Intracranial Nimodipine Implant: Feasibility and Implications for the Treatment of Subarachnoid Hemorrhage – A Pre-Clinical Study

Intracranial aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition requiring immediate neurocritical care. A ruptured aneurysm must be isolated from arterial circulation to prevent rebleeding. Open surgical clipping of the neck of the aneurysm or intra-arterial filling of the aneurysm sack with platinum coils are major treatment strategies in an acute phase. About 40% of the patients suffering from aSAH die within a year of the bleeding despite the intensive treatment. After aSAH, the patient may develop a serious complication called vasospasm. Major risk for the vasospasm takes place at days 5–14 after the primary bleeding. In vasospasm, cerebral arteries contract uncontrollably causing brain ischemia that may lead to death. Nimodipine (NDP) is used to treat of vasospasm and it is administrated intravenously or orally every four hours for 21 days. NDP treatment has been scientifically proven to improve patients’ clinical outcome. The therapeutic effect of L-type calcium channel blocker NDP is due to the ability to dilate cerebral arteries. In addition to vasodilatation, recent research has shown the pleiotropic effect of NDP such as inhibition of neuronal apoptosis and inhibition of microthrombi formation. Indeed, NDP inhibits cortical spreading ischemia. Knowledge of the pathophysiology of the vasospasm has evolved in recent years to a complex entity of early brain injury, secondary injuries and cortical spreading ischemia, instead of being pure intracranial vessel spasm. High NDP levels are beneficial since they protect neurons and inhibit the cortical spreading ischemia. One of the drawbacks of the intravenous or oral administration of NPD is systemic hypotension, which is harmful particularly when the brain is injured. Maximizing the beneficial effects and avoiding systemic hypotension of NDP, we developed a sustained release biodegradable NDP implant that was surgically positioned in the basal cistern of animal models (dog and pig). Higher concentrations were achieved locally and lower concentrations systemically. Using this treatment approach in humans, it may be possible to reduce incidence of harmful hypotension and potentiate beneficial effects of NDP on neurons. Intracellular calcium regulation has a pivotal role in brain plasticity. NDP blocks L-type calcium channels in neurons, substantially decreasing intracellular calcium levels. Thus, we were interested in how NDP affects brain plasticity and tested the hypothesis in a mouse model. We found that NDP activates Brain-derived neurotrophic factor (BDNF) receptor TrkB and its downstream signaling in a reminiscent of antidepressant drugs. In contrast to antidepressant drugs, NDP activates Akt, a major survival-promoting factor. Our group’s previous findings demonstrate that long-term antidepressant treatment reactivates developmental-type of plasticity mechanisms in the adult brain, which allows the remodeling of neuronal networks if combined with appropriate rehabilitation. It seems that NDP has antidepressant-like properties and it is able to induce neuronal plasticity. In general, drug induced neuronal plasticity has a huge potential in neurorehabilitation and more studies are warranted.Siirretty Doriast

Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain

The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75(NTR)) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75(NTR) q in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75(NTR) for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level.Peer reviewe

Withdrawal from long-term use of unusually high-dose oxazepam

Publisher Copyright: Copyright © 2021 Antti Mustonen et al.Benzodiazepine (BZD) misuse is a worldwide problem that healthcare professionals encounter in daily practice. High-dose BZD withdrawal is usually a long process that may require referral to an inpatient rehabilitation unit. Relapses after withdrawal are common. BZD withdrawal can cause complications including seizures, suicidal behavior, anxiety, and depression. Guidelines describe tapering protocols for modest doses; however, protocols for exceptionally high-dose BZD withdrawal are not well described. Herein, we describe a BZD tapering protocol for a patient with daily use of high-dose (1800 mg) oxazepam (OXP). The BZD tapering was administered in an inpatient psychiatric hospital, and the outcome was evaluated monthly after discharge for three months. This report describes a unique case of high-dose OXP withdrawal and also outlines an optional protocol to apply when clinicians encounter these unusual cases.Peer reviewe

Aivokavernooma - pitääkö olla huolissaan?

Aivokavernooma on laskimoepämuodostumasairaus, jonka nykyisiä hoitovaihtoehtoja ovat seuranta, leikkaus ja sädehoito. Aivokavernoomasta tunnetaan sporadinen ja familiaalinen muoto. Magneettikuvausten saatavuuden lisäännyttyä aivokavernoomia diagnosoidaan entistä enemmän, joten moni kliinikko saattaa törmätä tähän tautiin. Sen luonnollinen kulku on yleensä hyvälaatuinen. Pelätyin tapahtuma, aivokavernooman vuoto, on harvinainen. Uusimpia tautiin liittyviä tutkimushavaintoja on tehty vuodon ennustamisesta sekä mikrobiomin osuudesta taudin synnyssä ja kulussa. Tutkimustiedon lisääntymisen myötä uusia hoito- ja seurantamahdollisuuksia tulee kliiniseen käyttöön merkittävästi todennäköisesti jo lähivuosina. Aivokavernoomasta ei pidä olla huolissaan, mutta taudin erityispiirteiden vuoksi sen seurannasta ja hoidosta tulisi konsultoida yliopistosairaaloiden moniammatillista neurovaskulaarihoitotyöryhmää

Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain

The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75NTR) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75NTR in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75NTR for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level.</p

A SQUAMOSA MADS-box gene involved in the regulation of anthocyanin accumulation in bilberry fruits

Anthocyanins are important health promoting phytochemicals that are abundant in many fleshy fruits. Bilberry (Vaccinium myrtillus L.) is one of the best sources of these compounds. Here we report on the expression pattern and functional analysis of a SQUAMOSA (SQUA) class MADS-box transcription factor, VmTDR4, associated with anthocyanin biosynthesis in bilberry. Levels of VmTDR4 expression were spatially and temporally linked with colour development and anthocyanin-related gene expression. Virus induced gene silencing (VIGS) was used to suppress VmTDR4 expression in bilberry resulting in substantial reduction in anthocyanin levels in fully ripe fruits. Chalcone synthase was used a positive control in the VIGS experiments. Additionally, in sectors of fruit tissue in which the expression of the VmTDR4 gene was silenced, the expression of R2R3 MYB family transcription factors related to the biosynthesis of flavonoids were also altered. We conclude that VmTDR4 plays an important role in the accumulation of anthocyanins during normal ripening in bilberry; probably through direct or indirect control of transcription factors belonging to the R2R3 MYB family

The meristem-associated endosymbiont Methylorubrum extorquens DSM13060 reprograms development and stress responses of pine seedlings

Microbes living in plant tissues-endophytes-are mainly studied in crop plants where they typically colonize the root apoplast. Trees-a large carbon source with a high capacity for photosynthesis-provide a variety of niches for endophytic colonization. We have earlier identified a new type of plant-endophyte interaction in buds of adult Scots pine, where Methylorubrum species live inside the meristematic cells. The endosymbiont Methylorubrum extorquens DSM13060 significantly increases needle and root growth of pine seedlings without producing plant hormones, but by aggregating around host nuclei. Here, we studied gene expression and metabolites of the pine host induced by M. extorquens DSM13060 infection. Malic acid was produced by pine to potentially boost M. extorquens colonization and interaction. Based on gene expression, the endosymbiont activated the auxin- and ethylene (ET)-associated hormonal pathways through induction of CUL1 and HYL1, and suppressed salicylic and abscisic acid signaling of pine. Infection by the endosymbiont had an effect on pine meristem and leaf development through activation of GLP1-7 and ALE2, and suppressed flowering, root hair and lateral root formation by downregulation of AGL8, plantacyanin, GASA7, COW1 and RALFL34. Despite of systemic infection of pine seedlings by the endosymbiont, the pine genes CUL1, ETR2, ERF3, HYL, GLP1-7 and CYP71 were highly expressed in the shoot apical meristem, rarely in needles and not in stem or root tissues. Low expression of MERI5, CLH2, EULS3 and high quantities of ononitol suggest that endosymbiont promotes viability and protects pine seedlings against abiotic stress. Our results indicate that the endosymbiont positively affects host development and stress tolerance through mechanisms previously unknown for endophytic bacteria, manipulation of plant hormone signaling pathways, downregulation of senescence and cell death-associated genes and induction of ononitol biosynthesis.Peer reviewe

A comprehensive p75 neurotrophin receptor gene network and pathway analyses identifying new target genes

P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n=235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (pPeer reviewe

Compensatory IgM to the Rescue: Patients with Selective IgA Deficiency Have Increased Natural IgM Antibodies to MAA-LDL and No Changes in Oral Microbiota

IgA is the most abundant Ab in the human body. However, most patients with selective IgA deficiency (SIgAD) are asymptomatic. IgM, and to lesser extent IgG Abs, are generally presumed to compensate for the lack of IgA in SIgAD by multiplying and adopting functions of IgA. We used data from the Northern Finland Birth Cohort 1966 to investigate whether SIgAD patients have differences in levels of natural Abs to oxidized epitopes compared with 20 randomly selected healthy controls. First, we screened the saliva and serum samples from the Northern Finland Birth Cohort 1966 cohort (n 5 1610) for IgA concentration. We detected five IgA-deficient subjects, yielding a prevalence of 0.3%, which is consistent with the general prevalence of 0.25% in the Finnish population. To detect natural Abs, we used malondialdehyde acetaldehyde–low-density lipoprotein (MAA–LDL), an Ag known to bind natural Abs. In this study, we show that natural secretory IgM and IgG Abs to MAA–DL were significantly increased in subjects with SIgAD. Given that secretory IgA is an important part of mucosal immune defense and that, in the gut microbiota, dysbiosis with SIgAD patients has been observed, we characterized the oral bacterial microbiota of the subjects with and without SIgAD using high-throughput 16S rRNA gene sequencing. We found no significant alterations in diversity and composition of the oral microbiota in subjects with SIgAD. Our data suggest that increased levels of secretory natural Abs in patients with SIgAD could be a compensatory mechanism, providing alternative first-line defense against infections and adjusting mucosal milieu to maintain a healthy oral microbiota. ImmunoHorizons, 2021, 5: 170–181.Peer reviewe