Calcitonin gene-related peptide inhibits neuronal apoptosis in heatstroke rats via PKA/p-CREB pathway / 中华创伤杂志(英文版)

PURPOSE@#The incidence of heatstroke (HS) is not particularly high; however, once it occurs, the consequences are serious. It is reported that calcitonin gene-related peptide (CGRP) is protective against brain injury in HS rats, but detailed molecular mechanisms need to be further investigated. In this study, we further explored whether CGRP inhibited neuronal apoptosis in HS rats via protein kinase A (PKA)/p-cAMP response element-binding protein (p-CREB) pathway.@*METHODS@#We established a HS rat model in a pre-warmed artificial climate chamber with a temperature of (35.5 ± 0.5) °C and a relative humidity of 60% ± 5%. Heatstress was stopped once core body temperature reaches above 41 °C. A total of 25 rats were randomly divided into 5 groups with 5 animals each: control group, HS group, HS+CGRP group, HS+CGRP antagonist (CGRP8-37) group, and HS+CGRP+PKA/p-CREB pathway blocker (H89) group. A bolus injection of CGRP was administered to each rat in HS+CGRP group, CGRP8-37 (antagonist of CGRP) in HS+CGRP8-37 group, and CGRP with H89 in HS+CGRP+H89 group. Electroencephalograms were recorded and the serum concentration of S100B, neuron-specific enolase (NSE), neuron apoptosis, activated caspase-3 and CGRP expression, as well as pathological morphology of brain tissue were detected at 2 h, 6 h, and 24 h after HS in vivo. The expression of PKA, p-CREB, and Bcl-2 in rat neurons were also detected at 2 h after HS in vitro. Exogenous CGRP, CGRP8-37, or H89 were used to determine whether CGRP plays a protective role in brain injury via PKA/p-CREB pathway. The unpaired t-test was used between the 2 samples, and the mean ± SD was used for multiple samples. Double-tailed p < 0.05 was considered statistically significant.@*RESULTS@#Electroencephalogram showed significant alteration of θ (54.50 ± 11.51 vs. 31.30 ± 8.71, F = 6.790, p = 0.005) and α wave (16.60 ± 3.21 vs. 35.40 ± 11.28, F = 4.549, p = 0.020) in HS group compared to the control group 2 h after HS. The results of triphosphate gap terminal labeling (TUNEL) showed that the neuronal apoptosis of HS rats was increased in the cortex (9.67 ± 3.16 vs. 1.80 ± 1.10, F = 11.002, p = 0.001) and hippocampus (15.73 ± 8.92 vs. 2.00 ± 1.00, F = 4.089, p = 0.028), the expression of activated caspase-3 was increased in the cortex (61.76 ± 25.13 vs. 19.57 ± 17.88, F = 5.695, p = 0.009) and hippocampus (58.60 ± 23.30 vs. 17.80 ± 17.62, F = 4.628, p = 0.019); meanwhile the expression of serum NSE (5.77 ± 1.78 vs. 2.35 ± 0.56, F = 5.174, p = 0.013) and S100B (2.86 ± 0.69 vs. 1.35 ± 0.34, F = 10.982, p = 0.001) were increased significantly under HS. Exogenous CGRP decreased the concentrations of NSE and S100B, and activated the expression of caspase-3 (0.41 ± 0.09 vs. 0.23 ± 0.04, F = 32.387, p < 0.001) under HS; while CGRP8-37 increased NSE (3.99 ± 0.47 vs. 2.40 ± 0.50, F = 11.991, p = 0.000) and S100B (2.19 ± 0.43 vs. 1.42 ± 0.30, F = 4.078, p = 0.025), and activated the expression caspase-3 (0.79 ± 0.10 vs. 0.23 ± 0.04, F = 32.387, p < 0.001). For the cell experiment, CGRP increased Bcl-2 (2.01 ± 0.73 vs. 2.15 ± 0.74, F = 8.993, p < 0.001), PKA (0.88 ± 0.08 vs. 0.37 ± 0.14, F = 20.370, p < 0.001), and p-CREB (0.87 ± 0.13 vs. 0.29 ± 0.10, F = 16.759, p < 0.001) levels; while H89, a blocker of the PKA/p-CREB pathway reversed the expression.@*CONCLUSIONS@#CGRP can protect against HS-induced neuron apoptosis via PKA/p-CREB pathway and reduce activation of caspase-3 by regulating Bcl-2. Thus CGRP may be a new target for the treatment of brain injury in HS.

Calcitonin as a Pharmacological Anchorage in Orthodontics

Objective: This study aimed to evaluate the effects of salmon calcitonin administration as a pharmacological anchoring agent in orthodontics and to determine the influence of locally applied calcitonin on serum calcium levels. The secondary aim was to observe the response of dental and periodontal tissues using light microscopy. Methods: Fourteen healthy male adult Wistar rats with an average weight of 250 g had their teeth moved, seven of which received a local injection of salmon calcitonin in the furcation region of the left upper first molar. Concurrently, the remaining seven were used as controls. In the control group, saline solution was injected in the bifurcation region of tooth 26 to subject these animals to the same stress level as those of the experimental group. After 14 days, a 6 mm diameter orthodontic elastic band was inserted between teeth 26 and 27 in all animals to induce the movement of these teeth. The rats were anaesthetised and exsanguinated on day 21. In both groups, tooth movement and serum calcium levels were measured. The jaws were dissected with straight scissors, and tissue blocks containing gingiva, bone and teeth were identified, fixed and demineralised. Then, the pieces were cut into semi?serial slices, stained with hematoxylin, eosin, and Mallory’s trichrome, and analysed under an Axiophot light microscope. Results: There was significantly less tooth movement in the experimental group ( ±X DP ; 0,150 mm ± 0,037) than in the control group (0,236 mm ± 0,044; P = 0,003), while there was no significant difference in serum calcium levels between the two groups (control ±X DP ; 9,53 mg/dl ± 1,53; experimental 10,81 mg/dl ± 1,47; P = 0,15). Conclusion: While calcitonin did not completely inhibit osteoclast activity, it promoted orthodontic anchorage, apparently, by local action.

Distribution of calcitonin gene-related peptide and vascular endothelial growth factor in the mouse lung at the embryonic and postnatal stages / Distribución del péptido relacionado con el gen de la calcitonina y el factor de crecimiento endotelial vascular en el pulmón de ratón en las etapas embrionaria y posnatal

SUMMARY: Neuropeptide calcitonin gene-related peptide (CGRP) is a neurotransmitter related to vasculogenesis during organ development. The vascular endothelial growth factor A (VEGF-A) is also required for vascular patterning during lung morphogenesis. CGRP is primarily found in organs and initially appears in pulmonary neuroendocrine cells during the early embryonic stage of lung development. However, the relationship between CGRP and VEGF-A during lung formation remains unclear. This study investigates CGRP and VEGF-A mRNA expressions in the embryonic, pseudoglandular, canalicular, saccular, and alveolar stages of lung development from embryonic day 12.5 (E12.5) to postnatal day 5 (P5) through quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Further, we analyzed the expression of CGRP via immunohistochemistry. The VEGF-A mRNA was mainly scattered across the whole lung body from E12.5. CGRP was found to be expressed in a few epithelial cells of the canalicular and the respiratory bronchiole of the lung from E12.5 to P5. An antisense probe for CGRP mRNA was strongly detected in the lung from E14.5 to E17.5. Endogenous CGRP may regulate the development of the embryonic alveoli from E14.5 to E17.5 in a temporal manner.

El péptido relacionado con el gen de la calcitonina (CGRP) es un neurotransmisor vinculado con la vasculogénesis durante el desarrollo de órganos. El factor de crecimiento endotelial vascular A (VEGF-A) también se requiere para el patrón vascular durante la morfogénesis pulmonar. El CGRP se encuentra principalmente en los órganos y aparece inicialmente en las células neuroendocrinas pulmonares durante la etapa embrionaria temprana del desarrollo pulmonar. Sin embargo, la relación entre CGRP y VEGF-A durante la formación de los pulmones sigue sin estar clara. Este estudio investiga las expresiones de ARNm de CGRP y VEGF-A en las etapas embrionaria, pseudoglandular, canalicular, sacular y alveolar del desarrollo pulmonar desde el día embrionario 12,5 (E12,5) hasta el día postnatal 5 (P5) a través de la reacción en cadena de la polimerasa cuantitativa en tiempo real. (qRT-PCR) e hibridación in situ. Además, analizamos la expresión de CGRP mediante inmunohistoquímica. El ARNm de VEGF-A se dispersó principalmente por todo parénquima pulmonar desde E12,5. Se encontró que CGRP se expresaba en unas pocas células epiteliales de los bronquiolos canaliculares y respiratorios del pulmón desde E12,5 a P5. Se detectó fuertemente una sonda antisentido para ARNm de CGRP en el pulmón de E14,5 a E17,5. El CGRP endógeno puede regular el desarrollo de los alvéolos embrionarios de E14,5 a E17,5 de manera temporal.

Correlation between sputum culture results and serum levels of C-reactive protein, amyloid A and procalcitonin in patients with acute exacerbations of chronic obstructive pulmonary disease / 中国基层医药

Objective:To investigate the correlation between sputum culture results and serum levels of C-reactive protein, amyloid A, and procalcitonin in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).Methods:The clinical data of 131 older adult patients with AECOPD who received treatment in the Affiliated Hospital of Shaoxing University between January 2019 and January 2021 were retrospectively analyzed. According to sputum culture results, these patients were divided into a sputum culture positive group ( n = 52) and a sputum culture negative group ( n = 79). The sputum of patients was collected aseptically for isolation and identification of pathogens. The general data [age, gender, history of smoking, underlying diseases (hypertension, diabetes mellitus, coronary heart disease), albumin level, mechanical ventilation, method of sputum suction, duration of antibiotics medication, length of hospital stay] were recorded for each group. The risk factors for positive sputum culture were analyzed using binary logistic regression techniques. The efficiency of serum levels of C-reactive protein, amyloid A, and procalcitonin for predicting positive sputum culture was analyzed using the receiver operating characteristic curve. Results:There were 67 strains of pathogens isolated from 52 older adult patients with positive sputum culture of AECOPD. The main pathogens were Gram-negative bacteria (67.16%) [Klebsiella pneumonia (31.34%)], followed by Gram-positive bacteria (25.37%) and fungi (7.47%). Logistic regression analysis showed that mechanical ventilation ( OR = 2.75, P = 0.020), usage of broad-spectrum antibiotics ( OR = 2.95, P = 0.012), serum C-reactive protein level ≥ 20.96 mg/L ( OR = 2.44, P = 0.007), serum amyloid A level ≥ 18.03 mg/L ( OR = 2.67, P = 0.016) and serum procalcitonin level ≥ 2.08 μg/L ( OR = 2.51, P = 0.013) were independent risk factors of positive sputum culture in older adult patients with AECOPD. The receiver operating characteristic curve analysis showed that the area under the receiver operating characteristic curve depicting serum levels of C-reactive protein, amyloid A, and procalcitonin in combination for predicting AECOPD was 0.896, which is of predictive efficiency for positive sputum culture ( P < 0.05). Conclusion:The sputum culture pathogens in older adult patients with AECOPD are mainly Gram-negative bacteria. Increased serum levels of C-reactive protein, amyloid A, and procalcitonin are independent risk factors for Gram-positive bacteria. Combined detection of serum levels of C-reactive protein, amyloid A, and procalcitonin is highly efficient in the diagnosis of AECOPD and can be used to evaluate the sputum culture results in older adult patients with AECOPD.

Effect of Anchang Decoction on intestinal flora and fecal calcitonin in rats with severe ulcerative colitis / 国际中医中药杂志

Objective:To investigate the effects of Anchang Decoction on intestinal microflora and faecal calprotectin (FC) in rats with severe ulcerative colitis based on probiotics.Methods:Totally 50 rats were taken to prepare a model of severe ulcerative colitis. The rats who successfully modeled were divided into model group, Anchang Decoction low-, medium-, high-dosage groups, Lizhu Changle group, and mesalazine group, with 5 rats in each group. Another 6 rats were set and the blank group. Lizhu Changle group received Lizhu Changle suspension (containing 50 million live bacteria/ml) for gavage; Anchang Decoction low-, medium-, high-dosage groups received Anchang Decoction 1, 5, 10 ml/(kg·d) for gavage; Mesalazine group received Mesalazine suspension (10.5 mg/100 g) for gavage. Rats in the blank group and model group were gavaged with the same volume of normal saline for 7 days. Body mass and disease activity index (DAI) before and after administration were measured. 16s rDNA of lactobacillus and bifidobacterium in feces of rats was detected. FC content of rats was detected by ELISA.Results:Compared with the model group, the weight of rats in each administration group increased ( P<0.05), DAI score decreased ( P<0.05), and the level of calprotectin in feces decreased ( P<0.05), and there was no significant difference in the levels of lactobacillus and bifidobacterium in each administration group ( P>0.05). Conclusion:Anchang Decoction can improve the intestinal micro-ecology by regulating the level of calprotectin in rats with severe ulcerative colitis, thereby playing a therapeutic role.

Epitope identification of calcitonin gene-related peptide antibodies based on ELISA and NMR methods / 中国生物制品学杂志

@#Objective To develop an indirect ELISA-based peptide scanning method combined with nuclear magnetic resonance(NMR)technique for the epitope identification of calcitonin gene-related peptide(CGRP)antibodies.Methods The antigen binding activities of two antibodies(new CGRP antibody and control antibody)were determined by indirect ELISA using each truncated CGRP fragment as coating antigen,and the linear epitope was analyzed according to the EC50value of four-parameter curve. Two-dimensional hydrogen-nitrogen correlation(2D1H-15N HSQC)spectrum of CGRP were acquired by NMR technique,and the binding of antibodies to the arginine of CGRP were analyzed through the disturbance of the antibodies to CGRP signals. Specific arginine modifications were detected by liquid chromatography-mass spectrum(LCMS) and NMR technique,and two arginine resonances were assigned on CGRP by correlating the rank order of the modification rate.ResultsThe antigen binding activities of two antibodies with CGRP(1-37),CGRP(19-37)and CGRP(25-37)showed dose-response relationships,and were fitted with four-parameter equation. However,there were no significant antigen binding with CGRP(1-18),CGRP(19-24)and CGRP(25-37)without C-terminal amide. The linear epitopes of both antibodies were located at the C-terminal of CGRP. The resonances of arginine ε-NH in 2D1H-15N HSQC spectrum disappeared in the presence of the control antibody;and the resonances appeared in the presence of the new antibody. The arginine R11 and R18 of CGRP could bind to the control antibody,but not to the new antibody. The NMR assignment for the arginine resonances were made by correlating the relative ranking of the modification rate where signals A and B arose from R11 ε-NH and R18 ε-NH respectively.ConclusionIn this study,the linear and conformational epitopes of new CGRP antibody and control antibody were identified based on the methods of ELISA and NMR,which may provide a theoretical basis for the design of the candidate therapeutic CGRP antibodies.

Sexual Dimorphism in Mechanical Hypersensitivity Induced by Subcutaneous Injection of M-CSF / 中山大学学报(医学科学版)

ObjectiveTo investigate whether there exists gender differences in mechanical pain hypersensitivity induced by the subcutaneous injection of macrophage colony-stimulating factor （M-CSF） in normal mice and to explore the preliminary mechanism. MethodsThirty 10-week-old C57BL/6J mice were randomly divided into three groups， (n = 10 mice/group, half male and half female). The albumin control group （BSA， 0.3 μg）， low dose M-CSF group （L M-CSF， 0.075 μg） and high dose M-CSF group （H M-CSF， 0.3 μg） received 50 μL BSA or M-CSF injected subcutaneously into the left medial thigh once daily for 3 consecutive days. Before and after drug administration， von-Frey mechanical sensitivity test was used to detect the mechanical paw withdrawal threshold （PWT） in each group. Immunofluorescence was performed to examine the expression changes of Ionized calcium-binding adaptor molecule 1 (Iba1) in skin， calcitonin gene-related peptide （CGRP） and phosphorylated ERK1/2 （p-ERK） in L5-L6 DRG and lumbar spinal dorsal horn. ResultsIn female mice， only high dose of M-CSF caused mechanical allodynia， whereas in male mice both doses produced marked allodynia. Mechanically， high-dose M-CSF induced massive aggregation of subcutaneous macrophages （marked by Iba1） in male and female mice， but more dramatic dependence in female mice. Similar gender differences were also found in the increase of p-ERK and CGRP expression in dorsal root ganglion （DRGs）. Notably， CGRP expression was especially elevated in the fibers of DRG in male mice. Correspondingly， the expressions of p-ERK and CGRP+ terminals in the superficial spinal dorsal horn of male mice were significantly higher than those of female mice after M-CSF treatment. ConclusionSubcutaneous injection of M-CSF triggers sexual dimorphism in mechanical pain hypersensitivity, which is related with differential changes in peripheral macrophage expansion and sensitization of the nociceptive pathway.

Effect of Electroacupuncture at Proximal and Distal Acupoints on Pain-inducing Substances， Macrophages and Related Inflammatory Factors in Myofascial Pain Syndrome Model Rats / 中医杂志

ObjectiveTo explore the possible peripheral analgesic mechanism of electroacupuncture （EA） at promimal and distal acupoints in treatment of myofascial pain syndrome （MPS）. MethodsTwenty-four SD rats were randomly divided into blank group， model group， proximal group， and distal group， with six rats in each group. MPS model was prepared by “strike combined with centrifugal exercise” in all groups except for the blank group. After modeling， the rats in the proximal group received EA at the local myofascial trigger points （MTrPs）， namely the Ashi points， with dilatational waves of frequency of 2/100 HZ and voltage of 2-4 V， current intensity depending on a slight trembling of the left lower limbs， once a day， 15min each time，for 14 days. The rats in the distal group received EA at “Yanglingquan” （GB 34） and “Yinlingquan” （SP 9）， with the same operations as the proximal group. The rats in the blank group and the model group were only grasped and hedged， without other interventions. After intervention， the paw withdrawl mechanical threshold （PWMT） was measured， and variability between the left and right hind paws was calculated. Musculoskeletal ultrasound imaging and electromyography monitoring were performed on the left lower extremity vastus medialis. The morphological changes of vastus medialis muscle of the left lower extremity were observed by HE staining. The positive expression of substance P （SP）， calcitonin gene-related peptide （CGRP）， CD68 and CD206 in muscle tissue was detected by immunohistochemistry. Abdominal aortic serum interleukin-1β （IL-1β）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， interleukin-10 （IL-10）， and interleukin-8 （interleukin-8） were detected by ELISA. ResultsCompared to those in the blank group， the fibers of the vastus medial muscle of the rats in the model group were broken and distorted with thickness in variation， and the myofascia was broken， with fibrillation potential， enlarged muscle cells， inward moved nucleus， and widened muscle space； the variability of PWMT between the left and right hind paws significantly increased， as well as the levels of SP， CGRP， CD68， and CD206 in the vastus medialis muscle （P＜0.01）， and the serum IL-8 and TNF-αlevels were significantly elevated （P＜0.05 or P＜0.01）. Compared to those in the model group， the muscle fibers in the proximal and distal group were complete in shape and arranged in an orderly manner， with continued non-broken myofascia， regular shape of muscle cells， and significantly reduced level of IL-8 （P＜0.01）； the amplitude and frequency of spontaneous discharge in the proximal group significantly decreased， as well as the variability of PWMT between the left and right hind paws， and the levels of SP， CGRP， and CD68 in the vastus medialis muscle， while the CD206 level increased significantly （P＜0.05 or P＜0.01 ）； there was complex discharges in the distal group， with significantly decreased level of CD68 in the vastus medialis muscle and increased level of CD206 （P＜0.01）. Compared to the proximal group， the level of IL-8 in the distal group was significantly higher （P＜0.05）. ConclusionsEA at proximal acupoints can significantly improve the pain threshold and local muscle tissue morpho-logy in rats， and its mechanism may be related to reducing the levels of pain-causing substances and related inflammatory factors and promoting the polarization of macrophages. The analgesic effect of EA at distal acupoints is not obvious， and the mechanism is still unclear.

Calcitonin gene-related peptide (CGRP) concentrations outside migraine attacks in peripheral blood as a potential biomarker for chronic migraine / Concentrações de peptídeo relacionado ao gene da calcitonina (CGRP) fora dos ataques de enxaqueca no sangue periférico como um potencial biomarcador para enxaqueca crônica

Introduction: Chronic migraine is a debilitating condition that affects a significant portion of the population. Accurate diagnosis and treatment of chronic migraine remain a challenge due to the lack of objective biomarkers. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in the pathophysiology of migraine and has been proposed as a potential biomarker for migraine. Methods: We measured CGRP levels in peripheral blood samples collected from 142 participants with chronic or episodic migraine and 24 healthy controls during ictal periods, i.e., outside migraine attacks. We compared CGRP levels between the three groups and assessed the correlation between CGRP levels and clinical features of chronic migraine. Conclusion: Our study provides evidence that CGRP levels in peripheral blood during ictal periods may serve as a potential biomarker for chronic migraine. Further studies are needed to validate these findings and to explore the clinical utility of CGRP as a biomarker for chronic migraine.

Introdução: A enxaqueca crônica é uma condição debilitante que afeta uma parcela significativa da população. O diagnóstico preciso e o tratamento da enxaqueca crónica continuam a ser um desafio devido à falta de biomarcadores objetivos. O peptídeo relacionado ao gene da calcitonina (CGRP) é um neuropeptídeo envolvido na fisiopatologia da enxaqueca e foi proposto como um potencial biomarcador para enxaqueca. Métodos: Medimos os níveis de CGRP em amostras de sangue periférico coletadas de 142 participantes com enxaqueca crônica ou episódica e 24 controles saudáveis ​​durante períodos ictais, ou seja, fora das crises de enxaqueca. Comparamos os níveis de CGRP entre os três grupos e avaliamos a correlação entre os níveis de CGRP e as características clínicas da enxaqueca crônica. Conclusão: Nosso estudo fornece evidências de que os níveis de CGRP no sangue periférico durante os períodos ictais podem servir como um potencial biomarcador para enxaqueca crônica. Mais estudos são necessários para validar estes resultados e explorar a utilidade clínica do CGRP como biomarcador para enxaqueca crónica.

Evaluation of the use of CGRP monoclonal antibodies (mAbs) in migraine prophylaxis in a private clinic / Avaliação do uso de anticorpos monoclonais (mAbs) CGRP na profilaxia de enxaqueca em clínica privada

Introduction: Migraine is considered the second most prevalent neurological disorder in the population and highly disabling. Objective: The aim of this study is to evaluate the use of calcitonin gene-related peptide (CGRP) monoclonal antibodies in migraine prophylaxis, with emphasis on therapeutic response, adverse effects, and impacts on quality of life. Method; A quantitative, retrospective, and descriptive study was carried out, through the analysis of medical records and telephone interviews with patients seen at the Serviço de Neurologia e Neurocirurgia, in the city of Passo Fundo, RGS, Brazil, currently or previously having used at least one dose of the medication. Conclusion: Thus, it is understood that CGRP monoclonal antibodies are able to reduce monthly headache days, reduce pain intensity and promote improvement in work capacity. Therefore, they can be considered effective, safe and well-adhered medications for migraine prophylaxis.

Introdução: A enxaqueca é considerada o segundo distúrbio neurológico mais prevalente na população e altamente incapacitante. Objetivo: O objetivo deste estudo é avaliar o uso de anticorpos monoclonais do peptídeo relacionado ao gene da calcitonina (CGRP) na profilaxia da enxaqueca, com ênfase na resposta terapêutica, efeitos adversos e impactos na qualidade de vida. Método; Foi realizado um estudo quantitativo, retrospectivo e descritivo, por meio de análise de prontuários e entrevistas telefônicas com pacientes atendidos no Serviço de Neurologia e Neurocirurgia, na cidade de Passo Fundo, RGS, Brasil, que já usaram ou usaram pelo menos uma dose do medicamento. Conclusão: Assim, entende-se que os anticorpos monoclonais CGRP são capazes de reduzir os dias mensais de cefaleia, reduzir a intensidade da dor e promover melhora na capacidade de trabalho. Portanto, podem ser considerados medicamentos eficazes, seguros e de boa adesão para a profilaxia da enxaqueca.

Cherubism in Saudi population: a rare case report / Querubismo na população Saudi: relato de um caso raro

Cherubism is a rare hereditary benign fibro-osseous disorder characterised by bilateral swelling of the mandible and/or maxilla with varying severity of involvement. It occurs because of dominant mutations in SH3BP2 gene on the chromosome 4p16.3. On radiography cherubic lesions appear as multilocular cystic radiolucencies in the jaw bones giving a soap bubble appearance. These lesions usually heal by themselves by the time the patient attains puberty. Treatment is necessary only in aggressive cases where there is severe facial deformity or vital functions are hampered. Surgical corrections are preferred when the lesion is in its dormant phase. The aim of the present case report is to illustrate a case of cherubism in a 9-year-old Saudi boy which is a very rare occurrence as only 1 case of cherubism has been reported so far in the Saudi Arabian population (AU)

Querubismo é uma desordem fibro-óssea hereditária rara caracterizada por aumento de volume bilateral da mandíbula e/ou maxila com graus variáveis de severidade. Ocorre devido a mutação dominante no gene SH3BP2 no cromossomo 4p16.3. Radiograficamente as lesões de querubismo aparecem como radiolucência multilocular semelhantes a bolhas de sabão nos ossos maxilares. Geralmente as lesões involuem espontaneamente quando o paciente atinge a puberdade. O tratamento se faz necessário apenas nos casos mais agressivos que demonstram deformidade facial severa ou comprometimento de funções vitais. Correções cirúrgicas são preferíveis quando a lesão está na fase dormente. O objetivo do presente relato é ilustrar um caso de querubismo em um paciente de 9 anos da Arábia Saudita, sendo este um evento raríssimo com apenas um outro caso relatado na população da Arábia Saudita (AU)

Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice / 中山大学学报(医学科学版)

ObjectiveTo investigate the analgesic action and mechanism of intrathecal 2R， 6R-hydroxynorketamine （2R， 6R-HNK） on spared nerve injury （SNI）-induced chronic neuropathic pain （CNP） in female mice. MethodsSNI was used to establish acute and chronic CNP models in female mice. The mice were randomly divided into different groups with administration of vehicle， 2R， 6R-HNK or S-ketamine （10 mg/kg intraperitoneal injection/i.p. or 7， 21 μmol/L intrathecal injection/i.t.） at 3 weeks after or 30 min/1 d before operation （n = 3 - 7 mice/group）. The curative or preventive effect of 2R， 6R-HNK was evaluated by mechanical paw withdrawal threshold （PWT） and the analgesic efficiency. Finally， immunofluorescence and RT-PCR of dorsal root ganglion （DRG） and spinal dorsal horn （SDH） were used to explore the possible mechanisms. ResultsCompared with vehicle， intrathecal injection of 2R， 6R-HNK largely reversed SNI-induced bilateral mechanical allodynia in a delayed-and-dose-dependent way. Among them， 21 μmol/L 2R， 6R-HNK reached its maximum analgesic efficiency （75.32±7.69） % at 2 d. Pre-intrathecal delivery of 2R， 6R-HNK also delayed the development of bilateral mechanical hypersensitivity 2 - 3 d induced by SNI. Mechanically， 2R， 6R-HNK reversed not only the abnormal excitability of neurons in bilateral DRG and superficial SDH， but also the upregulation of calcitonin gene-related peptide （CGRP） and brain-derived nerve growth factor （BDNF） in DRG. ConclusionIntrathecal administration of 2R， 6R-HNK exerts an analgesic effect against CNP， probably via suppressing abnormal neuronal excitability in ascending pain pathway as well as down-regulating CGRP and BDNF expression in DRG neurons.

Reassess the value of calcitonin and carcinoembryonic antigen in the diagnosis and treatment of medullary thyroid cancer / 国际外科学杂志

In patients with medullary thyroid carcinoma (MTC), calcitonin (Ctn) and carcinoembryonic antigen (CEA) were the most important serum biomarkers for diagnosis, evaluation and follow-up. Approximately 0.3% to 5.9% of the thyroid nodule population could present with elevated Ctn on screening, and a diagnosis of MTC can be basically confirmed when serum Ctn > 100 pg/ml.. Ctn and CEA levels could reflect tumor burden and help determine the extent and timing of surgery. When preoperative serum Ctn >200 pg/mL or CEA >30 ng/mL, nearly more than one-third of patients had lateral neck lymph node metastasis. Few patients developed distant metastasis when Ctn<500 pg/mL, however the proportion of distant metastasis could reach 75% when CEA>100 ng/mL. In inherited MTC patients, tumors with Ctn<30 pg/mL were usually localized in the gland without metastasis. The time to normalization of serum Ctn and CEA postoperatively was one month in most patients. According to the response to initial therapy, patients with undetectable Ctn and normal CEA had a low risk of relapse and death in the follow-up period. The risk of local recurrence, LNM and distant metastasis increased as Ctn levels rose. The Ctn/CEA doubling time could predict the disease prognosis, and when it was less than 0.5 years, most patients would die.

It is time anti-CGRP monoclonal antibodies be considered first-line prophylaxis for migraine / Já é tempo de os anticorpos monoclonais anti-CGRP serem reconhecidos como profilaxia de primeira linha para a migrânea

ABSTRACT The result of more than thirty years of research, anti-CGRP monoclonal antibodies are currently the state of the art for migraine preventive therapy. Their efficacy and safety, supported by an already large and growing body of evidence, are added by many other advantages: an early onset of action, favorable posology, negligible pharmacological interaction, and a broad-reaching efficacy in many challenging clinical contexts. When compared to standard prophylactics, these novel medications seem at least as efficacious, clearly more tolerable and, consequently, with a superior adherence profile. Furthermore, recently published analyses indicate that they are cost-effective, especially among those with chronic migraine. Yet, current guidelines endorse their use only after multiple other preventives have failed or have been deemed not tolerable. Although this recommendation may have been sensible at first, the now available data strongly point that time has come for anti-CGRP monoclonal antibodies to be acknowledged as first-line treatments for migraine patients with severe disability. For these individuals, delaying treatment until several other alternatives have failed incurs in significant losses, both economically and to many relevant aspects of their lives.

RESUMO Frutos de mais de 30 anos de pesquisa, os anticorpos monoclonais anti-CGRP são atualmente o que há de mais moderno no tratamento preventivo da migrânea. À sua eficácia e segurança, já bem estabelecidos por um grande corpo de evidências, acrescentam-se outras vantagens: um início precoce de ação, posologia favorável, mínima interação farmacológica, e eficácia comprovada em uma variedade de contextos clínicos frequentemente desafiadores. Quando comparados a outros profiláticos, estas medicações aparentam ser ao menos tão eficazes, evidentemente mais toleráveis e, portanto, com melhor perfil de adesão. Ademais, estudos recentemente publicados indicam que elas são custo-efetivas, especialmente entre pacientes com migrânea crônica. Ainda assim, as diretrizes atuais orientam o seu uso apenas caso haja refratariedade ou intolerância a múltiplos outros preventivos. Apesar de esta recomendação poder ter sido sensata a priori, os dados disponíveis atualmente corroboram que já é tempo de estes anticorpos monoclonais serem reconhecidos como tratamentos de primeira linha para a migrânea associada à incapacidade grave. Para estes pacientes, demorar a oferecer este tratamento até que outras múltiplas alternativas tenham falhado, leva a perdas significativas, tanto economicamente quanto em múltiplos outros aspectos relevantes das suas vidas.

Risk Factors of lateral cervical lymph node metastases and survival analysis in patients with medullary thyroid carcinoma / 中华内分泌外科杂志

Objective:To investigate the risk factors of cervical lymph node metastasis (LNM) and survival analysis in patients with medullary thyroid carcinoma (MTC) .Methods:93 patients with MTC admitted to the Department of General Surgery and Department of Otorhinolaryngology, First Medical Center of PLA General Hospital from Sep. 2008 to Aug. 2020 were analyzed retrospectively, including 45 males and 48 females, with an average age of 47 years old. SPSS 26.0 statistical software was used for data processing of the initial surgical year and procedures, tumor pathological stages, preoperative calcitonin (Ctn) level, preoperative carcinoembryonic antigen (CEA) level, LNM status, recurrence free survival (RFS) , etc. The risk factors of LNM and prognosis of MTC patients were analyzed by COX univariate and multivariate regression. Kaplan Meier method was used to estimate the survival rates of independent risk factors affecting prognosis and draw their survival curves.Results:The median follow-up time of 93 patients was 53 months, ranging from 2 to 192 months. The 1-year, 3-year, 5-year and 10-year survival rates were 97.8%, 96.6%, 94.6% and 88.9% respectively. Multivariate COX regression analysis showed that Initial surgical procedures ( P=0.018) and preoperative Ctn level ( P=0.012) were independent risk factors of central cervical LNM. Preoperative Ctn level ( P=0.028) and Capsule invasion ( P=0.024) were the independent risk factors of lateral cervical LNM. Preoperative Ctn level≥180.30 pg/ml and ≥234.15pg/ml indicated central and lateral cervical LNM respectively (all P<0.001) . Distant metastasis was an independent risk factor of RFS ( P=0.037) of MTC. Conclusions:Standardized surgical procedures are recommended for initial treatment of MTC, which can reduce the possibility of residual occult metastasis and the risk of reoperation. Distant metastasis affects prognosis of MTC.

Modulating effects of RAMPs on signaling profiles of the glucagon receptor family

Receptor activity-modulating proteins (RAMPs) are accessory molecules that form complexes with specific G protein-coupled receptors (GPCRs) and modulate their functions. It is established that RAMP interacts with the glucagon receptor family of GPCRs but the underlying mechanism is poorly understood. In this study, we used a bioluminescence resonance energy transfer (BRET) approach to comprehensively investigate such interactions. In conjunction with cAMP accumulation, Gα q activation and β-arrestin1/2 recruitment assays, we not only verified the GPCR-RAMP pairs previously reported, but also identified new patterns of GPCR-RAMP interaction. While RAMP1 was able to modify the three signaling events elicited by both glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), and RAMP2 mainly affected β-arrestin1/2 recruitment by GCGR, GLP-1R and glucagon-like peptide-2 receptor, RAMP3 showed a widespread negative impact on all the family members except for growth hormone-releasing hormone receptor covering the three pathways. Our results suggest that RAMP modulates both G protein dependent and independent signal transduction among the glucagon receptor family members in a receptor-specific manner. Mapping such interactions provides new insights into the role of RAMP in ligand recognition and receptor activation.

Association between functional dyspepsia and serum levels of brain-gut peptides in children / 中国当代儿科杂志

OBJECTIVES@#To study the association between functional dyspepsia (FD) and serum levels of brain-gut peptides including calcitonin gene-related peptide (CGRP), nesfatin-1, and ghrelin in children.@*METHODS@#A total of 38 children with FD who attended Shengjing Hospital of China Medical University from November 2019 to December 2020 were enrolled as the FD group. Thirty-four healthy children were enrolled as the control group. Serum samples were collected from all of the children. Enzyme-linked immunosorbent assay was used to measure serum levels of CGRP, ghrelin, and nesfatin-1 for comparison between the two groups. The scores of clinical symptoms were determined for the children with FD. Spearman rank correlation analysis was used to investigate the correlation of symptom scores with the serum levels of brain-gut peptides.@*RESULTS@#The FD group had significantly higher serum levels of nesfatin-1 and CGRP than the control group (P<0.05), while there was no significant difference in the serum level of ghrelin between the two groups (P>0.05). The serum level of nesfatin-1 was positively correlated with the symptom score of early satiety (rs=0.553, P<0.001), but was not significantly correlated with the total score of FD (rs=0.191, P=0.250). The serum level of CGRP was positively correlated with the scores of abdominal pain (rs=0.479, P=0.002) and belching (rs=0.619, P<0.001) and the total score of FD (rs=0.541, P<0.001).@*CONCLUSIONS@#CGRP and nesfatin-1 may play an important role in the pathophysiological process of FD.

Expression of neuropeptide Y, calcitonin gene related peptide and inducible nitric oxide synthase in myocardium of rats with heart failure / 解剖学报

Objective To explore the relationship between the content of neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), inducible nitric oxide synthase (iNOS) and the changes of the corresponding receptors in myocardial tissue and the development of heart failure. Methods Doxorubicin was used to prepare rat heart failure models(10 rats), control group (10 rats), Cardiac ultrasound testing evaluated its cardiac function, the distribution of nerve fibers was detected by nerve staining kit method, the tissue expression levels of NPY, CGRP, iNOS and neuropeptide Y receptor Y1 (NPY1R), receptor activity modifying protein 1 (RAMP1), guanylate cyclase beta 1(GCYB1) were observed by immunofluorescence and immunohistochemical staining method. Western blotting was used to detect the protein expression levels of NPY, CGRP, iNOS and NPY1R, RAMP1, GCYB1 receptors in myocardial tissue. Results Compared with the control group, the protein expression level and tissue expression distribution of CGRP in the myocardial tissue of the heart failure group were significantly decreased (P<0.05), while the density of nerve fibers, the protein expression level and tissue expression distribution of NPY and iNOS were significantly increased (P<0.05). The protein expression levels of GCYB1 and RAMP1 in myocardial tissue of the heart failure group were significantly increased, while the protein expression levels of NPY1R were significantly decreased (P<0.05). Conclusion Heart failure can lead to remodeling of the content and distribution of nerve fibers, CGRP, NPY, iNOS and their receptors in myocardial tissue, which may be one of the causes of cardiac innervation disorders.

Clinicopathological and prognostic analysis of medullary thyroid carcinoma co-existent with Hashimoto's thyroiditis / 中华普通外科杂志

Objective:To investigate the clinicopathological features and prognosis of medullary thyroid carcinoma (MTC) co-existent with Hashimoto's thyroiditis (HT).Methods:Seven cases of MTC co-existent with HT were collected from Fujian Cancer Hospital between Jan 2007 and May 2021. Its clinicopathological features were analyzed.Results:All patients were adult female with a median age of 49 years, and 6 of them were unilateral MTC. The tumor diameter ranged from 0.4 to 7.0 cm. The thyroid tissue surrounding the tumor showed HT. The follow-up time was 16 to 152 months, with a median time of 61 months, 5 patients (tumor diameter <1 cm) were biochemically cured, 1 patient (tumor diameter >1 cm) was anatomically cured. The another patient died due to tumor progression 30 months after surgery, the tumor cells in which were highly atypia and more mitoses (5~8/10HPF) necrosis and vascular invasion were also observed.Conclusion:MTC with HT are mostly sporadic cases, and most of them have a fair prognosis.

Expression and significance of calcitonin and osteopontin in peripheral blood of patients with atrial fibrillation / 中国综合临床

Objective:To investigate the expression levels of serum calcitonin (CT) and osteoponin (OPN) in peripheral blood of patients with atrial fibrillation (AF) and their relationship with AF.Methods:A case control study was conducted, 160 AF patients treated in Shaanxi Provincial People's Hospital from June 2020 to December 2021 were selected as case group, and 160 healthy people in the same period were selected as control group. The expression levels of serum CT and OPN in the two groups were analyzed retrospectively, and the correlation between them and AF was analyzed. The value of CT and OPN levels in predicting the occurrence of AF was analyzed by receiver operating characteristic (ROC). Kappa consistency test was used to analyze the efficacy of the combination of them in predicting the occurrence of AF.Results:The serum calcitonin level ((13.5±3.2) ng/L) in the case group was lower than that in the control group ((17.3±3.1) ng/L), and the osteopontin level ((53.8±8.2) μg/L) was higher than that of the control group ((44.1±6.8) μg/L), the difference between the two groups was statistically significant ( t=10.79, P<0.001; t=11.50, P<0.001). The results of binary logistic regression analysis showed that serum calcitonin was the protective factor of atrial fibrillation ( OR=0.723, 95% CI: 0.661-0.790, P<0.001), and osteopontin was the risk factor ( OR=1.183, 95% CI: 1.131-1.237, P<0.001). ROC analysis showed that the area under curve (AUC) of CT, OPN and their combination in predicting AF were 0.794, 0.824, and 0.892, respectively. The predictive critical value for serum CT was <15.0 ng/L and >48.5 μg/L for OPN. The sensitivity, specificity of the combination in AF prediction were 67.50% and 93.75% respectively, and Kappa value was 0.613. Conclusion:The expression of serum CT and OPN was abnormal in patients with atrial fibrillation. The prediction of AF by combined examination of the two had a high degree of consistency with the actual results, which could provide reference for early diagnosis and treatment of AF. However, the rate of missed diagnosis was relatively high, which needs attention in clinical application.