Reversed-phase liquid chromatographic mass spectrometry (rpLC-MS) is a universal, platformed, and essential analytical technique within pharmaceutical and biopharmaceutical research. Typical rpLC ...method gradient times can range from 5 to 20 min. As monoclonal antibody (mAb) therapies continue to evolve and bispecific antibodies (BsAbs) become more established, research stage engineering panels will clearly evolve in size. Therefore, high-throughput (HT) MS and automated deconvolution methods are key for success. Additionally, newer therapeutics such as bispecific T-cell engagers and nucleic acid-based modalities will also require MS characterization. Herein, we present a modality and target agnostic HT solid-phase extraction (SPE) MS method that affords the analysis of a 96-well plate in 41.4 min, compared to the traditional rpLC-MS method that would typically take 14.4 h. The described method can accurately determine the molecular weights for monodispersed and highly polydispersed biotherapeutic species and membrane proteins; determine levels of glycosylation, glycation, and formylation; detect levels of chain mispairing; and determine accurate drug-to-antibody ratio values.
Purpose The corpus callosum (CC), with its central position in the cerebrum, has an essential role in relaying sensory, motor, and cognitive information from homologous brain regions across cerebral ...hemispheres. Corpus callosum agenesis (CCA) is a rare congenital malformation which is caused by an alteration in embryonic development.
Methods We report the case of a 3 year old child who was diagnosed of complete corpus callosum agenesis with a normal karyotype. The neurological findings were spastic tetraparesis with dystonia, several delayed psychomotor and epilepsy. In ophthalmology examination he presented esotropia, bilateral optic nerve hypoplasia, delayed visual evoked potential flash type and altered corneal sensibility in both eyes which is manifested clinically by recurrent corneal ulcers and epithelial disruption associated with stromal edema.
Results After Neurotrophic keratopathy suspected, treatment with autologous serum was decided and response to treatment was favorable in both eyes with closure of ulcers and good management of symptoms. CCA has also been described in association with other ocular abnormalities such as optic nerve hypoplasia, retinal detachments, cataracts, morning glory syndrome, iris and optic nerve colobomas, among many others.
Conclusion In all patients diagnosed with agenesis of the corpus callosum, the possible alteration of corneal sensitibility is a fact that will be suspected to perform early diagnosis and appropriate treatment and follow‐up.
Galantamine is a drug currently used to treat Alzheimer's disease (AD); in this group of patients it has been observed that concomitant ischemic brain injury can accelerate their cognitive deficit. ...We have previously shown that galantamine can afford neuroprotection on
in vitro and
in vivo models related to brain ischemia. In this context, this study was planned to investigate the intracellular signaling pathways implicated in the protective effect of galantamine on an
in vitro brain ischemia-reperfusion model, namely rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) followed by reoxygenation. Galantamine protected hippocampal slices subjected to OGD in a concentration-dependent manner; at 15 μM, cell death was reduced to almost control levels. The neuroprotective effects of galantamine were reverted by mecamylamine and AG490, but not by atropine, indicating that nicotinic receptors and Jak2 participated in this action. Galantamine also prevented p65 translocation into the nucleus induced by OGD; this effect was also linked to nicotinic receptors and Jak2. Furthermore, galantamine reduced iNOS induction and production of NO caused by OGD via Jak2. ROS production by NADPH oxidase (NOX) activation was also inhibited by galantamine. In conclusion, galantamine afforded neuroprotection under OGD-reoxygenation conditions by activating a signaling pathway that involves nicotinic receptors, Jak2 and the consequent inhibition of NOX and NFκB/iNOS.
This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.
► We describe the protective mechanism of galantamine against “
in vitro” ischemia. ► Galantamine has neuroprotective, antioxidant and anti-inflammatory signal via Jak2. ► Jak2 activation inhibits p65 translocation and iNOS overexpression induced by OGD. ► Galantamine inhibit NADPH oxidase, the main enzyme in the reoxygenation period.
BACKGROUND:The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through ...pharmacological intervention, in particular, because the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection.
METHODS:We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (BmxCreER-driven)–specific or smooth muscle cell (SMC, SmmhcCreER- or TaglnCre-driven)–specific deficiency of CXCR4 in an apolipoprotein E–deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques.
RESULTS:The cell-specific deletion of CXCR4 in arterial endothelial cells (n=12–15) or SMCs (n=13–24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4 deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4 deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259 796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease.
CONCLUSIONS:Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.
Abstract Negative symptoms prevalent in schizophrenia are associated with poor outcome. Developing new instruments to identify new treatments was highlighted at the NIMH-MATRICS Consensus Development ...Conference on Negative Symptoms. The new Brief Negative Symptoms scale (BNSS) demonstrated strong psychometric properties, but there is a need for validating it in non-English languages. A multi-center study was conducted to validate the Spanish version of the BNSS (BNSS-Sp) in 20 schizophrenia patients, following the original BNSS validation methodology. We found strong inter-rater, test–retest and internal consistency properties (for the total BNSS-Sp, intraclass correlation coefficient = 0.97, Pearson's correlation coefficient r = 0.95 (p < 0.001), Cronbach's alpha = 0.98).
The aim of this article was to study the influence of anxiety (both state and trait) in postoperative recovery after extraction of third molar together, to establish the role of each of the aspects ...of anxiety in the results you obtained in an independent and complementary way.
We performed a prospective study of a consecutive series of 88 patients who underwent lower third molar extractions. Before being provided with any information about the operation, patients were asked to complete the Spielberger State-Trait Anxiety Inventory- Trait and State. We have evaluated postoperative swelling and pain, patients completed a 10-point visual analog scale (VAS) at home each day (at approximately the same time of day as the operation) until day 8 after surgery, when the sutures were removed.
Regarding postoperative variables between positive and negative trait anxiety groups, consumption of analgesic drugs was higher in positive trait anxiety group in a statistically significant way, while these differences were detected only on specific occasions regarding pain and swelling.
In the present study, anxiety was taken into account and showed a significant effect in explaining postoperative pain and taking analgesics.
Highlights ► Creatine produced a protective effect against 6-hydroxydopamine-induced cell death. ► The protective effect of creatine involves PI3K/AKT, PKA and PKC. ► ERK1/2 and CaMKII modulation is ...implicated in the protective effect of creatine. ► Creatine reversed the decline in GSK-3β phosphorylation induced by 6-OHDA. ► Creatine could be a potent protective factor for catecholaminergic cell survival.
In recent years, stagnation in the number of kidneys from after brain-dead donors (DBD) has stimulated the use of non–heart beating donors (NHBDs). Herein we present our 5-year experience with type ...II Maastricht NHBDs in renal transplantation.
All patients (n = 50) in this study received type II Maastricht NHBD kidneys (March 2012 to February 2017), with a median follow-up of 33 months.
Mean donor age was 39 ± 12 years, mean creatinine 1.24 ± 0.2 mg/dL, and the most frequently observed blood group (donors and recipients) was type A (64%). Recipients were slightly younger (51 ± 11 years old), with mean time on dialysis of 30 ± 24 months. Almost all were primary transplants. Pre-transplant panel-reactive antibodies (PRA) were <25%; initial immunosuppression was thymoglobulin, corticosteroids, mycophenolate mofetil, and delayed introduction of tacrolimus. Six percent were nonfunctioning kidneys; 79.6% presented with delayed renal function (mean duration 14 ± 9 days). Acute rejection was seen in 6% of patients. Mean creatinine at month 3 was 1.7 ± 0.8 mg/dL, and 1.5 ± 0.8 mg/dL in the first year. The last available mean creatinine was 1.54 ± 0.7 mg/dL. Proteinuria in the third month, first year, and third year was 0.70, 0.41, and 0.26 g/d, respectively. Recipient survival at the first, third, and fifth year was 100%, 100%, and 86%, and when graft-censored for death was 94%, 91%, and 91%, respectively. The incidence of acute rejection during first year was 6%, and 2% in the second year. Exitus incidence was 4% and cytomegalovirus infection was 21.3%. BK viremia between 1000 and 10,000 copies/mL was seen in 4.3%, and reached >10,000 copies/mL in 2.1%.
Type II NHBD has shown limited frequency of nonfunctioning kidney and high functional delay. The results in survival and renal function are very acceptable, comparable with levels seen in donation after brain death.
Summary
Apical periodontitis (AP) is an inflammatory lesion around the apex of a tooth caused by bacterial infection of the pulp canal system. AP appears radiographically as a radiolucent periapical ...lesion (RPL). The elective treatment for teeth with AP is root canal treatment (RCT). No study is available about the frequency of RPL and RCT in patients with inherited coagulation disorders (ICD). The aim of this study was to investigate the prevalence of RPL and RCT in patients with ICD and control subjects. In a cross‐sectional study, the radiographic records of 58 patients with haemophilia A, haemophilia B or von Willebrand's disease (study group) and 58 control subjects were examined. The frequency of RPL and RCT was assessed using digital panoramic radiographs and the Periapical Index. RPL in one or more teeth was found in 67.2% of patients with ICD and in 48.3% of control subjects (odds ratio = 2.20; P = 0.038). At least one RCT was found in 34.5% and 65.5% of subjects in the study and control groups respectively (odds ratio = 0.28; P = 0.001). Multivariate logistic regression analysis indicated that subjects with ICD had RPL with higher likelihood than control subjects (odds ratio = 7.4; P = 0.0005). Patients with ICD disorders showed a significantly higher prevalence of RPL and lower frequency of RCT than control patients.
IntroductionAdvancements in and accessibility to effective antiretroviral therapy has improved the life expectancy of people living with HIV, increasing the proportion of people living with HIV ...reaching older age (≥60 years), making this population's health‐related quality of life (HRQoL) more relevant. Our aim was to identify the determinants of poor HRQoL in people living with HIV aged ≥60 years and compare them with those of their younger counterparts.MethodsWe used data from the ‘Vive+’ study, a cross‐sectional survey conducted between October 2019 and March 2020, nested within the PISCIS cohort of people living with HIV in Catalonia and the Balearic Islands, Spain. We used the 12‐item short‐form survey (SF‐12), divided into a physical component summary (PCS) and a mental component summary (MCS), to evaluate HRQoL. We used the least absolute shrinkage and selection operator for variable selection and used multivariable regression models to identify predictors.ResultsOf the 1060 people living with HIV (78.6% males) who participated in the study, 209 (19.7%) were aged ≥60 years. When comparing older people living with HIV (≥60 years) and their younger counterparts, older people exhibited a worse PCS (median 51.3 interquartile range {IQR} 46.0–58.1 vs. 46.43 IQR 42.5–52.7, p < 0.001) but a similar MCS (median 56.0 IQR 49.34–64.7 vs. 57.0 IQR 48.9–66.3, p = 0.476). In the multivariable analysis, cognitive function correlated with a PCS (β correlation factor β −0.18, p = 0.014), and depressive symptoms and satisfaction with social role correlated with an MCS (β 0.61 and β −0.97, respectively, p < 0.001) in people living with HIV aged ≥60 years.ConclusionDepressive symptoms, poor cognitive function, and lower satisfaction with social roles predict poorer HRQoL in older people living with HIV. These factors need to be considered when designing targeted interventions.
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