Human cytomegalovirus DNA detection in a recurrent glioblastoma multiforme tumour,but not in whole blood: a case report and discussion about the HCMV latency and therapy perspectives

Journal of NeuroVirology - In the current study, a 58-year-old male patient presented with recurrent glioblastoma multiforme (GBM). The patient underwent surgical resection, 4 months...     

The alpha2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition.

OBJECTIVE: To test the acute effects of the alpha2-adrenoceptor agonist guanfacine (GFC) on motor excitability in intact humans. METHODS: Eight healthy right-handed adults received a single oral dose of 2 mg of GFC. Motor cortex excitability was tested by focal transcranial magnetic stimulation of the hand area of the left motor cortex. Motor evoked potentials (MEP) were recorded from the right abductor pollicis brevis muscle. In addition, spinal and neuromuscular excitability were tested. All measures were obtained immediately before GFC intake (baseline), and 2, 6, and 24 h later. RESULTS: GFC decreased the slope of the MEP intensity curve, increased paired-pulse short-interval intracortical inhibition, and decreased paired-pulse intracortical facilitation and I-wave facilitation. These effects were maximal at 2-6 h and returned to baseline at 24 h. Motor threshold, cortical silent period, and the measures of spinal (peripheral silent period, F waves) and neuromuscular excitability (maximum M wave) remained unaffected. CONCLUSIONS: This is the first study on the effects of an anti-noradrenergic drug on human motor cortex excitability. GFC reduced cortical excitability by disfacilitation and increased inhibition. These findings support the idea that anti-noradrenergic drugs are detrimental for cortical plasticity and learning which are down-regulated by disfacilitation or increased inhibition.     

Complex modulation of human motor cortex excitability by the specific serotonin re-uptake inhibitor sertraline

Monoamines are powerful modulators of cortical function. Serotonin has complex excitatory and inhibitory effects on animal cortex. Here, the effects of a single oral dose (100mg) of the selective serotonin re-uptake inhibitor sertraline on human motor cortex excitability were investigated in healthy subjects. Transcranial magnetic stimulation was used to test motor threshold, motor evoked potential intensity curve, cortical silent period, paired-pulse inhibition and facilitation and I-wave facilitation. Sertraline resulted in a steeper intensity curve and in depressed paired-pulse facilitation (PPF). All other measures and spinal and neuromuscular excitability remained unaffected. The steeper intensity curve points to an increased excitability of the cortico-spinal neurone, while the depressed PPF suggests an enhanced control of the cortico-spinal neurone by inhibitory interneurones. These features may improve the signal-to-noise ratio of output cells in human motor cortex.     

Peanut-induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background

Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents.

Methods

Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre.

Results

3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004).

Conclusions

The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.

     

Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene

Von Hippel-Lindau syndrome is an autosomal-dominant disease characterized by the formation of various tumours and cysts in many different parts of the body. Von Hippel-Lindau syndrome is caused by VHL gene mutations leading to production of impaired tumor suppressor Von Hippel-Lindau syndrome protein or its complete absence. Purpose: To study five patients with clinically suspected Von Hippel-Lindau syndrome, who were referred for molecular genetic testing. Methods: Sanger sequencing of the coding regions of the VHL gene. Results: Five clinically relevant germline mutations were detected. One of the pathogenic variants has not been previously reported. This novel mutation is a complex mutation event combining a duplication and an indel, rearranging exon 3 of the VHL gene - c. [516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA], p. (Glu173Serfs*4). Conclusion: Overall, our results showed that the diagnosis of Von Hippel-Lindau syndrome in our country is difficult most probably because of its heterogeneous clinical manifestation and insufficient knowledge on the diagnostic criteria for the disease. From genetic point of view our results add some novel data on the mutation profile of the VHL gene. In order to prove or revise the diagnosis, early genetic testing is strongly recommended in affected patients and their family members to ensure appropriate follow-up and treatment of the malignancies.     

高强度聚焦超声治疗不能手术胰腺癌的1年生存分析：中国和保加利亚的多中心临床研究

目的:通过多中心临床研究分析高强度聚焦超声治疗不能手术胰腺癌的1年生存情况。方法:2013年1月到2014年1月,中国和保加利亚的不能手术的胰腺癌患者32例,男/女=20/12,年龄41~81(59.8±9.1)岁。胰腺癌病灶最大径20~60(39.3±9.6)mm,远处转移/无转移的患者18/14例。接受HIFU和/或化疗。记录术后并发症,疼痛变化和生存情况。使用Kaplan-Meier法计算总生存率和中位生存时间,比较化疗与否、是否发生远处转移的患者生存率有无差异(Log-Rank检验)。结果:术后1月,皮肤浅Ⅱ°烧伤者2例,经保守处理后1~2周愈合。伴有胰腺癌相关性疼痛症状的患者30例与术前比较,减轻的24例(80.0%),不变的5例(16.7%),加重的1例(3.3%)。所有患者的1年生存率为38.4%,中位生存时间为12个月。接受辅助化疗的患者1年生存率为57.4%,中位生存时间12月;未接受辅助化疗的患者1年生存率为20.8%,中位生存时间为6月;二者间比较有显著性差异。伴有远处转移的患者1年生存率为0%,中位生存时间为7月;无远处转移的患者1年生存率为49.2%,中位生存时间为12月;二者间比较无统计学差异。结论:中国和保加利亚的不能手术胰腺癌患者均能安全完成HIFU治疗,1年生存率和中位生存时间优于其它非手术治疗手段。辅助化疗能增加生存受益,远处转移是预后不良因素。     

Met-enkephalin modulates lipid peroxidation and total sialic acid level in CBA mice in age- and sex-dependent manners

Age- and sex-associated differences in lipid peroxidation (LPO), and total sialic acid content (TSA) in response to abuse of drugs have been reported both in humans and experimental animals. However, no data on the influence of gender and age on these parameters have been reported for methionine-enkephalin (MENK). In this study we examined the influence of age and gender on MENK-induced LPO levels in the liver and TSA content in splenocytes of CBA mice. LPO production, which was age- and gender-associated was differentially regulated by MENK at a dose of 10 mg or 2.5 mg/kg body weight. At the higher dose, MENK stimulated LPO production in younger males and females but suppressed only in older male mice. At the lower dose, MENK induced strong suppression in males while being without any effect in females. In TSA levels, the age-associated increase was greater in males and much lower in females, with higher TSA levels in younger (2.5, 4.5 months) and decreased levels in older female mice (9 months) being observed. Contrary to the effect on LPO level, TSA level in MENK-treated mice was suppressed in both sexes but only in young 2.5-month-old mice. These data provide evidence that some immunomodulatory properties of MENK are age- and gender-associated which may be relevant to the potential use of MENK as adjuvant therapy in patients with immunocompromised status.     

Precise nail tip positioning after tibial intramedullary nailing prevents anterior knee pain

Purpose

Anterior knee pain (AKP) is a common complication following intramedullary nailing of tibial shaft fractures. Our aim was, by analysing the postoperative lateral knee X-rays and clinical status (VAS score), to find the best intramedullary tip position of a non protruded nail that will provide the best postoperative outcome avoiding AKP.

Methods

We evaluated the postoperative outcome of 221 patients, from the last four years, with healed fractures initially treated with intramedullary reamed nails with two or three interlocking screws proximally and distally through a medial paratendinous incision for nail entry portal. Our aim was to analyse a possible relationship between AKP according to the VAS scale, and nail position marked as a distance from tip of nail to tibial plateau (NP) and to tibial tuberosity (NT), measured postoperatively on lateral knee X-rays.

Results

Two groups of patients were formed on the basis of presence of pain related to AKP (the level of pain was neglected): group A were patients with pain and group B without pain. The difference between the two groups concerning NP and NT measurements appeared to be statistically significant concerning NT measurement (p < 0.05), with high accuracy according to the classification tree.

Conclusions

We presume that the position of the proximal tip of the nail and its negative influence on the innervation pattern of the area dorsal to patellar tendon could be the key factor of AKP. We conclude that the symptoms of AKP will not appear if the tip of the nail position is more than 5.5 mm from the tibial plateau (NP) and more than 2.5 mm from the tibial tuberosity (NT).     

Design,synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as Escherichia coli DNA gyrase inhibitors

Discovery of novel DNA gyrase B inhibitors remains an attractive field in the search for new antibacterial drugs to overcome the known bacterial resistance mechanisms. In the present study, we designed and synthesized novel ethylurea derivatives of 4,5,6,7‐tetrahydrobenzo[1,2‐d]thiazole‐2,6‐diamine, 2‐(2‐aminothiazol‐4‐yl)acetic acid, and benzo[1,2‐d]thiazole‐2,6‐diamine and evaluated their Escherichia coli DNA gyrase inhibition. The most potent DNA gyrase inhibitors in the prepared library of compounds were benzo[1,2‐d]thiazoles 32–34 , 36 , and 37 with IC₅₀ values in the low micromolar range. The most promising inhibitors identified were evaluated against selected Gram‐positive and Gram‐negative bacterial strains. Compound 33 showed a MIC of 50 μM against an E. coli efflux pump‐defective strain, which suggests that efflux decreases the on‐target concentrations of these compounds.     

Imaging reveals the focal area of spreading depolarizations and a variety of hemodynamic responses in a rat microembolic stroke model

Spreading depolarizations (SDs) occur in stroke, but the spatial association between SDs and the corresponding hemodynamic changes is incompletely understood. We applied multimodal imaging to visualize the focal area of selected SDs, and hemodynamic responses with SDs propagating over the ischemic cortex. The intracarotid infusion of polyethylene microspheres (d=45 to 53 μm) produced multifocal ischemia in anesthetized rats (n=7). Synchronous image sequences captured through a cranial window above the frontoparietal cortex revealed: Changes in membrane potential (voltage-sensitive (VS) dye method); cerebral blood flow (CBF; laser speckle contrast (LSC) imaging); and hemoglobin (Hb) deoxygenation (red intrinsic optical signal (IOS) at 620 to 640 nm). A total of 31 SD events were identified. The foci of five SDs were seen in the cranial window, originating where CBF was the lowest (56.9±9%), but without evident signs of infarcts. The hyperemic CBF responses to propagating SDs were coupled with three types of Hb saturation kinetics. More accentuated Hb desaturation was related to a larger decrease in CBF shortly after ischemia induction. Microsphere-induced embolization triggers SDs in the rat brain, relevant for small embolic infarcts in patients. The SD occurrence during the early phase of ischemia is not tightly associated with immediate infarct evolution. Various kinetics of Hb saturation may determine the metabolic consequences of individual SDs.