电刺激构建大鼠皮层网络癫痫的海马细胞电生理特征

本文旨在探讨急性强直电刺激右后背海马（hippocampus，HPC）诱导出现双侧皮层网络癫痫的前背HPC神经元电生理机制。实验共用雄性SD大鼠35只，急性强直电刺激（60Hz，2s，0．4-0．6mA）大鼠右侧后背HPC（a—cute tetanization of the right posterior dorsal hippocampus，ATPDH）诱发癫痫模型。四通道同步记录双侧皮层电图（electrocorticogram，ECoG）或前背HPC深部电图和双侧前背HPC单位放电。结果显示，ATPDH可以引起以下效应：（1）双侧皮层癫痫样电活动起源于同侧HPC单位后放电，继而引起对侧HPC单位后放电，最终形成对侧和同侧皮层电图癫痫发作样电振荡；（2）增强双侧皮层4—10Hz节律性电振荡或诱发双侧HPCI00—250Hz电振荡，与此同时双侧HPC神经元均表现为非对称性电活动；（3）双侧HPC神经元锋电位间期（interspike interval，ISI）点呈现非规则性环状分布。同侧HPC爆发式单位放电IsI点分布的环状分层较规则、发生率较高，并与同侧HPC电振荡最大振幅的正弦式波动形成明显的时间对应关系。结果表明：ATPDH可诱导双侧皮层和HPC电图形成癫痫电网络。当皮层或HPC癫痫网络重建过程中，HPC神经元放电具有特征性ISI点环状分布等编码形式。     

6-羟多巴胺毁损的帕金森病模型大鼠脚桥核神经元放电频率和放电形式的变化

目的　观察6- 羟多巴胺毁损的帕金森病(Parkinson’sdisease, PD)模型大鼠脚桥核(pedunculopontinenu cleus, PPN)神经元放电频率和放电形式的变化。方法　采用在体玻璃微电极细胞外记录法,记录正常对照组和PD模型组大鼠PPN神经元的电活动。结果　对照组和PD组大鼠PPN神经元的放电频率分别为(9. 0±0. 8)Hz[ (0. 5 25. 2)Hz, n=56]和(16. 1±1. 6)Hz[ (1. 2 49. 7)Hz, n=57],PD组大鼠的放电频率显著高于对照组(P<0. 001)。在对照组大鼠脚桥核, 68% (38 /56)的神经元呈现规则放电, 27% (15 /56)呈现不规则放电, 5% (3 /56)为爆发式放电;在PD组大鼠脚桥核,具有规则、不规则和爆发式放电的神经元比例分别为39% (22 /57)、47%(27 /57)和14% (8 /57),PD组大鼠具有不规则放电的神经元比例明显高于对照组(P<0. 05)。结论　PD大鼠PPN中神经元的放电频率增高和不规则放电增多, 这可能在帕金森病的病理生理变化中具有重要作用。     

胆碱能M2受体激动剂及拮抗剂对大鼠脚桥核神经元电活动的影响

目的　在体水平上观察选择性胆碱能M2 受体激动剂oxotremorine和拮抗剂methoctramine对大鼠PPN神经元自发放电频率的影响。方法　 采用玻璃微电极细胞外记录和脚桥核 (pedunculopontinenucleus ,PPN)内微量注射法。 结果　11个神经元在PPN内微量注射高浓度 (每 2 0 0nl含 4 μg)oxotremorine后 ,10个神经元被兴奋 ,放电频率较注射前升高 (2 82± 5 9) % ,1个神经元放电频率无明显变化 ;低浓度 (每 2 0 0nl含 0 .2 μg)oxotremorine注射后 ,11个神经元中 ,有 6个神经元被抑制 ,放电频率较注射前降低 (98± 2 ) % ,5个神经元被兴奋 ,放电频率较前对照升高(6 80± 32 4 ) %。 12个神经元在PPN内微量注射高浓度 (每 2 0 0nl含 4 μg)methoctramine后 ,4个神经元被兴奋 ,放电频率较前对照升高 (4 0 9± 133) % ,6个神经元被抑制 ,放电频率较注射前降低 (86± 8) % ,2个放电频率无显著变化 ;低浓度 (每 2 0 0nl含 0 .4 μg)methoctramine注射后 ,12个神经元中 ,有 5个神经元被兴奋 ,放电频率较前对照升高 (117± 15 ) % ,6个神经元被抑制 ,放电频率较注射前降低 (79± 11) % ,1个放电频率未受明显影响。 结论　 胆碱能M2 受体通过直接和间接作用对PPN神经元的电活动进行调节     

Kir 2.3过表达抑制原代海马神经元样放电

目的探究内向整流钾(Kir) 2. 3通道过表达对环噻唑诱导的原代海马神经元样放电的影响。方法分离培养大鼠原代海马神经元,分别使用GFP质粒或Kir 2. 3-GFP质粒转染神经元。通过免疫荧光染色和电压钳技术检测转染效果。使用环噻唑诱导神经元样放电,电流钳记录膜电位钳制在-70 m V条件下的自发放电,膜片钳记录各组神经元的膜电位。结果转染Kir 2. 3-GFP质粒的神经元Kir 2. 3表达水平显著增高(P 0. 05)。环噻唑能够诱导未转染神经元(n=12)及GFP质粒转染神经元(n=6)出现样爆发放电,但是未能诱导Kir 2. 3-GFP质粒转染神经元(n=5)出现样爆发放电。Kir 2. 3-GFP质粒转染组出现样爆发放电神经元的比例显著低于未转染组(P 0. 01)及GFP质粒转染组(P 0. 05)。此外,Kir 2. 3-GFP质粒转染组(n=10)神经元膜电位较未转染组(n=6)及GFP质粒转染组(n=8)显著增高。结论 Kir 2. 3过表达能显著抑制环噻唑诱导的原代海马神经元样放电,其作用机制可能与静息膜电位增高相关。     

帕金森病大鼠苍白球神经元簇发放电及峰峰间期序列的研究

目的 观察帕金森病大鼠模型苍白球神经元的电活动.方法 30只大鼠注射6-羟基多巴胺(6-hydroxydopamine, 6-OHDA)建立PD模型,并通过跑步机测试、注射阿朴吗啡诱发旋转和免疫组化检测黑质对模型进行评价;10只大鼠注射含0.2%抗坏血酸的人工脑脊液建立对照组.在立体定向仪引导下记录大鼠在PD病理及正常生理状态下GP神经元的自发放电活动.结果 模型组大鼠中有13只行为学及病理学检测结果符合PD模型标准.电生理记录显示对照组大鼠GP神经元放电频率为(6.04±2.12)Hz,模型组大鼠GP神经元放电频率为(21.10±3.21)Hz(P=0.001).模型组GP神经元簇发放电模式的比例术后4周为59%,术后8周为61%,而对照组GP神经元簇发放电模式的比例在术后4周和8周均为11%.模型组大鼠神经元放电的峰峰间期散点图在100ms以下有一分布密集条带.结论 PD模型大鼠GP神经元较生理状态下放电频率明显增加,簇状放电模式比例增大,ISI序列发生明显变化.     

书写痉挛患者丘脑腹外侧核团细胞电活动特点

目的 探讨书写痉挛(WC)患者丘脑腹外侧核团(VL)细胞电活动特点,为临床治疗提供可靠的依据.方法 10例WC患者在行立体定向VL毁损术的同时,应用微电极和肌电记录技术采集VL细胞和手术对侧肢体肌电活动.分析不同细胞的放电模式和平均自发放电频率(MSFR),并探讨VL细胞放电活动与肢体肌电的关系.结果 在10个针道中共甄别出85个VL神经元,61.2%的神经元呈不规则放电活动,MSFR为(20.3±14.9)Hz,变异系数(CV)为1.38±0.40;38.8%的神经元为紧张性放电活动,MSFR为(44.4±21.5)Hz,CV为0.84±0.11.功率谱相关性分析发现VL细胞放电活动的改变与WC相关(P＜0.05,n=12).结论 VL参与WC的病理生理过程.     

NR2B受体拮抗剂抑制成年大鼠齿状回新生神经元诱导的长时程增强

背景: 新生神经元可诱导产生长时程增强,NMDA受体亚基NR2B的激活在成熟神经元诱导的长时程增强中有重要作用,但其对由新生神经元诱导的长时程增强的影响尚未见报道。 目的：观察NR2B受体拮抗剂Ro25-6981在大鼠齿状回新生神经元诱导的长时程增强中的作用。 设计、时间及地点：脑片电生理实验,于2007-02/06在山西医科大学神经生物实验室完成。 材料：3月龄雄性Wistar大鼠26只,由山西医科大学实验动物中心提供。 方法：大鼠麻醉后断头取脑,分离海马,制备400 μmol/L脑片。采用细胞外微电极记录技术,于海马齿状回分子层内侧1/3处采用双极钨电极进行低频刺激,获得稳定的刺激曲线后,在高频强直刺激下诱导长时程增强。长时程增强的诱导程序为每串刺激频率100 Hz,持续500 ms,间隔20 s,共4串刺激,记录到兴奋性突触后电位>1 mV以上的脑片用于下述两项实验。①NR2B拮抗剂Ro25-6981阻断人工脑脊液诱导的长时程增强：脑片分为2组,人工脑脊液组持续通以含有95% O2和5% CO2的人工脑脊液,人工脑脊液+Ro25-6981组在强直刺激前应用3 μmol/L NR2B拮抗剂Ro25-6981作用10 min,后续步骤同上组。②NR2B拮抗剂Ro25-6981抑制荷包牡丹碱诱导的长时程增强：脑片分为2组,荷包牡丹碱组在强直刺激前给予10 μmol/L荷包牡丹碱灌流10 min,荷包牡丹碱+Ro25-6981组在强直刺激前同时给予3 μmol/L Ro25-6981和10 μmol/L荷包牡丹碱灌流10 min。 主要观察指标：长时程增强记录结果。 结果：①强直刺激后50~60 min,人工脑脊液组长时程增强(107.85±1.34)%,人工脑脊液+Ro25-6981组长时程增强(100.75±2.75）%,两组比较差异有显著性意义(P < 0.05)。②强直刺激后50~60 min,荷包牡丹碱组长时程增强(164.67±2.40)%,荷包牡丹碱+Ro25-6981组长时程增强(147.56±6.63）%,两组比较差异有显著性意义(P < 0.05)。 结论：在大鼠海马齿状回区域,NR2B受体拮抗剂Ro25-6981阻断了人工脑脊液诱导的长时程增强,并部分抑制了荷包牡丹碱诱导的长时程增强,提示NR2B受体拮抗剂可以抑制新生神经元诱导的长时程增强。     

帕金森病猴丘脑底核神经元的电生理特性

目的探讨帕金森病(PD)猴模型丘脑底核(STN)神经元的电生理特性,为研究帕金森病的病理生理过程提供动物实验依据。方法应用颈内动脉注射MPTP建立PD猴模型。在立体定向仪引导下应用细胞外记录的方法记录"造模"前后猴病理及正常生理状态下STN神经元的放电活动,并对其放电模式进行分析。结果电生理记录显示STN神经元放电频率在生理状态下为2.03±1.12Hz;在病理状态下为9.58±0.85 Hz(P<0.01)。在生理状态下有20个(20/35,57.14%)神经元呈现簇发放电,有15个(15/35,42.86%)神经元呈现连续放电;在PD病理状态下有10个(10/12,85.71%)神经元呈现簇发放电,有2个(2/12,14.29%)神经元呈现连续放电(P<0.05)。生理状态下STN神经元的ISI序列散在分布于30～980ms之间;在PD病理状态下当STN神经元呈连续放电时,ISI分布于50～360ms之间,在150ms以下有一个分布密集条带,当STN神经元呈簇发放电时,ISI分布于30～470ms之间,在40ms以下有一个分布密集条带。结论PD猴模型STN神经元较生理状态下放电频率明显增加,其放电模式也有明显变化,簇状放电模式比例增大,ISI序列发生明显变化。     

4种非经典抗精神病药对精神分裂症患者心电图校正QT间期的影响

目的评估利培酮、喹硫平、奥氮平、齐拉西酮4种非经典抗精神病药对精神分裂症患者心电图校正QT间期(corrected QT interval,QTc)的影响。方法 97例精神分裂症患者随机分为利培酮组(n=25)、喹硫平组(n=23)、奥氮平组(n=28)、齐拉西酮组(n=21),口服4种药物中的单一药物治疗。治疗前连续3次心电图检查,血药浓度达稳态后(1次常规服药前30分钟、估计Tmax、Tmax后60分钟)再连续3次心电图检查,测量QT间期,以Bazett’s公式校正为QTc。计算治疗前后QTc均值并进行比较。结果与治疗前相比,治疗后4组QTc都有延长,利培酮组[(382.4±16.3)ms vs.(378.6±13.9)ms]、奥氮平组[(379.2±15.6)ms vs.(376.7±15.13)ms]、喹硫平组[(382.8±16.9)ms vs.(377.5±14.3)ms]、齐拉西酮组[(402.4±33.8)ms vs.(377.1±14.6)ms],与治疗前比较差异有统计学意义(P<0.05)。治疗后QTc各组之间比较差异有统计学意义(P<0.05),齐拉西酮组延长最明显,其中1例女性患者QTc达534 ms。结论 4种非经典抗精神病药均不同程度延长精神分裂症患者QTc。     

慢性应激致大鼠海马长时程增强和氨基酸类神经递质改变及苯妥英钠的效应

目的　探讨慢性应激对大鼠海马长时程增强 (LTP)和氨基酸类神经递质的影响 ,以及苯妥英钠对LTP和氨基酸神经递质改变的效应。方法　将 2 4只SD雄性大鼠随机分为对照组、应激 生理盐水 (10ml/kg)组和应激 苯妥英钠 (40mg/kg)组 ,每组 8只。采用离体海马脑片结合电生理的方法观测海马CA1区LTP的变化。以群体峰电位 (PS)的幅值和场兴奋性突触后电位 (fEPSP)的斜率作为观察LTP变化的指标。应用高效液相色谱 紫外检测法检测海马氨基酸类神经递质的含量。结果　 (1)应激 生理盐水组PS幅值和fEPSP斜率在高频串刺激后增大的幅度低于对照组和应激 苯妥英钠组 (P <0 0 5 )。 (2 )应激 生理盐水组和应激 苯妥英钠组的天冬氨酸含量 [分别为(4 74 6± 0 6 0 9) μmol/g和 (4 94 8± 0 75 1) μmol/g]高于对照组 [(2 4 2 5± 0 2 11) μmol/g ,P <0 0 1];应激 生理盐水组的谷氨酸含量 [(8 0 94± 1 0 35 ) μmol/g]高于对照组 [(6 0 16± 0 6 77) μmol/g]和应激 苯妥英钠组 [(6 970± 0 6 4 7) μmol/g];P <0 0 5 ;应激 苯妥英钠组的γ 氨基丁酸 (GABA)含量[(5 14 2± 0 6 6 2 ) μmol/g]高于对照组 [(4 2 2 9± 0 4 4 9) μmol/g]和应激 生理盐水组 [(4 2 4 9± 0 4 6 3)μmol/g],P <0 0     

视频脑电图在小儿癫痫诊断中的应用

目的评价视频脑电图(video-EEG)在小儿癫诊断中的应用价值。方法对126例具有发作性症状的患儿进行连续8h的包括清醒、睡眠、诱发试验及必要的认知测验的视频脑电图监测。结果经发作期视频脑电图证实,39例初诊为癫性发作的患儿中14例(35%)为非癫性发作;15例其他症状发作中13例(86%)为非癫性发作。64例样放电患儿中51例(80%)确定发作类型,22例(34%)确定癫类型。视频脑电图可发现短暂轻微的癫发作及样放电引起的一过性认知损伤。结论视频脑电图在排除非癫性发作、确定癫性发作的类型、评价脑电-临床关系方面可提供准确可靠的证据,进一步提高癫的临床诊断水平。     

Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity

The pathogenesis of stroke, trauma and chronic degenerative diseases, such as Alzheimer's disease (AD), has been linked to excitotoxic processes due to inappropriate stimulation of the N-methyl-D-aspartate receptor (NMDA-R). Attempts to use potent competitive NMDA-R antagonists as neuroprotectants have shown serious side-effects in patients. As an alternative approach, we were interested in the anti-excitotoxic properties of memantine, a well-tolerated low affinity uncompetitive NMDA-R antagonist presently used as an anti-dementia agent. We explored in a series of models of increasing complexity, whether this voltage-dependent channel blocker had neuroprotective properties at clinically relevant concentrations. As expected, memantine protected neurons in organotypic hippocampal slices or dissociated cultures from direct NMDA-induced excitotoxicity. However, low concentrations of memantine were also effective in neuronal (cortical neurons and cerebellar granule cells) stress models dependent on endogenous glutamate stimulation and mitochondrial stress, i.e. exposure to hypoxia, the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) or a nitric oxide (NO) donor. Furthermore, memantine reduced lethality and brain damage in vivo in a model of neonatal hypoxia-ischemia (HI). Finally, we investigated functional rescue (neuronal capacity to migrate along radial glia) by memantine in cerebellar microexplant cultures exposed to the indirect excitotoxin 3-nitropropionic acid (3-NP). Potent NMDA-R antagonists, such as (+)MK-801, are known to block neuronal migration in microexplant cultures. Interestingly, memantine significantly restored the number of neurons able to migrate out of the stressed microexplants. These findings suggest that inhibition of the NMDA-R by memantine is sufficient to block excitotoxicity, while still allowing some degree of signalling.     

Storage of lipofuscin in neurons in mucopolysaccharidosis

Summary A histochemical and ultrastructural study was made on the brain of a 23-year-old man with Sanfilippo's syndrome. In accordance with previous reports the cortical nerve cells contained a PAS-positive lipid storage substance. This showed intense autofluorescence in UV-light and was positive with various stains for lipofuscin. The storage material appeared ultrastructurally as inclusion bodies composed of short lamellated membranes, granular material, and vacuoles. In addition, concentrically and transversely lamellated membranous cytoplasmic bodies were observed in the nerve cells. It is concluded that the PAS-positive lipid storage material in the neurons was composed partly of lipofuscin in addition to other lipids presumably glycosphingolipids.Supported by a grant from the Expressen Prenatal Research Foundation     

Role of vincristine in the inhibition of angiogenesis in glioblastoma

Objective: Vincristine, a microtubule-destabilizing drug, was found to exhibit anti-angiogenic effects and anti-tumoral activity. However, the precise mechanism by which vincristine inhibits angiogenesis in glioblastomas is not well understood. Our aim was to investigate whether vincristine affects vascular endothelial growth factor (VEGF) expression in glioblastoma cells and determine whether it is mediated by the downregulation of hypoxia-inducible factor-1α (HIF-1α).

Methods: We investigated the expression of HIF-1α in glioblastoma tissues resected from patients and in human glioblastoma cell lines using immunohistochemistry, Western blot analysis, and immunocytochemistry. In addition to an MTT assay assessing the effect of vincristine on cell proliferation and viability, the effects of vincristine on VEGF mRNA expression and HIF-1α protein were examined using real-time RT-PCR and Western blot analysis under 1% O₂ (hypoxia).

Results: HIF-1α was expressed in the majority of glioblastoma tissues and was detected mainly in the nucleus. Strong immunoreactivity for HIF- 1 α was found often in the hypercellular zones. Under hypoxic conditions, HIF-1α protein levels in the glioblastoma cell lines increased, primarily localizing into the nucleus similar to glioblastoma tissues. Exposure of glioblastoma cells to vincristine resulted in enrichment of the G₂-M fraction of the cell cycle, which suggests that vincristine-mediated growth inhibition of glioblastoma is correlated with mitotic inhibition. Using doses lower than those found to reduce the viability and proliferation of cells by 50% (IC₅₀), vincristine decreased both the expression of VEGF mRNA and the level of HIF-1α protein in hypoxic glioblastoma cells. In addition, following exposure to vincristine, the expression of VEGF mRNA was correlated with HIF-1α protein levels.

Conclusions: Our results suggest that the mechanism by which vincristine elicits an anti-angiogenic effect in glioblastomas under hypoxic conditions might be mediated, in part, by HIF-1α inhibition.     

脑电图预测痫性发作研究进展

癫痫(epilepsy)是由脑部神经元高度同步化异常放电所致的临床综合征,系神经系统的常见病,困扰着全世界约1%的人群.每次神经元的阵发性放电或短暂的脑功能异常称为痫性发作(seizures).     

Midazolam in treatment of various types of seizures in children

Midazolam is a recently developed water-soluble benzodiazepine that shares anxiolytic, muscle relaxant, hypnotic and anticonvulsant actions with other members of this class. There are limited studies that midazolam can be used successfully to treat seizures in adults and children. In this study, 0.2 mg/kg intramuscular (IM) midazolam was administered to 11 children (eight boys and three girls), aged 3 days to 4 years (mean age 1.8±1.4 years), with seizures of various types. In all but one child, seizures stopped in 15 s–5 min after injection. No side effects were observed. These results suggest that IM administration of midazolam may be useful in a variety of seizures during childhood, especially in case of intravenous (IV) line problem.     

自噬参与帕金森病发病的研究进展

近年来,蛋白质的降解障碍被认为是帕金森病（Parkinson’Sdisease,PD）发病过程中的重要因素,人们已经公认泛素一蛋白酶体系统（ubiquitin--pro—teasomesystem,UPS）功能异常或衰竭能够导致细胞内异常蛋白蓄积、细胞功能障碍,甚至细胞凋亡。与此同时,蛋白降解的另一条途径——自噬-溶酶体途径（autophagy—lysosomepathway,ALP）也已成为了生命科学领域的研究热点,自噬与神经变性疾病,尤其是PD的关系日益受到人们的重视。     

Developmental effects of in vivo and in vitro inhibition of nitric oxide synthase in neurons

The diffusible chemical messenger nitric oxide (NO) is involved in neuronal plasticity and it is, therefore, supposed to play a role in brain development. A shortage of NO during the critical period of brain maturation may theoretically have long-lasting consequences on the organization of the adult brain. We have performed in neonatal rats a chronic inhibition of the enzyme responsible for NO production, nitric oxide synthase (NOS), from postnatal day 3 to postnatal day 23, through administration of the competitive antagonist N-nitro-L-arginine methylester (L-NAME). The calcium-dependent catalytic activity resulted almost completely inhibited throughout the period of treatment and it took more than 4 days after its suspension to get a full recovery. The expression of the neuronal isoform of the enzyme (nNOS), revealed by immunoblotting, was unchanged during the treatment and after it. The histochemical reaction for NADPH diaphorase was reduced at the end of the treatment and recovered in concomitance with the recovery of the catalytic NOS activity. No gross structural alterations were detected in brain morphology. The levels of three neurotransmitter-related and one astrocytic marker were unchanged in the cerebellum, hippocampus and cortex of 60-day-old rats which had been neonatally treated. A similar lack of significant effects on neurochemical brain maturation was also noticed in a parallel series of experiments, in which a short pulse of NOS inhibition was performed at a critical prenatal time of brain development, from gestational day 14 to gestational day 19. In vitro, chronic exposure of cerebellar granule cells to L-NAME (500 microM) resulted in slight decrease of surviving neurons after 8 days in culture and in better resistance to the challenge of stressful culture conditions. The present results suggest that the basic plan of brain organization can be achieved despite an almost complete NOS inhibition during the maturation period. In vitro, NOS inhibition may bring to more pronounced consequences on neuronal viability and function.     

The Burden of Agoraphobia in Worsening Quality of Life in a Community Survey in Italy

ObjectiveCurrent nosology redefined agoraphobia as an autonomous diagnosis distinct from panic disorder. We investigated the lifetime prevalence of agoraphobia, its association with other mental disorders, and its impact on the health-related quality of life (HR-QoL). MethodsCommunity survey in 2,338 randomly selected adult subjects. Participants were interviewed with the Advanced Neuropsychiatric Tools and Assessment Schedule (ANTAS), administered by clinicians. The diagnoses were based on the ICD-10 criteria. The Short-Form Health Survey (SF-12) was used to quantify HR-QoL. ResultsIn the sample, 35 subjects met the criteria for agoraphobia (1.5%), with greater prevalence among women (2.0%) than men (0.9%): odds ratio (OR) 2.23; 95% CI: 1.0-5–2. Agoraphobia was more often seen among those with (n=26; 1.1%) than without (n=9; 0.4%) panic disorder: OR=8.3; 2.9–24.4. Co-morbidity with other mental disorders was substantial. The mean score of SF-12 in people with agoraphobia was 35.2±7.8, with similar levels of HR-QoL in people with (35.3±7.9) or without (34.8±7.3) panic disorder: ANOVA: F(1;33)=0.0; p=1.00. ConclusionOne out of seventy people may suffer from agoraphobia in their lifetime. The attributable burden in terms of HR-QoL is substantial and comparable to the one observed for chronic mental disorders such as major depression, post-traumatic stress disorder, or obsessive-compulsive disorder.