Analysis of gene expression in MOG-induced experimental autoimmune encephalomyelitis after treatment with a novel brain-penetrating antioxidant

Accumulating data from experimental studies indicate that oxidative stress has a major role in the pathogenesis of multiple sclerosis (MS). It has been suggested that local production of reactive oxygen species, probably by macrophages, mediates axonal damage in both MS patients and the mouse model experimental autoimmune encephalomyelitis (EAE). We have shown previously that our novel brain-penetrating antioxidant, N-acetylcysteine amide (AD4), reduces the clinical and pathological symptoms, including inflammation and axonal damage in myelin oligodendrocyte glycoprotein (MOG)-induced chronic EAE in mice. The aim of this study was to examine the molecular mechanism by which AD4 exerts protection in MOG-induced EAE mice. Therefore, we analyzed gene-expression profile in the spinal cords of MOG-induced chronic EAE mice and compared them with MOG-induced mice treated with AD4, using a cDNA microarray. We found that MOG treatment up-regulated genes encoding growth factors, cytokines, death receptors, proteases, and myelin structure proteins, whereas MOG- and AD4-treated mice demonstrated gene expression profiles similar to that seen in na?ve healthy mice. In conclusion, our study shows that chronic AD4 administration suppresses the induction of various pathological pathways that play a role in EAE and probably in MS.     

抑酸药对马来酸多潘立酮在健康人体相对生物利用度的影响

目的观察抑酸药(法莫替丁、鼠李铋镁)对马来酸多潘立酮(健胃药)在健康人体药代动力学的影响。方法10名健康受试者未服和服用抑酸药后,单剂量口服马来酸多潘立酮10mg,用LC/MS/MS测定血药浓度,用Win-NonLin5.0软件计算药代动力学参数,并用Spss12.0软件比较主要药代动力学参数。结果未服和服用抑酸药后,单剂量口服马来酸多潘立酮,其药代动力学参数如下:tmax分别为(0.85±0.24)、(2.20±1.78)h,Cmax分别为(9.68±5.37)、(7.18±4.12)μg.L-1,AUC0～tn分别为(38.18±19.76)、(49.96±10.35)μg.h.L-1。显示服用抑酸药后,马来酸多潘立酮的tmax延长,有显著性差异(P=0.04);AUC0-tn增加,峰浓度降低,但无显著性差异(分别为P=0.1、0.06)。结论在健康人体内,法莫替丁、鼠李铋镁不影响马来酸多潘立酮的吸收程度;但使其吸收速度减慢。     

Fate and distribution of brevetoxin (PbTx) following lysis of Karenia brevis by algicidal bacteria, including analysis of open A-ring derivatives

Flavobacteriaceae (strain S03) and Cytophaga sp. (strain 41-DBG2) are algicidal bacteria active against the brevetoxin (PbTx)-producing, red tide dinoflagellate, Karenia brevis. Little is known about the fate of PbTx associated with K. brevis cells following attack by such bacteria. The fate and distribution of PbTx in K. brevis cultures exposed to these algicidal strains were thus examined by receptor binding assay and liquid chromatography/mass spectrometry (LC/MS) in three size fractions (>5, 0.22–5, <0.22 μm) over a 2-week time course. In control cultures, brevetoxin concentrations in the >5 μm particulate size fraction correlated with changes in cell density, whereas significant increases in dissolved (i.e., <0.22 μm) toxin were observed in the later stages of culture growth. Exposure of K. brevis to either of the two algicidal bacteria tested caused cell lysis, coinciding with a rapid decline in the >5 μm PbTX size fraction and a simultaneous release of dissolved toxin into the growth medium. Upon cell lysis, dissolved brevetoxin accounted for ca. 60% of total toxin and consisted of 51–82% open A-ring derivatives. Open A-ring PbTx-2 and PbTx-3 derivatives bound with lower affinity (approximately 22- and 57-fold, respectively) to voltage-gated sodium channels and were considerably less cytotoxic (86- and 142-fold, respectively) to N2A cells than their individual parent toxins (i.e., PbTx-2 and PbTx-3). These novel findings of changes in PbTx size-fractioned distribution and overall reduction in K. brevis toxicity following attack by algicidal bacteria improve our understanding of potential trophic transfer routes and the fate of PbTx during red tide events. Moreover, this information will be important to consider when evaluating the potential role of algicidal bacteria in harmful algal bloom (HAB) management strategies involving control of bloom populations.     

HPLC-MS/MS测定血浆中的牡荆素及其大鼠体内药动学研究

目的:建立高效液相色谱-质谱/质谱联用法(HPLC-MS/MS)测定血浆中牡荆素的方法,并用于大鼠药动学研究。方法:采用Capcell Pak C18柱(50 mm×2.0 mm,I.D.,5μm),柱温25℃,流动相为甲醇∶水(95∶5,0.1%甲酸),流速为0.2 mL/min。用负离子电喷雾电离源,多反应方式检测,选择监测的离子反应为m/z 431～311(牡荆素)和m/z 269～225(大黄素,内标)。结果:牡荆素在0.5～2 000 ng/mL线性关系良好,相关系数为0.9960,最低定量限为0.5 ng/mL。加样回收率76.1%～89.0%,日内日间精密度RSD均小于11%。结论:该方法分析速度快、操作简单、灵敏度高,可用于大鼠血浆中牡荆素的浓度测定及药动学研究。     

Multiple brain networks support processing speed abilities of patients with multiple sclerosis

Objectives: Many people affected by multiple sclerosis (MS) experience cognitive impairment, especially decreases in information processing speed (PS). Neural disconnection is thought to represent the neural marker of this symptom, although the role played by alterations of specific functional brain networks still remains unclear. The aim is to investigate and compare patterns of association between PS-demanding cognitive performance and functional connectivity across two MS phenotypes.

Methods: Forty patients with relapsing-remitting MS (RRMS) and 25 with secondary progressive MS (SPMS) had neuropsychological and MRI assessments. Multiple regression models were used to investigate the relationship between performance on tests of visuomotor and verbal PS, and on the verbal fluency tests, and functional connectivity of four cognitive networks, i.e. left and right frontoparietal, salience and default-mode, and two control networks, i.e. visual and sensorimotor.

Results: Patients with SPMS were older and had longer disease history than patients with RRMS and presented with worse overall clinical conditions: higher disease severity, total lesion volume, and cognitive impairment rates. However, in both patient samples, cognitive performance across tests was negatively correlated with functional connectivity of the salience and default-mode networks, and positively with connectivity of the left frontoparietal network. Only the visuomotor PS scores of the RRMS group were also associated with connectivity of the sensorimotor network.

Conclusions: PS-demanding cognitive performance in patients with MS appears mainly associated with strength of functional connectivity of frontal networks involved in the evaluation and manipulation of information, as well as the default mode network. These results are in line with the hypothesis that multiple neural networks are needed to support normal cognitive performance across MS phenotypes. However, different PS measures showed partially different patterns of association with functional connectivity. Therefore, further investigations are needed to clarify the contribution of inter-network communication to specific cognitive deficits due to MS.     

Intentional ingestion of cyanoacrylate

Abstract

Background. Diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) are substances with dissociative effects that were recently introduced for “recreational” purpose through the online-based sale of new psychoactive substances (NPS). A number of analytically confirmed non-fatal intoxications associated with diphenidine or MXP have occurred in Sweden and were included in the STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS and requiring intensive treatment in an emergency room and hospitalization in Sweden. Patients and methods. Blood and urine samples were collected from intoxicated patients presenting at emergency departments all over the country. NPS analysis was performed by multi-component liquid chromatography–mass spectrometry methods. Data on clinical features were collected during telephone consultations with the Poisons Information Centre and retrieved from medical records. Information was also obtained from online drug discussion forums. Case series. Over a 12-month period from January to December 2014, 750 cases of suspected NPS intoxication originating from emergency departments were enrolled in the STRIDA project of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) tested positive for MXP. Co-exposure to several other NPS (e.g., 5-/6-(2-aminopropyl)benzofuran, 2-4-bromomethcathinone, butylone, 3,4-dichloromethylphenidate, 5-methoxy-N-isopropyltryptamine, methiopropamine, and α-pyrrolidinopentiothiophenone), also including other dissociative substances (3-/4-methoxyphencyclidine), and classical drugs of abuse (e.g., cannabis and ethanol) was documented in 87% of these cases. The 17 patients were aged 20–48 (median: 32) years, and 13 (76%) were men. They commonly presented with hypertension (76%), tachycardia (47%), anxiety (65%), and altered mental status (65%) including confusion, disorientation, dissociation, and/or hallucinations. Eight patients (47%) displayed severe intoxication (Poisoning Severity Score 3). The diphenidine- or MXP-positive patients required hospitalization for 1–3 (median: 2) days. In addition to standard supportive therapy, half of the cases were treated with benzodiazepines and/or propofol. Conclusion. The adverse effects noted in analytically confirmed cases of NPS intoxication involving diphenidine or MXP were similar to those reported for other dissociative substances such as ketamine and methoxetamine. However, the high proportion of polysubstance use might have played a role in the intoxication and clinical features in some cases.     

Proton magnetic resonance spectroscopy of normal appearing white matter in asymptomatic relatives of multiple sclerosis patients

Proton magnetic resonance spectroscopy of normal appearing white matter (NAWM) was performed in 25 first-degree relatives of patients with multiple sclerosis (MS). In relatives of MS patients, insignificant trends in the NAA/Cho ratio (to be lower) and in the Cho/Cr ratio (to be higher) were found when compared with healthy controls. These results demonstrated that there are only minimal, insignificant changes in commonly identified metabolite concentrations in NAWM of relatives of MS patients when compared with healthy subjects.     

Hemodynamic effects of an oral dopamine receptor agonist (fenoldopam) in patients with congestive heart failure

Dopamine receptor stimulation causes vascular and neurohumoral responses that may be beneficial in patients with heart failure. Oral inactivity, emesis and adrenergic-induced arrhythmias have limited the use of currently available compounds. Fenoldopam (SKF-82526-J) is a new, orally available, selective, dopamine-receptor agonist with potent renal vasodilating properties (six times that of dopamine) without positive inotropic or adrenergic activity. Drug efficacy was clinically evaluated in 10 patients with heart failure after single oral doses of placebo and 50, 100 and 200 mg of medication. Placebo produced no changes. Peak efficacy was noted 30 minutes to 1 hour after the 200 mg dose with mean blood pressure decreasing from 96 +/- 15 (mean +/- SD) to 83 +/- 8 mm Hg (p less than 0.05), pulmonary capillary wedge pressure decreasing from 23 +/- 6 to 20 +/- 8 mm Hg (p less than 0.05) and mean pulmonary artery pressure decreasing from 32 +/- 9 to 29 +/- 8 mm Hg (p less than 0.05). Systemic vascular resistance decreased from 1,987 +/- 887 to 1,191 +/- 559 dynes.s.cm-5 (p less than 0.05) with a subsequent 55% increase in cardiac index from 2.2 +/- 1.1 to 3.1 +/- 1.3 liters/min per m2 (p less than 0.05). Heart rate and right atrial pressure did not change (p greater than 0.05). No emesis or new tachycardia was noted at any dose. Baseline hemodynamics generally returned within 3 to 4 hours. Fenoldopam, therefore, is a short-acting, orally effective drug that decreases systemic vascular resistance and increases cardiac index in patients with heart failure and represents a new class of oral compounds that may be useful in treating such patients.     

Proteome analysis of round-headed and normal spermatozoa by 2-D fluorescence difference gel electrophoresis and mass spectrometry

Globozoospermia is a severe form of teratozoospermia characterized by round-headed spermatozoa with an absent acrosome, an aberrant nuclear membrane and midpiece defects. Globozoospermia is diagnosed by the presence of 100% round-headed spermatozoa on semen analysis, and patients with this condition are absolutely infertile. The objective of this study was to investigate the differences in protein expression between human round- headed and normal spermatozoa. Two-dimensional （2-D） fluorescence difference gel electrophoresis （DIGE） coupled with mass spectrometry （MS） was used in this study. Over 61 protein spots were analysed in each paired normal/round-headed comparison, using DIGE technology along with an internal standard. In total, 35 protein spots identified by tandem mass spectrometry （MS/MS） exhibited significant changes （paired t-test, P 〈 0.05） in the expression level between normal and round-headed spermatozoa. A total of nine proteins were found to be upregulated and 26 proteins were found to be downregulated in round-headed spermatozoa compared with normal spermatozoa. The differentially expressed proteins that we identified may have important roles in a variety of cellular processes and structures, including spermatogenesis, cell skeleton, metabolism and spermatozoa motility.     

中医治疗代谢综合征的循证思维方法

现代研究证明,胰岛素抵抗在代谢综合征的病因机制中处于中心地位。作者试图探讨中医在治疗代谢综合征中的循证思维方法。