The patient's own bone marrow-derived stromal cells:disease modifiers in (neuro)degenerative disorders

The aim of this thesis was to identify a standardized stem cell product that can be used to treat secondary inflammation in neurodegenerative diseases to improve the clinical outcome. In a comprehensive literature search, the concept of the patient’s own fresh naïve stem cells was developed, tested in animal models in order to prepare for the first clinical trials in patients suffering a neurodegenerative disorder. A standardized human stem cell product (Neuro-Cells®) was developed and patented, which is produced on the Brightlands campus in the good manufacturing product (GMP) facility. In animal experiments, using human GMP processed stem cells (Neuro-Cells), the researchers were able to proof safety and efficacy in the indications spinal cord injury, amyotrophic Lateral sclerosis and Frontotemporal lobar degeneration. The stem cells act as an anti-inflammatory drug and proved to be superior to methylprednison, Celecoxib and Riluzole. They concluded that in preclinical trials, a transplantation with human stem cells might be seen as a disease modifier, acting on the secondary inflammatory mechanisms and thereby decreasing disability. With the results of the spinal cord injury experiments, they were able to start a phase I study with chronic spinal cord injured patients together with the Hospital Nacional de Parapléjicos de Toledo in Spain. All 10 patients are treated with their stem cells and so far no side effects were reported. A multi-centre Phase II/III is planned to start in June 2021

Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?

Gangliosides are molecules widely present in the plasma membranes of mammalian cells, participating in a variety of processes, including protein organization, transmembrane signalling and cell adhesion. Gangliosides are abundant in the grey matter of the brain, where they are critically involved in postnatal neural development and function. The common precursor of the majority of brain gangliosides, GM3, is formed by the sialylation of lactosylceramide, and four derivatives of its a- and b-series, GM1, GD1a, GD1b and GT1b, constitute 95% of all the brain gangliosides. Impairments in ganglioside metabolism due to genetic abnormalities of GM-synthases are associated with severe neurological disorders. Apart from that, the latest genome-wide association and translational studies suggest a role of genes involved in brain ganglioside synthesis in less pervasive psychiatric disorders. Remarkably, the most recent animal studies showed that abnormal ganglioside functions result in dysregulated neuroinflammation, aberrant myelination and altered insulin receptor signalling. At the same time, these molecular features are well established as accompanying developmental psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). This led us to hypothesize a role of deficient ganglioside function in developmental neuropsychiatric disorders and warrants further gene association clinical studies addressing this question. Here, we critically review the literature to discuss this hypothesis and focus on the recent studies on ST3GAL5-deficient mice. In addition, we elaborate on the therapeutic potential of various anti-inflammatory remedies for treatment of developmental neuropsychiatric conditions related to aberrant ganglioside functions. Keywords: insulin receptor signalling; major brain gangliosides; mice; myelination; neurodevelopmental disorders; neuroinflammatio

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p

Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant

Major depression (MD) and posttraumatic stress disorder (PTSD) share common brain mechanisms and treatment strategies. Nowadays, the dramatically developing COVID-19 situation unavoidably results in stress, psychological trauma, and high incidence of MD and PTSD. Hence, the importance of the development of new treatments for these disorders cannot be overstated. Herbal medicine appears to be an effective and safe treatment with fewer side effects than classic pharmaca and that is affordable in low-income countries. Currently, oxidative stress and neuroinflammation attract increasing attention as important mechanisms of MD and PTSD. We investigated the effects of a standardized herbal cocktail (SHC), an extract of clove, bell pepper, basil, pomegranate, nettle, and other plants, that was designed as an antioxidant treatment in mouse models of MD and PTSD. In the MD model of “emotional” ultrasound stress (US), mice were subjected to ultrasound frequencies of 16–20 kHz, mimicking rodent sounds of anxiety/despair and “neutral” frequencies of 25–45 kHz, for three weeks and concomitantly treated with SHC. US-exposed mice showed elevated concentrations of oxidative stress markers malondialdehyde and protein carbonyl, increased gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and other molecular changes in the prefrontal cortex as well as weight loss, helplessness, anxiety-like behavior, and neophobia that were ameliorated by the SHC treatment. In the PTSD model of the modified forced swim test (modFST), in which a 2-day swim is followed by an additional swim on day 5, mice were pretreated with SHC for 16 days. Increases in the floating behavior and oxidative stress markers malondialdehyde and protein carbonyl in the prefrontal cortex of modFST-mice were prevented by the administration of SHC. Chromatography mass spectrometry revealed bioactive constituents of SHC, including D-ribofuranose, beta-D-lactose, malic, glyceric, and citric acids that can modulate oxidative stress, immunity, and gut and microbiome functions and, thus, are likely to be active antistress elements underlying the beneficial effects of SHC. Significant correlations of malondialdehyde concentration in the prefrontal cortex with altered measures of behavioral despair and anxiety-like behavior suggest that the accumulation of oxidative stress markers are a common biological feature of MD and PTSD that can be equally effectively targeted therapeutically with antioxidant therapy, such as the SHC investigated here

Naive BM-derived stem cells (Neuro-Cells) may modify acute and chronic neurodegenerative disorders by modulating macrophage behaviors

In acute traumatic or hypoxic brain and spinal cord lesions, as well as in chronic idiopathic neurodegenerative disorders induced by a genetic/environmental/idiopathic protein misfolding with aggregation, emerging evidence indicates that primary necrosis, as induced by the underlying event, initiates a secondary inflammatory process. In this secondary process, responsible for significant neurological deterioration, a microglia type M1/M2 misbalance plays a major role. Indeed, both acute and chronic neurodegenerative disorders share a common pathway: a M1/M2 misbalance-induced hyperinflammatory process with a lack of response to conventional anti-inflammatory interventions. In recent literature, however, both in preclinical and clinical neurodegenerative conditions, these processes were suggested to be sensitive for interventions with stem cells. Intrathecal interventions with a fresh, not-manipulated (naïve) bone marrow-derived stem cell preparation, after positive selection of pro-inflammatory substances (Neuro-Cells), were found to prevent/reduce secondary necrosis-induced pro-inflammatory and pro-apoptotic processes in both immune-compromised and otherwise healthy experimental animal models. Therefore, it seems justified to further encourage clinical trials applying autologous BM-derived naïve stem cells in patients suffering from those debilitating neurodegenerative conditions

Vertebral Osteomyelitis or Infected Abdominal Aortic Endograft? A Rare Case of Q Fever

Coxiella burnetii is the etiological agent of Q fever, a zoonosis. Vascular infections are associated with significant morbidity and mortality. Osteoarticular Q fever infections are rare. We describe a case of vertebral osteomyelitis with associated infection of an abdominal aortic endograft, caused by C. burnetii. Most probably, an initial pyogenic vertebral osteomyelitis extended locally to the endograft. Treatment consisted of antibiotic therapy and surgical resection of the infected aortic endograft and in situ reconstruction with autogenous superficial femoral vein grafts.status: publishe

Prediction of recovery in trauma patients using Latent Markov models

Purpose:  Patients’ expectations during recovery after a trauma can affect the recovery. The aim of the present study was to identify different physical recovery trajectories based on Latent Markov Models (LMMs) and predict these recovery states based on individual patient characteristics.  Methods:  The data of a cohort of adult trauma patients until the age of 75 years with a length of hospital stay of 3 days and more were derived from the Brabant Injury Outcome Surveillance (BIOS) study. The EuroQol-5D 3-level version and the Health Utilities Index were used 1 week, and 1, 3, 6, 12, and 24 months after injury. Four prediction models, for mobility, pain, self-care, and daily activity, were developed using LMMs with ordinal latent states and patient characteristics as predictors for the latent states.  Results:  In total, 1107 patients were included. Four models with three ordinal latent states were developed, with different covariates in each model. The prediction of the (ordinal) latent states in the LMMs yielded pseudo-R2 values between 40 and 53% and between 21 and 41% (depending of the type R2 used) and classification errors between 24 and 40%. Most patients seem to recover fast as only about a quarter of the patients remain with severe problems after 1 month.  Conclusion:  The use of LMMs to model the development of physical function post-injury is a promising way to obtain a prediction of the physical recovery. The step-by-step prediction fits well with the outpatient follow-up and it can be used to inform the patients more tailor-made to manage the expectations

Prediction of recovery in trauma patients using Latent Markov models

Purpose:  Patients’ expectations during recovery after a trauma can affect the recovery. The aim of the present study was to identify different physical recovery trajectories based on Latent Markov Models (LMMs) and predict these recovery states based on individual patient characteristics.  Methods:  The data of a cohort of adult trauma patients until the age of 75 years with a length of hospital stay of 3 days and more were derived from the Brabant Injury Outcome Surveillance (BIOS) study. The EuroQol-5D 3-level version and the Health Utilities Index were used 1 week, and 1, 3, 6, 12, and 24 months after injury. Four prediction models, for mobility, pain, self-care, and daily activity, were developed using LMMs with ordinal latent states and patient characteristics as predictors for the latent states.  Results:  In total, 1107 patients were included. Four models with three ordinal latent states were developed, with different covariates in each model. The prediction of the (ordinal) latent states in the LMMs yielded pseudo-R2 values between 40 and 53% and between 21 and 41% (depending of the type R2 used) and classification errors between 24 and 40%. Most patients seem to recover fast as only about a quarter of the patients remain with severe problems after 1 month.  Conclusion:  The use of LMMs to model the development of physical function post-injury is a promising way to obtain a prediction of the physical recovery. The step-by-step prediction fits well with the outpatient follow-up and it can be used to inform the patients more tailor-made to manage the expectations

Blood pressure and BMI in adolescents in Aracaju, Brazil

Objective: To assess the prevalence of high blood pressure (BP) and the association of overweight and obesity with high BP among adolescents in Aracaju, Brazil. Design: Cross-sectional study. The main outcome measure was the proportion of adolescents with high BP (sex-, age- and height-specific >= 95th percentile). The main predictor variables were overweight and obesity defined according to the criteria of the International Obesity Task Force. Other covariates included age, socio-economic status and leisure-time physical activity. Setting: Aracaju, Brazil, capital city of Sergipe State, north-eastern Brazil. Subjects: A random sample of 1002 adolescents (442 boys and 560 girls) aged 12-17 years selected from twenty public schools and ten private schools were studied. Results: The prevalence of high BP was 16.9% (95% CI 13.1, 21.7) in boys and 12.9% (95% CI 9.0, 18.0) in girls. After adjusting for age, socio-economic status and leisure-time physical activity in both boys and girls, overweight (prevalence ratio (PR) 51.93, 95% CI 1.08, 3.48; PR = 4.34, 95% CI 2.58, 7.30, respectively) and obesity (PR = 4.87, 95% CI 2.35, 10.11; PR = 5.18, 95% CI 2.67, 10.06, respectively) were found to be associated with high BP. Conclusions: These findings indicate a high prevalence of high BP in both boys and girls in Aracaju, Brazil. Overweight and obesity were strongly associated with high BP. These findings underscore the urgent need for public health measures to prevent increasing high BP in adolescents in Brazil. Targeting intervention in adolescence may be a critical method for preventing high BP in later lif