Preclinical exploration of combined glucagon inhibition and liver-preferential insulin for treatment of diabetes using in vitro assays and rat and mouse models.

AIMS/HYPOTHESIS: Normalisation of blood glucose in individuals with diabetes is recommended to reduce development of diabetic complications. However, risk of severe hypoglycaemia with intensive insulin therapy is a major obstacle that prevents many individuals with diabetes from obtaining the recommended reduction in HbA1c. Inhibition of glucagon receptor signalling and liver-preferential insulin action have been shown individually to have beneficial effects in preclinical models and individuals with diabetes (i.e. improved glycaemic control), but also have effects that are potential safety risks (i.e. alpha cell hyperplasia in response to glucagon receptor antagonists and increased levels of liver triacylglycerols and plasma alanine aminotransferase activity in response to glucagon receptor antagonists and liver-preferential insulin). We hypothesised that a combination of glucagon inhibition and liver-preferential insulin action in a dual-acting molecule would widen the therapeutic window. By correcting two pathogenic mechanisms (dysregulated glucagon signalling and non-physiological distribution of conventional insulin administered s.c.), we hypothesised that lower doses of each component would be required to obtain sufficient reduction of hyperglycaemia, and that the undesirable effects that have previously been observed for monotreatment with glucagon antagonists and liver-preferential insulin could be avoided. METHODS: A dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule was designed and tested in rodent models (normal rats, rats with streptozotocin-induced hyperglycaemia, db/db mice and mice with diet-induced obesity and streptozotocin-induced hyperglycaemia), allowing detailed characterisation of the pharmacokinetic and pharmacodynamic properties of the dual-acting molecule and relevant control compounds, as well as exploration of how the dual-acting molecule influenced glucagon-induced recovery and spontaneous recovery from acute hypoglycaemia. RESULTS: This molecule normalised blood glucose in diabetic models, and was markedly less prone to induce hypoglycaemia than conventional insulin treatment (approximately 4.6-fold less potent under hypoglycaemic conditions than under normoglycaemic conditions). However, compared to treatment with conventional long-acting insulin, this dual-acting molecule also increased triacylglycerol levels in the liver (approximately 60%), plasma alanine aminotransferase levels (approximately twofold) and alpha cell mass (approximately twofold). CONCLUSIONS/INTERPRETATION: While the dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule showed markedly improved regulation of blood glucose, effects that are potential safety concerns persisted in the pharmacologically relevant dose range.

A Comparison of Risk Factors Among Discharged Military Veterans and Civilians Involuntarily Hospitalized Under California's Sexually Violent Predator Act.

While military veterans have a lower overall rate of incarceration for criminal offenses than civilians, they have a higher rate of incarceration for violent sexual offenses. Despite military veteran overrepresentation among individuals adjudicated for violent sexual offenses, little is known about their risk factors for sexual offending. This study compared military veterans and civilians who had been involuntarily hospitalized and discharged pursuant to California's Sexually Violent Predator Act. Pedophilic disorder appeared nearly twice as often among veterans than civilians (62.7% vs. 38.7%), whereas antisocial personality disorder was twice as common among civilians compared to veterans (48.1% vs. 23.9%). Consistent with the result for pedophilic disorder, veterans were more likely to target male victims age 13 and below, while civilians tended to target female victims over the age of 13. The results suggest different risk profiles for veterans compared to civilians who have been convicted of sexually violent offenses.

Veterans in Prison for Sexual Offenses: Characteristics and Reentry Service Needs.

Among prison-incarcerated men in the United States, more veterans (35%) have a sexual offense conviction than nonveterans (23%). Limited research has investigated factors explaining the link between military service and sexual offending. Nationally representative data from prison-incarcerated men (n = 14,080) were used to examine the association between veteran status and sexual offenses, adjusting for demographic, childhood, and clinical characteristics. Veterans had 1.35 higher odds (95% confidence interval = [1.12, 1.62], p < .01) of a sexual offense than nonveterans. Among veterans, those who were homeless or taking mental health medications at arrest had lower odds and veterans with a sexual trauma history had higher odds of a sexual offense compared with other offense types. Offering mental health services in correctional and health care settings to address trauma experiences and providing long-term housing options can help veterans with sexual offenses as they transition from prison to their communities.

Use of Veterans Health Administration Mental Health and Substance Use Disorder Treatment After Exiting Prison: The Health Care for Reentry Veterans Program.

The Veterans Health Administration (VA) Health Care for Reentry Veterans (HCRV) program links veterans exiting prison with treatment. Among veterans served by HCRV, national VA clinical data were used to describe contact with VA health care, and mental health and substance use disorder diagnoses and treatment use. Of veterans seen for an HCRV outreach visit, 56 % had contact with VA health care. Prevalence of mental health disorders was 57 %; of whom 77 % entered mental health treatment within a month of diagnosis. Prevalence of substance use disorders was 49 %; of whom 37 % entered substance use disorder treatment within a month of diagnosis. For veterans exiting prison, increasing access to VA health care, especially for rural veterans, and for substance use disorder treatment, are important quality improvement targets.

Sex differences in mental health and substance use disorders and treatment entry among justice-involved Veterans in the Veterans Health Administration.

BACKGROUND: Over half of veterans in the criminal justice system have mental health or substance use disorders. However, there is a critical lack of information about female veterans in the criminal justice system and how diagnosis prevalence and treatment entry differ by sex. OBJECTIVES: To document prevalence of mental health and substance use disorder diagnoses and treatment entry rates among female veterans compared with male veterans in the justice system. RESEARCH DESIGN: Retrospective cohort study using national Veterans Health Administration clinical/administrative data from veterans seen by Veterans Justice Outreach Specialists in fiscal years 2010-2012. SUBJECTS: A total of 1535 females and 30,478 male veterans were included. MEASURES: Demographic characteristics (eg, sex, age, residence, homeless status), mental health disorders (eg, depression, post-traumatic stress disorder), substance use disorders (eg, alcohol and opioid use disorders), and treatment entry (eg, outpatient, residential, pharmacotherapy). RESULTS: Among female veterans, prevalence of mental health and substance use disorders was 88% and 58%, respectively, compared with 76% and 72% among male veterans. Women had higher odds of being diagnosed with a mental health disorder [adjusted odds ratio (AOR)=1.98; 95% confidence interval (CI), 1.68-2.34] and lower odds of being diagnosed with a substance use disorder (AOR=0.50; 95% CI, 0.45-0.56) compared with men. Women had lower odds of entering mental health residential treatment (AOR=0.69; 95% CI, 0.57-0.83). CONCLUSIONS: Female veterans involved in the justice system have a high burden of mental health disorders (88%) and more than half have substance use disorders (58%). Entry to mental health residential treatment for women is an important quality improvement target.

Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4.

Factors associated with repeat sexual offending among U.S. military veterans compared to civilians.

Although veterans have lower incarceration rates than civilians, large national surveys find higher rates of incarceration for sexual offenses among veterans compared to non-veterans. However, little is known about the factors associated with repeat sexual offending among veterans. This study examines characteristics of veterans who committed sexual offenses and how they differ from civilians with those offenses. It also examined if the factors that differ between veterans and civilians who have a history of repeat sexual offenses and those who do not. Based on previous research related to risk in veterans, we expected there may be veteran-specific risk factors. This study used the Survey of Inmates in State and Federal Correctional Facilities. Predictors were identified through a review of the literature regarding sexual offense risk assessment and justice-involved veterans. Risk factors were examined using logistic regression analysis. In a multivariate logistic regression, there were significant interactions between veteran status and age, race, and education in the prediction of repeat offense status. Prior incarceration for a non-sexual offense was also associated with repeat offense status. Findings suggests that civilian risk factors are relevant to veteran risk assessment, an important finding that can help inform intervention and risk management with veterans.

Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls.

During recent years combining GLP-1 and glucagon receptor agonism with the purpose of achieving superior weight loss and metabolic control compared to GLP-1 alone has received much attention. The superior efficacy has been shown by several in preclinical models but has been difficult to reproduce in humans. In this paper, we present the pre-clinical evaluation of NN1177, a long-acting GLP-1/glucagon receptor co-agonist previously tested in clinical trials. To further investigate the contribution from the respective receptors, two other co-agonists (NN1151, NN1359) with different GLP-1-to-glucagon receptor ratios were evaluated in parallel. In the process of characterizing NN1177, species differences and pitfalls in traditional pre-clinical evaluation methods were identified, highlighting the translational challenges in predicting the optimal receptor balance in humans. In diet-induced obese (DIO) mice, NN1177 induced a dose-dependent body weight loss, primarily due to loss of fat mass, and improvement in glucose tolerance. In DIO rats, NN1177 induced a comparable total body weight reduction, which was in contrast mainly caused by loss of lean mass, and glucose tolerance was impaired. Furthermore, despite long half-lives of the three co-agonists, glucose control during steady state was seen to depend on compound exposure at time of evaluation. When evaluated at higher compound exposure, glucose tolerance was similarly improved for all three co-agonists, independent of receptor balance. However, at lower compound exposure, glucose tolerance was gradually impaired with higher glucagon receptor preference. In addition, glucose tolerance was found to depend on study duration where the effect of glucagon on glucose control became more evident with time. To conclude, the pharmacodynamic effects at a given GLP-1-to-glucagon ratio differs between species, depends on compound exposure and study length, complicating the identification of an optimally balanced clinical candidate. The present findings could partly explain the low number of clinical successes for this dual agonism.

Coming home from prison: Adapting military resilience training to enhance successful community reintegration for justice-involved Iraq-Afghanistan veterans.

We propose a veteran-centric justice model of resilience training developed by the military for assisting service members coming home from war and modify it to assist Iraq/Afghanistan veterans coming home from prison. Incarceration has been identified as a stress aftereffect of the prolonged Iraq and Afghanistan combat deployments. Notably, the rate of Iraq and Afghanistan-era incarcerated veterans increased from 4% to 13% between 2004 and 2012 for all incarcerated veterans. Successful reentry to the community from prison incarceration is difficult, with rearrest and reincarceration a frequent occurrence. Moreover, combat stress conditions may weaken the justice-involved Iraq/Afghanistan's veteran's ability to face challenges posed by the return home from prison. As in the war zone, the return home from prison may be idealized with unrealistic expectations and/or goals, thus setting up the returning veteran for disappointment, anger, deepening of alienation and disconnection from larger civilian society, and the risk of return to maladaptive mechanisms for coping. Resilience training can be provided in psychoeducational venues prior to prison release and with follow-up postrelease. Resilience building offers promise as an intervention to enhance the justice-involved veteran's successful community reentry. (PsycINFO Database Record

Receipt of Pharmacotherapy for Alcohol Use Disorder by Male Justice-Involved U.S. Veterans Health Administration Patients.

This study examined whether, among Veterans Health Administration (VHA) patients, veterans with recent or current justice involvement have equal receipt of pharmacotherapy for alcohol use disorder compared to veterans with no justice involvement. Using national VHA records, we calculated the overall and facility rates of receipt as the number of patients who received pharmacotherapy for alcohol use disorder divided by the number of patients diagnosed with an alcohol use disorder. Using a mixed-effects logistic regression model, we tested whether justice involvement was associated with pharmacotherapy receipt. Male veterans with jail/court involvement had significantly higher odds of receiving pharmacotherapy for alcohol use disorder compared to other male veterans. Justice-involved veterans had equal or better receipt of pharmacotherapy for alcohol use disorder compared to veterans with no justice involvement. Pharmacotherapy rates are low overall, suggesting that more work can be done to connect veterans to these medications.

Novel class III phosphoribosyl diphosphate synthase: structure and properties of the tetrameric, phosphate-activated, non-allosterically inhibited enzyme from Methanocaldococcus jannaschii.

The prs gene encoding phosphoribosyl diphosphate (PRPP) synthase of the hyperthermophilic autotrophic methanogenic archaeon Methanocaldococcus jannaschii has been cloned and expressed in Escherichia coli. Subsequently, M.jannaschii PRPP synthase has been purified, characterised, crystallised, and the crystal structure determined. The enzyme is activated by phosphate ions and only ATP or dATP serve as diphosphoryl donors. The K(m) values are determined as 2.6 mM and 2.8 mM for ATP and ribose 5-phosphate, respectively, and the V(max) value as 2.20 mmol (minxmg of protein)(-1). ADP is a potent inhibitor of activity while GDP has no effect. A single ADP binding site, the active site, is present per subunit. The crystal structure of the enzyme reveals a more compact subunit than that of the enzyme from the mesophile Bacillus subtilis, caused by truncations at the N and C terminus as well as shorter loops in the M.jannaschii enzyme. The M.jannaschii enzyme displays a tetrameric quaternary structure in contrast to the hexameric quaternary structure of B.subtilis PRPP synthase. Soaking of the crystals with 5'-AMP and PRPP revealed the position of the former compound as well as that of ribose 5-phosphate. The properties of M.jannaschii PRPP synthase differ widely from previously characterised PRPP synthases by its tetrameric quaternary structure and the simultaneous phosphate ion-activation and lack of allosteric inhibition, and, thus, constitute a novel class of PRPP synthases.

Receipt of pharmacotherapy for opioid use disorder by justice-involved U.S. Veterans Health Administration patients.

BACKGROUND: Pharmacotherapy - methadone, buprenorphine, or naltrexone - is an evidence-based treatment for opioid use disorder, but little is known about receipt of these medications among veterans involved in the justice system. The current study examines receipt of pharmacotherapy for opioid use disorder among veterans with a history of justice involvement at U.S. Veterans Health Administration (VHA) facilities compared to veterans with no justice involvement. METHODS: Using national VHA clinical and pharmacy records, we conducted a retrospective cohort study of veterans with an opioid use disorder diagnosis in fiscal year 2012. Using a mixed-effects logistic regression model, we examined receipt of pharmacotherapy in the 1-year period following diagnosis as a function of justice involvement, adjusting for patient and facility characteristics. RESULTS: The 1-year rate of receipt for pharmacotherapy for opioid use disorder was 27% for prison-involved veterans, 34% for jail/court-involved veterans, and 33% for veterans not justice-involved. Compared to veterans not justice-involved, those prison-involved had 0.75 lower adjusted odds (95% confidence interval [CI]: 0.65-0.87) of receiving pharmacotherapy whereas jail/court-involved veterans did not have significantly different adjusted odds. CONCLUSIONS: Targeted efforts to improve receipt of pharmacotherapy for opioid use disorder among veterans exiting prison is needed as they have lower odds of receiving these medications.

A Longitudinal Examination of Veterans Treatment Courts' Characteristics and Eligibility Criteria.

Although the number of Veterans Treatment Courts (VTCs) has been growing at a rapid rate, thus far, VTC components have not been standardized, due in part to a lack of empirical evidence on the extent to which components vary across VTCs nationwide and change over time. This study analyzed data collected by the Department of Veterans Affairs' Veterans Justice Program, on VTCs in 2012 (n = 173 Courts), 2013 (n = 266), and 2014 (n = 351), to describe Court characteristics, participant eligibility criteria, and Courts' mentoring component. Despite growth in VTC numbers, the survey found consistency over time in these aspects of VTCs. Regarding characteristics, the majority of Courts had jurisdiction at the county level. Across survey years, the range of means was 22-24 for veteran participant census, 10-14 for number of months spent in the Court for misdemeanors, and 18-19 for number of months spent in the Court for felonies. Eligibility requirements suggested openness to veterans of different backgrounds and status. Less than two thirds of Courts had the mentoring component; Courts with the mentoring component had a higher participant census and a longer duration of participants' time under Court supervision than Courts without this component. Existing mentoring programs were organized mainly by volunteers. VTCs' adherence to policies supportive of veterans may benefit from having paid mentor coordinators in order to further ensure this hallmark of VTCs.

U.S. Department of Veterans Affairs Veterans Justice Outreach Program: Connecting Justice-Involved Veterans with Mental Health and Substance Use Disorder Treatment.

The Veterans Justice Outreach (VJO) program of the U.S. Veterans Health Administration has a primary mission of linking military veterans in jails, courts, or in contact with law enforcement to mental health and substance use disorder treatment. National data of veterans with VJO contact were used to describe demographic characteristics, and mental health and substance use disorder diagnoses and treatment use and test correlates of treatment entry and engagement using multi-level logistic regression models. Of the 37,542 VJO veterans, treatment entry was associated with being homeless and having a mental health disorder or both a mental health and a substance use disorder versus a substance use disorder only. Being American Indian/Alaskan Native was associated with lower odds of treatment entry. Engagement was associated with female gender, older age, Asian race, urban residence, and homeless status. Increased utilization of substance use disorder treatment, especially pharmacotherapy, is an important quality improvement target.

Potential for proteomic profiling of Helicobacter pylori and other Helicobacter spp. using a ProteinChip array.

The Helicobacter genus is associated with a wide spectrum of pathologies in the gastrointestinal tract. However, in contrast to Helicobacter pylori, few data are available regarding proteomic characteristics of enterohepatic helicobacters. Proteomic analysis of this genus has predominantly utilised two-dimensional gel electrophoresis methodology. In the present study we applied an innovative technique using ProteinChip arrays coupled with surface-enhanced laser desorption/ionisation time of flight mass spectroscopy to accurately assess the M(r) of proteins for comparative proteomic profiling. We analysed binding of outer membrane fractions to a weak cation exchange array for strains of H. pylori from culture collections and compared these profiles to fresh clinical isolates. In addition, we analysed profiles from Helicobacter pullorum, Helicobacter bilis and 'Helicobacter sp. flexispira'. The system proved rapid, accurate and reproducible. Distinct specific profiles for all the strains studied were identified. However, strains from culture collections that have undergone numerous subcultures had almost identical profiles. In contrast, profiles from fresh clinical isolates were markedly different. Moreover, certain features of the profiles from the enterohepatic species were conserved.

Co-location of health care services for homeless veterans: a case study of innovation in program implementation.

This case study examines how the Veterans Affairs Greater Los Angeles Healthcare System (GLA) improved homeless veteran service utilization through program innovation that addressed service fragmentation. The new program offered same-day co-located mental health, medical, and homeless services with a coordinated intake system. The program is analyzed using a framework proposed by Rosenheck (2001) that has four phases: the decision to implement, initial implementation, sustained maintenance, and termination or transformation. GLA was able to successfully implement a new program that remains in the sustained maintenance phase five years after the initial decision to implement. Key factors from the Rosenheck innovation model in the program's success included coalition building, linking the project to legitimate goals, program monitoring, and developing communities of practicing clinicians. The key lesson from the case study is the need for a coalition to persistently problem solve and act as advocates for the program, even after successful initial implementation. Social work leadership was critical in all phases of program implementation.

The rapid detection of low molecular mass proteins differentially expressed under biological stress for four Helicobacter spp. using ProteinChip technology.

Helicobacter pylori is one of the most prevalent human pathogens in the world and is the aetiological agent of gastritis, peptic ulcer disease and gastric malignancies. In addition H. pylori and other novel members of the genus are capable of successfully colonising the bile-rich niche of the upper intestine and are associated with a diverse range of intestinal pathologies. Surface-enhanced laser desorption/ionisation-time of flight mass spectrometry was used to analyse surface extracts from H. pylori, Helicobacter bilis, Helicobacter pullorum and "Helicobacter sp. flexispira" to characterise cell surface changes following bile stress. The system detected two distinct response patterns to bile stress on the cell surface of Helicobacter spp. in vitro. The first involved the increase under bile stress of peaks at 7.6 and 7.9 kDa for H. billis and H. pullorum, respectively. In contrast both "Helicobacter sp. flexispira" and a clinical isolate of H. pylori had similar response profiles to bile stress. Both strains had at least three low mass peaks decreased under bile stress and a single peak induced by bile stress. The present study has established the use of ProteinChip(R) technology to analyse helicobacter-related proteomics. Specifically this study has established that different patterns are generated in response to bile stress among various pathogenic Helicobacter spp. which may give insights into the ability of these strains to colonise different niches.

Developing programs for homeless veterans: understanding driving forces in implementation.

Between 1992 and 2003, services for homeless veterans at the Veterans Affairs Greater Los Angeles Healthcare System went from inappropriate utilization of hospital medical and psychiatric beds, to a continuum of residential treatment, transitional housing, and employment programs through arrangements with private agencies. The authors use elements of Hasenfeld and Brock's Political Economy Model (1991) to explain this transformation in service delivery that was spearheaded by a VA social work leadership team. It is argued that three driving forces crucial to program implementation were present: technological certainty, economic stability, and concentration of power. Evidence of the implementation's impact includes creation of new homeless program beds, a reduction in use of medical/psychiatric beds, and a large number of formerly homeless veterans with housing and employment at program discharge. Study limitations and implications for future studies are discussed.

Efficacy and compatibility with mass spectrometry of methods for elution of proteins from sodium dodecyl sulfate-polyacrylamide gels and polyvinyldifluoride membranes.

The resolving power of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) combined with isoelectric focusing in two-dimensional gel electrophoresis has made it one of the most important techniques for resolving complex mixtures, and it is of great importance for proteome mapping projects. As a result of this, methods for postelectrophoretic protein characterization are of great interest as exemplified by in situ protease digestion combined with mass spectrometry (MS), which is the method of choice for identification of proteins. In this study we have developed and compared methods for recovering intact proteins from polyacrylamide gels and electroblotting membranes to define efficient methods compatible with MS. These methods complement in situ digestion protocols and allow determination of the molecular mass of whole proteins separated by SDS-PAGE. Passive elution of proteins from SDS-PAGE gels was efficient only in the presence of SDS, whereas electroelution was achieved using buffers without SDS. Surface-enhanced laser desorption/ionization MS (SELDI-MS) analysis of proteins eluted in the presence of SDS was possible using ion exchange ProteinChip arrays for concentration of sample and removal of SDS. Comparison of different electroblotting methods verified that the different membranes and buffers were equally efficient for transfer of proteins in the range 20-100 kDa. Elution from polyvinyldifluoride membranes was most efficient using either concentrated solutions of trifluoroacetic acid (TFA) or combinations of 8M urea and 1% Triton X-100, 1% Tween 20, or 40% isopropanol. The same result was obtained using nitrocellulose membranes, except that these were incompatible with organic solvent and TFA. Elution by TFA was compatible with matrix-assisted laser desorption/ionization MS (MALDI-MS) but was complicated by a high degree of trifluoroacetylation of the proteins. Alternatively, elution by 8M urea+1% Triton X-100, 1% Tween 20, or 40% isopropanol was compatible with both SELDI-MS and MALDI-MS. Eluted proteins were identified in MS experiments by intact mass determination, by peptide mapping, and by MS/MS analysis.