Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.

Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

GLP-1/glucagon receptor co-agonism for treatment of obesity.

Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.

Ecological Assessment of Clinicians' Antipsychotic Prescription Habits in Psychiatric Inpatients: A Novel Web- and Mobile Phone-Based Prototype for a Dynamic Clinical Decision Support System.

BACKGROUND: Electronic prescribing devices with clinical decision support systems (CDSSs) hold the potential to significantly improve pharmacological treatment management. OBJECTIVE: The aim of our study was to develop a novel Web- and mobile phone-based application to provide a dynamic CDSS by monitoring and analyzing practitioners' antipsychotic prescription habits and simultaneously linking these data to inpatients' symptom changes. METHODS: We recruited 353 psychiatric inpatients whose symptom levels and prescribed medications were inputted into the MEmind application. We standardized all medications in the MEmind database using the Anatomical Therapeutic Chemical (ATC) classification system and the defined daily dose (DDD). For each patient, MEmind calculated an average for the daily dose prescribed for antipsychotics (using the N05A ATC code), prescribed daily dose (PDD), and the PDD to DDD ratio. RESULTS: MEmind results found that antipsychotics were used by 61.5% (217/353) of inpatients, with the largest proportion being patients with schizophrenia spectrum disorders (33.4%, 118/353). Of the 217 patients, 137 (63.2%, 137/217) were administered pharmacological monotherapy and 80 (36.8%, 80/217) were administered polytherapy. Antipsychotics were used mostly in schizophrenia spectrum and related psychotic disorders, but they were also prescribed in other nonpsychotic diagnoses. Notably, we observed polypharmacy going against current antipsychotics guidelines. CONCLUSIONS: MEmind data indicated that antipsychotic polypharmacy and off-label use in inpatient units is commonly practiced. MEmind holds the potential to create a dynamic CDSS that provides real-time tracking of prescription practices and symptom change. Such feedback can help practitioners determine a maximally therapeutic drug treatment while avoiding unproductive overprescription and off-label use.

Fundamentals for Future Mobile-Health (mHealth): A Systematic Review of Mobile Phone and Web-Based Text Messaging in Mental Health.

BACKGROUND: Mobile phone text messages (short message service, SMS) are used pervasively as a form of communication. Almost 100% of the population uses text messaging worldwide and this technology is being suggested as a promising tool in psychiatry. Text messages can be sent either from a classic mobile phone or a web-based application. Reviews are needed to better understand how text messaging can be used in mental health care and other fields of medicine. OBJECTIVE: The objective of the study was to review the literature regarding the use of mobile phone text messaging in mental health care. METHODS: We conducted a thorough literature review of studies involving text messaging in health care management. Searches included PubMed, PsycINFO, Cochrane, Scopus, Embase and Web of Science databases on May 25, 2015. Studies reporting the use of text messaging as a tool in managing patients with mental health disorders were included. Given the heterogeneity of studies, this review was summarized using a descriptive approach. RESULTS: From 677 initial citations, 36 studies were included in the review. Text messaging was used in a wide range of mental health situations, notably substance abuse (31%), schizophrenia (22%), and affective disorders (17%). We identified four ways in which text messages were used: reminders (14%), information (17%), supportive messages (42%), and self-monitoring procedures (42%). Applications were sometimes combined. CONCLUSIONS: We report growing interest in text messaging since 2006. Text messages have been proposed as a health care tool in a wide spectrum of psychiatric disorders including substance abuse, schizophrenia, affective disorders, and suicide prevention. Most papers described pilot studies, while some randomized clinical trials (RCTs) were also reported. Overall, a positive attitude toward text messages was reported. RCTs reported improved treatment adherence and symptom surveillance. Other positive points included an increase in appointment attendance and in satisfaction with management and health care services. Insight into message content, preventative strategies, and innovative approaches derived from the mental health field may be applicable in other medical specialties.

SIAM (Suicide intervention assisted by messages): the development of a post-acute crisis text messaging outreach for suicide prevention.

BACKGROUND: Suicidal behaviour and deliberate self-harm are common among adults. Research indicates that maintaining contact either via letter or postcard with at-risk adults following discharge from care services can reduce reattempt risk. Feasibility trials demonstrated that intervention through text message was also effective in preventing suicide repetition amongst suicide attempters. The aim of the current study is to investigate the effect of text message intervention versus traditional treatment on reducing the risk of suicide attempt repetition among adults after self-harm. METHODS/DESIGN: The study will be a 2-year multicentric randomized controlled trial conducted by the Brest University Hospital, France. Participants will be adults discharged after self-harm, from emergency services or after a short hospitalization. Participants will be recruited over a 12-month period. The intervention is comprised of an SMS that will be sent at h48, D7, D15 and monthly. The text message enquires about the patients' well-being and includes information regarding individual sources of help and evidence-based self help strategies. Participants will be assessed at the baseline, month 6 and 13. As primary endpoint, we will assess the number of patients who reattempt suicide in each group at 6 months. As secondary endpoints, we will assess the number of patients who reattempt suicide at 13 month, the number of suicide attempts in the intervention and control groups at 6 and 13 month, the number of death by suicide in the intervention and control groups at month 6 and 13. In both groups, suicidal ideations, will be assessed at the baseline, month 6 and 13. Medical costs and satisfaction will be assessed at month 13. DISCUSSION: This paper describes the design and deployment of a trial SIAM; an easily reproducible intervention that aims to reduce suicide risk in adults after self-harm. It utilizes several characteristics of interventions that have shown a significant reduction in the number of suicide reattempts. We propose to assess its efficacy in reducing suicide reattempt in the suicide attempter (SA) population. TRIAL REGISTRATION: The study was registered on Clinical Trials Registry (clinicaltrials.gov): NCT02106949, registered on 06 June 2014.

A Possible Perspective of Recultivation with Arbuscular Mycorrhiza-Inoculated Drought-Tolerant Herbaceous Plants.

Using native species for urban green space is rather important nowadays. Plant cover on soil is necessary for agronomical and architectural investments as well as conservational programs, which all need minimal maintenance and have to be cost efficient. Commercially available seed mixtures for grasslands and lawns include species that partly originated from other mesoclimatic zones, and thus they may not be able to survive in the long-term, nor will they be adventive to the local ecosystem. With a focus on climate change, the most arid part of the Pannon geographical region was selected (near Törökszentmiklós in Nagykunság, Hungarian Great Plain). The local flora has adapted effectively to the environment; therefore, many species growing there were candidates for this study. Annuals and herbaceous perennials were investigated with respect to harvestability, reproducibility, decorativity, seed production, seed morphological characters (size, mass) and germination features. The selected 20 taxa were inoculated with INOQ Agri mycorrhiza (Rhizophagus irregularis) to increase the drought tolerance and biomass of the plants. Mycorrhizal frequency was significantly different among the taxa, reflecting various responses to the symbiotic interaction and possibly various mycorrhizal dependence of the plant species examined. We did not observe significantly higher colonization rate in most cases of the samples with artificial inoculation treatment. We conclude that the degraded mowed lawn soil that we used could contain propagules of AM fungi in a sufficient amount, so in the artificial grassland restorations, the additional AM inoculation treatment is not necessary to achieve a higher AM colonization rate.

The SDQ dysregulation profile is associated with self-injurious thoughts and behaviors in adolescents evaluated at a clinical setting. / El perfil de disregulación del SDQ y su relación con conductas y pensamientos de suicidio en adolescentes evaluados en contexto clínico.

INTRODUCTION: Suicidal ideation, suicidal behavior, and non-suicidal self-injury behavior are serious public health problems among adolescents. A significant proportion of adolescents evaluated in clinical settings meet criteria for the dysregulation profile (DP). DP is characterized by restlessness, irritability, "affective storms", mood instability, and aggression in a disproportionate grade to the situation. This DP might be related to increased risk of self-injurious thoughts and behaviors. METHODS: Two hundred and thirty-nine adolescents from the Child and Adolescent Outpatient Psychiatric Services of the Jimenez Diaz Foundation, Madrid, were assessed with the Strengths and Difficulties Questionnaire-Dysregulation Profile, the Self-Injurious Thoughts and Behaviors Interview and socio-demographic questionnaires. RESULTS: Logistic regression showed that DP adolescents were at increased risk for suicide plans, gestures, and suicide attempts. They also tended to present more self-injurious behaviors than adolescents without DP. CONCLUSIONS: Our results point to the role of self-regulatory problems in the presence of suicide plans, suicide gestures, suicide attempts, and in non-suicidal self-injury behavior. Longitudinal studies are needed to confirm the relationship between the Strengths and Difficulties Questionnaire-Dysregulation Profile and self-injurious thoughts and behaviors.

Gut hormone polyagonists for the treatment of type 2 diabetes.

Chemical derivatives of the gut-derived peptide hormone glucagon-like peptide 1 (GLP-1) are among the best-in-class pharmacotherapies to treat obesity and type 2 diabetes. However, GLP-1 analogs have modest weight lowering capacity, in the range of 5-10%, and the therapeutic window is hampered by dose-dependent side effects. Over the last few years, a new concept has emerged: combining the beneficial effects of several key metabolic hormones into a single molecular entity. Several unimolecular GLP-1-based polyagonists have shown superior metabolic action compared to GLP-1 monotherapies. In this review article, we highlight the history of polyagonists targeting the receptors for GLP-1, GIP and glucagon, and discuss recent progress in expanding of this concept to now allow targeted delivery of nuclear hormones via GLP-1 and other gut hormones, as a novel approach towards more personalized pharmacotherapies.

Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity.

In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk.

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications.

PURPOSE: The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. METHOD: A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. RESULTS: The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. CONCLUSIONS: In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system.

Interaction of TRH and CCK in the satiation of alcohol intake.

Thyrotropin-releasing hormone (TRH) and cholecystokinin octapeptide (CCK) are endogenous neuropeptides known to inhibit intake of alcohol. Although both peptides are released by alcohol consumption and are hypothesized to satiate alcohol intake, their interaction has not been examined. We deprived ad-lib-fed male (n=6) and female (n=4) Wistar rats of water for 23 h and then gave them 30 min access to 5% w/v ethanol, followed by 30 min access to water. After adaptation to this schedule, rats were randomly assigned to receive intraperitoneal injections of either saline+saline, CCK (4 microg/kg)+saline, saline+TRH (10 mg/kg) or CCK+TRH immediately before alcohol access. Analyses of variance revealed a significant (P<.05) effect of CCK, and a significant interaction of CCK and TRH in control of ethanol consumption. CCK reliably reduced alcohol intake, and TRH blocked this satiation effect of CCK, increasing intake by 88.8% and 34.6% in males and females, respectively. TRH increased water intake in females, and CCK blocked this effect of TRH. Results indicate an infra-dose-additive interaction of CCK and TRH in satiation of alcohol intake, which may reflect a natural, endogenous neuropeptide interaction in the regulation of caloric intake.

[Factors influencing lycopene content of foods, and lycopene intake of Hungarian population]. / Az élelmiszereink likopintartalmát befolyásoló tényezôk és a hazai lakosság likopinbevitele.

Lycopene is an acyclic, biologically active carotenoid that constitutes foods, its preventive role in several cancerous diseases have been proved by epidemiological and experimental data. Its beneficial role in maintenance of human health is related to its significant antioxidant properties. Data of dietary lycopene intake of the Hungarian population is not available. The aims of the present complex study were 1) to measure the lycopene content of foods frequently consumed in Hungary, 2) to investigate the effect of agrotechnological procedures and food processing on lycopene content of tomatoes, 3) to estimate the lycopene intake in two groups of the Hungarian population with the use of a three-day dietary record. The best lycopene sources are the raw (5.0-16.0 mg/100 g) and processed tomatoes and tomato products (3.0-80.0 mg/100 g), and also watermelon (3.6-6.2 mg/100 g). The variety of the plants, the growing circumstances, and the weather conditions significantly influence the lycopene content of freshly consumed and processed tomato fruits. Mild technological processes can preserve a considerable amount of the original lycopene content in tomato. The estimated average dietary intakes of the Hungarian children (n=521) and adults (n=205) were 2.98 +/- 4.71 mg/day/capita, and 4.24 +/- 8.47 mg/day/capita, respectively. Optimal climate conditions of Hungary makes possible to produce tomato fruits with high dietary value including significant amount of health protective lycopene. Increased consumption of tomato and tomato products with high concentration of lycopene may improve the antioxidant capacity of human body, and the risk of several cancerous diseases may be reduced.

A survey of nonmedical use of tranquilizers, stimulants, and pain relievers among college students: patterns of use among users and factors related to abstinence in non-users.

BACKGROUND: This study examined lifetime non-medical prescription drug use among college students at a small liberal arts college in the Northeast. We assessed the motives, frequency of use, sources, and perceived emotional/physical risks of nonmedical prescription drugs. Specifically, we examined the non-medical use of prescription pain relievers, stimulants, and anti-anxiety medication. METHODS: We sent an internet-based survey to 1/3 of the student body and 303 students completed the survey. RESULTS: We found that 36.8% of the sample reported using prescription drugs for non-medical purposes. First-year students were less likely to have used the drugs than those in other class years. Of those reporting use, 48% reported non-medical use of pain relievers, 72.8% reported using stimulants, and 39.8% reported using anti-anxiety medication. The most commonly used pain relievers were Vicodin (hydrocodone/acetaminophen), OxyContin (oxycodone), and codeine (acetaminophen/codeine). The most commonly used stimulants were Adderall (amphetamine/dextroamphetamine) and Ritalin (methylphenidate), while the most commonly used anti-anxiety medication was Xanax (alprazolam). When non-users were asked what factors influenced their choice not to abuse prescription drugs, 82% cited a lack of interest, 61% responded it was due to a fear of damaging their physical health, and 60.1% responded fear of damaging their mental health. CONCLUSION: This study supports recent findings that show widespread non-medical use of prescription drugs among college students. Our report brings a more detailed understanding of the patterns of drug usage, and the factors influencing both drug use in those who use them and abstinence in those who choose not to use them.

Redox potentials of Ti(IV) and Fe(III) complexes provide insights into titanium biodistribution mechanisms.

Transferrin, the human iron transport protein, binds Ti(IV) even more tightly than it binds Fe(III). However, the fate of titanium bound to transferrin is not well understood. Here we present results which address the fate of titanium once bound to transferrin. We have determined the redox potentials for a series of Ti(IV) complexes and have used these data to develop a linear free energy relationship (LFER) correlating Ti(IV) <==> Ti(III) redox processes with Fe(III) <==> Fe(II) redox processes. This LFER enables us to compare the redox potentials of Fe(III) complexes and Ti(IV) complexes that mimic the active site of transferrin and allows us to predict the redox potential of titanium-transferrin. Using cyclic voltammetry and discontinuous metalloprotein spectroelectrochemistry (dSEC) in conjunction with the LFER, we report that the redox potential of titanium-transferrin is lower than -600 mV (lower than that of iron-transferrin) and is predicted to be ca. -900 mV vs. NHE (normal hydrogen electrode). We conclude that Ti(IV)/Ti(III) reduction in titanium-transferrin is not accessible by biological reducing agents. This observation is discussed in the context of current hypotheses concerning the role of reduction in transferrin mediated iron transport.