Restoration of Serotonin Neuronal Firing Following Long-Term Administration of Bupropion but Not Paroxetine in Olfactory Bulbectomized Rats

Background:

Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine.

Methods:

Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats.

Results:

Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin_1A receptors; paroxetine (10mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin_1A receptors.

Conclusions:

The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin_1A receptors in hippocampus.     

CRISPR,animals, and FDA oversight: Building a path to success

Technological advances, such as genome editing and specifically CRISPR, offer exciting promise for the creation of products that address public health concerns, such as disease transmission and a sustainable food supply and enable production of human therapeutics, such as organs and tissues for xenotransplantation or recombinant human proteins to treat disease. The Food and Drug Administration recognizes the need for such innovative solutions and plays a key role in bringing safe and effective animal biotechnology products to the marketplace. In this article, we (the Food and Drug Administration/Center for Veterinary Medicine) describe the current state of the science, including advances in technology as well as scientific limitations and considerations for how researchers and commercial developers working to create intentional genomic alterations in animals can work within these limitations. We also describe our risk-based approach and how it strikes a balance between our regulatory responsibilities and the need to get innovative products to market efficiently. We continue to seek input from our stakeholders and hope to use this feedback to improve the transparency, predictability, and efficiency of our process. We think that working together, using appropriate science- and risk-based oversight, is the foundation to a successful path forward.     

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta?=????1.167, P_Adj?=?2.75?×?10^?4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.

     

A Higher Angiogenin Expression is Associated With a Nonnuclear Maspin Location in Laryngeal Carcinoma

Objectives

In numerous malignancies, angiogenin (ANG) and Maspin are important proangiogenic and antiangiogenic regulators, respectively. The aim of this study was to identify potential relationships between the biological roles of these two proteins in laryngeal squamous cell carcinoma (LSCC).

Methods

Immunohistochemical staining for ANG and Maspin was performed on specimens from 76 consecutive LSCC patients treated with surgery alone, considering the subcellular pattern of Maspin expression. Univariate and multivariate statistical models were used for prognostic purposes.

Results

On univariate analysis, a different level of ANG expression was seen for patients stratified by subcellular Maspin expression pattern: the mean ANG expression was higher in cases with a nonnuclear MASPIN expression than in those with a nuclear pattern (P=0.002). Disease-free survival (DFS; in months) differed significantly when patients were stratified by N stage (P=0.01). Patients whose Maspin expression was nonnuclear (i.e., it was cytoplasmic or there was none) had a significantly higher recurrence rate (P<0.001), and shorter DFS (P=0.01) than those with a nuclear Maspin pattern. The mean ANG expression was significantly higher in cases with loco-regional recurrent disease (P=0.007); and patients with an ANG expression ≥5.0% had a significantly shorter DFS than those with an ANG expression <5.0% (P=0.007). On multivariate analysis, ANG expression ≥5.0% was a significant, independent, negative prognostic factor in terms of DFS (P=0.041).

Conclusion

Our results support the hypothesis that a higher ANG expression is associated with a nonnuclear Maspin expression pattern in patients with LSCC. Further studies are needed to clarify the relationship between the ANG and Maspin pathways, and their potential diagnostic and therapeutic role in LSCC.     

Chelators controlling metal metabolism and toxicity pathways: applications in cancer prevention, diagnosis and treatment

Chelating drugs and chelator metal complexes are used for the prevention, diagnosis and treatment of cancer. Cancer cells and normal cells require essential metal ions such as iron, copper and zinc for growth and proliferation. Chelators can target the metabolic pathways of cancer cells through the control of proteins involved in the regulation of these metals and also of other molecules involved in cell cycle control, angiogenesis and metastatic suppression. Other targets include the inhibition of specific proteins such as ribonucleotide reductase involved in DNA synthesis, the inhibition of free radical damage on DNA caused by iron and copper catalytic centers, the inhibition of microbial growth in immuno compromised cancer patients and the decorporation of radioactive and other toxic metals causing cancer. Chelating drugs and metal ions can affect the metabolism, efficacy and toxicity of anti-cancer drugs such as doxorubicin, mitozantrone, bleiomycin and hydroxyurea (HU). Although many experimental chelators have been shown to be effective as anti-cancer agents, only a few, e.g., dexrazoxane, deferoxamine (DFO) and triapine, have reached the stage of clinical testing or application. In many experimental models, deferiprone (L1) has been shown to be effective in cancer prevention and treatment, and in the inhibition of doxorubicin-induced cardiotoxicity. New anti-cancer drugs could be developed using chelators and chelator complexes with platinum and other metals, and also new protocols of combinations of chelators with known anti-cancer drugs.     

Clinical characteristics and long-term outcome in patients with heart failure complicating acute myocardial infarction

INTRODUCTION AND OBJECTIVES: To evaluate the clinical characteristics and prognosis of heart failure (HF) development in patients hospitalized for acute myocardial infarction (AMI). PATIENTS AND METHOD: Between May 1990 and March 2000, 836 consecutive patients were admitted with a diagnosis of AMI within 24 h of symptom onset. HF was defined as the presence of rales and a third heart sound with gallop, and evidence of pulmonary congestion on chest x-ray. It was diagnosed in 263 subjects (31.5%). RESULTS: The mean age of patients with HF (group 1) was 63.4 (11.4) years compared with 59.9 (11.6) years in those without HF (group 2) (P<.01). There were differences between groups 1 and 2 in history of diabetes (36% vs 20%; P<.001) or previous HF (9.2% vs 1.1%; P<.001). The reperfusion strategy used in patients with Q-wave infarction, with or without HF, was primary angioplasty in 15% and 14%, respectively (P=.81), and thrombolytic agents in 28% and 37%, respectively (P=.013). Patients with HF were more likely to develop recurrent angina (26.8% vs 19.6%; P=.02), pericarditis (17.5% vs 6.3%; P<.001), and atrial fibrillation (12.3% vs 5.1%; P<.01). In-hospital mortality in groups 1 and 2 was 15.6% and 2.3% (P<.001), respectively, and 10-year survival was 10% and 30%, respectively (P<.001). The variables associated with mortality were: age (HR=1.022; P<.001), hyperglycemia (HR=1.748 per 1.0-g/L increase; P<.001), leukocytosis (HR=1.035 per 1000-cell/.L increase; P<.001), and HF (HR=1.308; P=.028). CONCLUSIONS: AMI is still frequently complicated by HF, which increases short- and long-term morbidity and mortality. Heart failure, age, hyperglycemia, and leukocytosis at admission were independent predictors of mortality during follow-up.     

Multifocal diffuse glomus tumor. A case report of glomangiomyoma and review of the literature

The case examined was a multifocal diffuse glomus tumor covering most of the right leg of a 24-year-old woman. The lesion, present at birth, had never caused any symptoms. Macroscopically, it had a simulangiomatous aspect, whereas histologically it was identified as a glomangiomyoma. The Authors have examined 26 (46.4%) of the 56 cases of multiple tumors reported to date. Multiple glomus tumors are benign lesions, which generally appear at an early age (70% by the age of 20), with no clear distinction between the two sexes. The lesions usually occur on the upper limbs, which account for 80% of the cases. Pain is reported in half of the cases. There are 3 histological types: "sensu strictu" glomus tumor, glomangioma and glomangiomyoma; the glomangioma being the most frequent (80.8%) as compared to 19.2% for the glomangiomyomatosis type. No case of "sensu strictu" glomus tumor was observed.     

A syndemic of psychosocial health problems is associated with increased HIV sexual risk among Nigerian gay,bisexual, and other men who have sex with men (GBMSM)

ABSTRACT

Nigerian gay, bisexual and other men who have sex with men (GBMSM) experience negative psychosocial health problems, which may increase their risk for HIV infection. Few studies have explored the syndemic effect of co-occurring psychosocial health problems on HIV sexual risk among Nigerian GBMSM. We investigated the co-occurrence of syndemic psychosocial health problems and their synergistic effect on HIV risk behaviors. We assessed depressive symptoms, post-traumatic stress disorder, alcohol dependence, tobacco use, and hard-drug use. The outcome variables were the number of male sexual partners and consistent condom use. In a multivariable model, experiencing 4 or more psychosocial health problems – compared to experience none or one psychosocial health problem – was significantly associated with increasing number of male sexual partners. We found no statistically significant association between the number of syndemic psychosocial health problems and consistent condom use. Our study findings provides evidence of a synergistic relationship between negative psychosocial health factors and HIV sexual risk behavior. These findings underscore the importance of developing HIV prevention programming aimed at reducing HIV transmission risk that incorporate substance use and mental health treatments, in order to improve the overall health and quality of life for Nigerian GBMSM.