Miracle-dz/UniFAR-FTUs huggingface dataset:
Are the PCSK9 inhibitors the panacea of atherosclerosis treatment?

Since the initial publication in 2012 of the first human studies showing dramatic reductions in low density lipoprotein cholesterol (LDL-C) by inhibiting PCSK9 with a monoclonal antibody, speculation has focused on the ability of these agents to reduce atherosclerotic cardiovascular disease (CVD) [1,2]. Skeptics, and some guideline committees, suggested further reductions in LDL-C below 70 mg/dL or >50%, achievable by high intensity statin with or without ezetimibe, would have little if any additional CVD benefit as a plateau had been reached [3–5]. They also expressed concern that reductions to very low LDL-C levels, such as ≤25 mg/dL, could be harmful, increasing the risk of hemorrhagic stroke, cognitive impairment, cataracts and diabetes [6–9]. Similar concerns regarding greater LDL-C reductions and low LDL-C plagued the use of later generation, more efficacious, statins, or statins plus ezetimibe, and took decades, until results from PROVE-IT and IMPROVE-IT trials, to resolve [10,11]. However PCSK9 inhibitors, in a mere 5 years, have provided conclusive evidence of CVD benefit from the results of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial with evolocumab[12]. We now know there is continued CVD benefit down to very low LDL-C with none of the predicted untoward adverse effects[12]. The issues surrounding PCSK9 inhibitors, LDL-C reduction, CVD benefit and safety can be best discussed as outlined in the Table 1 below. The current PCSK9 inhibitors are expensive and their cost effectiveness and patient access subject to ongoing debate, however a detailed discussion of these issues is beyond the scope of this review.
Successful treatment of cutaneous sarcoid by photodynamic therapy with minimal discomfort using a fractionated dosing regime

We report the case of a 42‐year‐old lady with an 8‐year history of a persistent tumid plaque on her forehead. Investigations and presentation were consistent with cutaneous sarcoid with no systemic involvement. Multiple topical and oral treatments had been ineffective. She received seven sessions of 5‐aminolaevulinic acid photodynamic therapy (PDT) over the course of 16 months. Each treatment was delivered in discontinuous and fractionated time intervals. Improvement was seen after the first treatment and continued with subsequent treatments. She found the treatment almost painless and was pleased with the cosmetic outcome. We conclude that PDT is a useful therapy in the treatment of facial cutaneous sarcoid. Fractionated exposure may allow the treatment to be less painful and therefore better tolerated.
Revisiting the role of durable polymers in cardiovascular devices

ABSTRACT Introduction: Polymers are an essential component of drug-eluting stents (DES) used to control drug release but remain the most controversial component of DES technology. There are two types of polymers employed in DES: durable polymer based DES (DP-DES) and biodegradable polymer DES (BP-DES). First-generation DES were exclusively composed of DP and demonstrated increased rates of late stent failure due in part to poor polymer biocompatibility. Newer generations DES use more biocompatible durable polymers or biodegradable polymers. Areas covered: We will cover issues identified with 1st-generation DP-DES, areas of success and failure in 2nd-generation DP-DES and examine the promise and shortcomings of BP-DES. Briefly, fluorinated polymers used in 2nd-generation DP-DES have excellent anti-thrombogenicity and better biocompatibility than 1st-generation DES polymers. However, these devices lead to persistent drug exposure to the endothelium which impairs endothelial function and predisposes towards neoatherosclerosis. Meanwhile, BP-DES has shortened the duration of drug exposure which might be beneficial for endothelial functional recovery leading to less neoatherosclerosis. However, it remains uncertain whether the long-term biocompatibility of bare metal surfaces is better than that of polymer-coated metals. Expert commentary: Each technology has distinct advantages, which can be optimized depending upon the particular characteristics of the patient being treated.
Regulation of Schwann cell differentiation and proliferation by the Pax‐3 transcription factor

Pax‐3 is a paired domain transcription factor that plays many roles during vertebrate development. In the Schwann cell lineage, Pax‐3 is expressed at an early stage in Schwann cells precursors of the embryonic nerve, is maintained in the nonmyelinating cells of the adult nerve, and is upregulated in Schwann cells after peripheral nerve injury. Consistent with this expression pattern, Pax‐3 has previously been shown to play a role in repressing the expression of the myelin basic protein gene in Schwann cells. We have studied the role of Pax‐3 in Schwann cells and have found that it controls not only the regulation of cell differentiation but also the survival and proliferation of Schwann cells. Pax‐3 expression blocks both the induction of Oct‐6 and Krox‐20 (K20) by cyclic AMP and completely inhibits the ability of K20, the physiological regulator of myelination in the peripheral nervous system, to induce myelin gene expression in Schwann cells. In contrast to other inhibitors of myelination, we find that Pax‐3 represses myelin gene expression in a c‐Jun‐independent manner. In addition to this, we find that Pax‐3 expression alone is sufficient to inhibit the induction of apoptosis by TGFβ1 in Schwann cells. Expression of Pax‐3 is also sufficient to induce the proliferation of Schwann cells in the absence of added growth factors and to reverse K20‐induced exit from the cell cycle. These findings indicate new roles for the Pax‐3 transcription factor in controlling the differentiation and proliferation of Schwann cells during development and after peripheral nerve injury. © 2012 Wiley Periodicals, Inc.
Apolipoprotein E ϵ4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis

Apolipoprotein E allele 4 (apo E ϵ4) is known to be in genetic disequilibrium with Alzheimer's disease and is associated with an earlier age at onset of dementia. Whether apo E ϵ4 is a specific risk factor for Alzheimer's disease or is a more general susceptibility factor that shifts the age at onset of neurodegenerative diseases to earlier ages is unknown. To test these possibilities, we determined the apolipoprotein E genotypes of subjects with familial or sporadic amyotrophic lateral sclerosis (ALS). ApoE allele frequencies of the the apoE gene of the ALS subjects (n = 170, ϵ2 = 0.071, ϵ3 = 0.771, ϵ4 = 0.159) were found to be comparable to the allele frequencies of the general population. Furthermore, no significant association was observed between the age at onset or the duration of ALS and the inheritance of apoE ϵ4: subjects with at least one copy of ϵ4 (sporadic ALS: n = 15, onset at 57.7 ± 13.9 years; familial ALS: n = 23, onset at 53.6 ± 9.5 years, duration [n = 14] of 2.6 ± 1.6 years) had comparable ages at onset and durations to subjects without ϵ4 (sporadic ALS: n = 28, onset at 53.1 ± 17.0 years; familial ALS: n = 56, onset at 50.8 ± 12.1 years, duration [n = 30] of 1.9 ± 0.8 years). The lack of association of apoE ϵ4 with the age at onset and the duration of ALS suggests that apoE ϵ4 does not have a global effect on the pathogenesis of other neurodegenerative diseases.
Utility of Intravenous β-Blocker Administration in Patients with Acute Myocardial Infarction Undergoing Primary Percutaneous Intervention

The clinical effects of intravenous β-adrenoreceptor- blocking agents (β-blockers) administered during evolving acute myocardial infarction (AMI) have varied among published studies, depending on whether or not reperfusion therapy was employed. Primary percutaneous coronary intervention (PCI) is accepted as the superior form of reperfusion therapy for AMI if it can be performed by an experienced team in a timely fashion. Intravenous β-blockers are not routinely used in this setting and their role as adjunctive medical therapy to catheter-based reperfusion requires definition. Emerging data strongly indicate that in the absence of cardiogenic shock or specific contra-indications, pre-procedural intravenous β-blockade improves survival and recovery of left ventricular function after primary PCI, and that these effects are modulated by oral β-blocker use at the time of AMI onset. In the absence of contra-indications, the available evidence supports the routine administration of intravenous β-blockers to patients with ST-segment elevation AMI managed by catheter-based reperfusion therapy, especially in patients in whom oral β-blockers were not used before admission. While no data are available on the effects of intravenous β-blocker therapy with catheter-based intervention for acute coronary syndromes other than ST-segment elevation AMI, it is reasonable to apply the aforementioned recommendations regarding primary PCI to these patients as well.
Intraventricular injection of FGF‐2 promotes generation of oligodendrocyte‐lineage cells in the postnatal and adult forebrain

FGF2 is considered a key factor in the generation of oligodendrocytes (OLs) derived from neural stem cells (NSCs) located within the subventricular zone (SVZ). Here, we have examined FGF2 signaling in the forebrain of postnatal and adult mice. Using qPCR of microdissected microdomains of the dorsal SVZ (dSVZ) and lateral SVZ (lSVZ), and prominin1‐sorted NSCs purified from these microdomains, we show that transcripts for FGF receptor 1 (FGFR1) and FGFR2 are enriched in the dSVZ, from which OLs are largely derived, whereas FGFR3 are significantly enriched within prominen1‐sorted NSC of the lSVZ, which mainly generate olfactory interneurons. We show that direct administration of FGF2 into the lateral ventricle increased the generation of oligodendrocyte progenitors (OPCs) throughout the SVZ, both within the dSVZ and ectopically in the lSVZ and ependymal wall of the SVZ. Furthermore, FGF2 stimulated proliferation of neural progenitors (NPs) and their differentiation into OPCs. The results indicate that FGF2 increased specification of OPCs, inducing NPs to follow an oligodendrocyte developmental pathway. Notably, FGF2 did not block OPC differentiation and increased the number of oligodendrocytes in the periventricular white matter (PVWM) and cortex. However, FGF2 markedly disrupted myelination in the PVWM. A key finding was that FGF2 had equivalent actions on the generation of OPCs and myelin disruption in postnatal and adult mice. This study demonstrates a central role for FGF2 in promoting oligodendrocyte generation in the developing and adult brain. © Wiley Periodicals, Inc.
Differential glial activation during the degeneration of Purkinje cells and mitral cells in the PCD mutant mice

Purkinje Cell Degeneration (PCD) mice harbor a nna1 gene mutation which leads to an early and rapid degeneration of Purkinje cells (PC) between the third and fourth week of age. This mutation also underlies the death of mitral cells (MC) in the olfactory bulb (OB), but this process is slower and longer than in PC. No clear interpretations supporting the marked differences in these neurodegenerative processes exist. Growing evidence suggests that either beneficial or detrimental effects of gliosis in damaged regions would underlie these divergences. Here, we examined the gliosis occurring during PC and MC death in the PCD mouse. Our results demonstrated different glial reactions in both affected regions. PC disappearance stimulated a severe gliosis characterized by strong morphological changes, enhanced glial proliferation, as well as the release of pro‐inflammatory mediators. By contrast, MC degeneration seems to promote a more attenuated glial response in the PCD OB compared with that of the cerebellum. Strikingly, cerebellar oligodendrocytes died by apoptosis in the PCD, whereas bulbar ones were not affected. Interestingly, the level of nna1 mRNA under normal conditions was higher in the cerebellum than in the OB, probably related to a faster neurodegeneration and stronger glial reaction in its absence. The glial responses may thus influence the neurodegenerative course in the cerebellum and OB of the mutant mouse brain, providing harmful and beneficial microenvironments, respectively. © 2012 Wiley Periodicals, Inc.
MT1 melatonin receptor internalization underlies melatonin‐induced morphologic changes in Chinese hamster ovary cells and these processes are dependent on Gi proteins, MEK 1/2 and microtubule modulation

Abstract: Melatonin induces cellular differentiation in numerous cell types. Data show that multiple mechanisms are involved in these processes that are cell‐type specific and may be receptor dependent or independent. The focus of this study was to specifically assess the role of human MT1 melatonin receptors in cellular differentiation using an MT1‐Chinese hamster ovary (CHO) model; one that reproducibly produces measurable morphologic changes in response to melatonin. Using multiple approaches, we show that melatonin induces MT1‐CHO cells to hyperelongate through a MEK 1/2, and ERK 1/2‐dependent mechanism that is dependent upon MT1 receptor internalization, Gi protein activation, and clathrin‐mediated endocytosis. Using immunoprecipitation analysis, we show that MT1 receptors form complexes with Giα 2,3, Gqα, β‐arrestin‐2, MEK 1/2, and ERK 1/2 in the presence of melatonin. We also show that MEK and ERK activity that is induced by melatonin is dependent on Gi protein activation, clathrin‐mediated endocytosis and is modulated by microtubules. We conclude from these studies that melatonin‐induced internalization of human MT1 melatonin receptors in CHO cells is responsible for activating both MEK 1/2 and ERK 1/2 to drive these morphologic changes. These events, as mediated by melatonin, require Gi protein activation and endocytosis mediated through clathrin, to form MT1 receptor complexes with β‐arrestin‐2/MEK 1/2 and ERK 1/2. The MT1‐CHO model is invaluable to mapping out signaling cascades as mediated through MT1 receptors especially because it separates out MEK/ERK 1/2 activation by MT1 receptors from that of receptor tyrosine kinases.
Astrocyte‐derived adenosine modulates increased sleep pressure during inflammatory response

Activation of the immune system elicits several behavioral changes collectively called sickness. Among the behavioral changes, systemic infections induce an increase in time spent in nonrapid‐eye‐movement (NREM) sleep and an increase of slow wave activity (or “sleep pressure”). Using an inducible, astrocyte‐specific transgenic dominant negative SNARE (dnSNARE) mouse line we recently demonstrated that gliotransmission plays an important role in sleep homeostasis through an adenosine receptor 1 (A1R)‐sensitive pathway. It has been hypothesized that systemic infection, mimicked by peripheral administration of lipopolysaccharide (LPS), increases sleeping behavior in part through upregulation of central adenosine levels. Moreover, as a source of immunologically relevant factors, astrocytes play a pivotal role in the central nervous system immune and inflammatory responses. However, little is known about the role of astrocytes in the CNS response to a peripheral immune challenge. We hypothesize that LPS impacts sleep homeostasis through the modulation of astrocyte‐derived adenosine accumulation. We therefore used dnSNARE mice to determine whether astrocytes contribute to the increased sleep pressure under immune challenge and whether this is a result of changes in adenosine signaling. We demonstrate that dnSNARE‐mediated gliotransmission is required for the ability of LPS to elevate sleep pressure as measured by the power of slow wave activity during NREM sleep. Moreover, in agreement with a role of astrocyte‐derived adenosine in modulating sleep homeostasis, we find that intracerebroventricular infusion of the A1R antagonist 8‐cyclopentyl‐1,3‐dimethylxanthine (CPT) mimics this dnSNARE phenotype. Taken together, our data demonstrate that astrocytic adenosine acting through A1 receptors contributes to the modulation of sleep pressure by LPS. GLIA 2013
EGF stimulates müller glial proliferation via a BMP‐dependent mechanism

Müller glia, the major type of glia in the retina, are mitotically quiescent under normal conditions, though they can be stimulated to proliferate in some pathological states. Among these stimuli, EGF is known to be a potent mitogen for Müller glia. However, the signaling pathways required for EGF‐mediated proliferation of Müller glia are not clearly understood. In this study, postnatal day 12 (P12) or adult trp53−/− mouse retinas were explanted and cultured in the presence of EGF to stimulate Müller glial proliferation. Treatment with signaling inhibitors showed that activation of both MEK/ERK1/2 and PI3K/AKT pathways is required for EGF‐induced proliferation of Müller glia. Interestingly, BMP/Smad1/5/8 activation downstream of PI3K/AKT signaling was also necessary for robust Müller glial proliferation, though activation of BMP/Smad1/5/8 signaling alone failed to stimulate their proliferation. In dissociated Müller glial culture, treatment with EGF induced the upregulation of Bmp7, and this upregulation was blocked significantly by co‐treatment with the BMP inhibitor dorsomorphin, suggesting that BMP/Smad1/5/8 activation is mediated at least in part by an autocrine mechanism in Müller glia. A better understanding of how BMP/Smad1/5/8 signaling is involved in glial proliferation may have important implications for proliferative disorders, as well as for retinal regeneration in mammalian retinas.
Effects of vaccine on rotavirus disease in the pediatric population

Purpose of review Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. Two effective rotavirus vaccines are available and recommended for routine immunization of all infants. These vaccines have been introduced in both developed and developing countries. As rotavirus vaccines are implemented, studies have been undertaken that assess the effects of vaccination on rotavirus disease in children. This review summarizes the results of these studies. Recent findings Studies that assess health impact, indirect benefits, and strain changes after the introduction of rotavirus vaccine have been reported. In industrialized countries, rotavirus vaccination has led to dramatic drops in severe rotavirus-related hospitalizations and has reduced emergency room visits. Data from clinical trials in developing counties in Asia and Africa have demonstrated that rotavirus vaccines significantly reduce severe diarrhea episodes due to rotavirus. Herd (community) immunity has also been noted after routine rotavirus immunization in several countries. There have been no significant strain shifts or escape mutants noted since the introduction of rotavirus vaccines. Summary Two well tolerated and effective rotavirus vaccines have reduced the health burden of rotavirus gastroenteritis in both developed and developing countries.
Are we missing at-risk babies? Comparison of customised growth charts v. standard population charts in a diabetic population

Background. Diabetes in pregnancy is associated with both accelerated fetal growth and intrauterine growth restriction. Objective. To compare the difference in occurrence of large-for-gestational-age (LGA) and small-for-gestational-age (SGA) fetuses in a pregnant diabetic population using population-based growth charts and customised growth charts. Methods. Retrospective observational study at Steve Biko Academic and Kalafong hospitals, Pretoria, South Africa. Information from an electronic database was used to retrospectively generate customised centiles using a web-based tool (www.gestation.net). The first fetal growth scan of the third trimester, as determined by ultrasound, was plotted for each patient on both the population-based and customised growth charts. We compared the growth category on the population-based growth chart with the that on the customised growth chart. Results. Of the patients, 44 had type 1 diabetes, 66 type 2 diabetes and 173 gestational diabetes. The growth of 79/283 fetuses would have been reclassified had customised growth charts been used. Of cases in which fetal growth was classified as appropriate for gestation on the population-based growth charts, 58 fetuses would have been LGA and 14 SGA had customised growth charts been used. Four of the fetuses that were SGA and three that were LGA on the population-based growth charts would have been classified as appropriately grown on the customised growth charts. This was a statistically significant difference ( p <0.001), with a Cohen’s kappa of 0.45 indicating moderate agreement. Conclusions. Customised growth charts identified more babies with aberrations of growth, who may need vigilant antenatal care and elective delivery and may be at increased health risk in the future.
β‐amyloid and ATP‐induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type‐5 receptors

β‐Amyloid (Aβ) oligomers initiate synaptotoxicity following their interaction with the plasma membrane. Several proteins including metabotropic glutamate type 5 receptors (mGluR5s) contribute to this process. We observed an overexpression of mGluR5s in reactive astrocytes surrounding Aβ plaques in brain sections from an Alzheimer's disease mouse model. In a simplified cell culture system, using immunocytochemistry and single molecule imaging, we demonstrated a rapid binding of Aβ oligomers on the plasma membrane of astrocytes. The resulting aggregates of Aβ oligomers led to the diffusional trapping and clustering of mGluR5s. Further, Aβ oligomers induced an increase in ATP release following activation of astroglial mGluR5s by its agonist. ATP slowed mGluR5s diffusion in astrocytes as well as in neurons co‐cultured with astrocytes. This effect, which is purinergic receptor‐dependent, was not observed in pure neuronal cultures. Thus, Aβ oligomer‐ and mGluR5‐dependent ATP release by astrocytes may contribute to the overall deleterious effect of mGluR5s in Alzheimer's disease. GLIA 2013;61:1673–1686
Microglial polarization and plasticity: Evidence from organotypic hippocampal slice cultures

Increasing evidence indicates that “functional plasticity” is not solely a neuronal attribute but a hallmark of microglial cells, the main brain resident macrophage population. Far from being a univocal phenomenon, microglial activation can originate a plethora of functional phenotypes, encompassing the classic M1 proinflammatory and the alternative M2 anti‐inflammatory phenotypes. This concept overturns the popular view of microglial activation as a synonym of neurotoxicity and neurogenesis failure in brain disorders. The characterization of the alternative programs is a matter of intense investigation, but still scarce information is available on the course of microglial activation, on the reversibility of the different commitments and on the capability of preserving molecular memory of previous priming stimuli. By using organotypic hippocampal slice cultures as a model, we developed paradigms of stimulation aimed at shedding light on some of these aspects. We show that persistent stimulation of TLR4 signaling promotes an anti‐inflammatory response and microglial polarization toward M2‐like phenotype. Moreover, acute and chronic preconditioning regimens permanently affect the capability to respond to a later challenge, suggesting the onset of mechanisms of molecular memory. Similar phenomena could occur in the intact brain and differently affect the vulnerability of mature and newborn neurons to noxious signals. GLIA 2013;61:1698–1711