This meta-analysis aimed to evaluate the efficacy and safety of Javanica oil emulsion injection (JOI) combined with chemotherapy versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).  Electronic databases including EMBASE, PUBMED, the Cochrane library, and Chinese Biological Medical disc (CBM) were searched until May 2018. The clinical trials reporting efficacy and immune function of JOI combined with chemotherapy versus chemotherapy in advanced NSCLC were included according to the inclusion and exclusion criteria. Stata 11 and RevMan 5.3 were used for meta-analysis. P < 0.05), improvement in Karnofsky Performance Status (standard mean difference (SMD) = 1.59; 95% CI: 1.41–1.77; P < 0.01), incidence of adverse events , percentage changes of CD3+ cells , CD4+ cells , natural killer cells , but not CD8+ , and value of CD4+/CD8+  between the JOI combination group and control group. Funnel plot and Begg's and Egger's analysis indicated that there was no significant publication bias (P > 0.05).  Twenty-four studies involving 2089 cases were included. The results of the meta-analysis showed that there were significant differences in objective response rate (risk ratio (RR) = 1.17; 95% confidence interval (CI): 1.05–1.29;  JOI may be effective to improve the efficacy of chemotherapy in advanced NSCLC patients, accompanied with better levels of immune cells. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80%–85% of lung cancer . It has 3+, CD4+, and CD8+ cell subsets belong to T lymphocytes and play important roles in antitumor immunity [8+ cell subpopulation, also known as cytotoxic T cells, participates in the regulation of the body's immune balance [4+/CD8+ ratio is an important indicator reflecting the body's immune status and cellular immune function [The CDimmunity , 6. The  balance . CD4+/CDfunction , 10. Chefunction .Brucea javanica [Brucea javanica oil have specific affinity with the tumor cells and can adhere to the tumor cells for a long time, which is beneficial for the penetration of antitumor components into the tumor cells. This may result in reducing the damage to the normal tissue cells and the risk of adverse events of chemotherapy [Brucea javanica oil injection on efficacy and immunity in patients with advanced NSCLC is needed.Javanica oil emulsion injection (JOI) is a traditional Chinese medicine preparation that proves to kill tumor cells while protecting the body's immune function –14. The javanica –14. The javanica –14. Precjavanica –16. At totherapy –19. JOI otherapy , 21. Theotherapy . Althougotherapy  evaluateIn this study, we systematically searched several databases, extracted relevant data, and analyzed the impact of JOI combined with chemotherapy versus chemotherapy on efficacy and immune function in advanced NSCLC patients.This study was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The sea3+), helper T lymphocytes (CD4+), cytotoxic T lymphocytes (CD8+), ratio of CD4+/CD8+ and natural killer cells (NK), quality of life, and incidence of adverse events related to chemotherapy. Animal studies, case reports, reviews, clinical experience, and duplicated literature were excluded.(1) Patients: advanced NSCLC diagnosed by sufficient evidence, such as cytology and/or pathology and imaging exams. The advanced disease was defined as stage III B and/or IV NSCLC; (2) type of study: RCTs and/or retrospective studies; (3) intervention: JOI plus platinum-based chemotherapy versus platinum-based chemotherapy; (4) outcomes: primary endpoints were efficacy and survival rates. Secondary endpoints were cellular immune function indicators such as percentages of total T lymphocytes , overall response rate (ORR), disease control rate (DCR), quality of life (QoL), Karnofsky Performance Scores (KPS), survival rates, and incidence of adverse events. The author was contacted via email if it was necessary to access sufficient data.The extracted data were: (1) general information, such as study title, name of the first author, time of publication, and source of the literature; (2) baseline data including sex, age, diagnostic criteria, number of participants, description of the reasons for withdrawal, or follow-up visits lost; (3) design and implementation data including study type, duration of follow-up, interventions, and measurement units; (4) Outcome indicators, such as changes of cellular immune function indicators , so the fixed effect model was used. As shown in P < 0.05), indicating that the rate of disease control in the JOI-combined chemotherapy group was significantly better than that in the chemotherapy alone group (P > 0.05), JOI + NP vs NP alone , JOI + GP vs GP alone . The results of the sensitivity analysis suggested that neither the RR nor the 95% CI would change significantly if excluding either one of the included studies.A total of 21 studies , 42–47 rne group . The resP > 0.05).Only three RCTs , 37, 46 P < 0.01, Another concern was the impact on the quality of life. We extracted data about number of patients who had improved quality of life, and the combined estimate from eight RCTs , 42, 44 3+ cells after treatment. The random effect model applied as a statistical significant heterogeneity was found . The results showed that the SMD was 2.00 , indicating that adding JOI to chemotherapy was associated with increased percentage of total lymphocytes in advanced NSCLC , so the random effect model was applied. As shown in P < 0.01).Twenty-one articles , 31–47 eI2% >50%), and the random effect model was used. The results illustrated that the changes of CD8+ cells were similar between the JOI combination group and chemotherapy alone group  . As shown in 4+/CD8+ ratio between the JOI plus chemotherapy group versus chemotherapy group .The ratio of CD studies –45, 47. I2 test found that there was no homogeneity among the included studies (I2% >50%), so the random effect model was used. As shown in P < 0.01).Ten articles , 41, 43 P > 0.1). Therefore, the combined effects were calculated using relative risk based on the fixed effect model. As shown in There were 12 , 45, 47,P=0.928; Egger's test: P=0.495).The funnel plot analysis of the included studies was conducted using data of the total response rate. The symmetry of the funnel graph is good , suggest3+, CD4+, and NK cells. With regard to safety, the incidences of myleosuppression in JOI combined with chemotherapy were significantly lower than that of the chemotherapy group. JOI-combined chemotherapy group and chemotherapy alone group shared similar incidences in gastrointestinal adverse events and liver function damage.In this study, clinical studies of JOI combined with chemotherapy versus chemotherapy alone in the treatment of advanced NSCLC were included to evaluate the efficacy and safety after treatments. The meta-analysis confirmed that the JOI-combined chemotherapy was significantly better than the chemotherapy alone in terms of overall response rate, disease control rate, and improvement in quality of life, along with better changes of cellular immune function indicators, such as percentages of CDPreviously, three meta-analyses , 22, 48 3+ T lymphocytes accounts for 10% to 20% of the first trimester human decidual leukocyte population. Among these CD3+ lymphocytes, 40% to 75% of them are CD8+ cytotoxic T lymphocytes (CTLs), and 30% to 45% are CD4+ helper T cells (Th) [3+ and CD4+ cells were decreased in either JOI combination therapy group or chemotherapy alone group. We found that the percentages of CD3+ and CD4+ cells in the combination group were 2% and 1.55% more than those in the chemotherapy group, respectively. This indicates that JOI may protect these cells from chemotherapy. The CD8+ cell subpopulation is known as cytotoxic T cell, with the function of regulating the body's immune balance [8+ cells when comparing different treatment groups, as well as the CD4+/CD8+ ratio, which is an important indicator reflecting the body's immune status and cellular immune function [As previously reported, CDlls (Th) . T lymphlls (Th) , 49. In  balance , 7. We dI2% was found to be relatively high in some evaluations, indicating that there was obvious heterogeneity among these analyses. The main reason may be as following: the types of some research were retrospective studies, though there were also randomized controlled trials; the purpose and size of each trial varied; the patient's baseline characteristics , treatment, severity of the disease, dose of medication, and the duration of treatment also varied in some extent. Although the random effect model was used in the analysis, and the influence of heterogeneity was eliminated to some extent, it could not completely avoidable. Therefore, large sample, multi-center studies are needed to confirm the findings.In this meta-analysis, the The results of the quality assessment of the research literature showed that the included studies were of moderate quality and only few of them showed specific randomization method was used during the process of randomization. The rest of the studies did not show their specific stochastic and allocation concealment methods. Although our study included as many as 24 articles, the number of patients in each trial was relatively small, and the existence of publication bias may be inevitable. This may be related to the published literature had positive findings. The lost ones could be grey literature, such as unpublished literature, unpublished results due to negative results, special reports, and so on. These factors were bound to affect the results of our meta-analysis and may even amplify interventions. With regards to the materials, methods, and timing of analysis about immune function, we found that the materials used for analysis were peripheral blood samples, the methods used to detect the percentages of different immune cells were flow cytometry, and the methods used to measure the concentrations of cytokines were enzyme-linked immunosorbent assay. The timings to test the samples were at baseline and posttreatment. As all the samples were peripheral blood, and the measurement methods were the same type, we consider there was low risk of selection and measurement bias with regards to the samples and methods. Although all the included studies reported the test timings were before and after treatments, the exact time to collect the samples were not mentioned, increasing the risk of selective reporting. In view of the above defects and problems, it was suggested that the results of this study should be applied cautiously.The results of this study showed that JOI combined with chemotherapy was effective in treatment of advanced NSCLC patients, and accompanied with better percentages of immune cells. However, the overall quality of our evidence is moderate. Further research is needed to verify the efficacy of this therapy.


The most common site of metastasis was the nasal cavity (n = 8). Five patients received radical tumor resection and the others underwent radiotherapy, chemotherapy, or combined chemoradiotherapy. The 2-year survival was 28%. In summary, metastasis to the sinonasal cavity remains extremely rare. A high degree of suspicion regarding the possibility of metastatic spread to the sinonasal region is necessary for patients with a previous history of malignancy who present with new sinonasal symptoms. The treatment strategy of sinonasal metastatic cancer is usually palliative therapy and the prognosis remains poor. However, early detection and diagnosis, coupled with aggressive treatment, may improve patient quality of life.Extranasal cancers that metastasize to the sinonasal cavity are very rare. To date, there are only limited reports regarding this rare condition within the literature. Therefore, we retrospectively reviewed all patients diagnosed with metastatic cancer of the sinonasal tract from 2003 to 2018 at a tertiary academic medical center. Patient demographic data, clinical presentation, treatment modalities, and outcomes were investigated. There were a total of 17 patients  included in the analysis. The mean age was 56.8 years (range 27–80). The most common primary malignancies were hepatocellular carcinoma ( Sinonasal malignancies are extremely rare and generally present as primary malignancies. They account for approximately 3% of upper respiratory tract malignancies ,2,3,4. TDue to its limited occurrence, information regarding sinonasal metastases remains to be investigated. In the current study, we present tumor clinicopathologic characteristics, treatment modalities, and prognosis of 17 patients diagnosed with sinonasal metastases.This was a retrospective review of patients diagnosed with sinonasal metastases and treated at Taipei General Veterans Hospital in Taiwan between 1 January 2003 and 31 December 2018. Institutional Review Board approval was obtained. Data regarding patient demographics, presenting signs and symptoms, tumor pathology, primary tumor site, metastatic sites, laboratory studies, relevant imaging scans, treatment modalities, complications, and outcomes were collected.Quantitative data were summarized as the mean ± standard deviation (SD) and categorical variables as percentages. IBM SPSS 20.0 software  was used for the statistic analysis. The Kaplan–Meier method was used to calculate survival trends.Demographic data are summarized in n = 7), headache (n = 3), nasal obstruction (n = 2), diplopia (n = 1), extraocular movement limitation (n = 1), and facial swelling (n = 1)  . For cas (n = 1) . CT or M (n = 1) .n = 3), gastrointestinal tract adenocarcinoma (n = 3), invasive ductal carcinoma of the breast (n = 2), retroperitoneal leiomyosarcoma (n = 2), poorly differentiated thyroid carcinoma (n = 1), thyroid papillary carcinoma (n = 1), melanoma of the foot (n = 1), osteosarcoma of the tibia (n = 1), laryngeal mucoepidermoid carcinoma (n = 1), retrorectal neuroendocrine carcinoma (n = 1), and lung adenocarcinoma (n = 1)  ( (n = 1)   . There wThere were five patients who underwent radical tumor excision, and one who underwent tumor debulking. Five patients received radiotherapy, and 10 patients underwent palliative chemotherapy .The follow-up duration ranged from 1 month to 35 months. One patient was lost to follow-up (case No. 1). At the last follow-up, three patients were free from disease , four patients were still receiving regular follow-ups or treatment for residual and/or recurrent disease , and nine patients died from disease  . The 1-ySinonasal metastases from distant extranasal sites is exceedingly rare. In the literature, nearly half of sinonasal metastases originated from the kidneys, followed by the lungs, breasts, colon, prostate, urogenital ridge, gastrointestinal tract, thyroid, and pancreas  1,5,9,1,17,18,19It is well-established that chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important risk factors for the development of HCC ,30. InciPrior reports have identified the maxillary sinus as the most common site of metastasis, followed by the sphenoid, ethmoid, frontal sinuses, and, finally, the nasal cavity ,33,34,35The symptoms for such tumors are usually non-specific, similar to that of primary sinonasal tumors , and arep > 0.05). Tumor biology may play a major role in metastatic duration, though the small sample size of this study limits more in-depth analysis.Time from treatment to the development of metastases ranged from 2 months to 18 years and 7 months. The wide variation may be related to the initial M (the presence of metastasis) stage of the patient when diagnosed with the cancer. For cases with initial presentation of other metastatic sites, which suggests widespread disease, the duration of the development of sinonasal metastasis should be shorter. However, in our study, the mean metastatic duration for an initial M0 stage was 22 months (4 cases), which was shorter compared to patients with an initial M1 stage , with no significant difference between the two groups  ahead of time to rule out intracranial extension, as well as to determine the vascularity of the lesion, and also for pre-operative surgical evaluation. For extranasal primary cancers, expression of specific biomarkers, such as carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA), may be considered. For instance, if the patient had a history of breast cancer, the expression of human epidermal growth factor receptor 2 (HER2) and glandular morphology in malignant cells should be checked. Primary sinonasal malignancies and sinonasal metastases may overlap in clinical behavior and histopathologic appearance. Three of our cases were metastatic adenocarcinomas of gastrointestinal or colorectal origins. This is to be distinguished from primary sinonasal intestinal-type adenocarcinoma, which may share similar morphology and immunophenotyping, such as immunoreactivity for CK20 and cdx2. In our study, there were also two metastatic breast carcinomas, of which the morphology may be variable and may lack specificity. Therefore, the lesion may not be easily separated from a high-grade non-intestinal type adenocarcinoma. One of our patients was a metastatic rectal neuroendocrine carcinoma, and its pathologic findings were identical to that of a primary sinonasal neuroendocrine carcinoma. Therefore, the precise diagnosis of sinonasal metastases relies on the combination of clinical, radiological, and pathologic information. Metastases to the sinonasal cavity represent advanced distant disease and are naturally associated with poor prognosis, and, in the vast majority of cases, may not be treated with a curative intent. Mickel and Zimmerman reviewed the survival in 26 cases of malignancies that metastasized to the sphenoid sinus. Only nine cases lived for more than six months and four cases survived for at least two years . MultifoIn our study, 10 (58.8%) of the 17 patients died in the follow-up period. The shortest survival time was 2 months and the longest was 35 months. There were three patients alive without obvious residual sinonasal metastatic lesions, and three patients alive with either residual sinonasal metastases or other distant metastases. The 1-year survival was 47%, and the 2-year survival was 28.1%. There are studies that showed that differences in prognosis are apparent based on the presence of isolated or widespread disseminated disease . In addiIndeed, pathology may play a major role in patient survival. All patients with HCC and melanoma died of the disease, which is characteristic of the known poor survival when compared to other tumor types. One case with thyroid papillary carcinoma, a malignancy with a good prognosis, received surgical excision of a nasal septal metastatic lesion and was still alive without obvious recurrence. In regard to targeted therapy for metastatic breast cancer, one patient receiving target therapy was still alive, while another who did not receive targeted therapy died of the disease. Four out of seven patients receiving target therapy died regardless of the cancer type, including one case of HCC, one case of lung adenocarcinoma, one case of gastric adenocarcinoma, and one case of cecal adenocarcinoma. Since this was a retrospective study, there may be some bias to stratify the patients based on receiving targeted therapy, due to its recent development. Cancer cases in more recent years would be more likely to receive the novel targeted therapies compared to those from prior years. In our study, 11 patients had widespread metastatic disease when sinonasal metastasis  was diagnosed, while 5 cases presented with isolated sinonasal metastasis. In our study, gastrointestinal adenocarcinoma and hepatocellular carcinoma were the top two common primary tumors that metastasized to the sinonasal tract, which is quite different from reports on Western countries. The nasal cavity was the most common site for metastasis, which is also quite different from previous reports where the maxillary sinus was the most common site. The similar findings included the mean age, the sex distribution, and the poor prognosis . There aSinonasal metastases from extranasal primary malignancies are rare, and patients usually suffer from non-specific symptoms. Treatment modalities differ based on the origin and characteristics of the primary tumor. The prognosis remains poor, though early detection and aggressive treatment may help to improve quality of life.


Patients with ischemic stroke (IS) often suffered from the problem of erectile dysfunction (ED) and psychological disease. However, they are often ignored because these symptoms are more obvious in the convalescent stage of stroke, which affects the quality of sexual life of patients. This study aimed to investigate the incidence of ED, sexual quality of life, and mental state of patients after stroke, as well as analyze the relevant risk factors affecting their psychological status.A total of 361 IS patients were enrolled. The international erectile function index-5 scale was used to diagnose ED. Accordingly, the patients were divided into ED group and non-ED group. Magnetic resonance imaging was used to evaluate the brain lesions of patients. We assessed neurological deficits by the National Institutes of Health Stroke Scale score and patient health questionnaire-9 (PHQ-9) and general anxiety disorder-7 (GAD-7) were used to evaluate the depression and anxiety. The differences between the ED group and the non-ED group clinical factors were compared.P < .01) and GAD-7  scores, were more likely to have the frontal lobe  and lateral ventricle  lesions, with hypertension  and hyperlipidemia (48.2% vs 25.4%), and on antihypertensive  and hypolipidemic drug . Multivariate logistic regression analysis showed that antihypertensive drug , depression  and anxiety  might be the independent risk factors for ED group.The response rate was 88.6% (n = 320), and more than two-thirds of patients reported ED (77.8%). Patients with ED had higher PHQ-9 (8.40 ± 4.18 vs 4.94 ± 3.73, ED is more common in male IS patients. Antihypertensive drug, depression and anxiety are the main factors affecting ED. The number of deaths due to IS in China is second only to tumors. Epidemiological studies have shown that there are between 1.5 million and 2 million new IS in China each year.,3Ischemic stroke (IS) refers to the sudden decrease or stop of local blood supply to the brain tissue, resulting in ischemia and hypoxia, leading to necrosis and softening of the brain tissue, accompanied by clinical symptoms such as hemiplegia and aphasia.,5 ED can be caused by many different diseases, including psychological stress, vascular disease, decreased hormone levels, relationship between husband and wife, and socioeconomic status.,7 In addition to causing limb movement, psychological and cognitive impairment, IS also has important impacts on the patient's sexual function, especially sexual life frequency, erectile function, sexual desire, sexual excitement, and so on. However, there is limited information on the incidence of ED in men and related risk factors. Whether IS is an explicit cause for ED is uncertain. Therefore, this study aimed to investigate the erectile function of male patients after IS, and analyze the influencing factors related to erectile function.Erectile dysfunction (ED) is manifested by the penis unable to reach or maintain sufficient hardness to obtain a more satisfactory coitus.2This study was a cross-sectional and clinical-based survey and had been approved by the Ethics Committee of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine. Male stroke patients who hospitalized in the Department of Neurology, Dongzhimen Hospital from June 2016 to January 2018 were investigated by questionnaire. The inclusion criteria were:(1)male patients aged ≤65 years;(2);met the diagnostic criteria for IS(3)stable for at least 6 months;(4)those who volunteered to complete the questionnaire.Exclusion criteria were:(1)sexual dysfunction before the patient's stroke;(2)patients with unconsciousness or severe language dysfunction after the onset of illness, inability to make informed consent or adequate cooperation in the study;(3)local lesions that affect erectile function before onset, such as penile sclerosis, anatomical malformation, penile cancer, or neurosis;(4)pre-onset severe arrhythmia, severe liver and kidney dysfunction, severe lumbar disc herniation, hematopoietic system disease, patients with neurological diseases;(5)history of pelvic surgery before onset.During the visit survey, these subjects completed the questionnaire independently to the doctor and/or medical visitor. Before participating, each participant was informed of the research purpose and privacy, and participation in the study was entirely voluntary and anonymous.In this survey, each enrolled patient would be followed up 6 months after IS to investigate the patient's erectile function and related risk factors. A total of 361 subjects were eligible for inclusion and exclusion. Among them, 2 patients died unexpectedly during follow-up, 15 patients lost follow-up, and 24 patients did not return to the questionnaire. Finally, 320 patients completed the survey, with a total response rate of 94.40%  data were collected from all admitted patients. The simple depression and anxiety rating scale patient health questionnaire-9 score and general anxiety disorder-7 score scale were used to evaluate patients’ anxiety and depression status.–12 The international index of erectile function-5 (IIEF-5) scale was used to diagnose the ED in patients 6 months after stroke. The subjects were divided into ED group (<22 points) and non-ED group (≥22 points) according to the score. A set of identified risk factors for stroke or factors were record, including hypertension (using antihypertensive drugs or systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg), diabetes . Two glucose during hospitalization (>7 mmol), hypercholesterolemia (using lipid-lowering drugs or low-density lipoprotein cholesterol >1 g /L), current smoking, drinking and overweight, (body mass index (BMI) ≥26 kg/m2).The severity of stroke-induced neurological damage was assessed by the National Institutes of Health Stroke Scale (NIHSS). The NIHSS score ranged from 0 to 42 and the higher the score was, the more severe the neurological damaged., and t test or nonparametric test was used for comparison between groups. The 2 sample rates were compared between the count data sets using the χ2 test. Logistic regression analysis was performed on risk factors associated with the disease. P < .05 had a statistically significant difference.All data were analyzed and processed by SPSS 21.0 as statistical software. The measurement data were expressed as mean ± standard deviation 3P > .05).Of the 320 patients enrolled in the study, the mean age was 55.58 ± 6.3 years, and 88.8% and 74.4% of patients reported having the habit of smoking and drinking. The mean BMI was 26.11 ± 2.63, which was in the overweight range. A total of 249 patients had ED, the incidence rate was 77.8%. There was no significant difference in the age, smoking, alcohol consumption and BMI between the ED group and the non-ED group (P = .01), and 18.1% in the temporal lobe.Compared with the non-ED group, the IIEF-5 score was significantly lower in the ED group. The decrease in the NIHSS score also showed that the ED group had a more severe stroke. Correspondingly, anxiety and depression were also more severe in the ED group. According to the MRI, the infarction of the cerebral infarction caused by stroke patients was mainly, and the infarction in a single site was rare. There were 257 cases of multi-site infarction, and 63 cases of single infarction. The location of the cerebral infarction was concentrated in the frontal lobe, lateral ventricle, parietal lobe, basal ganglia, and thalamus. Compared with the non-ED group, 75.1% of patients had infarction in the frontal lobe, 73.9% had lesions in the lateral ventricle  After stroke, patients’ brain function impaired and nerve sensitivity decreased, leading to the appearance of ED.the advanced central nervous system that regulates sexual function is located in the cerebral cortex and subcortical center, mainly sensing visual, auditory, tactile, olfactory, and hallucinatory to induce sexual impulsivity.(2) decreased sexual satisfaction, and emotional changes.The patients surveyed in this study were older and often accompanied by a variety of underlying diseases, which could affect the erectile function. Sexual dysfunction in patients after IS mainly includes sexual decline in sexual frequency, The quality of sexual life of patients after IS has decreased, which seriously affects the patient's life and family relationship. During the follow-up, if there was a significant decline in sexual function or psychological problems, the patients would get rational treatment.A case-control study of up to 7 years of follow-up showed that the life satisfaction of the spouse of the stroke survivor was significantly lower than that of the control group. The life satisfaction of the spouse is related to the survivor's age, gender, support, and the degree of disability of the stroke. Similar studies have confirmed that post-stroke erectile function decline is associated with lesions in the right occipital-parietal region, with visual and somatosensory information, as well as lesions in the left and adjacent sacral regions, with the primary role of generating and mapping visceral arousal states.It can be seen from the results of MRI that obstruction of the frontal and lateral ventricles of the brain may have an effect on erectile function. The structure of each lateral ventricle is similar to a C-shape, starting at a lower-angled lobes, the body traveling in the parietal and frontal lobes, and ending most in the interventricular space, where each lateral ventricle is connected to the central third ventricle. Along the path, a posterior angle extends rearward into the occipital lobe, extending further into the frontal lobes with an anterior horn. Studies have shown that the cortical area that promotes erectile function during sexual stimulation is located in the medial frontal and lower frontal lobes, both of which are areas of the lateral ventricle. Ischemic injury in these areas may affect erectile function. At the same time, depression can also lead to a variety of male diseases, especially the occurrence of ED. Almost all men with depression have different degrees of ED, affecting male sexual desire, penile erection, ejaculation function, and other aspects. In patients with depression, platelet nitric oxide synthase activity decreases, plasma NO concentration decreases. In addition, patients have an emotional state of anxiety for a long time, leading to sympathetic excitation, promoting the release of norepinephrine, causing vasoconstriction, and decreasing plasma NO concentration. In the central nervous system, stroke patients have hypothalamic-pituitary-gonadal axis function decline, due to reduced gonadotropin secretion, resulting in less androgen, loss of libido, which leads to ED. Therefore, the presence of ED after stroke may be the result of anxiety and depression.,26This study also investigated the psychological status of patients after onset, and proved that patients in the ED group had more serious anxiety and depression. The meta-analysis showed that the proportion of patients with anxiety after stroke was significantly higher, and the prevalence of post-stroke depression in the general population was about 29%. In this study, we confirmed that stroke and ED have common risk factors, including hypertension and hyperlipidemia. The diameter of the penile blood vessels is smaller than that of large blood vessels such as cardiovascular and cerebrovascular vessels, and is more susceptible to factors such as arteriosclerosis and inflammatory factors. Therefore, penile blood vessels are more susceptible to first-ever effects such as hypertension and hyperlipidemia than cardiovascular diseases. Multivariate logistic regression analysis demonstrated that taking antihypertensive drugs was an independent risk factor for stroke ED. Studies have shown that antihypertensive drugs can lower blood pressure, induce systemic vascular remodeling, and cause arteriosclerosis, causing narrowing of the cavernous lumen of the cavernous body, and reducing blood flow to the penile artery, which is insufficient to produce or maintain an erection. At the same time, hypertension can cause ED by damaging vascular endothelial cells, causing endothelial dysfunction and structural abnormalities, weakened endothelium-dependent diastolic function, or enhanced endothelium-dependent contractile function. In the study, more than half of IS patients used antihypertensive drugs (67.9%).Previous studies have shown that cardiovascular risk factors such as diabetes, high blood pressure, smoking, and hyperlipidemia also have an impact on ED. Because they promote changes in arteriosclerosis and subsequent blood supply to endothelial dysfunction.In this article, there were still some limitations. For example, as the sample size of the study was relatively insufficient, and there was a lack of investigation on the psychological status on patients’ spouses. As this study paid more attention to recovery of sexual function of patients 6 months post IS. So in the future, investigation will be designed to evaluate the neurological status and ED symptoms in different time points and care about the association between IS severity with the ED.5The results of this study indicated that the incidence of ED was higher in male stroke patients. Antihypertensive drug, depression and anxiety were the independent risk factors for ED in male stroke patients. Paying attention to diagnosis and treatment of ED after male stroke has certain significance for improving their quality of life.Conceptualization: Hengheng Dai, Jisheng Wang, Bin Wang.Data curation: Qi Zhao.Project administration: Jianxiong Ma, Haisong Li.Resources: Xihao Gong.Software: Lu Wang, Binghao Bao.


Data collection was conductedthrough interviews using a form containing data on sociodemographic,clinical and epidemiological aspects, hypertension risk factors, bloodpressure, weight, height, body mass index and abdominal circumference. Mean,standard deviation, odds ratio and confidence interval were calculated,t-test and Chi-square test were used, considering P < 0.05 asstatistically significant. Hypertension associated variables were selectedfor logistic regression. patients were male (70.7%), self-reported as mixed-race (68.2%), hadschooling between 9 and 12 years of study (46.6%), had no children (47.6%),were single (44.2%), in the sexual exposure category (72.1%) andheterosexual (60.6%). The prevalence of people with acquiredimmunodeficiency syndrome and arterial hypertension was 17.3%. Logisticregression confirmed the influence of age greater than 45 years, familyhistory of hypertension, being overweight and antiretroviral therapy formore than 36 months for hypertension to occur. the prevalence of hypertension was 17.3%. Patients with acquiredimmunodeficiency syndrome and hypertension were older than 45 years, hadfamily history of hypertension, were overweight and under antiretroviraltherapy for more than 36 months. Acquired immunodeficiency syndrome (aids) represents one of the greatest contemporaryhealth problems, due to its pandemic character and severity, being a challenge dueto the nonexistence of an effective treatment that results in cure, in addition tosocioeconomic barriers that interfere with the adherence to the treatmentregimen--).Moreover, an increase in the frequency of cardiovascular disease in people with aidshas been observed, especially hypertension, which is characterized by systolic bloodpressure greater than or equal to 140 mmHg and diastolic blood pressure greater thanor equal to 90 mmHg,-Studies also show that many people with aids have unhealthy lifestyles regardingtheir feeding, exercise, alcohol consumption and smoking habits, in addition totraditional hypertension risk factors, which include advanced age, male gender,African ascent, high body mass index (BMI) and high cholesterol--Data on prevalence of hypertension among people with aids are variable. Although someauthors report higher prevalence of hypertension in this group,There are justifications for a study on the risk factors for hypertension and itsprevalence among aids patients. The first is that the prevention of cardiovasculardiseases is important for these patients due to predisposition, the HIV infection,the use of ART and aging due to the increase in the survival rateThe efforts of health professionals, scientific community and government agencies areessential to treat and control hypertension. Such studies are important so healthcare professionals can perform preventive and treatment measures of cardiovasculardiseases, given that health promotion practices are critical for these patients,whom require specialized care to maintain their quality of life.Given this context, an interdisciplinary approach is required in the follow-up ofpeople living with HIV/aids, mainly due to changes in lifestyle and frequentmonitoring. Among health professionals, nurses have a strategic role and providecare to aids patients in different health areas. The nurse must comprehend thedisorder, improve routine practices, adopt preventive measures to avoid theaccidental exposure to HIV, and acquire knowledge of clinical treatment in itsdifferent aspectsIn this perspective, considering the increase in the survival rate of people withaids by the implementation of ART, the known actions of HIV on the body, the adverseevents of ART and the increase of cardiovascular diseases in these individualsshowed by the studies cited - having hypertension as one of its primary precursors-,the general objective of this study was to verify the prevalence of hypertension andits risk factors among people with aids under antiretroviral therapy. This researchcan direct health practices of nurses and other professionals who provide care forthese patients.This is a cross-sectional, descriptive and quantitative study, developed in theinfectious diseases outpatient clinic of the University Hospital Walter Cantídio ofthe Universidade Federal do Ceará (UFC), in Fortaleza, Ceará, Brazil, from August2015 to August 2017. The study population was constituted by aids patients whom weretreated in the clinic.2×p× (1 -p) ×N/ε2× (N- 1) + z2×p× (1-p). In this formula, 2z is equal to the value of the z statistic (1.96) for theadopted degree of confidence (95%) and p, N and εcorrespond to the assumed prevalence (0.50), to the population (450) and to thetolerable error (0.05), respectively. Thus, a sample of 208 patients wascalculated.A sample was scaled to estimate the prevalence of aids patients served in theoutpatient clinic and who had hypertension and its risk factors, with 95% confidencethat the estimation error does not exceed 5%, considering that such prevalence isunknown in the population, being stipulated in 50%  - as itprovides the largest sample size -, and that there were 450 patients under ART beingserved during the study period. For such, the following expression was used: n =zInclusion criteria were people with aids of both genders, aged 18 years or older, whowere under ART for at least three months and who were in outpatient follow-up.Exclusion criteria were pregnancy, mental illness, persons deprived of theirliberty, people living in collective shelters or any other condition capable ofinterfering in an individual’s participation in the research.The sampling strategies adopted were non-probability and convenience. Patients wereinvited to participate in the study when they attended to routine consultations inthe outpatient clinic. Those who agreed to participate in the research signed aninformed consent form, and were interviewed for approximately 40 minutes in aprivate environment.2; overweight: ≥ 25kg/m2;obesity: ≥ 30 kg/m2) and waist circumference .A form divided into two parts was used: I. sociodemographic, epidemiological andclinical variables ;II. variables related to hypertension and its risk factors , blood pressuremeasurement , weight, height,body mass index  were selected tobe part of the logistic regression model, identifying those that, independently,were factors associated with hypertension. For such, the stepwise backward methodwas used. The criterion for removing variables from the model was defined by theWald test. This analysis was used to calculate the adjusted odds ratio, accuracy and significance  of the estimate. TheStatistical Package for the Social Sciences (SPSS) software 20.0 version was usedfor the statistical procedures.The project was approved by the Research Ethics Committee of UFC on March 12, 2015,under opinion nº 983.195. All participants signed the informed consent form. Theparticipants’ privacy was maintained and the research data used only for scientificpurposes. This study also considered the STROBE Statement guidelines.Of the 208 people with aids evaluated, most were male (70.7%), self-reported asmixed-race (68.2%), schooling from 9 to 12 years of study (46.6%), single (44.2%) ormarried (41.1%) and had no children (47.6%). Most reported being Catholic (66.4%),were employed at the time of the study (55.3%) and had monthly family income greaterthan three minimum wages (26.4%). Most were in the sexual exposure category (72.1%),straight (60.6%) and 88 had lipodystrophy (42.3%). Data presented in 3)  and viral load (copies/ml) .Among the antiretroviral drugs used were: lamivudine , tenofovir , efavirenz , zidovudine , atazanavir ,lopinavir , nevirapine  and raltegravir . Regarding thevalues of HIV-related laboratory tests, considering the 208 patients, was found:CD4+ T lymphocytes  and 26 patients(12.5%) used a salt shaker on the table during meals. Regarding food, most patientsreported daily consumption of fruits (92.3%), vegetables (91.3%), fried and fattyfoods (78.8%). A considerable number of patients used alcohol (40.4%), 54 (26%) hadstopped smoking and 19.7% were smokers. Most did not practice physical exercises(61.5%), 141 (67.8%) had family history of hypertension, and the main personalhistory was diabetes (6.7%) .In the sample of 208 patients, 36 had hypertension, with 17.3% prevalence . The antihypertensive drugs used were: losartan, hydrochlorothiazide , enalapril , propranolol , atenolol , amlodipine , captopril , carvedilol, chlortalidone , furosemide  and metoprolol .The association between sex and hypertension was evaluated by the Chi-square test.The t-test was used for unpaired data to compare the two strata in relation to othervariables. It was found that people with aids and hypertension had higher mean age(P < 0.001), greater waist circumference (P < 0.001), longer time of infection(P = 0.005) and longer time of use of ART (P = 0.002) .The association between the risk factors for hypertension and the occurrence ofhypertension was evaluated by the Chi-square test, and by determining the odds ratioand its respective 95% confidence interval (95% CI). Logistic regression analysis was used to determine the adjusted odds ratio, as wellas the accuracy  and significance  of theestimate. The variables that integrated the logistic regression model (P < 0.2)were: age, family history of hypertension, smoking, overweight, obesity, waistcircumference, time of HIV diagnosis and time of use of ART. The results of theanalyses showed that in the considered sample, the risk of hypertension increasedwith the following variables: age greater than 45 years (P = 0.01), family historyof hypertension (P = 0.005), being overweight (P = 0.019) and time of use of ART (P= 0.002) .-Most of the sample of this study were men, corroborating with other studies, showingthat HIV is still affecting more men than women-The patients’ schooling was relatively high, similar to the findings of otherstudiesParticipants whom did not had children were the majority. On this aspect, a studyshowed that the care demands of several children, especially if they are young, canlead to problems in the treatment routine, due to competing needs from thechildren’s routineMost patients were employed during the study period. Having a steady job can helppeople with aids to replace their identity as patients, since those who work reportsignificant improvements in their quality of life when compared to those who areunemployed; however, usually the main cause of cessation of work is the stigmaresulting from the diseaseThe antiretroviral drugs used the most were lamivudine, tenofovir efavirenz andzidovudine. Considering these drugs, nucleoside analogue reverse transcriptaseinhibitors such as lamivudine, zidovudine and tenofovir, may cause mitochondrial andliver toxicity, lipoatrophy, anemia, myopathy, peripheral neuropathy andpancreatitis. On the other hand, non-nucleoside analogue reverse transcriptaseinhibitors like efavirenz, may elevate liver enzymes, cause dyslipidemia, exanthemaand Stevens-Johnson syndrome-Regarding the risk factors for hypertension, most aids patients presented moderatesalt consumption and some used salt shaker on the table during meals. Low saltconsumption and not using a salt shaker on the table are hypertension preventionstrategies that must be adopted by everyoneIn this study, the prevalence of hypertension among people with aids was 17.3%.However, data on prevalence of hypertension among this type of patient are variable.A survey found 19.3% prevalence of people with aids before starting ART, but after12 months of ART initiation, 31% of the patients were hypertensiveIn this study, the antihypertensive drugs most frequently used by people with aidswere losartan, hydrochlorothiazide and enalapril.It was found that people with aidsand hypertension had higher mean age, greater circumference waist, longer time ofinfection and longer time of use of ART.Patients with aids had higher chances of presenting hypertension when the age wasgreater than 45 years, had family history of hypertension, were overweight, hadincreased waist circumference and time of use of ART greater than 36 months.Logistic regression analysis showed that the risk of hypertension increasedaccording to age greater than 45 years, family history of hypertension, beingoverweight and time of use of ART.We can assume that the incidence of cardiovascular diseases in people with aidsincreases due to the profile of high risk factors and increased the survival rate ofthese patients. Therefore, the estimation of cardiovascular risk and the managementof these risk factors among individuals with aids must be part of the regulartreatment approachConsidering the limitations of the study, one of them was not thoroughly verifyingwhat types of antiretroviral drugs were more associated with hypertension, becauseall aids patients used a combination of distinct classes of antiretroviral drugs.Another relevant aspect would be the inclusion of a control group of patients withaids whom were not under ART. This was not possible due to recent guidelines for thetreatment of people with aids, which advocate the use of ART as soon as possibleafter the positive diagnosis of anti-HIV serology, as a measure to decrease themorbidity and mortality among these patients.This study concludes that the prevalence of people with aids and hypertension was17.3%. In the studied sample, patients with aids and hypertension were older than 45years, had family history of hypertension, were overweight (BMI ≥ 25), had increasedwaist circumference and used ART for more than 36 months. Finally, the logisticregression analysis confirmed the influence of age greater than 45 years, familyhistory of hypertension, being overweight (BMI ≥ 25) and use of ART for more than 36months in the process of hypertension of patients with aids assessed in thisresearch.We emphasize the importance of this study, given that ART reduced the morbidity andmortality of people with aids, providing greater survival rates. Therefore, theanalysis of diseases that affect the general population is important among peoplewith aids, seeking to provide a better quality of life for these individuals.


Although sodium channels have been a hot multidisciplinary focus for decades and most of nerve system drugs worked on alerting sodium channel function, the trends and future directions of sodium channel studies have not been comprehensive analyzed bibliometrically. Herein, we collected the scientific publications of sodium channels research and constructed a model to evaluate the current trend systematically.Publications were selected from the Web of Science Core Collection (WoSCC) database from 2013 to 2017. Microsoft Excel 2016, Prism 6, and CiteSpace V software were used to analyze publication outputs, journal sources, countries, territories, institutions, authors, and research areas. A total of 4,275 publications on sodium channel research were identified. PLoS ONE ranked top for publishing 170 papers. The United States of America had the largest number of publications , citation frequency , and H-index (53). S. G. Waxman (62 publications) and W. A. Catterall (585 citations) were the most productive authors and had the greatest co-citation counts. This is the first report that shows the trends and future development in sodium channel publications, and our study provides a clear profile for the contribution to this field by countries, authors, keywords, and institutions. They arhannels) .Sodium channels were first discovered in the squid giant axon using the voltage clamp procedure . The volFurthermore, specific sodium channel perturbations affect many neurological diseases including epilepsy, Alzheimer’s disease, stroke, migraine and other headache diseases, multiple sclerosis, Parkinson’s disease, neurological infections, brain tumors, etc .Research on sodium channels began with the discovery of the sodium channel protein and the claim that sodium channels were composed of primary pore-forming subunits with auxiliary subunits . ThereafA bibliometric study is an effective way to calculate the longitudinal trends in research activity and clarify the connection between relevant research institutions. BibliomHowever, to date, no bibliometric studies regarding the trends in sodium channel research activity over the past few decades have been published. Although bibliometrics can measure publication trends in many disciplines, no related analysis of the research progression for sodium channels has been published and there has been a consequent lack of attention to this field.The purpose of our study was to provide researchers with some direction regarding sodium channel research using bibliometrics. To achieve this, we used bibliometrics to dissect the characteristics of scientific articles on the Web of Science (Thomson Reuters Company) into several components so that subjective factors are minimalized and then analyzed the overall publication trends. Our study confirmed that the United States has contributed greatly to sodium channel research, while S.D. Dib-Hajj, K. Dong, and Y. Yang may be good candidates for future research collaboration. We also identified “Protein,” “pyrethroid resistance,” “function mutation,” “sodium channel gene,” and “arrhythmia” as the latest research frontiers, and related studies may become pioneering in this field in the coming years.The data for analysis were extracted from the Science Citation Index Expanded (SCI-EXPANDED) of Thomas Reuters Web of Science Core Collection (WoSCC) bibliographic database. To ascertain the trend in publications, we collected five years’ worth of data from 2013 to 2017. The data were downloaded directly from the database as secondary data without further animal experiments; therefore, no ethical approval was required.The data search was conducted on 31 December 2017 and collected in one day to avoid any potential bias due to the daily updating of the database. The search keywords entered into the database were as follows: TS = (“sodium channel”) OR TS = (“sodium channels”) OR TS = (“sodium ion channel”)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (ARTICLE OR PROCEEDINGS PAPER).The txt data were downloaded from Web of Science and imported to Microsoft 2016, GraphPad Prism 6 , CiteSpace V. All data were analyzed both quantitatively and qualitatively.Bibliometrics is an essential tool to measure the output of an author, institution, journal, or country; it measures relevant parameters including impact factor, quantity, and the total number of citations of published articles .The retrieved documents were sorted by the number of citations they had received over a period of five years from highest to lowest . The “H-To stratify different countries’ publications by world region, we used Microsoft Excel 2016  to create a pie-chart. A comparison of publication quantity, citations, and H-indices between different countries were organized using GraphPad Prime 6. The statistical results were then displayed using CiteSpace V , a visualization software for analyzing data using network modeling . FinallyA total of 4175 publications were retrieved from the Web of Science Core Collection, most of which comprised research articles and reviews . Of the While the trend of world sodium channel research publications remained stable in these years, several countries had variable publication data outputs. For example, the USA’s publication output decreased between 2015 and 2017. In contrast, China’s research publications increased continuously from 2013. Apart from the Netherlands, other countries also continued to increase their output compared to 2013 ).Based on our analysis of the Web of Science database, all papers related to sodium channels were cited 51,471 times from 2013 . The average citation frequency of each paper was 9.81 times. Papers from the United States received the highest number of citations , accounting for 37.87% of the total number. The H-index of papers from the USA was 53. England ranked second with 4464 citations (8.67%) and a H-index of 33. Germany then followed with a citation frequency of 3909 (7.59%) and a H-index of 31 .10.1080/Researchers from 102 countries contributed to the development of sodium channel research. Stratified by world region, north America had the greatest share (43.01%), followed by the European Union and Asia ). The UnIn total, 313 journals have published more than four papers in the sodium channel field, comprising approximately 23.89% of all the published literature in this field. The top 10 journals in terms of number of publications are indicated in A dual-map overlay of journals is presented in Approximately 22,760 authors contributed over 4175 articles related to sodium channel biology. The networks shown in There was also a wide distribution of co-authors in the field of sodium channels. The connection network between co-authors was measured using CiteSpace V ). The paPayandeh J., 2011, Nature, v475, p353 ranked first in terms of co-cited article references at approximately 205. This was followed by Catterall W.A., 2005, Pharmacol Rev, v57, p397 which was co-cited 116 times, followed by Catterall W.A., 2000, Neuron, v26, p13 (108) see .10.1080/V1,” followed by cluster #2, the third largest, which was labeled “Brugada syndrome.” All mentioned clusters are also indicated in the timeline view . The moine view ).10.1080By extracting the 3684 relevant publications using CiteSpace V , keywordOur data regarding trends in publication year were consistent with two phases. The first phase (2013–2014) can be considered a popular period for sodium channel research, while the second phase (2015–2017) can be considered a stable period. Undoubtedly, the USA made significant contributions to sodium channel research, while China gradually came to pay more attention to this field.However, journal impact factor had several limitations in terms of sodium channel development; for example, only the Proceedings of The National Academy of Sciences of The United States of America  had the highest impact factor of over 6.000; the Journal of General Physiology (IF2016 5.988) and Epilepsia (IF2016 5.295) had an impact factor of between 5.000 and 6.000; finally, just five journals, comprising Scientific Reports (IF2016 4.259), Journal of General Physiology (IF2016 4.200), Journal of Biological Chemistry (IF2016 4.125), American Journal of Physiology-Renal Physiology (IF2016 3.611), and Parasites Vectors (IF2016 3.035), had an impact factor of greater than 3.000. Moreover, journals with high impact factors exceeding 3.000 published just 11.672% of all papers . Overall, therefore, it is a challenge to publish more high impact factor papers on sodium channel research.We found that the United States maintained the dominant position in terms of publications, citation frequency, and H-index in respect of which it has undoubtedly demonstrated both a high quantity and quality of sodium channel research papers. In contrast, Chinese publications had an advantage in terms of publication numbers , and with its citation and H-index at fourth and fifth respectively, it was the only developing country in the top 10 . A strong collaboration among countries can also stimulate research and strong collaborations were found between the United States, China, Australia, Japan, and South Korea; between France and Spain; and between England and Germany. There collaborations increased published paper and this also improved studies on sodium channels.Otherwise, except for University College London in England and the University of Queensland in Australia, the other eight institutions in the list of the top 10 were all from the United States. US institutions made up the largest proportion in the collaboration network, perhaps due to the fact that the United States had the highest number of publications.Similarly, a previous bibliometric research study indicated that the left part of the dual-map overlay of journals represented the citing-journal, whereas the right part represented the cited-journal. The label presented the disciplines of the above journals. The citation-links lines, connecting the cited-journal and citing-journal and pointing to the right map, demonstrate their relationship.V1.1, NaV1.2, NaV1.3, NaV1.5, NaV1.6, NaV1.7, NaV1.8, and NaV1.9) [VAb channels’ crystallographic snapshot from Arcobacter butzleri, which was captured in two potentially inactivate states [Of the top 10 authors identified in this analysis, each contributed to more than 20 papers. Consequently, they were verified as “prolific authors.” However, only three of these prolific authors were included in the top 10 co-cited authors. Annual co-citation is an essential factor in presenting the quality of authors’ work, suggesting that prolific authors should focus on the quality rather than the quantity of their publications ,17. The  NaV1.9) ; and J. The top 10 co-cited references numbered at least 68. They included Payandeh, J., 2011 Nature, v475, p353, which was claimed to be the representative paper of this author and ranked the first amongst co-cited references. This was followed by Catterall W.A., 2005, Pharmacol Rev, v57, p397, which introduced an overview of allostery as applied to receptor families and approaches for detecting, as well as providing recommendations for, the nomenclature of allosteric ligands and their properties and validating allosteric interactions . The thiThe frontiers of sodium channel research were predicted using the strongest citation bursts of publications. CiteSpace V captured the keywords that were identified as research frontiers over time. The top four research frontiers of sodium channel research were as follows:Pyrethroid resistance: Pyrethroid resistance, a kind of mosquito-borne disease , was claV1.7, causing an inability to experience pain [V1.7 functions as a relay station of the pain signal electrical transmission [Function mutation: Most of the functions that depended on voltage-gated sodium ion channels were significant to the generation of action potentials. Functionce pain . Meanwhismission ,30.Sodium channel gene: RNA interference (RNAi) had shown potential for selectively regulating sodium channels by changing gene function; this has been used in controlling agricultural insect pests .+ inward current to produce the LQTS phenotype, thereby prolonging the action potential duration [Arrhythmia: Cardiac arrhythmia modified the cardiac paralogue of the voltage-gated sodium channel by mutations in SCN5A . It was duration .Data on sodium channel publications were collected and retrieved from the Web of Science Core Collection (WoSCC) database . WoSCC is superior at providing detailed data , which are not provided by Google Scholar or PubMed. Thus, the data analysis was relatively sophisticated and objective. Furthermore, more than 95% of publications on the WoSCC are written in English. However, one limitation of our bibliometric analysis was that, compared with papers published several years ago, some recent articles did not have a high citation count. Nevertheless, bibliometrics can prove a useful tool for future research into sodium channels.Our study has demonstrated that numerous countries have focused on sodium channel research and made obvious contributions. Bibliometric analysis of the literature on the sodium channels of nerve system drugs is important in allowing clinicians and researchers to predict the frontiers of research. Junior researchers may use such analyzes to ascertain the top-cited articles, co-authors, leading authors, and journals. Clinicians, meanwhile, may use such analyzes to discover more about the mechanisms of nerve system disease drugs. Mapping the network of countries, institutions, and keywords can also be used to identify potential research cooperations. Despite the importance of the topic, the extent of annual publications should be focused on and encouraged. Organizations can refer to this article as a reference when deciding whether or not to provide repeat funding to a given research team. In the meantime, institutions should integrate their research fields on sodium channels.


These results suggest the potential for mixed berry preparations to improve post-prandial insulin response.Evidence supports the beneficial effects of berries on glucoregulation, possibly related to flavonoid content, fiber content, or both. The purpose of this study was to assess the potential of mixed berries to improve insulin sensitivity and to identify the potential role of flavonoids and fiber. In a randomized cross-over trial with four treatment periods, overweight/obese men and women were fed a controlled 45% fat diet for one week prior to a meal-based glucose tolerance test. The same base diet was provided during each feeding period with the addition of one of four treatments: whole mixed berries, sugar matched mixed berry juice, sugar matched gelatin, and sugar/fiber matched gelatin. Subjects then completed a meal-based oral glucose tolerance test. Serum glucose, insulin and non-esterified fatty acids were not different between individual treatments. However, in a secondary analysis, the combined berry preparations resulted in a lower serum insulin area under the curve (difference of 0.15 ± 0.066 ln pmol min/mL, mean ± SE,  Improvement of glucoregulation through diet has potential for a significant impact on public health . DiabeteBerry consumption has been investigated for its health-promoting effects, specifically the ability to attenuate the comorbidities of diet-induced obesity. Evidence from previous human intervention studies described the beneficial effects of berries on insulin sensitivity and glucoregulation ,18,19,20The objective of this study was to investigate the glucoregulatory effects of mixed berries to provide a wide array of anthocyanins under very highly controlled conditions and to identify the potential role of flavonoids/anthocyanins and/or fiber in these potential health benefits. For this study, berries and control foods were provided with a high-fat diet, similarly to preclinical studies demonstrating the preventative effects of berries on the development of adiposity and glucose dysregulation in rodent models ,36,37,38This study was conducted at the U.S. Department of Agriculture’s Beltsville Human Nutrition Research Center in Beltsville, MD, between January 2018 and March 2019 . The study was conducted as a randomized crossover with 4 treatment periods. Each treatment period was 8 days, with a 2-week break between treatment periods. During the first 7 days, the subjects consumed a fully controlled base diet with the addition of one of four treatment foods: whole mixed berries, pressed mixed berry juice, sugar matched gelatin, or sugar matched fiber-enriched gelatin. On the 8th day of each treatment period, subjects were administered a meal-based oral glucose tolerance test. Blood samples were collected prior to the test meal and every 30 minutes after the test meal for 3 hours. Serum was analyzed for glucose, insulin, and non-esterified fatty acids.2, not pregnant/lactating, and non-smoking. In addition, subjects were required to have no history of any of the following: bariatric surgery, gastrointestinal disorder, malabsorption disorder, metabolic disorder, diabetes, certain cancers, or use of blood thinners or other medications or supplements that could interfere with the study outcomes. All the procedures were approved by the Chesapeake Institutional Review Board , and all subjects provided written informed consent.Volunteers were recruited from the geographical area surrounding the Beltsville Human Nutrition Research Center, which is a population-dense area located between Baltimore, Maryland, and Washington, DC. Recruitment was conducted by email to the Beltsville Human Nutrition Center volunteer database (which contains approximately 1500 email address entries), local Federal agencies, and the University of Maryland. Subjects were required to have the following characteristics: between 21 and 75 years old, BMI greater than 25 kg/mFully controlled diets were provided to all subjects for the entirety of each 8-day treatment phase, because dietary pattern preceding a glucose tolerance test can affect results ,27,28. MThe subjects consumed breakfast at the Beltsville Human Nutrition Research Center Monday through Friday under the supervision of a dietician or diet tech. Lunches, dinners, and weekend meals were packed for carry-out and consumed off-site.The primary treatment food was whole mixed berries, to provide a wide array of anthocyanins, and the other treatment foods were designed to serve as different types of control foods for the whole berries. The berries were a combination of equal parts blackberries, blueberries, cranberries, raspberries, and strawberries. The berries were consumed daily at breakfast and dinner. Serving size was scaled according to overall energy needs, such that 100 grams of berries were consumed for every 450 kilocalories of overall energy requirement, resulting in a range of 400 g/day for subjects with the lowest energy intake to 800 g/day for subjects with the highest energy intake. Berries were provided in equal amounts, and each type of berry ranged from 80 to 160 grams per day, as scaled with energy requirement. Prior to the start of the intervention, the berries were analyzed for sugar (monosaccharide) and fiber (soluble and insoluble) content, and the sugar and fiber contents were used to plan the comparator foods.Three comparator foods were included in the study: sugar-sweetened gelatin, sugar-sweetened fiber enriched gelatin, and pressed berry juice. The sugar-sweetened gelatin was created from a recipe of water (91 g/100 g), gelatin powder (1.5 g/100 g), fructose powder (3.5 g/100 g), glucose powder (3.8 g/100 g), and red and blue food coloring (<0.1 g/100 g). The sugar-sweetened gelatin was matched to the berries for glucose, fructose, and mass consumed, and served as a control food devoid of the proposed active ingredients of anthocyanins and fiber. The sugar-sweetened fiber enriched gelatin was made from a recipe of water (89 g/100 g), gelatin powder (1.5 g/100 g), fructose powder (3.5 g/100 g), glucose powder (3.8 g/100 g), cellulose powder (1.8 g/100 g), and red and blue food coloring (<0.1 g/100 g). The sugar-sweetened fiber enriched gelatin was matched to the berries for glucose, fructose, fiber, and mass consumed, and served as a control food containing fiber but devoid of anthocyanins. The juice was pressed from berries in equal portions of each berry by weight from the same lots as those used for the whole berry treatment. The juice was extracted using a manual fruit press, then filtered through a cheese cloth. The juice was matched to the whole berries for sugar, serving as a control food containing phenolic compounds but no fiber.Berries and berry juice were analyzed for the following: sugar profile according to the method of Mason and Slover  and soluProfile of phenolic compounds in the mixed berries (after freeze-drying) and in the pressed berry juice was determined using the Waters UPLC Acquity H Class system  equipped with a QDa and a PDA detector based on previously published analyses with minor modifications . SeparatA meal-based oral glucose tolerance test was administered on the morning of day 8. Subjects fasted for 12 hours prior to the test and had engaged in no strenuous activity the morning of the test. An indwelling catheter was placed in the antecubital vein, after which 2 baseline blood samples were collected 15 minutes apart . Additional blood samples were collected every 30 minutes for 3 hours after consumption of the challenge meal. Serum was stored at −80 °C until analysis after samples were collected for the study.The challenge meal for the glucose tolerance test was designed using a newly created recipe to increase glucose load compared to standard recipes using sucrose as the sugar source. A recipe created using sucrose, a disaccharide of glucose and fructose, would have less impact on blood glucose than the same recipe created with glucose. The challenge meal was a pancake, syrup, berry or control treatment food, and an 8-ounce bottle of water. All these foods were consumed together within a 15-minute period between 6:30 and 7:00 AM. The pancake was made from all-purpose flour, egg, buttermilk, and glucose powder. Eighty grams of batter were weighed and pan-cooked for the glucose tolerance test. The pancake was served with a small container of pancake syrup made from 60 g light corn syrup (Karo) and 1.2 g artificial maple flavoring, together providing 68 g of glucose as monosaccharide. Subjects consumed the pancake and syrup with their assigned treatment food. The treatment food serving sizes for the glucose tolerance test were matched to provide equal amounts of sugar and were 300 grams for whole berries, 300 g for gelatin, 300 g for fiber-enriched gelatin, and 288 g for berry juice. The treatment foods provided an additional 11 g of glucose. The total glucose as monosaccharide provided from the meal-based glucose tolerance test was 79 g, which is similar to the standard dose of 75 g for an oral glucose tolerance test. Subjects were instructed to dip the pancake into the syrup, then to scrape the plate and syrup container clean with a small spatula to ensure complete consumption. Subjects also rinsed their treatment food containers with water and scraped sides with a spatula, again to ensure complete consumption.Serum glucose and nonesterified fatty acids (NEFA) were measured with a clinical chemistry analyzer  using colorimetric endpoint assays . Serum insulin was measured by immunoassay in a microfluidic cartridge .p < 0.05.A power calculation was performed based on data from a previously published study to detect a difference of 2546 mU/L*hour for insulin area under the curve with 80% power based on a previously published study of a similar design . VolunteSeventy-six individuals attended a study information meeting, sixty-four of which were screened for eligibility. Of the 58 individuals found eligible, 36 were enrolled. The CONSORT diagram for the study is found in 2, fasting glucose 94.2 mg/dL, fasting insulin 80.0 pmol/L, fasting triglycerides 122.1 mg/dL, systolic blood pressure 133.3 mm Hg, diastolic blood pressure 79.7 mm Hg , which are more readily extracted during pressing that the phenolic compounds. The gelatin control foods were devoid of phenolic compounds. A description of the carbohydrate and polyphenol content of treatment foods is found in Serum glucose  and seruBaseline glucose, insulin, and non-esterified fatty acids were not affected by treatment. Further, neither glucose incremental AUC nor insulin incremental AUC were significantly affected by treatment. Similarly, non-esterified fatty acid AUC was not affected by treatment. These results are shown in p = 0.023) when the berry treatments were consumed compared to the gelatin control foods. Further, the difference for serum glucose AUC was near statistical significance (p = 0.074) for a lowering when berry treatments were consumed. There was no effect on AUC for non-esterified fatty acids. These data are shown in As a secondary analysis, data from the berry treatments (whole berries plus pressed berry juice) were combined and compared to combined data from the non-berry treatments (sugar matched gelatin plus sugar matched fiber-enriched gelatin). The combined data demonstrated a significant reduction in serum insulin AUC (The purpose of this study was to investigate the potential glucoregulatory effects of mixed berries in adults consuming a high fat diet under very highly controlled conditions. Previous studies of glucoregulatory effects of berries have been mostly positive, although the results have been mixed. Possible reasons for mixed results include the lack of a controlled diet and differences in the berry products provided, which are usually extracts or powders.Despite the very careful development of the control foods and the investigator-provided diet controlling energy, macronutrients, micronutrients, and polyphenols preceding each glucose tolerance test, there were no differences among the individual treatments for serum insulin, serum glucose, or serum non-esterified fatty acid response despite the fact that some previous studies with berry preparations have demonstrated beneficial effects on these measures. Possible reasons for such a finding include higher than average variability amongst the study population, a less effective berry preparation, or an insufficient dose. Regarding population variability, there is no reason to suspect this population would have unusually large variability in response; the study population was recruited from healthy adults living in the Baltimore/DC vicinity and was as large or larger than study populations enrolled in most other similar studies. Regarding berry form, previous studies demonstrating glucoregulatory benefit have been conducted with whole berries as well as berry extracts or powders. An acute study of type 2 diabetics demonstrated significant reductions in insulin and glucose AUC after ingestion of 470 mg of a bilberry extract  and simiWhen the berry treatments were combined and compared to the combined gelatin treatments, the berry treatments showed improvement in serum insulin and a value close to statistical significance for improvement of serum glucose. This result generally supports the role of berries in improving glucoregulation and potentially reducing risk for diabetes, in accord with previous human intervention studies demonstrating beneficial effects of berries on insulin sensitivity and glucoregulation ,17,18,19The strengths of this study include the very tightly controlled diet prior to the glucose tolerance test and the very carefully designed control foods to provide the same types and amounts of sugar and fiber. The weakness of this study is the combination of pre-feeding berries prior to the glucose tolerance test and with the glucose tolerance test. Feeding berries both before and during the glucose tolerance test prevents determination of whether long-term feeding or acute feeding is important for harnessing the beneficial effects of berries. However, evidence from previous studies suggests that both shorter-term ,10,16,17These results suggest the potential for anthocyanin-rich mixed berry preparations to improve post-prandial insulin and possibly glucose response.


The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and processes. These include neuronal communication, post-translational processing, oxidative stress, intrinsically disordered protein regulation, and extracellular proteasomes. Taken together, these findings suggest that the 20S proteasome, like the well-studied 26S proteasome, is involved in multiple biological processes. Clarifying our understanding of its workings calls for a transformation in our perception of 20S proteasome-mediated degradation—no longer as a passive and marginal path, but rather as an independent, coordinated biological process. Nevertheless, in spite of impressive progress made thus far, the field still lags far behind the front lines of 26S proteasome research. Therefore, we also touch on the gaps in our knowledge of the 20S proteasome that remain to be bridged in the future. In eukaryotes, the two outer rings consist of seven distinct α-subunits each. Similarly, seven different subunits form the two inner β-rings, three of which are responsible for the proteasome’s proteolytic activities. The β1 subunit displays caspase-like activity, β2 shows trypsin-like activity, and the β5 subunit possesses a chymotrypsin-like function. Together, these catalytic subunits ensure the degradation of numerous protein substrates. Overall, 20S proteasome architecture creates a compartment whose proteolytic active sites are restricted to its interior, so that only proteins entering this chamber are degraded.The 20S proteasome is a conserved degradation machinery that is essential for maintaining cellular homeostasis ,2. The aThus far, the 20S proteasome was mainly seen as a component of the 26S proteasome complex, where it is known to be involved in the degradation of ubiquitin-modified proteins. During this process, the 20S proteasome associates with one or two 19S regulatory particles to form the 26S proteasome cooperative machinery. The 19S particle contributes to substrate recognition, unfolding, and delivery of the unfolded substrate into the 20S proteasome, where proteolysis occurs ,4. In adBiochemical analysis of HeLa cell extracts have revealed that free 20S proteasomes greatly outnumber capped proteasome species, such as the 26S proteasome ,8. MoreoStructure, or more precisely lack of structure, is the criterion for degradation by the 20S proteasome . The 20SHere, we will discuss the emerging view of how degradation by the 20S proteasome influences cellular processes . In doinCells utilize a broad array of mechanisms to cope with oxidative stress, including drastic reductions in endogenous levels of ATP ,14,15, wOxidized proteins can theoretically be degraded either by ubiquitin/ATP-dependent or -independent mechanisms, through the 26S or 20S proteasome, respectively. The 20S proteasome, however, appears to be the major machinery involved in this process. Initially, redox modifications induce a rapid increase in the catalytic activity and proteolytic capacity of pre-existing 20S proteasomes ,24,25. IHeat shock protein 70 (HSP70), a critical component of protein quality control in the cell, was also shown to mediate dissociation and then reassociation of the 26S proteasome during cellular adaptation to oxidative stress, by binding and preserving the dissociated 19S regulators for subsequent reassembly into 26S proteasomes . As a coThe shift in activity levels of the different proteasome complexes makes sense within the context of oxidative stress, since oxidized proteins are, by nature, partially unfolded and, as such, serve as natural substrates of the 20S proteasome. Moreover, unlike the 26S proteasome, which consumes ATP for substrate unfolding prior to degradation, the 20S proteasome activity does not depend on ATP, which is depleted during oxidative stress, thus lessening the functionality of the 26S proteasome ,15. FurtS-glutathionylations, and glycoxidations [S-glutathionylation of cysteines on the α5 subunit of 20S proteasomes was shown to induce an opening of the 20S proteasome gate and increase the degradation capacity of the complex [After oxidative insult, HSP70 not only acts as a 19S holdase, but it was also shown to interact with both the 20S proteasome and oxidized protein substrates. These interactions were found to increase the 20S-mediated degradation of oxidized proteins, possibly by shuttling the substrates toward the 20S proteasome for degradation . Moreoveidations . In seveidations . In yeas complex .Arabidopsis thaliana lines of weak loss-of-function mutations in 19S proteasome subunits exhibited higher levels of free 20S proteasomes, and an increase in the catalytic capacity of the complex. The rise in 20S proteasome levels in the mutant lines, compared to wild type (WT), enhanced the cellular ability to degrade oxidized proteins and, thus, increased the oxidative stress tolerance [Further support for the involvement of the 20S proteasome in combating oxidative stress comes from a study in plants. It was shown that several olerance . OverallIn addition to the direct, short-term effects of oxidative stress on the levels and activity of the 20S proteasome, cells activate an adaptive homeostasis mechanism that results in transient changes in gene expression and increased stress resistance . It was During aging, particularly through the last third of the organism’s lifespan, the capacity for adaptive homeostasis gradually declines. This, in turn, reduces the organism’s ability to resist oxidative stress insults . The decRecently, an additional means of regulating the 20S proteasome has been discovered. The two Rossman fold-containing proteins NQO1 and DJ-1 were shown to specifically bind the 20S proteasome, though not the 26S proteasome, and inhibit its activity, rescuing 20S proteasome substrates from degradation ,47,48. UWhile it is generally accepted that 20S proteasomes are localized to the cytoplasm and the nucleus, a recent landmark study discovered the presence of 20S proteasomes within the plasma membrane of neurons . These eThe outcome of proteolysis by the 20S proteasome is not restricted to the production of peptides since proteins are not always entirely degraded. Several studies have demonstrated that cleavage products are generated from proteins that are either partially degraded, or endo-proteolytically processed by the 20S proteasome. These cleaved protein products display altered functionality compared with that of their parent proteins, affecting their associated cellular processes and/or interaction partners . One of Various transcription factors have also been shown to be selectively cleaved by the 20S proteasome. Y-box protein 1 (YB-1) is known to interact with both mRNA in the cytoplasm and DNA in the nucleus, shuttling between these two cellular compartments as required. YB-1 contains both nuclear and cytoplasmic localization signals in its C-terminal domain, and selective cleavage by the 20S proteasome of the final 105 amino acids  facilitates its transition to the nucleus . This lip53, the so-called “guardian of the genome”, is a transcription factor known to exist in multiple isoforms, each produced by varying mechanisms, including alternative promotor usage and splicing. One of these isoforms, Δ40p53, which lacks the first 39 residues of full-length p53, can be produced in one of two ways. The first is via alternative translation initiation, and the second, recently discovered mechanism, is via 20S proteasomal processing . The p53The ubiquitin-like protein LC3 (microtubule-associated protein 1B Light Chain-3), a key player in the autophagic pathway, has also been shown to be processed by the 20S proteasome . LC3 binThe central chaperone HSP70, which is particularly active in controlling protein quality following environmental stresses, can also be endo-proteolytically cleaved by the 20S proteasome, which removes the unstructured C-terminus, and produces a stable 30 kDa fragment from the N-terminus of the protein . The funOne feature common to all of these processing events is that they occur at disordered regions within the protein’s structure, and, in most cases, end at the boundary between disorder and order. Thus, cleavage of these IDRs by the 20S proteasome reinforces our understanding of the substrate selectivity of the 20S proteasome. The ability of the 20S proteasome to specifically cleave fragments of its substrate proteins to modulate protein function and/or alter downstream processes constitutes an exciting phenomenon that may have broad implications for cell function and survival. Future research is expected to shed light on the regulatory principles of this process, and the repertoire of processed substrates.Traditionally, proteasomes were mainly studied as intracellular proteases. However, in recent years, a growing body of evidence indicates that active 20S proteasomes are also located in extracellular fluids . Not mucCirculating 20S proteasomes (c-20S) are physiologically present in human plasma, and their levels increase significantly under a variety of pathological conditions, including autoimmune diseases, cancerous tumors, trauma, sepsis, and acute respiratory distress ,63,64,65The origins of c-20S remain unclear. However, it is thought that they are secreted from the cells themselves by an as-yet unidentified mechanism ,74. EffoExtracellular vesicles (EVs), which are 30–500 nm lipid bilayer vesicles secreted by almost every cell type, have been recognized as vehicles of intercellular communication under both physiological and pathological conditions ,78. Theihttp://www.exocarta.org/), a manually curated database of exosomal proteins, RNA, and lipids, indicated the presence of 20S proteasome subunits in EVs isolated from a variety of cell lines. Furthermore, detailed proteomic analysis identified all the subunits comprising the 20S proteasome in EVs isolated from mouse models of prostate cancer [A search in the ExoCarta database . For exA recent attempt to systematically define the repertoire of 20S proteasome substrates was undertaken through proteomic analysis of heat-treated HeLa nuclear-rich extracts subjected to degradation by purified 20S proteasomes . HundredAntigenic peptides displayed by HLA class I molecules are primarily derived from proteasomal degradation of cellular proteins. These peptides were originally believed to be exclusively linear fragments of the degraded proteins. However, the discovery of non-contiguous peptides derived from fragments distant in the primary sequence of the parent protein uncovered a potential new source of antigenic peptides ,91. In tThis process can occur between peptides that are separated by only a few amino acids in the parental protein, such as the melanocytic glycoprotein gp100 derived peptide , as wellThe formation and presentation of spliced peptides is considered a relatively rare occurrence even though one recent study of the HLA-I immunopeptidome suggested that spliced peptides represent one-third of the diverse population of bound peptides, and comprise roughly 25% of total HLA-I bound peptide abundance . These pInitially, protein degradation by means of the 20S proteasome was questioned, since it was believed that proteins are only eliminated by the 26S ubiquitin-proteasome system. However, emerging evidence, summarized here, emphasizes the significance of the 20S proteasome complex as an independent cellular machine. The notion that arises is that the 20S proteasome is not only a clearance and recycling entity, but also acts as a regulator of cellular processes. In particular, findings indicate that the 20S proteasome complex can alter protein function by means of selective post-translational processing , and medCurrent knowledge of 20S proteasome substrates suggests that this group of proteins can be divided into two categories: (i) functional and (ii) pathological entities. Among the functional proteins are those containing IDRs. This set of proteins is dominated by those that interact with or function as hubs in protein interaction networks, performing central roles in the regulation of signaling pathways and crucial cellular processes . Patholo5 and α4 subunits, respectively [As biochemical methods and analytical tools are improving, it is becoming clear that the 20S proteasome is composed of a diverse population of functionally distinct entities . Thiectively ,99. An aectively . Many isLastly, as details related to 20S proteasomal activity are clarified, its links to diverse diseases and aging are coming into focus. As discussed above, high levels of extracellular proteasomes, both those circulating in plasma and those in extracellular vesicles, are correlated with a range of pathologies, cancer included, while gradual loss of 20S proteasomal function is associated with aging and neurodegenerative diseases. These observations exemplify the importance of in-depth exploration of the 20S proteasome degradation pathway, to determine its potential therapeutic efficacy. To date, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have been developed for treating certain cancers, especially multiple myeloma and mantle cell lymphoma and many other such inhibitors are currently being tested for their anti-tumor and anti-inflammatory effects, as well as for treating autoimmune diseases ,101. The