Instruments to assess appropriateness of hip and knee arthroplasty: a systematic review.

OBJECTIVE: To assess criteria and psychometric properties of instruments for assessing appropriateness of elective joint arthroplasty (JA) for adults with primary hip and knee osteoarthritis (OA). METHODS: A systematic review guided by Cochrane methods and PRISMA guidelines. Studies were searched in five databases. Eligible articles include all study designs developing, testing, and/or using an instrument to assess JA appropriateness. Two independent reviewers screened and extracted data. Instruments were compared with Hawker et al. JA consensus criteria. Psychometric properties of instruments were described and appraised guided by Fitzpatrick's and COSMIN approaches. RESULTS: Of 55 instruments included, none met all Hawker et al. JA consensus criteria. Criteria the most met were pain (n = 50), function (n = 49), quality of life (n = 33), and radiography (n = 24). Criteria the least met were clinical evidence of OA (n = 18), expectations (n = 15), readiness for surgery (n = 11), conservative treatments (n = 8), and patient/surgeon agree benefits outweigh risks (n = 0). Instrument by Arden et al. met the most criteria (6 of 9). The most tested psychometric properties were appropriateness (n = 55), face/content validity (n = 55), predictive validity (n = 29), construct validity and feasibility (n = 24). The least tested psychometric properties were intra-rater reliability (n = 3), internal consistency (n = 5), and inter-rater reliability (n = 13). Instruments by Gutacker et al. and Osborne et al. met the most psychometric properties (4 of 10). CONCLUSION: Most instruments included traditional criteria for assessing JA appropriateness but did not include a trial of conservative treatments or shared decision-making elements. There was limited evidence on psychometric properties.

Arabic validation of a cyberbullying assessment instrument.

INTRODUCTION: Cyberbullying is a new form of peer violence that has become a widespread problem in the world. The prevalence of this phenomenon is not known in Tunisia due to the absence of validated assessment instruments. The aim of this study was to translate and validate the questionnaire "Second Revision of the Revised Cyberbullying Inventory". METHODS: We translated this questionnaire into dialectal Tunisian Arabic using the back-translation method. To study the construct validity and the reliability, we conducted a cross-sectional study involving 962 Tunisian adolescents. Confirmatory factor analysis was performed to study construct validity for the two dimensions of the scale: cyber-victimization and cyber-aggression. To test reliability, the global internal consistency was computed for the two sections of the scale. RESULTS: The translated version was considered satisfactory. The adjustment indices of the confirmatory factor analysis were satisfactory for both sections confirming the two-dimensional nature of the scale. The values of the cyber-aggression section were as follows: Comparative Fit Index=0.92; Tucker-Lewis Index=0.9; Root Mean Square Error of Approximation=0.04; Standardized Root Mean Square Residual=0.01. As for the cyber-victimization section, fit indices were as follows: Comparative Fit Index=0.92; Tucker-Lewis Index=0.9; Root Mean Square Error of Approximation=0.01; Standardized Root Mean Square Residual=0.07. Both sections showed good reliability. The internal consistency of each section was optimal. In fact, the Cronbach alpha was respectively 0.79 for cyber-aggression and 0.73 for cyber-victimization. CONCLUSION: The Arabic version of the "Second Revision of the Revised Cyberbullying Inventory" is a psychometrically valid assessment. This scale could be useful to conduct further research and allow us to better understand the phenomenon of cyberbullying.

Effects of glutathione S-transferase M1 and T1 deletions on Parkinson's disease risk among a North African population.

PURPOSE: In this study, the effects of glutathione S-transferase polymorphisms Mu1 (GSTM1) and glutathione S-transferase polymorphisms Theta1 (GSTT1) on Parkinson's disease (PD) risk factor were evaluated in a Tunisian population. METHODS: These polymorphisms were analyzed in 229 healthy Tunisian subjects and 64 Tunisian patients with PD, using a polymerase chain reaction (PCR). Statistical analysis was performed using SPSS 18.0. The relative associations between the GST genotypes and PD were assessed by calculating the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The study results demonstrated that the individuals with GSTM1 [OR=3.93, 95% CI: 1.98-7.92, P=10-6] and GSTT1 [OR=5.45, 95% CI: 2.90-10.30, p=10-6] were statistically associated with the risk of PD. A significant association was also found between the individuals with both GSTM1/T1 null genotypes and PD risk [OR=22.10, 95% CI: 6.99-73.75, P=10-6]. CONCLUSION: These genotyping findings suggest that the absence of both GSTM1 and GSTT1 activity could be a contributory factor for the development of PD.

Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage.

Innate immune sensing of viral molecular patterns is essential for development of antiviral responses. Like many viruses, SARS-CoV-2 has evolved strategies to circumvent innate immune detection, including low cytosine-phosphate-guanosine (CpG) levels in the genome, glycosylation to shield essential elements including the receptor-binding domain, RNA shielding and generation of viral proteins that actively impede anti-viral interferon responses. Together these strategies allow widespread infection and increased viral load. Despite the efforts of immune subversion, SARS-CoV-2 infection activates innate immune pathways inducing a robust type I/III interferon response, production of proinflammatory cytokines and recruitment of neutrophils and myeloid cells. This may induce hyperinflammation or, alternatively, effectively recruit adaptive immune responses that help clear the infection and prevent reinfection. The dysregulation of the renin-angiotensin system due to down-regulation of angiotensin-converting enzyme 2, the receptor for SARS-CoV-2, together with the activation of type I/III interferon response, and inflammasome response converge to promote free radical production and oxidative stress. This exacerbates tissue damage in the respiratory system, but also leads to widespread activation of coagulation pathways leading to thrombosis. Here, we review the current knowledge of the role of the innate immune response following SARS-CoV-2 infection, much of which is based on the knowledge from SARS-CoV and other coronaviruses. Understanding how the virus subverts the initial immune response and how an aberrant innate immune response contributes to the respiratory and vascular damage in COVID-19 may help to explain factors that contribute to the variety of clinical manifestations and outcome of SARS-CoV-2 infection.

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

Neuroimmunology - the past, present and future.

Neuroimmunology as a separate discipline has its roots in the fields of neurology, neuroscience and immunology. Early studies of the brain by Golgi and Cajal, the detailed clinical and neuropathology studies of Charcot and Thompson's seminal paper on graft acceptance in the central nervous system, kindled a now rapidly expanding research area, with the aim of understanding pathological mechanisms of inflammatory components of neurological disorders. While neuroimmunologists originally focused on classical neuroinflammatory disorders, such as multiple sclerosis and infections, there is strong evidence to suggest that the immune response contributes to genetic white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric disorders, peripheral nervous system and neuro-oncological conditions, as well as ageing. Technological advances have greatly aided our knowledge of how the immune system influences the nervous system during development and ageing, and how such responses contribute to disease as well as regeneration and repair. Here, we highlight historical aspects and milestones in the field of neuroimmunology and discuss the paradigm shifts that have helped provide novel insights into disease mechanisms. We propose future perspectives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation.

Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes.

AIMS: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by progressive loss of motor neurons, muscle weakness, spasticity, paralysis and death usually within 2-5 years of onset. Neuroinflammation is a hallmark of ALS pathology characterized by activation of glial cells, which respond by upregulating small heat shock proteins (HSPBs), but the exact underlying pathological mechanisms are still largely unknown. Here, we investigated the association between ALS disease duration, lower motor neuron loss, TARDNA-binding protein 43 (TDP-43) pathology, neuroinflammation and HSPB expression. METHODS: With immunohistochemistry, we examined HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 expression in cervical, thoracic and sacral spinal cord regions in 12 ALS cases, seven with short disease duration (SDD), five with moderate disease duration (MDD), and ten age-matched controls. Expression was quantified using ImageJ to examine HSP expression, motor neuron numbers, microglial and astrocyte density and phosphorylated TDP-43 (pTDP-43+) inclusions. RESULTS: SDD was associated with elevated HSPB5 and 8 expression in lateral tract astrocytes, while HSP16.2 expression was increased in astrocytes in MDD cases. SDD cases had higher numbers of motor neurons and microglial activation than MDD cases, but similar levels of motor neurons with pTDP-43+ inclusions. CONCLUSIONS: Increased expression of several HSPBs in lateral column astrocytes suggests that astrocytes play a role in the pathogenesis of ALS. SDD is associated with increased microgliosis, HSPB5 and 8 expression in astrocytes, and only minor changes in motor neuron loss. This suggests that the interaction between motor neurons, microglia and astrocytes determines neuronal fate and functional decline in ALS.

Caloric restriction attenuates aging-induced cardiac insulin resistance in male Wistar rats through activation of PI3K/Akt pathway.

BACKGROUND AND AIM: Caloric restriction (CR) improves insulin sensitivity and is one of the dietetic strategies most commonly used to enlarge life and to prevent aging-induced cardiovascular alterations. The aim of this study was to analyze the possible beneficial effects of caloric restriction (CR) preventing the aging-induced insulin resistance in the heart of male Wistar rats. METHODS AND RESULTS: Three experimental groups were used: 3 months old rats (3m), 24 months old rats (24m) and 24 months old rats subjected to 20% CR during their three last months of life (24m-CR). After sacrifice hearts were mounted in a perfusion system (Langendorff) and heart function in basal conditions and in response to accumulative doses of insulin (10-9-10-7 M), in the presence or absence of Wortmannin (10-6 M), was recorded. CR did not attenuate the aging-induced decrease in coronary artery vasodilation in response to insulin administration, but it prevented the aging-induced downregulation of cardiac contractility (dp/dt) through activation of the PI3K/Akt intracellular pathway. Insulin stimulated in a greater extent the PI3K/Akt pathway vs the activation of the MAPK pathway and increased the protein expression of IR, GLUT-4 and eNOS in the hearts of 3m and 24m-CR rats, but not in the hearts of 24m rats. Furthermore, CR prevented the aging induced increase in endothelin-1 protein expression in myocardial tissue. CONCLUSION: In conclusion CR partially improves cardiac insulin sensitivity and prevents the aging induced decrease in myocardial contractility in response to insulin administration through activation of PI3K/Akt pathway.

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by demyelination, inflammation and neurodegeneration throughout the central nervous system. Although spinal cord pathology is an important factor contributing to disease progression, few studies have examined MS lesions in the spinal cord and how they differ from brain lesions. In this study we have compared brain and spinal cord white (WM) and grey (GM) matter from MS and control tissues, focusing on small heat shock proteins (HSPB) and HSP16.2. Western blotting was used to examine protein levels of HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 in brain and spinal cord from MS and age-matched non-neurological controls. Immunohistochemistry was used to examine expression of the HSPs in MS spinal cord lesions and controls. Expression levels were quantified using ImageJ. Western blotting revealed significantly higher levels of HSPB1, HSPB6 and HSPB8 in MS and control spinal cord compared to brain tissues. No differences in HSPB5 and HSP16.2 protein levels were observed, although HSPB5 protein levels were higher in brain WM versus GM. In MS spinal cord lesions, increased HSPB1 and HSPB5 expression was observed in astrocytes, and increased neuronal expression of HSP16.2 was observed in normal-appearing GM and type 1 GM lesions. The high constitutive expression of several HSPBs in spinal cord and increased expression of HSPBs and HSP16.2 in MS illustrate differences between brain and spinal cord in health and upon demyelination. Regional differences in HSP expression may reflect differences in astrocyte cytoskeleton composition and influence inflammation, possibly affecting the effectiveness of pharmacological agents.

Heat shock protein expression in cerebral X-linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss.

AIMS: X-linked adrenoleukodystrophy (X-ALD) is a genetic white matter disorder in which demyelination occurs due to accumulation of very long-chain fatty acids. Inflammation in the brain white matter is a hallmark of the pathology of cerebral X-ALD, but the underlying pathogenic mechanisms are still largely unknown. In other inflammatory demyelinating disorders, such as multiple sclerosis, the expression of heat shock proteins (HSPs) in combination with interferon-γ (IFN-γ) has been suggested to play a prominent role in the initiation of demyelination and inflammation. We therefore investigated these pathways in X-ALD lesions. METHODS: By immunohistochemistry, we examined the expression of small HSPs (HSPB1, HSPB5, HSPB6, HSPB8) and higher molecular weight HSPs (HSPA, HSPD1), and the expression of elements of the IFN-γ pathway on autopsy material of five patients with X-ALD. RESULTS: The expression of the larger HSPs, HSPA and HSPD1, as well as small HSPs is increased in X-ALD lesions compared with normal-appearing white matter. Such upregulation can already be detected before demyelination and inflammation occur, and it is predominant in astrocytes. The IFN-γ pathway does not seem to play a leading role in the observed inflammation. CONCLUSIONS: The finding that astrocytes show signs of cellular stress before demyelination suggests that they play a major role early in the pathogenesis of cerebral X-ALD, and may therefore be involved in the initiation of inflammation and demyelination.

Brain endothelial cell expression of SPARCL-1 is specific to chronic multiple sclerosis lesions and is regulated by inflammatory mediators in vitro.

AIMS: Cell matrix modulating protein SPARCL-1 is highly expressed by astrocytes during CNS development and following acute CNS damage. Applying NanoLC-MS/MS to CSF of RRMS and SPMS patients, we identified SPARCL-1 as differentially expressed between these two stages of MS, suggesting a potential as CSF biomarker to differentiate RRMS from SPMS and a role in MS pathogenesis. METHODS: This study examines the potential of SPARCL-1 as CSF biomarker discriminating RRMS from SPMS in three independent cohorts (n = 249), analyses its expression pattern in MS lesions (n = 26), and studies its regulation in cultured human brain microvasculature endothelial cells (BEC) after exposure to MS-relevant inflammatory mediators. RESULTS: SPARCL-1 expression in CSF was significantly higher in SPMS compared to RRMS in a Dutch cohort of 76 patients. This finding was not replicated in 2 additional cohorts of MS patients from Sweden (n = 81) and Switzerland (n = 92). In chronic MS lesions, but not active lesions or NAWM, a vessel expression pattern of SPARCL-1 was observed in addition to the expression by astrocytes. EC were found to express SPARCL-1 in chronic MS lesions, and SPARCL-1 expression was regulated by MS-relevant inflammatory mediators in cultured human BEC. CONCLUSIONS: Conflicting results of SPARCL-1's differential expression in CSF of three independent cohorts of RRMS and SPMS patients precludes its use as biomarker for disease progression. The expression of SPARCL-1 by BEC in chronic MS lesions together with its regulation by inflammatory mediators in vitro suggest a role for SPARCL-1 in MS neuropathology, possibly at the brain vascular level.

In-situ thermal annealing of on-membrane silicon-on-insulator semiconductor-based devices after high gamma dose irradiation.

In this paper, we investigate the recovery of some semiconductor-based components, such as N/P-type field-effect transistors (FETs) and a complementary metal-oxide-semiconductor (CMOS) inverter, after being exposed to a high total dose of gamma ray radiation. The employed method consists mainly of a rapid, low power and in situ annealing mitigation technique by silicon-on-insulator micro-hotplates. Due to the ionizing effect of the gamma irradiation, the threshold voltages showed an average shift of -580 mV for N-channel transistors, and -360 mV for P-MOSFETs. A 4 min double-cycle annealing of components with a heater temperature up to 465 °C, corresponding to a maximum power of 38 mW, ensured partial recovery but was not sufficient for full recovery. The degradation was completely recovered after the use of a built-in high temperature annealing process, up to 975 °C for 8 min corresponding to a maximum power of 112 mW, which restored the normal operating characteristics for all devices after their irradiation.

Effects of early overnutrition on the renal response to Ang II and expression of RAAS components in rat renal tissue.

BACKGROUND AND AIMS: The aim of this study was to analyze the effects of early overnutrition (EON) on the expression of the renin angiotensin aldosterone system (RAAS) components in renal cortex, renal arteries and renal perivascular adipose tissue (PVAT), as well as the vascular response of renal arteries to Angiotensin II (Ang II). METHODS AND RESULTS: On birth day litters were adjusted to twelve (L12-control) or three (L3-overfed) pups per mother. Half of the animals were sacrificed at weaning (21 days old) and the other half at 5 months of age. Ang II-induced vasoconstriction of renal artery segments increased in young overfed rats and decreased in adult overfed rats. EON decreased the gene expression of angiotensinogen (Agt), Ang II receptors AT1 and AT2 and eNOS in renal arteries of young rats, while it increased the mRNA levels of AT-2 and ET-1 in adult rats. In renal PVAT EON up-regulated the gene expression of COX-2 and TNF-α in young rats and the mRNA levels of renin receptor both in young and in adult rats. On the contrary, Ang II receptors mRNA levels were downregulated at both ages. Renal cortex of overfed rats showed increased gene expression of Agt in adult rats and of AT1 in young rats. However the mRNA levels of AT1 were decreased in the renal cortex of overfed adult rats. CONCLUSION: EON is associated with alterations in the vascular response of renal arteries to Ang II and changes in the gene expression of RAAS components in renal tissue.

Peritumoral adipose tissue as a source of inflammatory and angiogenic factors in colorectal cancer.

PURPOSE: Obesity is a risk factor for the development of human colorectal cancer (CC). The aim of this work is to report the inflammatory and angiogenic scenario in lean (BMI < 25 kg/m2) and obese (BMI > 30 kg/m2) patients with and without CC and to assess the role of peritumoral adipose tissue in CC-induced inflammation. MATERIAL AND METHODS: Patients were divided in four experimental groups: obese patients with CC (OB-CC), lean patients with CC (LEAN-CC), obese patients without CC (OB), and lean patients without CC (LEAN). RESULTS: Plasma levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-4, IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in OB-CC patients. Peritumoral adipose tissue (TF) explants and cultured mature adipocytes secreted higher amounts of nitrites and nitrates than did control and non-tumoral (NTF) adipose tissue both alone and in response to lipopolysaccharide (LPS). Nitrite and nitrate secretion was also increased in TF explants from OB-CC patients compared with that from LEAN-CC patients. Gene expression of adiponectin, tumor necrosis factor alpha (TNF-α), insulin-like growth factor type I (IGF-I), cyclooxygenase-2 (COX-2), and peroxisome proliferator-activated receptor γ (PPAR-γ) was increased in TF explants from CC patients. LPS increased the gene expression of IL-6, IL-10, TNF-α, vascular endothelial growth factor (VEGF), and COX-2 in OB and in TF explants from OB-CC patients. COX-2 and PPAR-γ inhibition further increased LPS-induced release of nitrites and nitrates in TF explants and adipocytes from OB-CC patients. CONCLUSIONS: In conclusion, OB-CC patients have increased plasma levels of pro-inflammatory and angiogenic factors. TF from OB-CC patients shows an increased secretion of inflammatory markers compared with both TF from LEAN-CC and non-tumoral adipose tissue (AT) through a COX-2- and PPAR-γ-independent mechanism.

Implications of metabolic parameters of carbamazepine in the therapeutic monitoring of Tunisian patients with epilepsy.

Carbamazepine (CBZ) is widely used in the control of simple and complex focal seizures and generalized tonic-clonic seizures in patients with epilepsy. The toxic effects of CBZ are not easily predicted, and this is due to the difficulty of delivering the optimal dose and/or plasma concentration of CBZ necessary to achieve beneficial effects, and especially to prevent the onset of toxicity associated with its use. Our study aimed to determine the relationship between the administered daily dose of CBZ and its pharmacokinetic parameters, including concentrations of CBZ and carbamazepine-10,11-epoxide (CBZ-E) plasma levels, and the metabolic ratio of CBZ-E to CBZ, in Tunisian patients with epilepsy. To accomplish this, a high-performance liquid chromatography method with ultraviolet detection was used for quantification in the simultaneous analysis of CBZ and one of its active metabolites, CBZ-E, in human plasma. A statistically significant positive correlation was found between the daily doses administered (mg/kg/day) and plasma concentrations of CBZ and CBZ-E, and the CBZ-E/CBZ ratio increased significantly as a function of the specific dose (in mg/kg/day). The increase in plasma concentrations of CBZ-E was non-linear in relation to plasma concentrations of CBZ, and there was no correlation between the CBZ-E/CBZ metabolic ratio and CBZ plasma concentrations. Our findings suggest that monitoring of CBZ as well as CBZ-E blood levels should be considered, as it may play a useful role in the therapeutic management of patients with epilepsy.

Characterization of a Campylobacter fetus-like strain isolated from the faeces of a sick leopard tortoise (Stigmochelys pardalis) using matrix-assisted laser desorption/ionization time of flight as an alternative to bacterial 16S rDNA phylogeny.

UNLABELLED: This article describes the isolation and characterization of a Campylobacter-like isolate originating from the faeces of a sick leopard tortoise. Molecular as well as matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) characterization suggests that it could correspond to a new Campylobacter species. SIGNIFICANCE AND IMPACT OF THE STUDY: The major impact of this work is the demonstration that proteomics and especially MALDI-TOF typing can be used as an alternative method to 16S rDNA sequencing for phylogeny and can lead to the discovery of new Campylobacters.

Asymmetric growth-limiting development of the female conceptus.

Introduction: Sex differences in prenatal growth may contribute to sex-dependent programming effects on postnatal phenotype. Methods: We integrated for the first time phenotypic, histomorphological, clinico-chemical, endocrine and gene expression analyses in a single species, the bovine conceptus at mid-gestation. Results: We demonstrate that by mid-gestation, before the onset of accelerated growth, the female conceptus displays asymmetric lower growth compared to males. Female fetuses were smaller with lower ponderal index and organ weights than males. However, their brain:body weight, brain:liver weight and heart:body weight ratios were higher than in males, indicating brain and heart 'sparing'. The female placenta weighed less and had lower volumes of trophoblast and fetal connective tissue than the male placenta. Female umbilical cord vessel diameters were smaller, and female-specific relationships of body weight and brain:liver weight ratios with cord vessel diameters indicated that the umbilico-placental vascular system creates a growth-limiting environment where blood flow is redistributed to protect brain and heart growth. Clinico-chemical indicators of liver perfusion support this female-specific growth-limiting phenotype, while lower insulin-like growth factor 2 (IGF2) gene expression in brain and heart, and lower circulating IGF2, implicate female-specific modulation of key endocrine mediators by nutrient supply. Conclusion: This mode of female development may increase resilience to environmental perturbations in utero and contribute to sex-bias in programming outcomes including susceptibility to non-communicable diseases.

FTY720 on the way from the base camp to the summit of the mountain: relevance for remyelination.

FTY720 (fingolimod; Gilenya®), a sphingosine 1-phosphate (S1P) receptor modulator, is the first oral disease-modifying therapy to be approved for the treatment of relapsing-remitting multiple sclerosis. FTY720 is rapidly converted in vivo to the active S-fingolimod-phosphate, which binds to S1P receptors. This action inhibits egress of lymphocytes from the lymph nodes, preventing entry into the blood and thus infiltration into the central nervous system. More recent studies, however, convincingly show that FTY720 crosses the blood-brain barrier, where it is thought to act on S1P receptors on cells within the central nervous system, such as astrocytes, oligodendrocytes or microglia. Here we discuss the evidence showing that FTY720 also plays a role in remyelination and repair within the brain. While the mechanisms of action still require firm elucidation, it is clear that FTY720 could also be reparative, extending its therapeutic potential for multiple sclerosis.

Marjoram extract prevents ischemia reperfusion-induced myocardial damage and exerts anti-contractile effects in aorta segments of male wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Marjoram (Origanum majorana L.) is an herb traditionally used as a medicine in different countries, as Morocco and Iran, because of its beneficial cardiovascular effects. Some studies suggest that these effects are due, at least in part, to the presence of phenolic compounds such as rosmarinic acid (RA) and luteolin. AIM OF THE STUDY: To analyze the possible cardiprotective effects of a marjoram extract (ME) reducing myocardial damage after coronary ischemia-reperfusion (IR) and its possible antihypertensive effects reducing the response of aorta segments to the vasoconstrictors noradrenaline (NA) and endothelin-1 (ET-1). MATERIALS AND METHODS: Male Wistar rats (300g) were used. After sacrifice, the heart was immediately removed and mounted in a perfusion system (Langendorff). The aorta was carefully dissected and cut in 2 mm segments to perform vascular reactivity experiments. RESULTS: In the heart, ME perfusion after IR reduced heart rate and prevented IR-induced decrease of cardiac contractility, possibly through vasodilation of coronary arteries and through the upregulation of antioxidant markers in the myocardium that led to reduced apoptosis of cardiomyocytes. In the aorta, ME decreased the vasoconstrictor response to NA and ET-1 and exerted a potent anti-inflammatory and antioxidant effect. Neither RA nor 6-hydroxi-luteolin-O-glucoside, major compounds of this ME, were effective in improving cardiac contractility after IR or attenuating vasoconstriction to NA and ET-1 in aorta segments. CONCLUSION: In conclusion, ME reduces the myocardial damage induced by IR and the contractile response to vasoconstrictors in the aorta. Thus, it may be useful for the treatment of cardiovascular diseases such as myocardial infarction and hypertension.

ICP27 protein of Marek's disease virus interacts with SR proteins and inhibits the splicing of cellular telomerase chTERT and viral vIL8 transcripts.

All herpesviruses have a post-transcriptional regulatory protein that prevents precursor mRNA splicing and leads to the shutting off of host protein synthesis. The ICP27 protein of herpes simplex virus 1 (HSV-1) is the prototype of these proteins. Marek's disease virus (MDV-1), an alphaherpesvirus that induces lymphoma in birds, also has an ICP27 protein that is produced in lytic MDV-1-infected cells. We characterized this protein. We demonstrated ICP27 production in latently infected MSB-1 cells, but only on MDV-1 reactivation. ICP27 was found predominantly in specific structures within the nucleus. The ICP27 of MDV-1 colocalized and interacted with SR proteins. We demonstrated inhibitory effects of MDV-1 ICP27 on the splicing of both the viral vIL8 and cellular chTERT (telomerase reverse transcriptase) genes. Thus, the ICP27 of MDV-1 plays a similar role to the ICP27 of HSV-1 and may be involved in MDV-1 replication and the development of Marek's disease.