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The pharmacy and physician assistant dual degree is one of the newest programs offered and has been predicted to have a high likelihood of growth in the future. With only an additional year of education, the PharmD-PA dual degree holder will have prescriptive authority upon graduation to expand their clinical roles. Additionally, by combining both medical and pharmacotherapeutics education, these mid-level practitioners could potentially improve healthcare shortages and allow for improvements in patient care. While there are established PharmD-PA dual degree programs, there is low enrollment coupled by rigorous curriculums and financial burdens that students must endure. Despite its limitations, this novel dual degree program offers pharmacy students another method to provide clinical care apart from the post-graduate opportunities. Schools of Pharmacy should look into the development of PharmD-PA dual degree programs as a unique marketing opportunity for admissions and as a non-traditional method of career advancement., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The aim of this study was to determine the differences in the characteristics of Mycoplasma pneumoniae pneumonia (MPP) in children with and without asthma and in children with asthma with and without inhaled corticosteroid (ICS) therapy in order to determine the risk factors for asthma exacerbation and the effect of regular ICS therapy on children with asthma with MPP., Materials and Methods: Children with MPP were divided into two groups according to whether they had a history of asthma. Children with asthma were further divided into an ICS therapy group and a group without ICS therapy. The clinical characteristics, laboratory test results, and pulmonary images were compared between the children with and without asthma. Differences in the severity of acute exacerbation were compared between the children with asthma in the ICS therapy and without ICS therapy groups. Multivariable logistic regression was used to determine the risk factors for exacerbation of MPP in children with asthma., Results: In children with MPP, the differences in the eosinophil counts; total immunoglobulin E (IgE), C-reactive protein, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels; and fever duration, wheezing, extrapulmonary complications, oxygen saturation < 92%, severe pneumonia, pleural effusion, co-infection with other pathogens, and lobar pneumonia between children with and without asthma were statistically significant. Among children with asthma with MPP, those in the ICS therapy group were less likely to experience an exacerbation, and exacerbations were less severe than those in the without ICS therapy group. The multivariable logistic regression analysis showed that the ICS therapy was an independent protective factor against exacerbation., Conclusion: Among children with MPP, the chance of wheezing was higher in children with asthma than in children without asthma. The ICS therapy was a protective factor against exacerbation in children with asthma with MPP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wei, Dang, Liu and Li.)

Objectives: To analyze the characteristics of diphenidol poisoning cases and to provide clues and technical means for the identification of such cases., Methods: Biological samples of 9 deaths caused by diphenidol poisoning were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and the characteristics of these cases were analyzed retrospectively., Results: Most of the deaths caused by diphenidol poisoning were young females. The dosage was between 60 and 300 tablets, and the mass concentration of diphenidol in the postmortem blood ranged from 0.87 to 99.00 μg/mL. There was no correlation between the dosage and the concentration of diphenidol in the blood., Conclusions: Diphenidol poisoning has the characteristics of high concealment and lethality. More attention should be paid to suicide cases, and diphenidol should be recommended as a routine detection item to avoid missing detection.

Histidine triad nucleotide-binding protein 1 (HINT1) is regarded as a haplo-insufficient tumour suppressor and is closely associated with many neuropsychiatric disorders, including major depressive disorders. In addition, HINT1 knockout (KO) mice exhibit anxiolytic-like behaviour, antidepression-like behaviour, and enhanced cognitive performance in several studies. However, it is still unclear whether aging contributes to these changes in the emotion and cognition of HINT1 KO mice. This study examined the role of aging in anxiety-like and depression-like behaviours and cognition behaviours in aged HINT1 KO mice compared with young HINT1 KO mice and their wild-type littermates, along with a number of molecular biological methods. In a battery of behavioural tests, aged wild-type mice showed increased anxiety-like and depression-like behaviours and decreased cognitive performance, along with lower expression levels of glutathione peroxidase, enhanced amount of malondialdehyde, and decreased expression levels of brain-derived neurotrophic factor and tyrosine kinase B in the hippocampus and PFC compared to young wild-type mice. HINT1 KO mice showed reduced anxiety-like and depression-like behaviours and enhanced cognitive performance compared to age-matched wild-type mice. In addition, HINT1 KO mice also showed increased GSH-Px and superoxide dismutase, and decreased malondialdehyde, together with enhanced BDNF and Trk-B expression in the hippocampus and PFC. However, when compared with young HINT1 KO mice, aged HINT1 KO mice did not show increased anxiety-like and depression-like behaviours. And there are no differences in the expression level of superoxide dismutase, malondialdehyde, BDNF, and Trk-B between aged and young HINT1 KO mice. In summary, HINT1 deficiency can counteract age-related emotion and cognition dysfunction., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: To explore the research hotspots and development trends of the field of forensic drowning from 1991 to 2020 by bibliometrics methods., Methods: Based on Web of Science, CNKI database, Wanfang Data knowledge service platform, python 3.9.2, CiteSpace 5.8.R3, Gephi 0.9.2, etc. were used to analyze the publishing trends, countries/regions, institutions, authors and topics of the study on drowning., Results: A total of 631 English literature were obtained, including 59 articles from Chinese authors, and 386 Chinese literature were obtained. The Chinese and English journals with the largest number of related literatures were Chinese Journal of Forensic Science (80 articles) and Forensic Science International (106 articles), respectively. Japan published the most articles in English, and China ranked third. Osaka City Univ (Japan, 28 articles) published the most English articles, and Guangzhou Forens Sci Inst (China, 22 articles) ranked second. Among Chinese literature, Guangzhou Forens Sci Inst (32 articles) published the most. The topic analysis of Chinese and English literature showed that diatom examination, virtual autopsy, postmortem biochemical examination, the nature of death, and postmortem submersion interval were the hot spots of current research, but English literature had more studies on new technologies and methods, while Chinese literature was more inclined to practice, application and experience summary., Conclusions: The number of literature in forensic medicine on drowning is relatively stable. The scope of international and domestic collaborations in this field is still limited. The automated examination of diatoms, the establishment of diatom DNA barcodes and virtual autopsy will be the most important research hotspots in the coming period and are expected to achieve breakthroughs in drowning diagnosis, drowning location inference, postmortem submersion interval estimation, etc.

Major depressive disorder (MDD) is a severe, highly heterogeneous, and life-threatening psychiatric disease which affects up to 21% of the population worldwide. A new hypothesis suggests that the mitochondrial dysfunction causing oxidative stress (OS) and dysregulation of apoptosis in brain might be one of the key pathophysiological factors in MDD. Histidine triad nucleotide binding protein 1 (HINT1), which was first supposed to be protein kinase C (PKC) inhibitor, has been gradually demonstrated to be involved in diverse neuropsychiatric diseases. It still remains elusive that how HINT1 involves in depression. The present study utilized a rat model exposed to chronic mild stress (CMS) to explore the involvement of HINT1 in depression. Face validity, construct validity and predictive validity of CMS model were comprehensive evaluated in this study. Behavioral tests including sucrose preference test, open field test, and elevated plus maze and forced swimming test revealed that stressed rats displayed elevated level of anxiety and depression compared with the controls. CMS rats showed a significant decrease of superoxide dismutase, and a marked increase malondialdehyde levels in prefrontal cortex (PFC). We also found the CMS rats had elevated expression of HINT1, decreased levels of phosphorylated-PKC ε and aldehyde dehydrogenase-two (ALDH-2), and accumulated 4-hydroxynonenal (4HNE) in PFC. Moreover, CMS increased the levels of cleaved caspase-3 and Bax, and decreased the level of Bcl-2 in PFC. The alterations in behavior and molecule were prevented by antidepressant venlafaxine. These results demonstrated that HINT1 was involved in the CMS elicited OS and apoptosis in PFC, probably through the PKC ε/ALDH-2/4HNE pathway. The results suggest that the suppression of HINT1 might have potential as a novel therapeutic strategy for depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Dong, Lei, Zhou, Liu and Dang.)

Objective: To investigate the changes of interleukin-35 (IL-35) level and CD14 + monocytes function in patients with chronic heart failure (CHF). Methods: A total of 74 patients with CHF who were hospitalized in the Department of Cardiology of the First Affiliated Hospital of Zhengzhou University between July 2018 and June 2019 as well as 29 healthy controls (HC) were continuously enrolled. 20 ml fasting anticoagulant peripheral blood was collected in the morning, and plasma was separated. IL-35 level was measured by ELISA. Peripheral CD14 + monocytes were purified, and the IL-35 receptor subunits (IL-12Rβ2 and gp130 mRNA) relative levels were semi-quantified by real-time PCR. CD14 + monocytes were stimulated with IL-35, and were cultured in direct contact or indirect contact with human umbilical vein endothelial cells (HUVEC). Cytokines and granzyme B secretion in the supernatants was measured by ELISA. The percentage of HUVEC death was calculated by measuring lactate dehydrogenase level. The difference of the above indicators were compared between the CHF group and the HC group. Results: The age for the CHF group was (59.4±12.1) years, and 58.1% (43 cases) of them were males. The age for the HC group was (53.9±9.8) years, and 65.5% (19 cases) of them were males. The plasma IL-35 level was higher in the CHF group than the HC group ((22.89±7.58) mg/L vs (16.42±5.47) mg/L, P< 0.001). The gp130 mRNA relative level was also higher in the CHF group than the HC group (1.07±0.19 vs 0.98±0.15, P= 0.022). CD14 + monocytes induced HUVEC death in the CHF group was lower in both direct contact and indirect contact culture system than the HC group (both P< 0.001). The granzyme B secretion was also lower in the CHF group than the HC group ( P< 0.001). The CD14 + monocytes induced HUVEC death was down-regulated in response to granzyme B inhibition ( P= 0.011). Both the CD14 + monocytes induced HUVEC death and the granzyme B secretion were reduced in response to IL-35 stimulation (both P< 0.001). Conclusion: CHF patients have the elevated IL-35 expression. IL-35 induces CD14 + monocytes dysfunction via the inhibition of granzyme B secretion. This process promoted the progression of heart failure.

Drug addiction is a recurrent, chronic brain disease. The existing treatment methods have limitations, such as poor adherence and inability to completely avoid relapse. Histidine triad nucleotide-binding protein 1 (HINT1) is involved in many neuropsychiatric diseases, such as schizophrenia, pain, and drug dependence. Studies have confirmed that there is a genetic link between HINT1 and addictions such as nicotine and cocaine. However, there is no research on the role of HINT1 protein in morphine addiction at home and abroad. Thus, we designed this project by constructing different types of morphine addiction animal models, including conditioned place preference and behavioral sensitization. We comprehensively examined the participation of HINT1 protein in key brain regions associated with addiction, including prefrontal cortex, nucleus accumbens, corpus striatum, and hippocampus, in different stages of different models. In addition, we used HINT1 knockout mice to establish the above models and physical dependence model to investigate the effect of HINT1 protein deletion on morphine addiction-related behaviors. We found that HINT1 has varying degrees of involvement in different stages of multiple addictive animal models. The absence of HINT1 can attenuate morphine-mediated addictive behavior to a certain extent and can alleviate the withdrawal symptoms of morphine., (© 2020 Society for the Study of Addiction.)

Purpose: To determine the attitudes and perceptions of pharmacy residency program participants regarding proposed expansion of postgraduate year 3 (PGY3) residency training opportunities., Methods: An online questionnaire was emailed to all directors of ASHP-accredited residency programs with a request to distribute the survey among program participants, including residents, preceptors, coordinators, and other pharmacists working with residents. Survey questions assessed participants' views and attitudes about PGY3 programs vs other avenues of career advancement, including potential benefits and limitations, program structure, and ramifications for the profession., Results: Eight hundred forty-five individuals participated in the survey, for a 22.47% response rate. Only 288 pharmacists (34.4%) were familiar with the PGY3 residency training concept. Perceived benefits of PGY3 training, by percentage of respondents citing them, included job specialization (34.41%), an additional year of training (19.93%), and obtaining research skills (5.44%). The main perceived limiting factors included personal finances (21.62%), lack of justification for PGY3 training (13.83%), and time commitments (12.94%). As alternatives to PGY3 training for career advancement, board certifications (49.5%), scholarly activity (19.8%), and leadership in pharmacy organizations (19.2%) were the 3 highest-rated areas. A majority of respondents were opposed to ASHP standardization of PGY3 residency programs (74.3%) and/or had negative preconceptions of the potential impact of expanded PGY3 training initiatives on the job market (80.94%)., Conclusion: Overall, surveyed pharmacy residency program participants were opposed to the concept of expanded PGY3 training initiatives and indicated their view that PGY3 training offers limited benefits in terms of professional development. Participants favored on-the-job training and other avenues of career advancement over PGY3 residency training., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The histidine triad nucleotide binding protein 1 (HINT1) is closely related to many neuropsychiatric disorders. Clinical studies supported that mutations in the Hint1 gene correlated potentially with schizophrenia. In addition, Hint1 gene knockout (KO) mice exhibited hyperactivity induced by amphetamine and apomorphine. However, it is still unclear whether this animal model exhibits schizophrenia-like behaviors and, if so, their underlying mechanisms remain to be elucidated. Thus, our study sought to evaluate schizophrenia-like behaviors in Hint1-KO mice, and explore the associated changes in neuronal structural plasticity and schizophrenia-related molecules. A series of behavioral tests were used to compare Hint1-KO and their wild-type (WT) littermates, alongside a number of morphological and molecular biological methods. Relative to WT mice, Hint1-KO mice exhibited reduced social interaction behaviors, aggressive behavior, sensorimotor gating deficits, apathetic and self-neglect behaviors, and increased MK-801-induced hyperactivity. Hint1-KO mice also showed partly increased dendritic complexity in the hippocampus (Hip) relative to WT mice. Total glutamate was decreased in the medial prefrontal cortex, nucleus accumbens (NAc), and Hip of KO mice. Expression of NR 1 , NR 2A , and D 4 R was decreased whereas that of D 1 R was increased in the NAc of KO relative to WT mice. The expression level of NR 2B was increased whereas that of D 1 R was decreased in the Hip of KO mice. Hint1-KO mice exhibited schizophrenia-like behaviors. Partly increased dendritic complexity and dysfunction in both the dopaminergic and glutamatergic systems may be involved in the abnormalities in Hint1-KO mice., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Drug addiction is a chronically relapsing disorder in humans yet the underlying mechanism remained unclear. Recent studies suggested that histidine triad nucleotide binding protein1 (HINT1) may play significant roles in diverse neuropsychiatric diseases including drug addiction., Methods: In the current study, we used different batches of mice to establish different stages of methamphetamine (METH)-induced behavioral sensitization (BS) to explore the dynamic changes throughout the process of addiction in different brain regions, including the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), and hippocampus (Hip). In addition, we used HINT1 knockout (KO) mice to investigate the effect of HINT1 protein deletion on METH-induced BS., Results: We found that in PFC of the METH group mice, the HINT1 expression level initially increased after development phase, and then dropped to the normal level during expression phase. However, there was no statistical difference in the HINT1 expression level in the other three encephalic regions (NAc, CPu, and Hip). The absence of HINT1 could promote METH-mediated addictive behavior to a certain extent, while the significant difference between genotypes only occurred in the development phase., Conclusions: Using the new technique, hip fractures were correctly predicted in 78% of cases compared with 36% when using the T-score. The accuracy of the prediction was not greatly reduced when using SSM and SAM (78% and 74% correct, respectively). Various geometric and BMD distribution traits were identified in the fractured and non-fractured groups.

Background: Despite the highly publicized health consequences, some college students do not perceive tobacco consumption as harmful. Historically-Black College and Universities (HBCUs) have the lowest rates of tobacco-free policies compared to other colleges, universities, and minority-serving institutions, making their students at higher risk for tobacco abuse. A campus Alcohol, Tobacco, and Other Drug Prevention Committee (ATDP) was formed and led by a pharmacist to develop all tobacco cessation policies at the HBCU., Objectives: (1) To determine the knowledge and attitudes of cigarettes, cigars, smokeless tobacco, electronic cigarettes, and hookah among college students in a rural area with high tobacco usage; (2) To assess perceptions on the effectiveness of smoking cessation resources on the college campus led by the ATDP committee., Methods: A cross-sectional study was conducted on 99 students between 18 - 26 years attending a HBCU in Maryland. The online survey was disseminated to assess student's health behaviors and attitudes towards tobacco products and their successfulness in abstinence using campus resources with the Health Belief Model., Results: Participants had more perceived harms with smoking tobacco (cigarettes and cigars) and smokeless tobacco, and greater perceived benefits with using electronic cigarettes and hookah (P < 0.001). Most students had limited knowledge of the four tobacco categories (5.8 ± 2.6 on a 10-point Likert scale). Self-efficacy to quit was 4.2 ± 1.7 on a 10-point Likert scale despite the current resources at the HBCU., Conclusion: Students had a perceived benefits sequential rank order with hookah, e-cigarettes, smokeless tobacco, followed by smoking tobacco. Campuses should investigate barriers for abstinence, raise awareness about the dangers of tobacco, and create programs that enhance self-efficacy when quitting., Innovation and Practice Implication: This is the first study of its kind that compares all major tobacco products head-to-head in a rural and underrepresented population. Additionally, the development of a campus-wide tobacco policy was novel as it was pharmacist-led. The results show this population has limited knowledge of tobacco products with more perceived benefits among newer nicotine delivery systems. Targeted education and public health programs should be implemented to prevent this susceptible group from initiating and continuing tobacco products., Competing Interests: Conflicts of Interest: I declare no conflicts of interest or financial interests that the author has in any product or service discussed in the manuscript, including grants (pending or received), employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties., (© Individual authors.)

Objective: The purpose of this study is to determine the effectiveness of individualized communication strategies and self-management action plans to improve A1c control at 3 months in patients with low health literacy., Methods: A prospective, open-labeled, pilot study was conducted on 23 patients with diabetes mellitus in a pharmacist-led ambulatory care clinic. Patients who had a Rapid Estimate of Adult Literacy in Medicine- Revised (REALM-R) score of 6 or less and an A1c greater than 7% upon study entry were included. The first group received the teach-back method, personalized actions, and follow-up phone calls to assess comprehension (N = 12). The second group was assigned to usual care (N = 11)., Results: Patients receiving literacy-appropriate interventions had greater A1c percent reduction (A1c difference of -2.0 ± 1.3 vs -1.0 ± 2.2; P = 0.02) and less hyperglycemic events per week (0.1 vs. 2.1; P = 0.04). There were no differences in the number of hypoglycemic events, testing frequency, medication-adherence rates, or hospitalizations and emergency room visits related to diabetes., Conclusion: Literacy-appropriate methods such as the teach-back method, personalized action plans, and telephone follow-ups may improve glycemic control in low health literate patients with diabetes., Practice Implications and Innovations: The findings from this study suggest that pharmacists may improve diabetes outcomes when managing patients who possess low health literacy using simplified teaching methods., Competing Interests: Conflicts of Interest: We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received), employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties., (© Individual authors.)

Objective: To investigate the expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) in patients with chronic heart failure and its modulatory activity on T lymphocytes. Methods: Eighty-six patients with chronic heart failure (CHF group) who were hospitalized in Department of Cardiology, the First Affiliated Hospital of Zhengzhou University between January and October 2018 were enrolled in the study. Meanwhile, thirty-two healthy controls (HC group) who received healthy examination were also selected. Peripheral blood mononuclear cells were isolated, and TIM-3 expression of CD4(+)and CD8(+)T cells was investigated by flow cytometry. CD4(+)and CD8(+)T cells were purified, and were stimulated by anti-TIM-3 antibody. Interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, IL-35, IL-17, and IL-22 expressions in the supernatants of cultured CD4(+)T cells and tumor necrosis factor-α (TNF-α) and IFN-γ expressions in the supernatants of cultured CD8(+) T cells were measured by enzyme-linked immunosorbent assay. mRNA expressions of T-bet, GATA-3, FoxP3, and RORγt in CD4(+)T cells and perforin and granzyme B in CD8(+)T cells were semi-quantified by real-time PCR. Student t test or paired t test was used for comparisons between the two groups. Results: TIM-3(+) CD4(+) T cell percentage significantly increased in CHF group than that of HC group (3.47%±1.06% vs 0.92%±0.27%, P< 0.001). TIM-3(+)CD8(+)T cell percentage also notably elevated in CHF group compared to HC group (6.12%±1.91% vs 1.77%±0.63%, P< 0.001). CD4(+)T and CD8(+)T cells were dysfunctional in chronic heart failure. The levels of IFN-γ, IL-17, and IL-22 secreted by purified CD4(+) T cells significantly reduced in CHF group, while IL-10 and IL-35 expressions elevated in CHF group (all P< 0.05). The relative mRNA expression levels of T-bet and RORγt in CD4(+) T cells remarkably decreased in CHF group than those of HC group (all P< 0.01), while relative expression level of FoxP3 mRNA increased in CHF group (1.93±0.88 vs 0.97±0.28, P= 0.031). The levels of TNF-α and IFN-γ produced by purified CD8(+)T cells notably reduced in CHF group than those of HC group (all P< 0.05), and relative mRNA expression levels of perforin and granzyme B also decreased in CHF group (all P< 0.05). The levels of anti-TIM-3 antibody stimulation-produced IFN-γ, IL-17, and IL-22 increased (all P< 0.05) but IL-35 secretion reduced [(61±13) ng/ml vs (72±17) ng/ml, P= 0.029] by CD4(+)T cells in CHF group. The relative mRNA expression levels of T-bet and RORγt also elevated in response to anti-TIM-3 antibody stimulation (all P< 0.05). Anti-TIM-3 antibody stimulation promoted TNF-α and IFN-γ production by CD8(+)T cells in CHF group (all P< 0.01). The relative mRNA expression levels of perforin and granzyme B also increased (all P< 0.05). Conclusion: TIM-3 was increasingly expressed in T cells from patients with chronic heart failure, and might take part in the regulation of T cell dysfunction in chronic heart failure.

Bis(2-aminoethyl)terephthalamide, an amide-containing diamine, was obtained from the aminolysis of waste poly(ethylene terephthalate) bottles. This diamine reacts with various aromatic dianhydrides to form novel polyamideimides (PAIs). The formation of amic acid or ammonium carboxylate salt intermediates depends strongly on the substituents of the dianhydrides. The electron-withdrawing substituents promote the creation of an ammonium carboxylate salt, whereas the electron donors assist with the amic acid intermediate formation. These salts and amic acids were further converted into polyimides by thermal treatment. The structures of the intermediates and PAIs were characterized by Fourier transform infrared, 1 H nuclear magnetic resonance (NMR), and 13 C NMR spectroscopies, and their thermal properties were determined by differential scanning calorimetry and thermogravimetry. X-ray diffraction patterns and inherent viscosity values of these PAIs were also reported. By using these chemical transformations, waste poly(ethylene terephthalate) bottles were converted into high-performance PAIs. These PAIs can be used as membrane-modifying agents for industrial separation applications., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Objective: To evaluate the diagnostic value of high-throughput sequencing (NGS) in screening the thalassemia genes., Methods: The peripheral blood of 2 858 cases of pre-pregnancy and pregnancy from October 2014 to October 2016 randomly were collected in department of obstetrics, the third people's hospital in Dongguan city. Peripheral blood was used for the blood routine examination, hemoglobin electrophoresis, traditional thalassaemia gene screening and NGS., Results: The rate of missed diagnosis for α-thalassemia and β-thalassemia using NGS was 0.87% and 1.59%, respectively. Meanwhile, the missed rate of screening for α-thalassemia and β-thalassemia by traditional screening models was 26.77% and 2.38%, respectively. The area under the ROC curve of α-thalassemia and β-thalassemia screened by NGS was 0.994 and 0.991, respectively, however, the area under the ROC curve of screening for α-thalassemia and β-thalassemia by the traditional screening model was 0.866 and 0.988, respectively. The sensitivity, rate of missed diagnosis, Youden index and negative predictive value of screening for α-thalassemia and β-thalassemia using NGS all were superior to those using traditional screening., Conclusion: Compared with the traditional screening model, the NGS screening for thalassemia genes shows a high accuracy, moreover can avoid missed diagnosis resulted from screening by conventional method, suggesting that the NCS possesses the accurate and diagnostic value for screening of thalassemia and can widely apply to clinical practise so as to provid the guarantee for early diagnosis of thalassemia.

Purpose: The objective of this study was to illustrate the global research productivity and tendency of forensic anthropology in recent ten years (2008-2017) by bibliometric analysis., Methods: "Forensic anthropology" was used as the Medical Subject Headings term and topic in PubMed and Web of Science Core Collection., Results: As 5130 articles retrieved, two independent investigators evaluated all of them respectively. After restricting the published year, excluding duplicated and irrelevant articles, 1663 articles were available. The total of 219 countries and regions contributed to this research and the United States was the most productive country. There were 201 peer-reviewed journals including all of articles and two of them were identified as core journals according to Bradford's law. Eight of the top 10 productive authors were from developed countries. The top 10 cited articles were published by authors from developed countries with half in the United States. Sex estimation and age estimation were the most popular topics., Conclusions: With the basic and recognized methodology administered in this study, it provided a relative broad view to evaluate the scientific research capacity of forensic anthropology and reveal the worldwide tendency in this field., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Through bibliometric analysis, this study aimed to reveal worldwide research productivity and trends in forensic entomology over the last two decades (1998-2017). As "forensic entomology" is yet to be established as a Medical Subject Headings term, we used "forensic entomology" and "legal entomology" as topics in Web of Science Core Collection, Medline, and PubMed searches. Two independent investigators retrieved and evaluated 3165 articles. After determining the cutoff for publication year and excluding repeated or irrelevant articles, 1087 articles remained for analysis. In terms of papers published, the United States was the most productive among the 136 countries (and disputed regions) that contributed to forensic entomological research. Among the 179 journals that published all articles, two were considered core journals based on Bradford's Law (i.e., the two journals published the majority of relevant articles). Most studies focused on the order Diptera and family Calliphoridae. The most common topics were estimation of postmortem interval and species identification., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of the present meta-analysis was to evaluate scientific evidence on the association between emotional disorder (depression and anxiety) and chronic periodontitis. An overall electronic literature search in PubMed, ISI Web of Science, Cochrane Library, and China National Knowledge Infrastructure was undertaken up to November 2017. Newcastle-Ottawa scale was applied to ascertain the validity of each eligible study. Stata statistical software was used to perform meta-analysis. The strength of the association between periodontitis and emotional disorder was measured by odds ratios (ORs) with their 95% confidence intervals (95% CIs). Subgroup analysis and sensitivity analysis were performed. Publication bias was assessed through funnel plots and Begger's test. A total of 14 eligible articles were included in the meta-analysis, 6 of them were focused exclusively on depression, whereas 8 studies investigated both depression and anxiety. There was significant association between emotional disorder and chronic periodontitis (OR = 1.54, 95% CI = 1.27-1.86). Sensitivity analyses confirmed the stability of the present results. No evidence of asymmetry was observed in Begger's test. This meta-analysis demonstrates significant association between emotional disorder (including anxiety and depression) and chronic periodontitis. Nevertheless, the result should be interpreted with caution because of the potential bias and confounding in the included studies.

In recent years, the environmental impact of artificial light at night has been a rapidly growing global problem, affecting 99% of the population in the US and Europe, and 62% of the world population. The present study utilized a mouse model exposed to long-term artificial light and light deprivation to explore the impact of these conditions on emotion and cognition. Based on the potential links between histidine triad nucleotide binding protein 1 (HINT1) and mood disorders, we also examined the expression of HINT1 and related apoptosis factors in the suprachiasmatic nucleus (SCN), prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus (Hip). Mice exposed to constant light (CL) exhibited depressive- and anxiety-like behaviors, as well as impaired spatial memory, as demonstrated by an increased immobility time in the tail suspension and forced swimming tests, less entries and time spent in the open arms of elevated plus-maze, and less platform site crossings and time spent in the target quadrant in the Morris water maze (MWM). The effects of constant darkness (CD) partially coincided with long-term illumination, except that mice in the CD group failed to show anxiety-like behaviors. Furthermore, HINT1 was upregulated in four encephalic regions, indicating that HINT1 may be involved in mood disorders and cognitive impairments due to altered light exposure. The apoptosis-related proteins, BAX and BCL-2, showed the opposite expression pattern, reflecting an activated apoptotic pathway. These findings suggest that exposure to CL and/or darkness can induce significant changes in affective and cognitive responses, possibly through HINT1-induced activation of apoptotic pathways.

Drug addiction is a chronically relapsing disorder in humans; yet, the underlying mechanism remained unclear. Recent studies suggested that the histidine triad nucleotide binding protein 1 (HINT1) may play significant roles in diverse neuropsychiatric diseases including drug addiction. In our present study, we used different batches of mice to establish the different stages of methamphetamine (METH)-induced conditioned place preference (CPP) to explore the dynamic changes throughout the process of addiction in different brain regions, including prefrontal cortex (PFC), nucleus accumbens (NAc), corpus striatum (CPu), and hippocampus (Hip). We found that in NAc of the METH group mice, the HINT1 expression level initially increased after acquisition phases, and then dropped to the normal level after extinction phase, and again increased after reinstatement phase. However, there was no statistical difference in the HINT1 expression level in other three encephalic regions (PFC, CPu, and Hip). Therefore, the HINT1 protein, particularly in the NAc, plays a vital role in the METH-induced CPP. However, the precise mechanisms will require further investigation.

The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities. Investigations recently suggest that HINT1 is closely related to many peripheral and central nervous system diseases,and plays a vital role in some of neuropsychiatric diseases such as inherited peripheral neuropathies,schizophrenia,mood disorder,drug addiction,and Down's syndrome. In this review,the role of HINT1 in above-mentioned neuropsychiatric disorders was summarised,and the research findings of HINT1 in each of the above diseases were summarized and analyzed,in order to provide some guidance for further research on this protein.

Background: Histidine triad nucleotide-binding protein 1 (HINT1) is regarded as a haplo-insufficient tumor suppressor and is closely associated with diverse neuropsychiatric diseases. Moreover, HINT1 is related to gender-specific acute behavior changes in schizophrenia and in response to nicotine. Stress has a range of molecular effects in emotional disorders, which can cause a reduction in brain-derived neurotrophic factor (BDNF) expression in the hippocampus, resulting in hippocampal atrophy and neuronal cell loss., Methods: This study examined the role of HINT1 deficiency in anxiety-related and depression-like behaviors and BDNF expression in the hippocampus under chronic immobilization stress, and investigated whether the sex-specific and haplo-insufficient effects exist in emotional-like behaviors under the same condition., Results: In a battery of behavior tests, the results of the control group, not exposed to stress, showed that knockout (KO) and heterozygosity (HT) of Hint1 had anxiolytic-like and antidepression-like effects on the male and female mice. However, both male and female Hint1 -KO mice showed elevated anxiety-related and antidepression-like behavior under chronic immobilization stress; moreover, both male and female Hint1 -HT mice displayed elevated anxiety-related behavior and increased depression-like behavior under chronic immobilization stress. There were no significant differences in general locomotor activity between Hint1 -KO and -HT mice and their wild-type (WT) littermates. Hint1 -KO mice under basal and chronic immobilization stress conditions expressed more BDNF in the hippocampus than did Hint1 -HT and WT mice; overall, there were no significant sex differences in emotional-like behaviors of Hint1 -KO and -HT mice. Additionally, Hint1-HT mice showed haplo-insufficient effects on emotional-like behaviors under basic conditions, rather than under chronic immobilization stress., Conclusions: Both male and female HINT 1 KO and HT mice had a trend of anxiolytic-like behavior and antidepression-like behavior at control group. However, both male and female HINT1 KO mice showed elevated anxiety-related and antidepression-like behavior under chronic immobilization stress; moreover, both male and female HINT1 HT mice displayed elevated anxiety-related behavior and increased depression-like behavior under chronic immobilization stress.

Background and Purpose: The purpose of this study was to evaluate the effect of a simplistic simulation exercise in a nephrology module on pharmacy students' learning in a three-year concentrated curriculum., Educational Activity and Setting: Second year pharmacy students participated in a two-part simulation on electrolyte imbalances and dialysis in a nephrology pharmacotherapeutics module. Students completed a seven-item anonymous survey at the end of the simulation on a five-point Likert scale to examine the effect of the simulation and their attitudes to the exercise. Additionally, exam scores were assessed at the end of the module to measure learning., Findings: A total of 65 students completed the activity. Seventy-eight percent of students agreed that the simulation was a valuable learning experience and 76.9% reported that the simulations gave them real-world knowledge. Exam scores in the group who performed the simulations were higher on the assessment compared to those without the experience (p < 0.01) DISCUSSION AND SUMMARY: Participation in the simulation had positive effects on students' attitudes, learning, and exam scores. This experience was a successful active-learning method for enhancing learning in pharmacy education., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aim: To investigate the evaluation of neogalactosylalbumin (NGA) for liver function assessment based on positron emission tomography technology., Methods: Female Kunming mice were assigned randomly to two groups: fibrosis group and normal control group. A murine hepatic fibrosis model was generated by intraperitoneal injection of 10% carbon tetrachloride (CCl 4 ) at 0.4 mL every 48 h for 42 d. 18 F-labeled NGA ([ 18 F]FNGA) was synthesized and administered at a dosage of 3.7 MBq/mouse to both fibrosis mice and normal control mice. Distribution of [ 18 F]FNGA amongst organs was examined, and dynamic scanning was performed. Parameters were set up to compare the uptake of tracers by fibrotic liver and healthy liver. Serologic tests for liver function were also performed., Results: The liver function of the fibrosis model mice was significantly impaired by the use of CCl 4 . In the fibrosis model mice, hepatic fibrosis was verified by naked eye assessment and pathological analysis. [ 18 F]FNGA was found to predominantly accumulate in liver and kidneys in both control group ( n = 21) and fibrosis group ( n = 23). The liver uptake ability (LUA), peak time (T p ), and uptake rate (LUR) of [ 18 F]FNGA between healthy liver ( n = 8) and fibrosis liver ( n = 10) were significantly different ( P < 0.05, < 0.01, and < 0.05, respectively). LUA was significantly correlated with total serum protein level (TP) ( P < 0.05). T p was significantly correlated with both TP and glucose (Glu) concentration ( P < 0.05 both), and LUR was significantly correlated with both total bile acid and Glu concentration ( P < 0.01 and < 0.05, respectively)., Conclusion: [ 18 F]FNGA mainly accumulated in liver and remained for sufficient time. Functionally-impaired liver showed a significant different uptake pattern of [ 18 F]FNGA compared to the controls., Competing Interests: Conflict-of-interest statement: All authors state that no conflicts of interest exist.

Both genetic factors and early life adversity play major roles in the etiology of schizophrenia. Our previous studies indicated that social isolation (SI) during early postnatal development leads to several lasting abnormal behavioral and pathophysiological features resembling the core symptoms of some human neuropsychiatric disorders in mice. The glutamate and dopamine hypotheses are tightly linked to the development of schizophrenia. The cross-talk between glutamate N-methyl-D-aspartate acid receptors and dopamine receptors is associated with histidine triad nucleotide binding protein 1 (HINT1), which is correlated with diverse psychiatric disorders. We examined the effects of SI on schizophrenia-like behavior and used enzyme-linked immunosorbent assays to investigate the expression levels of HINT1, the NR1 subunit of N-methyl-D-aspartate acid receptor, and dopamine type 2 receptor (D2R) in C57 mice. We found that SI leads to a series of schizophrenia-related deficits, such as social withdrawal, anxiety disorder, cognitive impairments, and sensorimotor gating disturbances. These abnormal phenotypes paralleled changes of HINT1, NR1, and D2R. SI may be considered a robust model of the effects of early life stress on the schizophrenia-related behaviors in mice. Potential interactions among HINT1, NR1, and D2R may underlie the behavioral deficits induced by SI.

Forensic dentistry is an interdiscipline of forensic medicine and stomatology, which provides legal information by collecting, testing and assessing the dental evidence scientifically. In this review, the present application of forensic dentistry has been described, such as the estimation of age, sex, species, occupation and living habit, as well as the identification of individual, domestic violence or abuse, which aims to enrich and improve forensic dentistry for making it be more useful in forensic medicine even in juridical practice., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Forensic Medicine.)

The purpose of the present study was to observe the depression-like behavior induced by social isolation; detect the antidepressant effect of a recombinant adeno-associated virus (AAV) expressing NAP on social isolation mice by intranasal delivery. After construction of NT4-NAP/AAV, expression of NAP was confirmed in vitro. 3-week-old C57/BL mice were bred individually in cages as social isolation-rearing. Six weeks later, the first subset of mice underwent behavioral tests and western blot; the second was for enzyme-linked immunosorbent assay. NT4-NAP/AAV was delivered quaque die by nasal administration for consecutive 10 days before behavioral test. Several depression-like behaviors were observed in social isolation mice, including decreased relative sucrose preference, longer immobility time in forced swimming test, lower plasma corticosterone and decreased brain-derived neurotrophic factor in hippocampus. Thus, social isolation procedure appears to be an animal model of depression with good face and construct validity. What's more, the antidepressant effect in social isolation-rearing mice was observed after intranasal administration of NT4-NAP/AAV, suggesting that this might be a promising therapeutic strategy for depressive disorder.

To facilitate an academic-community partnership for sustainable medical mis-sions, a 12-step process was created for an interprofessional, global health educational, and service-learning experience for students and faculty in a school of pharmacy and health professions. Lessons learned and practical guidance are provided to implement similar global health opportunities.

The present study was designed to construct a recombinant adeno-associated virus (rAAV) which can express NAP in the brain and examine whether this virus can produce antidepressant effects on C57 BL/6 mice that had been subjected to open field test and forced swimming test, via nose-to-brain pathway. When the recombinant plasmid pGEM-T Easy/NT4-NAP was digested by EcoRI, 297 bp fragments can be obtained and NT4-NAP sequence was consistent with the designed sequence confirmed by DNA sequencing. When the recombinant plasmid pSSCMV/NT4-NAP was digested by EcoRI, 297 bp fragments is visible. Immunohistochemical staining of fibroblasts revealed that expression of NAP was detected in NT4-NAP/AAV group. Intranasal delivery of NT4-NAP/AAV significantly reduced immobility time when the FST was performed after 1 day from the last administration. The effects observed in the FST could not be attributed to non-specific increases in activity since intranasal delivery of NT4-NAP/AAV did not alter the behavior of the mice during the open field test. The results indicated that a recombinant AAV vector which could express NAP in cells was successfully constructed and NAP may be a potential target for therapeutic action of antidepressant treatment.

Introduction: Previous studies have indicated a possible role of histidine triad nucleotide-binding protein 1 (HINT1) on sustaining the regulatory crosstalk of N-methyl-D-aspartate acid glutamate receptors (NMDARs) and G-protein-coupled receptors (GPCRs) such as the μ-opioid receptor (MOR). Both receptors are present in the midbrain periaqueductal gray neurons, an area that plays a central role in the supraspinal antinociceptive process., Methods: In the present study, a battery of pain-related behavioral experiments was applied to Hint1 knockout, heterozygous and wild-type mice. Both the male and female mice were investigated to assess the differences between genders., Results: Hint1-/- mice presented significant shorter latency at 50°C in both male and female in hot plate test while no significant difference was found in tail filck test. In Von Frey hairs test Hint1-/- mice were more sensitive than Hint1+/+ mice, presenting a lower withdrawal threshold and enhanced relative frequency of paw withdrawal. The average flinches and licking time of Hint1-/- mice were more than that of Hint1+/+ mice in formalin test., Conclusion: The absence of Hint1 gene-enhanced supraspinal nociceptive sensitivity in mice, including thermal, mechanical and inflammatory hyperalgesia. Meanwhile, there was no certain evidence indicating the haploinsufficiency and gender differences of Hint1 gene in pain-related behaviors.

Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy, and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD.

Consumption of high concentration of fluoride in the drinking water would cause the fluorosis and chronic pain. Similar pain syndrome appeared in the patients in fluoride therapy of osteoporotic. The aim of the current study was to examine whether exposing immature mice to fluoride would modify the peripheral pain sensitivity or even cause a pain syndrome. We gave developmental fluoride exposure to mice in different concentration (0mg/L, 50mg/L and 100mg/L) and evaluated their basal pain threshold. Von Frey hair test, hot plate test and formalin test were conducted to examine the mechanical, thermal nociceptive threshold and inflammatory pain, respectively. In addition, the expression of hippocampal brain-derived neurotrophic factor (BDNF) was also evaluated by Western blotting. Hyperalgesia in fluoride exposure mice was exhibited in the Von Frey hair test, hot plate test and formalin test. Meanwhile, the expression of BDNF was significantly higher than that of control group. The results suggest that early developmental fluoride exposure may lower the basal pain threshold and be associated with the increasing of BDNF expression in hippocampus., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The memories that are formed between rewarding and drug-associated contextual cues have been suggested to contribute to drug addiction relapse. Recent evidence has indicated that the ventrolateral orbital cortex (VLO) plays important roles in reward-based learning and reversal learning. However, whether the VLO is required for methamphetamine-induced contextual memory formation is not well understood. In the present study, a three-phase methamphetamine-induced conditioned place preference (CPP) model was used to investigate the effects of VLO lesions on the formation of drug-associated contextual memories in rats. We found that the VLO lesions themselves elicited no observable effects on place preferences. However, the VLO lesions delayed the acquisition and extinction phases of CPP without affecting the expression level. Furthermore, the VLO lesions did not have an obvious influence on CPP reinstatement. These results indicate that electrolytic lesions of the bilateral ventrolateral orbital cortex can inhibit the formation of methamphetamine-induced contextual memories in rats. Moreover, VLO may not be critically involved in memory storage and retrieval., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Social isolation (SI) rearing has been demonstrated to induce behavioral abnormalities like anxiety, impulsivity, aggression, and learning and memory deficits which are relevant to core symptoms in patients with some certain neuropsychiatric disorders. But the underlying pathophysiological mechanisms remain unclear. Recent studies have revealed HINT1 has close relation with diverse neuropsychiatric diseases. In this present study, the SI rearing mice exhibited depression-like and aggressive behavior. Besides, HINT1 protein levels decreased in PFC but increased in HIP. Based on the data obtained, we concluded that HINT1 is involved in the behavioral abnormalities induced by social isolation and exerts distinct roles in different encephalic regions., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

The present study was designed to examine whether somatostatin analog octreotide (OCT) was involved in antinociception in the ventrolateral orbital cortex (VLO) and determine whether this effect had a sex difference between male and female rats. The radiant heat-evoked tail flick (TF) reflex was used as an index of acute nociceptive response in lightly anesthetized rats. The number of flinches evoked by formalin injection into the hindpaw was used to evaluate inflammatory persistent pain in conscious rats. Administration of OCT (2.0, 5.0 10.0 ng in 0.5 µl) into the VLO depressed the TF reflex in a dose-dependent manner only in female rats, but not male rats. Pretreatment with a nonselective somatostatin receptor antagonist cyclo-somatostatin (c-SOM) (25.0 µg in 0.5 µl) into the VLO antagonized 10.0 ng OCT-induced inhibition of the TF reflex in female rats. Similarly, application of high dose of OCT (10.0 ng in 0.5 µl) into the VLO depressed formalin-induced flinching response in the early and late phases only in female rats, and had no any effects in male rats. Pretreatment with c-SOM (25.0 µg in 0.5 µl) into the VLO totally antagonized the 10 ng OCT-induced inhibition of the flinches in both phases in female rats. Additionally, single administration of c-SOM into the VLO failed to alter tail reflex latencies and formalin-induced nociceptive behaviors in female rats. The results provide the first valuable evidence that somatostatin and its receptors are involved in antinociception in acute heat-evoked nociception and inflammatory persistent pain only in female rats, not male rats, in the VLO., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3β (GSK3β) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3β signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3β at serine 9 and total GSK3β levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3β activity. We further investigated whether microinjection of VPA (300 μg/0.5 μl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3β at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3β activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity.

Objective: To investigate the imaging potential and biodistribution in vivo of a novel positron imaging agent,2-[(18)F]fluoropropionic,in breast cancer-bearing mice. Methods: 2-[(18)F]fluoropropionic acid (7.4-11.1 MBq)was injected into the breast cancer-bearing mice via tail vein,followed by micro positron emission tomography at 60 min and 120 min.The radioactivity per volume (Bq/ml) in organs was transferred to percentage injected dose per gram(% ID/g)by Inveon Research software and the biodistribution of 2-[(18)F]fluoropropionic acid in organs was deduce.The same operations were done with (18)F-FDG., Results: 2-[(18)F]fluoropropionic acid was mainly distributed in the urinary bladder,intestine,and liver between 60 min to 120 min.The breast cancer at right flank was visualized clearly,and the radioactivity uptake was (13.74±1.97)% ID/g and (14.84±1.06)% ID/g,respectively,at these two time points (P=0.454).The radioactivity uptakes in muscle and brown tissue were relatively low.The radioactivity uptake of (18)F-FDG was (10.27±2.34)% ID/g at the breast cancer 60 min after injection,and radioactivity uptake of the brown fat on the back was obvious., Conclusions: Positron imaging agent 2-[(18)F]fluoropropionic acid can be used to image breast cancer.It may be applied in the noninvasive imaging of breast cancer in clinical settings.

This study investigated the potential application of a zirconium oxide (ZrO2) ceramic foam culturing system to the production of glial cell line-derived neurotrophic factor (GDNF). Three sets of ZrO2 ceramic foams with different pore densities of 10, 20, and 30 pores per linear inch (PPI) were prepared to support a 3D culturing system. After primary astrocytes were cultured in these systems, production yields of GDNF were evaluated. The biomaterial biocompatibility, cell proliferation and activation of cellular signaling pathways in GDNF synthesis and secretion in the culturing systems were also assessed and compared with a conventional culturing system. In this study, we found that the ZrO2 ceramic foam culturing system was biocompatible, using which the GDNF yields were elevated and sustained by stimulated cell proliferation and activation of signaling pathways in astrocytes cultured in the system. In conclusion, the ZrO2 ceramic foam is promising for the development of a GDNF mass production device for Parkinson's disease treatment.

Histidine triad nucleotide-binding protein 1 (HINT1) is a member of a superfamily of histidine triad proteins named by the conserved nucleotide-binding motif histidine-x-histidine-x-histidine-xx, in which x represents hydrophobic amino acid. HINT1 is implicated in pathological progress of many human diseases including cancer and schizophrenia; however, little is known about the essential role and pathological consequences of HINT1 in cellular physiology and diseases. Therefore, we summarize the structure, distribution, and physiological function of HINT1 in cells and tissues as well as the correlation between HINT1 and human diseases.

DNA methylation and histone modification are two major epigenetic mechanisms involved in the pathophysiology of major depressive disorder (MDD) and the action of antidepressants. We and others have recently shown that epigenetic regulation through histone acetylation within ventrolateral orbital cortex (VLO) contributes to the antidepressant-like effects of histone deacetylase inhibitors [HDACi, such as valproic acid (VPA) and MS-275] observed in rats. However, there is so far no investigation focused on the effect of DNA methylation in VLO on depressive-like behaviors. Here, we examined the effects of the DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-aza) on rat forced swimming test (FST) and locomotor activity when microinjected into VLO. We found that bilateral intra-VLO injections of 5-aza increased the duration of immobility in FST in a dose-dependent manner compared to vehicle-treated controls. The effects of 5-aza observed in the FST paradigms could not be attributed to non-specific decreases in activity since the inhibition of DNA methylation in VLO did not cause general impairment in locomotor activity. These results add to the evidence that DNA hypomethylation in VLO is involved in regulating depressive-like behaviors, and suggest that the effect of DNA methylation on depressive-like behaviors appear to be brain region-dependent., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Previous studies have suggested that sodium fluoride (NaF) may have adverse effects on neurodevelopment. In the present study, we evaluated developmental neurotoxicity by assessing in cognitive function and emotional behavior in BalB/C mice treated with NaF. Mice were weaned at 4weeks, and water or different NaF concentrations (2, 5, or 10mg/L in drinking water) were provided for 4weeks. We found that exploration preference in the novel object recognition test was significantly altered in mice treated with 5 and 10mg/L NaF compared with the water-treated control animals. Furthermore, mice treated with 5 and 10mg/L NaF showed significantly longer escape latencies, less time in the target quadrant, and fewer platform-crossing numbers in the Morris water maze compared to those in the control group. In addition, mice treated with 10mg/L NaF spent a lower percentage of time in the open arms in the elevated-plus maze, while no significant changes were noted in the open and close arm entries or the total arm entries. We also found that the cumulative immobility time in the tail suspension test was longer in mice treated with 5 and 10mg/L NaF compared to the control group. Only 10mg/L NaF-treated mice showed longer immobility time compared with the control group. Collectively, our data indicate that developmental exposure to NaF induces cognitive deficits and anxiety-depression-like behaviors in mice., (© 2013.)

Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays an important role in the neurobiology and treatment of this disease. Currently, the non-competitive NMDA receptor antagonist ketamine is considered as one of the most attractive candidate drugs in therapy of treatment-resistant depression. A recent study demonstrated ketamine's rapid antidepressant activity in patients with treatment-resistant MDD and bipolar disorder. The response rate for ketamine ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion, with generally mild adverse effects. Based on the role of the NMDA receptor in depression, a number of therapeutic drugs which interact with this receptor have been developed. In this article, we reviewed recent findings concerning the role of glutamatergic signaling in the neurobiology of MDD and potential, novel therapeutic drugs, such as ketamine, memantine, AZD6765, traxoprodil, MK-0657, GLYX-13, NRX-1047, D-cycloserine, sarcosine, all of which target this system.

Levo-tetrahydropalmatine (l-THP), as an alkaloid purified from the traditional Chinese herbal medicine Corydalis and Stephania, has been widely used to produce many traditional Chinese herbal preparations. The effect of l-THP on methamphetamine-induced reward learning still remains unclear although it has been proved to be effective on treating allodynia and drug addiction. This experiment has been designed to examine the effect of l-THP on the acquisition, expression, extinction, and reinstatement of methamphetamine-induced conditioned place preference (CPP) in mice. The results show that methamphetamine (METH) could induce CPP in mice at doses of 0.5mg/kg, 1.0mg/kg and 2.0mg/kg respectively, but l-THP alone could not do so. Meanwhile, l-THP could not induce conditioned place aversion at doses of 1.25mg/kg to 20.0mg/kg in mice, but it could attenuate the acquisition and expression of METH-induced CPP and facilitate the extinction of METH-induced CPP in mice. Besides, l-THP could inhibit the reinstatement of METH-induced CPP at the dose of 10.0mg/kg whether it was given in the extinction training phase or 30min before the reinstatement. These results suggest that l-THP can globally suppress the rewarding properties of METH on all phases of the CPP task and it may have potential effects on the treatment of METH abuse., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To prepare the modified ZHER2V2 affibody with amino-terminal HEHEHE sequence and carboxyl-terminal GGGC sequence by gene recombinant expression,which is the basis for invasive HER2 imaging with affibody., Methods: The encoded affibody gene was optimized by codon preference of E. coli with gene designer software. The N-terminal of affibody was fused with HEHEHE sequence,while the C-terminal was fused with GGGC sequence. The synthetic gene was confirmed by Hind 3 endonuclease restriction and gene sequencing. The human epidermal growth factor receptor-2(HER2)affibody gene was sub-cloned into pET22b(+)plasmid and transformed into competent BL21(DE3)bacteria. The expression of modified affibody was induced with isopropyl Β-D-1-thiogalactopyranoside(IPTG)and identified by SDS-PAGE. The affibody was purified by nickel affinity binding and imidazole elution. The purified affibody was labeled with (68)Ga and its affinity was determined by saturation analysis with HER2-positive cells MDA-MB-361., Results: The affibody gene containing N-terminal HEHEHE and C-terminal GGGC sequences were confirmed by Hind 3 endonuclease restriction and gene sequencing. A newly expressed 8×10(3) protein was expressed from the induced recombinant bacteria identified by SDS-PAGE after sub-cloning HER2 affibody gene into pET22b(+)plasmid,transforming recombinant plasmid into competent BL21(DE3)bacteria and inducing the recombinant bacteria with IPTG. The expressed protein was purified from nickel agarose by 60 mmol/L imidazole eluting. The affinity Kd value of (68)Ga labeled affibody to HER2 positive MDA-MB-361 cells was 1.5 nmol/L., Conclusion: The affiibody ZHER2V2 containing N-terminal HEHEHE and C-terminal GGGC was successfully prepared by gene optimization,recombinant expression and affinity purification.

A central problem in understanding the dopamine system in anxiety and depression is to specify functions of different members of the dopamine receptor family. Recent studies have reported that the dopamine D2/D3 receptor agonist pramipexole exerts an antidepressant-like effect in the chronic mild stress model and in the behavioral despair model, suggesting dopamine D3 receptor may be an important target for antidepressant actions. The aim of the present study was to examine the role of dopamine D3 receptor on the anxiety-like and depression-like behaviors induced by immobilization stress. We subjected D3 receptor knockout (D3KO) mice to a series of behavioral paradigms after acute (1 h) or chronic (1 h a day for 14 days) immobilization stress. The results showed that immobilization stress significantly altered the anxiety-like behaviors (open field test and elevated plus maze) and depression-like behaviors (tail suspension test) in both D3KO mice and their wild-type littermates. Moreover, further analysis of the data indicated that the D3KO mice, but not their littermates, failed to show a change in immobility time in the tail suspension test after the acute and chronic stress as compared to intact controls, suggesting an increased resistance to the immobilization stress given before behavioral tests. Although our study did not suggest a significant role of D3 receptor in regulating basal anxiety-like and depression-like behaviors, it demonstrated the mice lacking D3 receptor might be more resistant to stressful procedure than their WT littermates., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is involved in the pathogenesis of atherosclerosis, especially in advanced plaques. In the present study, the abilities of darapladib, a selective Lp-PLA(2) inhibitor, and lentivirus-mediated Lp-PLA(2) silencing on inflammation and atherosclerosis in apolipoprotein E-deficient mice were compared., Methods: Apolipoprotein E-deficient mice were fed on a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC), darapladib and RNA interference (RNAi) groups. Eight weeks after surgery, lentivirus-mediated RNAi construct or darapladib were used to decrease the expression of Lp-PLA(2). Plaques were collected five weeks later for histological analysis. Inflammatory gene expression in the atherosclerotic lesions were then determined at the mRNA and protein level., Results: The expression of pro-inflammatory cytokines was significantly reduced in the treatment group, compared to nontreatment group, whereas the plasma concentration of anti-inflammatory cytokines increased markedly. Moreover, our results demonstrated a significant reduction in plaque lipid content, as well as a rise in collagen content following Lp-PLA(2) inhibition. Interestingly, when comparing the two methods of Lp-PLA(2) inhibition, animals treated with Lp-PLA(2) RNAi were found to exhibit lower plaque areas and enhanced improvement of plaque stability as compared with animals treated with darapladib. Darapladib had no attenuating effect on atherosclerotic plaque area. These therapeutic effects were independent of plasma lipoprotein levels., Conclusions: Lp-PLA(2) inhibition by darapladib or lentivirus-mediated RNAi ameliorated inflammation and atherosclerosis in apolipoprotein E-deficient mice. The effect was more prominent in the RNAi group.

There is collecting evidence suggesting that the process of chromatin remodeling such as changes in histone acetylation contribute to the formation of stress-related memory. Recently, the ventrolateral orbital cortex (VLO), a major subdivision of orbitofrontal cortex (OFC), was shown to be involved in antidepressant-like actions through epigenetic mechanisms. Here, we further investigated the effects of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) on stress-related memory formation and the underlying molecular mechanisms by using the traditional two-day forced swimming test (FST). The results showed that VPA significantly increased the immobility time on day 2 when infused into the VLO before the initial forced swim stress on day 1. The learned immobility response to the stress was associated with increased phosphorylation of extracellular signal-regulated kinase (ERK) in VLO and hippocampus on the first day. The levels of phosphorylated ERK (phospho-ERK) in VLO and hippocampus were significantly decreased when retested 24 h later. The pretreatment with intra-VLO VPA infusion further reduced the activation of ERK on day 2 and day 7 compared with the saline controls. Moreover, the VPA infusion pretreatment also induced a significantly decreased BDNF level in the VLO on day 2, whereas no change was detected in the hippocampus. These findings suggest that VPA enhance the memories of emotionally stressful events and the ERK activity is implicated in stimulating adaptive and mnemonic processes in case the event would recur.

Background: Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice., Methodology/principal Findings: Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice., Conclusions/significance: These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.