The use of methotrexate in rheumatoid arthritis

OBJECTIVE: To address the long-term efficacy and toxicity issues related to methotrexate (MTX) and compare it with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease. RESULTS: MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival. The toxicity profile of MTX is well established and includes serious and sometimes fatal liver disease, pneumonitis, and cytopenias. Hence, regular and careful monitoring of patients taking MTX is essential, particularly when MTX is combined with other DMARDs. Folate supplementation can reduce some of the most common side effects of MTX, but it has not yet been established whether this translates into a reduced risk of serious disease. Another potential approach to reducing the toxicity of MTX is therapeutic drug monitoring and dose individualization. However, correlations between pharmacokinetics and clinical response have been addressed in only a few studies and with conflicting results. CONCLUSIONS: MTX is an effective DMARD with a relatively safe profile compared with other therapies. Folate supplementation can significantly reduce the risk of MTX toxicity. Finally, it is essential that patients be monitored carefully to reduce the potential serious toxicities of MTX.     

Speech Perception with Noise Vocoding and Background Noise: An EEG and Behavioral Study

This study explored the physiological response of the human brain to degraded speech syllables. The degradation was introduced using noise vocoding and/or background noise. The goal was to identify physiological features of auditory-evoked potentials (AEPs) that may explain speech intelligibility. Ten human subjects with normal hearing participated in syllable-detection tasks, while their AEPs were recorded with 32-channel electroencephalography. Subjects were presented with six syllables in the form of consonant-vowel-consonant or vowel-consonant-vowel. Noise vocoding with 22 or 4 frequency channels was applied to the syllables. When examining the peak heights in the AEPs (P1, N1, and P2), vocoding alone showed no consistent effect. P1 was not consistently reduced by background noise, N1 was sometimes reduced by noise, and P2 was almost always highly reduced. Two other physiological metrics were examined: (1) classification accuracy of the syllables based on AEPs, which indicated whether AEPs were distinguishable for different syllables, and (2) cross-condition correlation of AEPs (r_cc) between the clean and degraded speech, which indicated the brain’s ability to extract speech-related features and suppress response to noise. Both metrics decreased with degraded speech quality. We further tested if the two metrics can explain cross-subject variations in their behavioral performance. A significant correlation existed for r_cc, as well as classification based on early AEPs, in the fronto-central areas. Because r_cc indicates similarities between clean and degraded speech, our finding suggests that high speech intelligibility may be a result of the brain’s ability to ignore noise in the sound carrier and/or background.     

Local inhibition of GABA affects precedence effect in the inferior colliculus

The precedence effect is a prerequisite for faithful sound localization in a complex auditory environment, and is a physiological phenomenon in which the auditory system selectively suppresses the directional information from echoes. Here we investigated how neurons in the inferior colliculus respond to the paired sounds that produce precedence-effect illusions, and whether their firing behavior can be modulated through inhibition with gamma-aminobutyric acid （GABA）. We recorded extracellularly from 36 neurons in rat inferior colliculus under three conditions： no injection, injection with saline, and injection with gamma-aminobutyric acid. The paired sounds that produced precedence effects were two identical 4-ms noise bursts, which were delivered contralaterally or ipsilaterally to the recording site. The normalized neural responses were measured as a function of different inter-stimulus delays and half-maximal interstimulus delays were acquired. Neuronal responses to the lagging sounds were weak when the inter-stimulus delay was short, but increased gradually as the delay was lengthened. Saline injection produced no changes in neural responses, but after local gamma-arninobutyric acid application, responses to the lagging stimulus were suppressed. Application of gamma-aminobutyric acid affected the normalized response to lagging sounds, independently of whether they or the paired sounds were contralateral or ipsilateral to the recording site. These observations suggest that local inhibition by gamma-aminobutyric acid in the rat inferior colliculus shapes the neural responses to lagging sounds, and modulates the precedence effect.     

The importance of distinguishing between the different eating disorders (sub)types when assessing emotion regulation strategies

People with eating disorders (ED) have difficulties regulating their emotions adaptively. Little is known about differences and similarities between different types of ED and how these regulation difficulties relate to other emotional problems. The present study examines maladaptive (suppression) and adaptive (cognitive reappraisal) emotion regulation strategies in women with different ED and relationships with anxiety and depression levels. In 32 women with AN restrictive subtype (ANR), 32 with AN binge-purge subtype (ANBP), 30 with bulimia nervosa (BN), 29 with binge eating disorder (BED), and 64 healthy women, the ERQ (emotion regulation) as well as STAI-T (anxiety), BDI-SF (depression), and EDDS (eating pathology) were administered. Women across different ED subtypes were inclined to suppress emotions and lacked the capacity to reappraise emotions (except women with ANBP). Correlational relations of suppression and reappraisal with anxiety and depression levels differed across ED groups. Emotion regulation problems were found across ED subtypes. However, the types of emotion regulation problems, and the effect of coexisting other emotional problems such as anxiety and depression may differ across ED subtypes. These findings illustrate the importance to of considering ED subtypes in emotion regulation research rather than consider ED as a whole.     

Ovarian function preservation with GnRH agonist in young breast cancer patients: Does it impede the effect of adjuvant chemotherapy?

BackgroundConcurrent endocrine therapy with chemotherapy had a concern of potential antagonism. However, gonadotropin-releasing hormone (GnRH) agonist has been used concurrently with chemotherapy to prevent premature ovarian failure for young breast cancer patients. The aim of this study was to determine the impact of concurrent use of GnRH agonists on relapse-free and overall survival, and to establish the oncologic safety of ovarian protection with GnRH agonists.MethodsPremenopausal women aged between 20 and 40 years who received adjuvant chemotherapy for breast cancer from January 2002 to April 2012 were classified into two groups; One treated with GnRH agonists for ovarian protection during chemotherapy, and the other without ovarian protection. A propensity score matching strategy was used to create matched sets of two groups with age, pathologic stage, hormone receptor, and Her2 status.ResultsA total of 101 patients treated with concurrent GnRH agonist during chemotherapy were compared with 335 propensity score matched patients. Among them, 81.2% were younger than 35 years and 58.4% were hormone responsive. Survival analysis using stratified Cox regression showed that women treated with concurrent GnRH agonists had better recurrence-free survival (adjusted Hazard ratio 0.21, p = 0.009; unadjusted Hazard ratio 0.33, p = 0.034).ConclusionsOvarian protection using GnRH agonists can be safely considered for young women with breast cancer in terms of oncologic outcomes. Further studies are needed to assess the long-term outcomes of concurrent GnRH agonist use with chemotherapy.     

Suppression of immunoglobulin production in human peripheral blood mononuclear cells by monocytes via secretion of heavy-chain ferritin

In vitro antigen stimulation of peripheral blood mononuclear cells (PBMCs) does not induce immunoglobulin (Ig) production. However, pretreatment of PBMCs with l-leucyl-l-leucine methyl ester (LLME) prior to in vitro stimulation removes the suppression of Ig production. In the present study, we attempted to identify the target cells of LLME and determine the mechanisms by which Ig production in PBMCs is suppressed. We found that CD14⁺ monocytes are involved in the suppression of Ig production in PBMCs. Furthermore, we confirmed that heavy-chain ferritin derived from CD14⁺ monocytes suppresses Ig production in PBMCs, possibly through iron sequestration.     

基于FAERS数据库挖掘曲拉西利的不良事件及分析

目的 基于美国食品药品管理局（FDA）不良事件报告系统（FAERS）收集曲拉西利的不良事件报告,挖掘新的严重的不良事件,为临床安全用药提供参考。方法 获取FAERS中2004年第1季度—2023年第4季度曲拉西利相关的不良事件报告,采取报告比值比法（ROR）、比例报告比值比（PRR）、贝叶斯可信区间递进神经网络（BCPNN）法与多项式伽马泊松分布缩减法（MGPS）联用对不良事件报告进行数据挖掘与分析。结果 共获得与曲拉西利相关的不良事件报告457例次,在已知性别、年龄或地区的不良事件报告中,男女比例相近,45～65岁不良事件报告数占比最大。曲拉西利的不良事件报告涉及19个系统器官分类（SOC）,包括全身性疾病及给药部位各种反应、各类检查、精神类疾病等,阳性信号主要包括超说明书使用、骨髓抑制呼吸困难、体力状态下降等。结论 曲拉西利不良事件信号有效与说明书基本一致,同时还发现了一些新的潜在曲拉西利信号,如焦虑、心境抑郁、神经紧张不安等,值得临床关注。