In this review we discuss the contribution of NO, prostacyclin and endothelium-derived relaxing factor - endothelium-derived hyperpolarizing factor, or EDHF, to vascular function. We also explore the ...hypotheses (1): that tissues can store NO as nitrosothiols (RSNOs) and (2) that such RSNO stores can be modulated by physiological and pathophysiological processes. Notably in the microcirculation, EDHF appears to play an important role in the regulation of vascular tone. Leading candidates for EDHF include extracellular potassium (K+), an epoxygenase product, hydrogen peroxide and/or a contribution from myoendothelial gap junctions. Data from our laboratory indicate that in mouse vessels, different endothelium-dependent vasodilators, such as acetylcholine and protease-activated receptor (PAR) agonists, release different endothelium-derived relaxing factors. The combination of two K-channel toxins, apamin and charybdotoxin, inhibits EDHF activity in most protocols. Endothelial dysfunction is considered as the major risk factor and a very early indicator of cardiovascular disease including the cardiovascular complications of type I & types II diabetes. Impaired endothelium-dependent vasodilatation results primarily from a decreased synthesis of endothelium-derived nitric oxide (NO) and/or an increase in the production of reactive oxygen species such as superoxide. We have shown that the administration of tetrahydrobiopterin, an important co-factor for nitric oxide synthase (NOS) partially restores endothelial function (1) in leptin-deficient mice (db/db) with spontaneous type II diabetes, as well as (2) in human vascular tissue harvested for coronary artery bypass grafting (CABG). These data suggest that a deficiency in the availability of tetrahydrobiopterin plays an important role in vascular dysfunction associated with Type II diabetes. In addition, changes in the contribution of EDHF occur in vascular tissue from the db/db mice suggesting a compensatory increase in EDHF production; whether this alteration in EDHF production is physiological or pathophysiological remains controversial.
Endothelium-derived hyperpolarizing factor (EDHF), notably in the microcirculation, plays an important role in the regulation of vascular tone. The cellular events that mediate EDHF are critically ...dependent, in a vessel dependent manner, on small conductance calcium-activated potassium channels (SK) and intermediate conductance calcium-activated potassium channels (IK) as well as the presence of the gap junction connexins 37, 40, and 43. We hypothesized that the expression levels of SK, IK, as well as vascular connexins, notably 37, 40 and 43 but, potentially, connexin 45, would show correlation with the contribution of EDHF to acetylcholine-mediated vasodilatation as well as, in the absence of endothelial-derived NO, higher expression levels in eNOS
−/− mice. Wire myograph studies were performed to confirm the contribution of EDHF to endothelium-dependent relaxation in 1st, 2nd and 3rd order small mesenteric arteries from C57BL/6J eNOS-expressing (eNOS
+/+) and eNOS-deficient C57BL/6J (eNOS
−/−) mice. Small mesenteric arteries, as well as the branch points between 1st and 2nd and 2nd and 3rd order vessels, were analysed for the expression of mRNA for SK1, SK2, SK3, IK and large conductance calcium-activated potassium channels (BK) and comparable studies were performed for connexins 37, 40, 43 and 45. Although the contribution of EDHF to endothelium-dependent relaxation was significantly greater in the 3rd order vessels from the eNOS
+/+ the real-time (RT) polymerase chain reaction (PCR) data showed no differences for the expression levels of mRNA for any of the channel subtypes or the connexins within the small mesenteric arteries from either the eNOS
+/+ or eNOS
−/− mice, nor, based on RT PCR analysis, were there differences in expression of the potassium channels studied in the branch points versus 1st, 2nd or 3rd order vessels. These data suggest that neither the gene expression of calcium-activated potassium channels nor vascular connexins are modulated by NO; however, their functional contribution to endothelium-dependent relaxation may be modulated by other physiological parameters.
Endothelium‐dependent vasodilatation (EDV) in the microcirculation is achieved by a combination of endothelium‐derived nitric oxide (NO), prostacyclin (PGI2) and endothelium‐derived hyperpolarizing ...factor (EDHF) with, as a generalization, the contribution of EDHF increasing inversely proportional to vessel size. The EDHF contribution to EDV is inhibited by a combination of the small and intermediate conductance calcium‐activated potassium channel, KCa, (SK and IK respectively) inhibitors apamin and charybdotoxin (or the more specific IK inhibitor TRAM‐34). Furthermore, myo‐endothelial gap junctions, made up of connexins (Cx), are likely key contributors to EDHF‐mediated EDV. In small mesenteric arteries (SMA) from the eNOS knock out mouse EDHF is the sole contributor to EDV, whereas in C57BL/6 mice EDV is mediated by NO + EDHF. In the present study we investigated the relative contribution of NO and EDHF in 1st vs. 2nd vs. 3rd order SMA from C57BL/6 mice and the ‘real‐time’ mRNA expression levels of IK, SK and BK (large conductance) channels and Cx 37, 40, 43 and 45 from C57BL/6 vs. eNOS −/−. Although the contribution of EDHF was greater in 3rd order vs. 2nd and greater in 2nd vs. 1st order vessels from C57BL/6 mice no difference, relative to the housekeeping gene beta‐actin, was found in expression levels of mRNA for SK1, SK2, SK3, IK, BK channels or Cx 37, 40, 43, 45; similar data was obtained in SMA from eNOS−/− mice. These data indicate that, at least at the level of mRNA, KCa channel and Cx expression in the SMA is not linked to expression of eNOS or the relative contribution of EDHF to EDV.
Despite recent improvements, complete motor recovery occurs in <15% of stroke patients. To improve the therapeutic outcomes, there is a strong need to tailor treatments to each individual patient. ...However, there is a lack of knowledge concerning the precise neuronal mechanisms underlying the degree and course of motor recovery and its individual differences, especially in the view of brain network properties despite the fact that it became more and more clear that stroke is a network disorder. The TiMeS project is a longitudinal exploratory study aiming at characterizing stroke phenotypes of a large, representative stroke cohort through an extensive, multi-modal and multi-domain evaluation. The ultimate goal of the study is to identify prognostic biomarkers allowing to predict the individual degree and course of motor recovery and its underlying neuronal mechanisms paving the way for novel interventions and treatment stratification for the individual patients. A total of up to 100 patients will be assessed at 4 timepoints over the first year after the stroke: during the first (T1) and third (T2) week, then three (T3) and twelve (T4) months after stroke onset. To assess underlying mechanisms of recovery with a focus on network analyses and brain connectivity, we will apply synergistic state-of-the-art systems neuroscience methods including functional, diffusion, and structural magnetic resonance imaging (MRI), and electrophysiological evaluation based on transcranial magnetic stimulation (TMS) coupled with electroencephalography (EEG) and electromyography (EMG). In addition, an extensive, multi-domain neuropsychological evaluation will be performed at each timepoint, covering all sensorimotor and cognitive domains. This project will significantly add to the understanding of underlying mechanisms of motor recovery with a strong focus on the interactions between the motor and other cognitive domains and multimodal network analyses. The population-based, multi-dimensional dataset will serve as a basis to develop biomarkers to predict outcome and promote personalized stratification toward individually tailored treatment concepts using neuro-technologies, thus paving the way toward personalized precision medicine approaches in stroke rehabilitation.
The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based ...heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009,
= 1.098 × 10
) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
GJA8
encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions.
GJA8
mutations have been linked to early onset cataracts in humans and animal models. In ...mice, missense mutations and homozygous
Gja8
deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that
Gja8
may play a role in both lens development and ocular growth. Following screening of
GJA8
in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg) and two novel p.(Phe70Leu) and p.(Val97Gly) likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of
GJA8
structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of
GJA8
variants and associated phenotypes, confirming the importance of this gene in early eye development.
Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely ...understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke.
Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation.
From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (
<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics.
The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.
Neoplastic meningitis is a central nervous system complication that occurs in 3–5% of patients with cancer. Although most commonly seen in patients with disseminated disease, in a small percentage of ...patients, it may be the initial manifestation of cancer or even primitive in origin. In the absence of cancer history, the diagnosis of neoplastic meningitis may be challenging even for expert neurologists. Prognosis is poor, with a median overall survival of weeks from diagnosis. In the retrospective study herein, we described three cases of meningeal melanomatosis in patients without previous cancer history. The patients were diagnosed with significant delay (17 to 47 weeks from symptom onset) mainly due to the deferral in performing the appropriate testing. Even when the diagnosis was suspected, investigations by MRI, cerebrospinal fluid, or both proved at times unhelpful for confirmation. Prognosis was dismal, with a median survival of 4 weeks after diagnosis. Our observations are a cue to analyze the main pitfalls in the diagnosis of neoplastic meningitis in patients without cancer history and emphasize key elements that may facilitate early diagnosis.
In recent years, herpes simplex encephalitis (HSE) has been reported with increasing frequency in settings of immunosuppression, such as acquired immunodeficiency, transplantation and cancer. As ...observed, in immunocompromised individuals HSE presents peculiar clinical and paraclinical features, and poorer prognosis.
Here we describe a retrospective series of seven cases of HSE in patients with high-grade glioma (HGG), collected among three institutions in a 5-year period (during this time, a total of 1750 patients with HGG were treated).
Diagnosis of the condition was particularly challenging due to the confounding clinical presentation and the atypical biological findings. As a result, antiviral treatment was started with a sharp delay compared with immunocompetent hosts. Prognosis was poor, with high short-term mortality and severe residual disability in survivors.
The substantial incidence of HSE observed in our centres together with the difficulty in diagnosing the condition suggest that the incidence of this complication may be highly underestimated. The aim of our report is to strengthen the observation of HSE in patients with HGG and outline the key elements that may allow its diagnosis.
PDF
