A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma

Introduction: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.

Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.

Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.     

Acceptance of multiple injectable vaccines in a single immunization visit in The Gambia pre and post introduction of inactivated polio vaccine

BackgroundAs the World Health Organization (WHO) currently recommends that children be protected against 11 different pathogens, it is becoming increasingly necessary to administer multiple injectable vaccines during a single immunization visit. In this study we assess Gambian healthcare providers’ and infant caregivers’ attitudes and practices related to the administration of multiple injectable vaccines to a child at a single immunization visit before and after the 2015 introduction of inactivated polio vaccine (IPV). IPV introduction increased the number of injectable vaccines recommended for the 4-month immunization visit from two to three in The Gambia.MethodsWe conducted a cross-sectional questionnaire-based survey before and after the introduction of IPV at 4 months of age in a representative sample of all health facilities providing immunizations in The Gambia. Healthcare providers who administer vaccines at the selected health facilities and caregivers who brought infants for their 4 month immunization visit were surveyed.FindingsPrior to IPV introduction, 9.9% of healthcare providers and 35.7% of infant caregivers expressed concern about a child receiving more than 2 injections in a single visit. Nevertheless, 98.8% and 90.9% of infants received all required vaccinations for the visit before and after IPV introduction, respectively. The only reason why vaccines were not received was vaccine stock-outs. Infant caregivers generally agreed that vaccinators could be trusted to provide accurate information regarding the number of vaccines that a child needed.ConclusionHealthcare providers and infant caregivers in this resource limited setting accepted an increase in the number of injectable vaccines administered at a single visit even though some expressed concerns about the increase.     

A comparison of conventional and fast spin-echo sequences for the measurement of lesion load in multiple sclerosis using a semi-automated contour technique

Changes on serial assessments of brain MRI lesion load are used for monitoring therapeutic efficacy in patients with multiple sclerosis (MS). We assessed the accuracy and reliability of conventional spin-echo (CSE) and fast spin-echo (FSE) sequences for measurement of lesion volume using a semiautomated contour technique. Cranial CSE and FSE examinations of 18 patients with secondary progressive MS were studied. The mean lesion load was slightly higher with the CSE sequence (p = 0.002). Intraobserver variability was significantly higher for FSE than for CSE, according to both the coefficient of variation between two measurements (mean 2.48 % and 1.35 % respectively, p < 0.05) and back-transformed 95 % limits of agreement (1.005–1.060 for FSE; 0.988–1.019 for CSE). Although FSE sequences are quicker and the total lesion volume measurements are similar to those obtained with CSE, the poorer reproducibility raises doubts about the use of FSE to replace CSE in clinical trials. Received: 26 March 1996 Accepted: 4 April 1996     

HLA-DPB1 gene polymorphism and multiple sclerosis: a large case-control study in the southwest of France

The polymorphism at the HLA-DPB1 locus has been characterized in a large number of patients with multiple sclerosis (n = 112) and in healthy controls (n = 115). Both patients and controls lived in the southwest of France (in the Pyrénées Atlantiques) and had similar ethnic background. The typing procedure involved the selective amplification of the second exon of the DPB1 locus by polymerase chain reaction, followed by hybridization of the amplified DNA with 14 sequence-specific oligonucleotide probes. Individual alleles were identified by the pattern of hybridization of the different probes. The distribution of the DPB1 alleles was not significantly different in multiple sclerosis patients and controls (p = 0.11). This does not corroborate the reported association of multiple sclerosis with the primed lymphocyte typing (PLT)-defined DPw4 specificity and is not in favour of a role played by polymorphic residues of the DP molecule in susceptibility to multiple sclerosis.     

How far do patients with sensory ataxia benefit from so-called “proprioceptive rehabilitation”?

A rehabilitation program including foot sensory stimulation, balance and gait training with limited vision was performed in 24 patients with clinically defined sensory ataxia. There were 15 patients with bilateral somatosensory loss related to chronic neuropathy and nine patients with unilateral loss-related to multiple sclerosis. After training, balance control assessed using the Berg Balance Test improved similarly in both groups, and Romberg's sign disappeared in some patients, suggesting an improvement in dynamic balance and in the proprioceptive contribution. Conversely, balance assessed on a static force platform remained similar in the open-eyes condition and improved in the closed-eyes condition only in patients with unilateral sensory loss. These results show that ataxic patients can improve their balance with better results in dynamic conditions and that the relative contribution of proprioceptive and visual inputs may depend on the extent of somatosensory loss.     

多发性骨髓瘤患者血浆尿激酶型纤溶酶原激活物及其可溶性受体的检测与临床意义

目的 :研究多发性骨髓瘤 ( MM)患者血浆尿激酶型纤溶酶原激活物 ( u- PA )及其可溶性受体 ( su PAR )的水平变化 ,并探讨其临床意义。方法 :用 ELISA法检测 34例 MM患者血浆 u- PA及 su PA R的浓度 ,同时观察其中6例 MM患者化疗前后血浆 u- PA及 su PAR的浓度变化。结果 :MM患者血浆 u- PA及 su PA R水平均明显高于正常对照组 ,其中进展期 MM患者血浆 u- PA及 su PAR水平明显高于正常对照组和稳定期 MM患者 ( P <0 .0 1) ,而稳定期 MM患者血浆 u- PA及 su PA R水平与正常对照组无显著性差异 ( P>0 .0 5)。 6例 MM患者化疗后血浆 u- PA及 su PA R水平 ,明显低于化疗前血浆 u- PA及 su PAR水平 ( P<0 .0 5)。骨髓涂片瘤细胞比例 >2 0 %的 MM患者血浆 u- PA及 su PA R水平 ,明显高于瘤细胞比例≤ 2 0 % M M患者 ( P<0 .0 5;P<0 .0 1)。M M患者血浆 u- PA及su PA R水平均与骨髓瘤细胞百分比及血清球蛋白呈正相关 ,而与血清白蛋白呈负相关。结论 :血浆 u- PA及 su PA R水平升高可能与多发性骨髓瘤的发生、发展有密切关系 ;其水平可作为临床分期、判断疗效、了解疾病进展情况及预后的一个重要指标。     

Blood pressure lowering effect of the aqueous extract of the stem of Ipomoea acanthocarpa (convolvulaceae) in spontaneously and salt-loaded hypertensive rats

Spontaneously hypertensive (SHR) and salt-loaded hypertensive rats (SLHR) were submitted to a daily treatment by gavage of 2 mL/100 g body weight of the aqueous extract of the stem of Ipomoea acanthocarpa (30 mg/mL stock solution). A fall in blood pressure of nearly 13% was observed after two successive administrations of the aqueous extract. After 14 days of treatment, the blood pressure fell by more than 30±8%. The hypotensive effect might be due to a direct vascular smooth muscle effect or to its already observed high diuretic effects or might be acting by some other mechanism.     

关附甲素对豚鼠乳头肌动作电位最大除极速度的频率依赖性抑制作用

应用标准微电极技术，研究了关附甲素对豚鼠右心室乳头肌动作电位最大除极速率(V_max)的频率依赖性抑制作用(RDB)，并与美西律，奎尼丁，劳卡尼进行了比较. 在相同刺激间隔(300 ms)，产生50%左右RDB的药物浓度下，美西律的RDB开始最快，其第2个V_max所产生的抑制已占RDB的64%，奎尼丁，劳卡尼和关附甲素的RDB开始速率常数分别为每个动作电位0.165, 0.076和0.136. 美西律，奎尼丁，劳卡尼和关附甲素产生RDB的恢复时间常数分别为1.4, 9.0, 18.2和44.0 s，而且它们的恢复时间常数是不依赖于药物浓度而变化的，结果提示，关附甲素是一个慢动力学钠通道阻滞剂.     

Differences in the temporal dynamics of the visual ON and OFF pathways

The temporal structure of spike trains recorded from optic fibers and single units of the lateral geniculate nucleus (LGN) and primary visual cortex of the cat was studied with a novel method of inter-spike interval analysis. ON type relay cells of the LGN exhibited a multimodal interval distribution preferring a distinct interval (fundamental interval) and its multiples during the sustained light response, whereas most OFF cells showed a broad, unimodal distribution. The general pattern of the interval distribution was relatively independent of stimulus size and contrast and the degree of light adaptation. Simultaneously recorded S-potentials originating from the retinal input generally produced only a single peak at the fundamental interval length. Therefore, the multimodal interval distribution of LGN cells seems to be a result of intra-geniculate inhibition. Cortical cells also showed a weak tendency to fire with spike intervals similar to LGN cells. Therefore, the regular firing pattern observed at peripheral stages of the visual pathway can persist at higher levels and might promote the occurrence of oscillatory activity.     

Pathogenesis of neuroimmunologic diseases

Animal models of autoimmune diseases have greatly improved our current understanding of the pathogenesis of human autoimmunity and have provided the potential for therapies based on manipulation of the immune system. In our laboratory, we have investigated the immunopathogenesis of autoimmune diseases of the nervous system and muscle. We have developed immune-based approaches for the suppression of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), and experimental autoimmune neuritis (EAN), a model for the Guillain-Barré syndrome (GBS). These approaches included induction of peripheral tolerance, immunotoxin targeting of activated T cells, and cytokine manipulations. In addition, we identified the antigen and characterized immunopathologically an autoimmune inflammatory disease of skeletal muscle, experimental autoimmune myositis (EAM), a model for the human inflammatory muscle disease polymyositis.