The World Health Organization estimates that ca. 11 million people worldwide have Alzheimer's disease (AD) and this population is expected to nearly double by 2030.1 This disease, which manifests in progressive neurodegeneration, is characterized by the presence of amyloid-β (Aβ) peptide aggregates.2 -4 The mechanism for the formation of Aβ aggregates is not entirely understood, though metal ions such as Cu II and Zn II have been shown to facilitate Aβ aggregation.2 -4 In particular, redox-active Cu II is implicated in the generation of reactive oxygen species (ROS), leading to an increase in oxidative stress, which is one proposed neuropathology of AD.2 -8 To elucidate Cu-mediated events in AD pathogenesis, Cu coordination to Aβ has been explored as well as effects on the removal of Cu from Cu-Aβ species using chelating agents.2 -13 These studies have demonstrated that the extent of metal-induced Aβ aggregation and ROS production can be modulated by metal chelators, which highlights metal-ion chelation therapy as a promising AD treatment.Many orthodox metal chelators show inhibition of metal-induced Aβ aggregation and ROS formation,2 -4 , 9 , 13 but they may not be suitable for AD therapeutics. Most of these chelators cannot cross the blood brain barrier (BBB) and are not able to specifically target metal ions in various Aβ forms without removing vital metals from other biological systems due to lack of an Aβ recognition ability. The metal chelator clioquinol (CQ) reveals decreased Aβ aggregate deposits and improved cognition in early clinical trials.14 The long-term use is, however, limited by an adverse side effect, subacute myelo-optic neuropathy.15 , 16 Our recent studies suggest that CQ assists, in part, in the disaggregation of Aβ aggregates, but could not completely prevent Aβ aggregation.17 Therefore, rational design of chelating agents capable of targeting metal ions in Aβ species followed by modulation of Aβ aggregation in the brain is essential toward metal-ion chelation therapy for AD. Only limited efforts have been made toward this goal.3 , 10 -12 Herein we present the preparation of bifunctional metal chelators (1 and 2) and their interaction with Cu-induced Aβ aggregates. Both chelators exhibit modulation of Cu-associated Aβ aggregation, which is more effective than that by the well-known metal chelating agents CQ, EDTA, and phen in this study.18Our strategy for developing metal chelators as potential AD therapeutics is to create bifunctional molecules that contain structural moieties for metal ion chelation and Aβ recognition (Figure 1). For the latter purpose, the basic frameworks of 1 and 2 are based on the Aβ aggregate-imaging probes 125 IMPY and p-125 I-stilbene,18 respectively, which show strong binding affinity to Aβ aggregates.19 These compounds are small, neutral, lipophilic, and thus able to penetrate the BBB. Furthermore, they are easily removed from normal brain mhlim@umich.edu . Supporting Information Available: Experimental procedures, preparation and characterization of 1 and 2, Ta...

IMPORTANCE Research into acupuncture and acupressure and their application for cancer pain has been growing, but the findings have been inconsistent. OBJECTIVE To evaluate the existing randomized clinical trials (RCTs) for evidence of the association of acupuncture and acupressure with reduction in cancer pain.DATA SOURCES Three English-language databases (PubMed, Embase, and CINAHL) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through March 31, 2019.STUDY SELECTION Randomized clinical trials that compared acupuncture and acupressure with a sham control, analgesic therapy, or usual care for managing cancer pain were included.DATA EXTRACTION AND SYNTHESIS Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. Random-effects modeling was used to calculate the effect sizes of included RCTs. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach.MAIN OUTCOMES AND MEASURES The primary outcome was pain intensity measured by the Brief Pain Inventory, Numerical Rating Scale, Visual Analog Scale, or Verbal Rating Scale. RESULTS A total of 17 RCTs (with 1111 patients) were included in the systematic review, and data from 14 RCTs (with 920 patients) were used in the meta-analysis. Seven sham-controlled RCTs (35%) were notable for their high quality, being judged to have a low risk of bias for all of their domains, and showed that real (compared with sham) acupuncture was associated with reduced pain intensity (mean difference [MD], −1.38 points; 95% CI, −2.13 to −0.64 points; I 2 = 81%). A favorable association was also seen when acupuncture and acupressure were combined with analgesic therapy in 6 RCTs for reducing pain intensity (MD, −1.44 points; 95% CI, −1.98 to −0.89; I 2 = 92%) and in 2 RCTs for reducing opioid dose (MD, −30.00 mg morphine equivalent daily dose; 95% CI, −37.5 mg to −22.5 mg). The evidence grade was moderate because of the substantial heterogeneity among studies. CONCLUSIONS AND RELEVANCEThis systematic review and meta-analysis found that acupuncture and/or acupressure was significantly associated with reduced cancer pain and decreased use of analgesics, although the evidence level was moderate. This finding suggests that more rigorous trials are needed to identify the association of acupuncture and acupressure with specific types of cancer pain and to integrate such evidence into clinical care to reduce opioid use. Research Original InvestigationAssociation of Acupuncture and Acupressure With Improved Cancer Pain 37. Tao WW, Jiang H, Tao XM, Jiang P, Sha LY, Sun XC. Effects of acupuncture, tuina, tai chi, qigong, and traditional Chinese medicine five-element music therapy on symptom management and quality of life for cancer patients: a meta...

For more than a century, hydrogen sulfide (H(2)S) has been regarded as a toxic gas. This review surveys the growing recognition of the role of H(2)S as an endogenous signaling molecule in mammals, with emphasis on its physiological and pathological pathways in the cardiovascular system. In biological fluids, H(2)S gas is a weak acid that exists as about 15% H(2)S, 85% HS(-), and a trace of S(2-). Here, we use "H(2)S" to refer to this mixture. H(2)S has been found to influence heart contractile functions and may serve as a cardioprotectant for treating ischemic heart diseases and heart failure. Alterations of the endogenous H(2)S level have been found in animal models with various pathological conditions such as myocardial ischemia, spontaneous hypertension, and hypoxic pulmonary hypertension. In the vascular system, H(2)S exerts biphasic regulation of a vascular tone with varying effects based on its concentration and in the presence of nitric oxide. Over the past decade, several H(2)S-releasing compounds (NaHS, Na(2)S, GYY4137, etc.) have been utilized to test the effect of exogenous H(2)S under different physiological and pathological situations in vivo and in vitro. H(2)S has been found to promote angiogenesis and to protect against atherosclerosis and hypertension, while excess H(2)S may promote inflammation in septic or hemorrhagic shock. H(2)S-releasing compounds and inhibitors of H(2)S synthesis hold promise in alleviating specific disease conditions. This comprehensive review covers in detail the effects of H(2)S on the cardiovascular system, especially in disease situations, and also the various underlying mechanisms.

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