Future targets for migraine treatment beyond CGRP.

BACKGROUND: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. FINDINGS: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. CONCLUSION: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis.

INTRODUCTION: Headache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce. MATERIAL AND METHODS: We searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8-18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted. RESULTS: Out of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9-14%], 8% for migraine without aura (MwoA) [95%CI: 5-12%], 3% for migraine with aura (MwA) [95%CI:2-4%] and 17% for tension-type headache (TTH) [95% CI: 12-23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53-70%], with prevalence in females and males of 38% [95% CI: 16-66%] and 27% [95% CI: 11-53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking. CONCLUSION: We found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

Systematic review of Shenqi Fuzheng Injection combined with chemotherapy for treatment of breast cancer / 中国中药杂志

Databases including China Biological Medicine database(CBM), Chinese scientific journals full-text database(VIP), China National Knowledge Infrastructure database(CNKI), WanFang Data, PubMed, and EMbase were searched from inception to March 2018 to collect the randomized controlled trials(RCTs) on Shenqi Fuzheng Injection combined with chemotherapy for the treatment of breast cancer. All included studies were critically appraised by two independent reviewers by following the cochrane systematic review method and using Revman 5.3 software and State 12.0 for data analysis. After screening, 20 RCTs involving 2 095 patients were included in the study. Meta-analysis showed that as compared with control group of chemotherapy alone, Shenqi Fuzheng Injection combined with chemotherapy could improve the clinical curative efficiency, the KPS score, and immune function indexes such as total T cells, Th cells and Ts cells; inhibit the decline of white blood cells(WBC), platelets in blood system, T-lymphocyte subsets such as CD3~+, CD4~+, CD4~+/CD8~+, alleviate myelosuppression and reduce the incidence of side effects such as gastrointestinal adverse reaction, liver and kidney dysfunction and abnormal electrocardiogram. The results revealed that for clinical breast cancer patients, Shenqi Fuzheng Injection combined with chemotherapy could significantly improve its clinical efficacy and reduce adverse reactions. However, the conclusions still need to be verified by high-quality, multi-center, large-sample, prospective, randomized and double-blind clinical trials. In conclusion, this study has systemically evaluated the efficacy and safety of Shenqi Fuzheng Injection combined with chemotherapy in treatment of breast cancer and provided the reference of evidence-based medicine for safe and effective clinical application of medicines.

Systematic review on efficacy and safety of Danshen Chuanxiongqin Injection in treatment of acute cerebral infarction / 中国中药杂志

To systemically evaluate the therapeutic efficacy and safety of Danshen Chuanxiongqin Injection in treatment of acute cerebral infarction and provide the reference of evidence-based medicine for its clinical safety and effective drug use. Databases including CNKI, WanFang Data, SinoMed, the Cochrane Library, EMbase and PubMed were searched from inception to April 2018 to collect the randomized controlled trials (RCTs) on Danshen Chuanxiongqin Injection in the treatment of acute cerebral infarction. The quality of all included studies was evaluated by two independent reviewers following the cochrane systematic review method and using Revman5.3 software and State13.0 for Meta-analysis. A total of 30 RCTs involving 3 233 patients with acute cerebral infarction were included in the study after literature quality evaluation. Meta-analysis showed that as compared with the control group of conventional western medicine alone, Danshen Chuanxiongqin Injection combined with conventional western medicine can achieve better efficacy in treatment of acute cerebral infarction, increase the clinical total effective rate (RR=1.22, 95% CI [1.18, 1.27], <0.000 01) and activities of daily living (MD=9.42, 95% CI [8.12, 10.72], <0.000 01), and improve the degree of neurological impairment (MD=-3.99, 95% CI [-4.89, -3.07], <0.000 01). Furthermore, the result showed that Danshen Chuanxiongqin Injection in the treatment of acute cerebral infarction can significantly decrease the whole blood high-shear viscosity, whole blood low-shear viscosity, plasma viscosity, fibrinogen level and other hemorheological indexes (<0.01). This Meta-analysis demonstrated that Danshen Chuan xiongqin injection in the treatment of acute cerebral infarction is safe and effective, but lacks the large multicenter clinical randomized trials to support the treatment outcome.

Effect of 1,25-dihydroxyvitamin D₃on regulatory T cells in ovariectomized mice / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate the correlation between regulatory T (Treg) cells and postmenopausal osteoporosis and the antiosteoporotic effect of 1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃] in relation to Treg cells.</p><p><b>METHODS</b>Fifty female BALB/c mice were randomly divided into five groups: the basal control (BAS), Sham, ovariectomy (OVX), OVX+diethylstilbestrol (OVX+DES), and OVX+1,25(OH)₂D₃. Tibias were harvested and processed with decalcification for quantitative bone histomorphometry. Femurs were stained by immunohistochemistry to detect Foxp3 protein expression. Spleens were used to detect Treg and Foxp3 gene expression by flow cytometry and quantitative RT-PCR, respectively.</p><p><b>RESULTS</b>In comparison with the Sham group, a significant decrease was found in the OVX group in such indices as trabecular bone volume/total tissue area (BV/TV), trabecular number (Tb.N) and trabecular thickness (Tb.Th). 1,25(OH)₂D₃and DES partly prevented the decrease in BV/TV, Tb.N, Tb.Th in OVX mice. Treg cell number, Foxp3 mRNA expression in spleen and Foxp3 protein expression in femur significantly decreased in the OVX-treated group compared with those in the sham group. 1,25(OH)2D₃and DES significantly increased Treg cell number and Foxp3 expression. Treg cells and Foxp3 gene expression were related to bone histomorphometric parameters.</p><p><b>CONCLUSION</b>The decrease in Treg cell numbers is relevant to the postmenopausal osteoporosis. The antiosteoporosis of 1,25(OH)₂D₃is related to regulatory T cells.</p>

Hemoglobinopathy: molecular epidemiological characteristics and health effects on Hakka people in the Meizhou region, southern China.

BACKGROUND: Hemoglobinopathies are the most common inherited diseases in southern China. However, there have been only a few epidemiological studies of hemoglobinopathies in Guangdong province. MATERIALS AND METHODS: Peripheral blood samples were collected from 15299 "healthy" unrelated subjects of dominantly ethnic Hakka in the Meizhou region, on which hemoglobin electrophoresis and routine blood tests were performed. Suspected cases with hemoglobin variants and hereditary persistence of fetal hemoglobin (HPFH) were further characterized by PCR, DNA sequencing, reverse dot blot (RDB) or multiplex ligation-dependent probe amplification (MLPA). In addition, 1743 samples were randomly selected from the 15299 subjects for thalassemia screening, and suspected thalassemia carriers were identified by PCR and RDB. RESULTS: The gene frequency of hemoglobin variants was 0.477% (73/15299). The five main subgroups of the ten hemoglobin variants were Hb E, Hb G-Chinese, Hb Q-Tahiland, Hb New York and Hb J-Bangkok. 277 cases (15.89%, 277/1743) of suspected thalassemia carriers with microcytosis (MCV<82 fl) were found by thalassemia screening, and were tested by a RDB gene chip to reveal a total of 196 mutant chromosomes: including 124 α-thalassemia mutant chromosomes and 72 ß-thalassemia mutant chromosomes. These results give a heterozygote frequency of 11.24% for common α and ß thalassemia in the Hakka population in the Meizhou region. 3 cases of HPFH/δß-thalassemia were found, including 2 cases of Vietnamese HPFH (FPFH-7) and a rare Belgian( G)γ((A)γδß)°-thalassemia identified in Chinese. CONCLUSIONS: Our results provide a detailed prevalence and molecular characterization of hemoglobinopathies in Hakka people of the Meizhou region. The estimated numbers of pregnancies each year in the Meizhou region, in which the fetus would be at risk for ß thalassemia major or intermedia, Bart's hydrops fetalis, and Hb H disease, are 25 (95% CI, 15 to 38), 40 (95% CI, 26 to 57), and 15 (95% CI, 8 to 23), respectively.