antibodies in routine pathology has to be applied with care. Consideration must be given to Vimentin specific binding epitopes otherwise a misdiagnosis of the patients' tumor samples may result.
Health-care personnel (HCP) are exposed to infectious diseases throughout the course of their work. The concerns of pregnant HCP are considerable because certain otherwise mild infections may affect fetal development. We studied 424 pregnant HCP at the University Hospital Frankfurt / Germany between March 2007 and July 2011. Serological tests were carried out for varicella zoster virus (VZV), measles, mumps, rubella (MMR), cytomegalovirus (CMV) and parvovirus B19. Our overall seroprevalence data with regard to VZV, MMR, CMV and parvovirus B 19 corresponded to the general population. It was striking that, only 57.1% of the study population was immune against the four vaccine-preventable diseases (MMR, VZV). Our study suggests that a comprehensive approach to improving the vaccination status of said HCP before pregnancy is paramount.
Purpose: Early detection of adenocarcinomas in the esophagus is crucial for achieving curative endoscopic therapy. Targeted biopsies of suspicious lesions, as well as four-quadrant biopsies, represent the current diagnostic standard. However, this procedure is time-consuming, cost-intensive, and examiner-dependent. The aim of this study was to test whether impedance spectroscopy is capable of distinguishing between healthy, premalignant, and malignant lesions. An ex vivo measurement method was developed to examine esophageal lesions using impedance spectroscopy immediately after endoscopic resection. Methods: After endoscopic resection of suspicious lesions in the esophagus, impedance measurements were performed on resected cork-covered tissue using a measuring head that was developed, with eight gold electrodes, over 10 different measurement settings and with frequencies from 100 Hz to 1 MHz. Results: A total of 105 measurements were performed in 60 patients. A dataset of 400 per investigation and a total of more than 42,000 impedance measurements were therefore collected. Electrical impedance spectroscopy (EIS) was able to detect dysplastic esophageal mucosa with a sensitivity of 81% in Barrett’s esophagus. Conclusion: In summary, EIS was able to distinguish different tissue characteristics in the different esophageal tissues. EIS thus holds potential for further development of targeted biopsies during surveillance endoscopy.
Dual-energy CT (DECT) has emerged into clinical routine as an imaging technique with unique postprocessing utilities that improve the evaluation of different body areas. The virtual non-calcium (VNCa) reconstruction algorithm has shown beneficial effects on the depiction of bone marrow pathologies such as bone marrow edema. Its main advantage is the ability to substantially increase the image contrast of structures that are usually covered with calcium mineral, such as calcified vessels or bone marrow, and to depict a large number of traumatic, inflammatory, infiltrative, and degenerative disorders affecting either the spine or the appendicular skeleton. Therefore, VNCa imaging represents another step forward for DECT to image conditions and disorders that usually require the use of more expensive and time-consuming techniques such as magnetic resonance imaging, positron emission tomography/CT, or bone scintigraphy. The aim of this review article is to explain the technical background of VNCa imaging, showcase its applicability in the different body regions, and provide an updated outlook on the clinical impact of this technique, which goes beyond the sole improvement in image quality.
Background: Computerized virtual patients (VP) have spread into many areas of healthcare delivery and medical education. They provide various advantages like flexibility in pace and space of learning, a high degree of teaching reproducibility and a cost effectiveness. However, the educational benefit of VP as an additive or also as an alternative to traditional teaching formats remains unclear. Moreover, there are no randomized-controlled studies that investigated the use of VP in a dental curriculum. Therefore, this study investigates VP as an alternative to lecturer-led small-group teaching in a curricular, randomized and controlled setting.
Methods: Randomized and controlled cohort study. Four VP cases were created according to previously published design principles and compared with lecturer-led small group teaching (SGT) within the Oral and Maxillofacial Surgery clerkship for dental students at the Department for Cranio-, Oral and Maxillofacial Plastic Surgery, Goethe University, Frankfurt, Germany. Clinical competence was measured prior (T0), directly (T1) and 6 weeks (T2) after the intervention using theoretical tests and a self-assessment questionnaire. Furthermore, VP design was evaluated using a validated toolkit.
Results: Fifty-seven students (VP = 32; SGT = 25) agreed to participate in the study. No competence differences were found at T0 (p = 0.56). The VP group outperformed (p < .0001) the SGT group at T1. At T2 there was no difference between both groups (p = 0.55). Both interventions led to a significant growth in self-assessed competence. The VP group felt better prepared to diagnose and treat real patients and regarded VP cases as a rewarding learning experience.
Conclusions: VP cases are an effective alternative to lecture-led SGT in terms of learning efficacy in the short and long-term as well as self-assessed competence growth and student satisfaction. Furthermore, integrating VP cases within a curricular Oral and Maxillofacial Surgery Clerkship is feasible and leads to substantial growth of clinical competence in undergraduate dental students.
Visible light is a better co-inducer of apoptosis for curcumin-treated human melanoma cells than UVA
(2013)
Curcumin attracts worldwide scientific interest due to its anti-proliferative and apoptosis inducing effects on different tumor cells at concentrations ranging from 10 to 150 µM (3.7–55 µg/ml). Unfortunately, because of a low oral bioavailability, only low and pharmacologically ineffective serum levels are achievable. In this study, an alternative treatment concept consisting of low concentration curcumin (0.2–5 µg/ml) and irradiation with UVA or visible light (VL) has been tested. The experimental results show clearly that this treatment decreases the proliferation and the viability of human melanoma cells while the cell membrane integrity remains intact. We identified the onset of apoptosis characterized by typical markers such as active caspases 8, 9 and 3 as well as DNA fragmentation accompanied by the loss of cell adhesion. The mitochondrial apoptosis signaling pathway is predominant due to an early activation of caspase-9. The present data indicate a higher efficacy of a combination of curcumin and VL than curcumin and UVA. Reduced effects as a result of light absorption by heavily pigmented skin are unlikely if VL is used. These results indicate that a combination of curcumin and light irradiation may be a useful additional therapy in the treatment of malignant disease.
Visual perception is highly variable and can be influenced by the surrounding world. Previous research has revealed that body perception can be biased due to adaptation to thin or fat body shapes. The aim of the present study was to show that adaptation to certain body shapes and the resulting perceptual biases transfer across different identities of adaptation and test stimuli. We designed two similar adaptation experiments in which healthy female participants adapted to pictures of either thin or fat bodies and subsequently compared more or less distorted pictures of their own body to their actual body shape. In the first experiment (n = 16) the same identity was used as adaptation and test stimuli (i.e. pictures of the participant’s own body) while in the second experiment (n = 16) we used pictures of unfamiliar thin or fat bodies as adaptation stimuli. We found comparable adaptation effects in both experiments: After adaptation to a thin body, participants rated a thinner than actual body picture to be the most realistic and vice versa. We therefore assume that adaptation to certain body shapes transfers across different identities. These results raise the questions of whether some type of natural adaptation occurs in everyday life. Natural and predominant exposure to certain bodily features like body shape – especially the thin ideal in Western societies – could bias perception for these features. In this regard, further research might shed light on aspects of body dissatisfaction and the development of body image disturbances in terms of eating disorders.
Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by problems in social behaviour, which are sometimes similar to some symptoms of autism-spectrum disorders (ASD). However, neuronal mechanisms of ASD-like deficits in ADHD have rarely been studied. The processing of biological motion–recently discussed as a marker of social cognition–was found to be disrupted in ASD in several studies. Thus in the present study we tested if biological motion processing is disrupted in ADHD. We used 64-channel EEG and spatio-temporal source analysis to assess event-related potentials associated with human motion processing in 21 children and adolescents with ADHD and 21 matched typically developing controls. On the behavioural level, all subjects were able to differentiate between human and scrambled motion. But in response to both scrambled and biological motion, the N200 amplitude was decreased in subjects with ADHD. After a spatio-temporal dipole analysis, a human motion specific activation was observable in occipital-temporal regions with a reduced and more diffuse activation in ADHD subjects. These results point towards neuronal determined alterations in the processing of biological motion in ADHD.
Background: Standardized neuropsychological testing serves to quantify cognitive impairment in multiple sclerosis (MS) patients. However, the exact mechanism underlying the translation of cognitive dysfunction into difficulties in everyday tasks has remained unclear. To answer this question, we tested if MS patients with intact vs. impaired information processing speed measured by the Symbol Digit Modalities Test (SDMT) differ in their visual search behavior during ecologically valid tasks reflecting everyday activities.
Methods: Forty-three patients with relapsing-remitting MS enrolled in an eye-tracking experiment consisting of a visual search task with naturalistic images. Patients were grouped into “impaired” and “unimpaired” according to their SDMT performance. Reaction time, accuracy and eye-tracking parameters were measured.
Results: The groups did not differ regarding age, gender, and visual acuity. Patients with impaired SDMT (cut-off SDMT-z-score < −1.5) performance needed more time to find and fixate the target (q = 0.006). They spent less time fixating the target (q = 0.042). Impaired patients had slower reaction times and were less accurate (both q = 0.0495) even after controlling for patients' upper extremity function. Exploratory analysis revealed that unimpaired patients had higher accuracy than impaired patients particularly when the announced target was in unexpected location (p = 0.037). Correlational analysis suggested that SDMT performance is inversely linked to the time to first fixation of the target only if the announced target was in its expected location (r = −0.498, p = 0.003 vs. r = −0.212, p = 0.229).
Conclusion: Dysfunctional visual search behavior may be one of the mechanisms translating cognitive deficits into difficulties in everyday tasks in MS patients. Our results suggest that cognitively impaired patients search their visual environment less efficiently and this is particularly evident when top-down processes have to be employed.
Introduction: The Vbeta12-transgenic mouse was previously generated to investigate the role of antigen-specific T cells in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. This mouse expresses a transgenic collagen type II (CII)-specific T-cell receptor (TCR) beta-chain and consequently displays an increased immunity to CII and increased susceptibility to CIA. However, while the transgenic Vbeta12 chain recombines with endogenous alpha-chains, the frequency and distribution of CII-specific T cells in the Vbeta12-transgenic mouse has not been determined. The aim of the present report was to establish a system enabling identification of CII-specific T cells in the Vbeta12-transgenic mouse in order to determine to what extent the transgenic expression of the CII-specific beta-chain would skew the response towards the immunodominant galactosylated T-cell epitope and to use this system to monitor these cells throughout development of CIA. Methods: We have generated and thoroughly characterized a clonotypic antibody, which recognizes a TCR specific for the galactosylated CII(260-270) peptide in the Vbeta12-transgenic mouse. Hereby, CII-specific T cells could be quantified and followed throughout development of CIA, and their phenotype was determined by combinatorial analysis with the early activation marker CD154 (CD40L) and production of cytokines. Results: The Vbeta12-transgenic mouse expresses several related but distinct T-cell clones specific for the galactosylated CII peptide. The clonotypic antibody could specifically recognize the majority (80%) of these. Clonotypic T cells occurred at low levels in the naïve mouse, but rapidly expanded to around 4% of the CD4+ T cells, whereupon the frequency declined with developing disease. Analysis of the cytokine profile revealed an early Th1-biased response in the draining lymph nodes that would shift to also include Th17 around the onset of arthritis. Data showed that Th1 and Th17 constitute a minority among the CII-specific population, however, indicating that additional subpopulations of antigen-specific T cells regulate the development of CIA. Conclusions: The established system enables the detection and detailed phenotyping of T cells specific for the galactosylated CII peptide and constitutes a powerful tool for analysis of the importance of these cells and their effector functions throughout the different phases of arthritis.
Aims: Understanding the orientation of fracture lines and mechanisms is the essential key to sufficient surgical therapy, but there is still a lack of visualization and teaching methods in traumatology and fracture theory. 3D-printed models offer easy approach to those fractures. This paper explains the use of the teaching possibility with 3-dimensional models of transitional fractures of the ankle.
Methods and results: For generating 3D printable models, already obtained CT data were used and segmented into its different tissues, especially parts concerning the fracture. After the segmentation process, the models were produced with FFF (fused filament fabrication) printing technology. The fracture models then were used for hands-on teaching courses in AO course (Arbeitsgemeinschaft für Osteosynthesefragen) of pediatric traumatology in 2020 in Frankfurt. In the course fracture anatomy with typical fracture lines, approaches, and screw placement could be shown, discussed and practiced.
Conclusion: The study shows the use of 3D-printed teaching models and helps to understand complicated fractures, in this case, transitional fractures of the ankle. The teaching method can be adapted to numerous other use cases.
The evaluation of pharmacological data using machine learning requires high data quality. Therefore, data preprocessing, that is, cleaning analytical laboratory errors, replacing missing values or outliers, and transforming data adequately before actual data analysis, is crucial. Because current tools available for this purpose often require programming skills, preprocessing tools with graphical user interfaces that can be used interactively are needed. In collaboration between data scientists and experts in bioanalytical diagnostics, a graphical software package for data preprocessing called pguIMP is proposed, which contains a fixed sequence of preprocessing steps to enable reproducible interactive data preprocessing. As an R-based package, it also allows direct integration into this data science environment without requiring any programming knowledge. The implementation of contemporary data processing methods, including machine-learning-based imputation techniques, ensures the generation of corrected and cleaned bioanalytical data sets that preserve data structures such as clusters better than is possible with classical methods. This was evaluated on bioanalytical data sets from lipidomics and drug research using k-nearest-neighbors-based imputation followed by k-means clustering and density-based spatial clustering of applications with noise. The R package provides a Shiny-based web interface designed to be easy to use for non–data analysis experts. It is demonstrated that the spectrum of methods provided is suitable as a standard pipeline for preprocessing bioanalytical data in biomedical research domains. The R package pguIMP is freely available at the comprehensive R archive network (https://cran.r-project.org/web/packages/pguIMP/index.html).
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 and Aims: Vitamin D has an inhibitory role in the inflammatory signaling pathways and supports the integrity of the intestinal barrier. Due to its immunomodulatory effect, vitamin D plays a role in chronic inflammatory bowel disease (IBD) and a deficiency is associated with an increased risk for a flare. We aimed to investigate to what extent the 25-hydroxyvitamin D (25(OH)D3) level correlates with disease activity and whether a cut-off value can be defined that discriminates between active disease and remission. Methods: Patients with IBD, treated at the University Hospital Frankfurt were analyzed retrospectively. The 25(OH)D3 levels were correlated with clinical activity indices and laboratory chemical activity parameters. A deficiency was defined as 25(OH)D3 levels <30 ng/mL. Results: A total of 470 (257 female) patients with IBD were included, 272 (57.9%) with Crohn’s disease (CD), 198 (42.1%) with ulcerative colitis (UC). The median age of the patients was 41 (18–84). In 283 patients (60.2%), a vitamin D deficiency was detected. 245 (53.6%) patients received oral vitamin D supplementation, and supplemented patients had significantly higher vitamin D levels (p < 0.0001). Remission, vitamin D substitution, and male gender were independently associated with the 25(OH)D3 serum concentration in our cohort in regression analysis. A 25(OH)D3 serum concentration of 27.5 ng/mL was the optimal cut-off value. Conclusion: Vitamin D deficiency is common in IBD patients and appears to be associated with increased disease activity. In our study, vitamin D levels were inversely associated with disease activity. Thus, close monitoring should be established, and optimized supplementation should take place.
Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo-controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N-stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain-length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified.
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.
Background: Hodkin s lymphoma is one of the most frequent lymphoma in western world. Despite an overall good prognosis some patients suffer relapsing tumors which are difficult to cure. Over a long period Vitamin D has been shown to be a potential treatment for cancer. Vitamin D acts via the vitamin D receptor, a nuclear receptor, acting as an inducible transcription factor. We aimed to investigate the expression of vitamin D receptor as potential therapeutic target structure in Hodgkin s lymphoma as well as in non Hodgkin s lymphoma.
Methods: We used a panel of 193 formalin fixed tissues of lymphoma cases consisting of 55 cases of Hodgkin s lymphoma and 138 cases on several non Hodgkin s lymphoma entities.
Results: Vitamin D receptor is strongly expressed in Hodgkin s lymphoma, regardless of the subentity with an overall positivity of 80% of all Hodgkin lymphoma cases. In contrast, only about 17% of the analyzed non Hodgkin s lymphoma of B-cell origin showed positivity for vitamin D receptor. Predominant nuclear localization of vitamin D receptor in Hodgkin s lymphoma suggests activated status of the vitamin D receptor.
Conclusions: From this study, we conclude that vitamin D receptor plays a potentially important role in pathogenesis of Hodgkin s lymphoma but not in non Hodgkin s lymphoma. Further investigations of mutational status and functional studies may shed some light in functional relevance of vitamin D receptor signaling in Hodgkin s lymphoma.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
1 Purpose of the Study:
The purpose of this retrospective study was to assess the volumetric changes of our institutional pediatric neuroblastoma in response to various therapeutic protocols.
2 Materials and Methods:
A retrospective study was conducted on children with neuroblastoma from different anatomical locations including suprarenal, paraspinal, pelvic, mediastinal and cervical neuroblastoma primaries. These children underwent tumor-stage based therapeutic protocols in Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany, between January 1996 and July 2008. The study included 72 patients (44 males and 28 females). Patient demographics (age and gender), disease-related symptoms, laboratory results (tumor biomarkers including ferritin, neuron specific enolase, and urine catecholamine) and histopathological reports were collected from the electronic medical archiving system and subsequently analyzed.
Patients were classified into following groups according the anatomical origin of the primary neuroblastoma into:
1) Suprarenal neuroblastoma Group: This group included patients with neuroblastoma arising from the suprarenal gland. This group composed of 54 patients with male to female ratio (32:22).
2) Paravertebral neuroblastoma Group: This group composed of 6 male patients.
3) Mediastinal neuroblastoma Group: This group included patients with mediastinal neuroblastoma and composed of 3 patients (1 male and 2 females).
4) Pelvic neuroblastoma Group: This group included patients with pelvic neuroblastoma and composed of 6 patients (3 males and 3 females).
5) Cervical neuroblastoma Group: This group included patients with cervical neuroblastoma and composed of 2 male patients.
3 Results:
The mean volume of all suprarenal neuroblastoma group involved in the study before therapy was 176.62 cm3 (SD: 234.15) range: 239.4-968.9cm3. The mean initial volume of all suprarenal neuroblastoma group who underwent observation protocol was 86.0378 cm3 (SD: 114.44) range: 5.2-347.94cm3. Volumetric evaluation of suprarenal neuroblastoma following observation (Wait and See) protocol revealed continuous reduction of the tumor volumes in a statistically significant manner during the follow up periods up to 12 months with p value of less than 0.05. The volumetric changes afterwards were statistically insignificant.
The mean initial volume of all suprarenal neuroblastoma group who underwent primary surgery protocol was 42.4 cm3 (SD: 28.5) range: 7.5-90cm3. Complete surgical resection of the tumor was not feasible in all lesions due to local tumor extension and / or infiltration with the associated risk of injury of nearby organs or structures. However statistical analysis of the volumetric changes in the successive follow up periods did not reveal statistical significance.
Volumetric estimation of the tumor in the subsequent follow up periods revealed significant changes within the period first (3-9 month periods). The changes afterwards were statistically non significant. On the other hand, the mean initial volume of all suprarenal neuroblastoma group who underwent combined chemotherapy and Stem cell transplantation protocol only without surgical interference was 99.98cm3 (SD:46.2) range: 48.48-160.48 cm3. In this group the volumetric changes were variable and difference in volumes in follow up was statistically non significant during the follow up period.
The mean initial volume of all abdominal paravertebral neuroblastoma group was 249.197cm3 (SD: 249.63) range: 9.6-934cm3. The mean initial volume of all pelvic neuroblastoma group was 118.88cm3 (SD: 50.61) range: 73.4-173.4cm3. The mean initial volume of all mediastinal neuroblastoma group was 189.7cm3 (SD: 139.057) range: 10.7-415 cm3. The mean initial volume of all cervical neuroblastoma group was 189.7cm3 (SD: 139.057) range: 10.7-415 cm3. The volumetric measurements in the corresponding follow up periods according to the therapeutic protocol of abdominal paravertebral neuroblastoma, pelvic neuroblastoma, mediastinal and cervical neuroblastoma revealed significant change in the tumor volume within the early 3-6 months from the initial therapy while subsequently the tumor volumetric changes were statistically non significant.
4 Conclusion:
In conclusion, the role of MRI volumetry in the evaluation of tumor response is dependent on the risk adapted concept of neuroblastoma with the combination of different imaging modalities as well the therapeutic protocol. MRI Volumetry in addition to new protocols such as Whole-body imaging and 3D visualization techniques are gaining more importance and acceptance.
Aim: To assess volumetric tissue changes at peri‐implantitis sites following combined surgical therapy of peri‐implantitis over a 6‐month follow‐up period.
Materials and Methods: Twenty patients (n = 28 implants) diagnosed with peri‐implantitis underwent access flap surgery, implantoplasty at supracrestally or bucally exposed implant surfaces and augmentation at intra‐bony components using a natural bone mineral and application of a native collagen membrane during clinical routine treatments. The peri‐implant region of interest (ROI) was intra‐orally scanned pre‐operatively (S0), and after 1 (S1) and 6 (S2) months following surgical therapy. Digital files were converted to standard tessellation language (STL) format for superimposition and assessment of peri‐implant volumetric variations between time points. The change in thickness was assessed at a standardized ROI, subdivided into three equidistant sections (i.e. marginal, medial and apical). Peri‐implant soft tissue contour area (STCA) (mm2) and its corresponding contraction rates (%) were also assessed.
Results: Peri‐implant tissues revealed a mean thickness change (loss) of −0.11 and −0.28 mm at 1 and 6 months. S0 to S1 volumetric variations pointed to a thickness change of −0.46, 0.08 and 0.4 mm at marginal, medial and apical regions, respectively. S0 to S2 analysis exhibited corresponding thickness changes of −0.61, −0.25 and −0.09 mm, respectively. The thickness differences between the areas were statistically significant at both time periods. The mean peri‐implant STCA totalled to 189.2, 175 and 158.9 mm2 at S0, S1 and S2, showing a significant STCA contraction rate of 7.9% from S0 to S1 and of 18.5% from S0 to S2. Linear regression analysis revealed a significant association between the pre‐operative width of keratinized mucosa (KM) and STCA contraction rate.
Conclusions: The peri‐implant mucosa undergoes considerable volumetric changes after combined surgical therapy. However, tissue contraction appears to be influenced by the width of KM.
Background: Serial volumetric changes of reconstructed breasts have not been studied in detail. In this study, we analyzed serial volumetric changes of reconstructed and contralateral normal breasts during long-term follow-up, with a focus on the effect of various adjuvant therapies.
Methods: Among all patients who underwent immediate breast reconstruction with a unilateral pedicled transverse rectus abdominis musculocutaneous (p-TRAM) flap, 42 patients with valid data from ≥3 postoperative positron emission tomography-computed tomography (PET-CT) scans were included. The volumes of the reconstructed and normal breasts were measured, and the ratio of flap volume to that of the contralateral breast was calculated. Serial changes in volume and the volume ratio were described, and the effects of chemotherapy, radiation therapy, and hormone therapy on volumetric changes were analyzed.
Results: The mean interval between the initial reconstruction and each PET-CT scan was 16.5, 30, and 51 months respectively. Thirty-five, 36, and 10 patients received chemotherapy, hormone therapy, and radiation therapy, respectively. The flap volume at each measurement was 531.0, 539.6, and 538.0 cm3, and the contralateral breast volume was 472.8, 486.4, and 500.8 cm3, respectively. The volume ratio decreased from 115.1% to 113.4%, and finally to 109.6% (P=0.02). Adjuvant therapies showed no significant effects.
Conclusions: We demonstrated that the p-TRAM flap maintained its volume over a long-term follow up, while the volume of the contralateral native breast slowly increased. Moreover, adjuvant breast cancer therapies had no statistically significant effects on the volume of the reconstructed p-TRAM flaps or the contralateral native breasts.
The thickness of the cerebral cortex can provide valuable information about normal and abnormal neuroanatomy. High resolution MRI together with powerful image processing techniques has made it possible to perform these measurements automatically over the whole brain. Here we present a method for automatically generating voxel-based cortical thickness (VBCT) maps. This technique results in maps where each voxel in the grey matter is assigned a thickness value. Sub-voxel measurements of thickness are possible using sub-sampling and interpolation of the image information. The method is applied to repeated MRI scans of a single subject from two MRI scanners to demonstrate its robustness and reproducibility. A simulated data set is used to show that small focal differences in thickness between two groups of subjects can be detected. We propose that the analysis of VBCT maps can provide results that are complementary to other anatomical analyses such as voxel-based morphometry.
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.
Understanding how to achieve efficient transduction of hematopoietic stem and progenitor cells (HSPCs), while preserving their long-term ability to self-reproduce, is key for applying lentiviral-based gene engineering methods. SAMHD1 is an HIV-1 restriction factor in myeloid and resting CD4+ T cells that interferes with reverse transcription by decreasing the nucleotide pools or by its RNase activity. Here we show that SAMHD1 is expressed at high levels in HSPCs cultured in a medium enriched with cytokines. Thus, we hypothesized that degrading SAMHD1 in HSPCs would result in more efficient lentiviral transduction rates. We used viral like particles (VLPs) containing Vpx, shRNA against SAMHD1, or provided an excess of dNTPs or dNs to study this question. Regardless of the method applied, we saw no increase in the lentiviral transduction rate. The result was different when we used viruses (HR-GFP-Vpx+) which carry Vpx and encode GFP. These viruses allow assessment of the effects of Vpx specifically in the transduced cells. Using HR-GFP-Vpx+ viruses, we observed a modest but significant increase in the transduction efficiency. These data suggest that SAMHD1 has some limited efficacy in blocking reverse transcription but the major barrier for efficient lentiviral transduction occurs before reverse transcription.
Sleep impairments are a hallmark of acute bipolar disorder (BD) episodes and are present even in the euthymic state. Studying healthy subjects who are vulnerable to BD can improve our understanding of whether sleep impairment is a predisposing factor. Therefore, we investigated whether vulnerability to BD, dimensionally assessed by the hypomanic personality scale (HPS), is associated with sleep disturbances in healthy subjects. We analyzed participants from a population-based cohort who had completed the HPS and had either a 7-day actigraphy recording or a Pittsburgh sleep quality index (PSQI) assessment. In addition, subjects had to be free of confounding diseases or medications. This resulted in 771 subjects for actigraphy and 1766 for PSQI analyses. We found strong evidence that higher HPS scores are associated with greater intraindividual sleep variability, more disturbed sleep and more daytime sleepiness. In addition, factor analyses revealed that core hypomanic features were especially associated with self-reported sleep impairments. Results support the assumption of disturbed sleep as a possibly predisposing factor for BD and suggest sleep improvement as a potential early prevention target.