An integrative collaborative care model for people with mental illness and physical comorbidities.

BACKGROUND: Many individuals with mental health problems have comorbid physical conditions, or may present with substance/alcohol misuse or abuse issues. This results in complex treatment challenges that may not be adequately addressed by a model of care that is solely delivered by an individual clinician using a sole intervention. Mainstream pharmacotherapeutic treatment of mental health problems often have limited effectiveness in completely resolving symptoms, and may cause adverse side effects. Adjunctive treatment approaches, including nutraceuticals, lifestyle and behaviour change interventions, are widely used to assist with treatment of mental health problems. However, whilst these can be generally safer with fewer side effects, they have varying levels of evidentiary support. These circumstances warrant reframing the current treatment approach towards a more evidence-based integrative model which may better address the real-world challenges of psychiatric disorders and comorbid physical conditions. In essence, this means developing an integrative model of care which embodies an evidence-informed, personalized stepwise approach using both conventional pharmacological treatments alongside novel adjunctive treatments (where applicable) via the application of a collaborative care approach. DISCUSSION: In order to inform this position, a brief review of findings on common patterns of comorbidity in mental illness is presented, followed by identification of limitations of conventional treatments, and potential applications of integrative medicine interventions. Advantages and challenges of integrative mental health care, collaborative models of care, review of research highlights of select integrative approaches, and comment on potential cost advantages are then discussed. We propose that a collaborative care model incorporating evidence-based integrative medicine interventions may more adequately address mental health problems with comorbid medical conditions. Robust research is now required of such a model, potentially within an integrative clinical practice.

Gd(III) complexes as paramagnetic tags: Evaluation of the spin delocalization over the nuclei of the ligand.

Complexes of the Gd(III) ion are currently being established as spin labels for distance determination in biomolecules by pulse dipolar spectroscopy. Because Gd(III) is an f ion, one expects electron spin density to be localized on the Gd(III) ion - an important feature for the mentioned application. Most of the complex ligands have nitrogens as Gd(III) coordinating atoms. Therefore, measurement of the (14)N hyperfine coupling gives access to information on the localization of the electron spin on the Gd(III) ion. We carried out W-band, 1D and 2D (14)N and (1)H ENDOR measurements on the Gd(III) complexes Gd-DOTA, Gd-538, Gd-595, and Gd-PyMTA that serve as spin labels for Gd-Gd distance measurements. The obtained (14)N spectra are particularly well resolved, revealing both the hyperfine and nuclear quadrupole splittings, which were assigned using 2D Mims ENDOR experiments. Additionally, the spectral contributions of the two different types of nitrogen atoms of Gd-PyMTA, the aliphatic N atom and the pyridine N atom, were distinguishable. The (14)N hyperfine interaction was found to have a very small isotropic hyperfine component of -0.25 to -0.37MHz. Furthermore, the anisotropic hyperfine interactions with the (14)N nuclei and with the non-exchangeable protons of the ligands are well described by the point-dipole approximation using distances derived from the crystal structures. We therefore conclude that the spin density is fully localized on the Gd(III) ion and that the spin density distribution over the nuclei of the ligands is rightfully ignored when analyzing distance measurements.

The motherhood choices decision aid for women with rheumatoid arthritis increases knowledge and reduces decisional conflict: a randomized controlled trial.

BACKGROUND: For many women with Rheumatoid Arthritis (RA) motherhood decisions are complicated by their condition and complex pharmacological treatments. Decisions about having children or expanding their family require relevant knowledge and consultation with their family and physician as conception and pregnancy has to be managed within the RA context. Relevant information is not readily available to women with RA. Therefore a randomized controlled study was conducted to evaluate the effectiveness of a new motherhood decision aid (DA) developed specifically for women with RA. METHODS: One hundred and forty-four women were randomly allocated to either an intervention or control group. All women completed a battery of questionnaires at pre-intervention, including, the Pregnancy in Rheumatoid Arthritis Questionnaire (PiRAQ), the Decisional Conflict Scale (DCS), the Hospital Anxiety and Depression Scale (HADS), and the Arthritis Self-Efficacy Scale (ASES), and provided basic demographic information. Women in the DA group were sent an electronic version of the DA, and completed the battery of questionnaires for a second time post-intervention. RESULTS: Women who received the DA had a 13 % increase in relevant knowledge (PiRAQ) scores and a 15 % decrease in scores on the decisional conflict (DCS), compared to the control group (1 %, 2 % respectively). No adverse psychological effects were detected as evident in unchanged levels of depression and anxiety symptoms. CONCLUSIONS: The findings of this study suggest that this DA may be an effective tool in assisting women with RA when contemplating having children or more children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au/ , ACTRN12615000523505.

Zero field splitting fluctuations induced phase relaxation of Gd3+ in frozen solutions at cryogenic temperatures.

Distance measurements using double electron-electron resonance (DEER) and Gd(3+) chelates for spin labels (GdSL) have been shown to be an attractive alternative to nitroxide spin labels at W-band (95GHz). The maximal distance that can be accessed by DEER measurements and the sensitivity of such measurements strongly depends on the phase relaxation of Gd(3+) chelates in frozen, glassy solutions. In this work, we explore the phase relaxation of Gd(3+)-DOTA as a representative of GdSL in temperature and concentration ranges typically used for W-band DEER measurements. We observed that in addition to the usual mechanisms of phase relaxation known for nitroxide based spin labels, GdSL are subjected to an additional phase relaxation mechanism that features an increase in the relaxation rate from the center to the periphery of the EPR spectrum. Since the EPR spectrum of GdSL is the sum of subspectra of the individual EPR transitions, we attribute this field dependence to transition dependent phase relaxation. Using simulations of the EPR spectra and its decomposition into the individual transition subspectra, we isolated the phase relaxation of each transition and found that its rate increases with |ms|. We suggest that this mechanism is due to transient zero field splitting (tZFS), where its magnitude and correlation time are scaled down and distributed as compared with similar situations in liquids. This tZFS induced phase relaxation mechanism becomes dominant (or at least significant) when all other well-known phase relaxation mechanisms, such as spectral diffusion caused by nuclear spin diffusion, instantaneous and electron spin spectral diffusion, are significantly suppressed by matrix deuteration and low concentration, and when the temperature is sufficiently low to disable spin lattice interaction as a source of phase relaxation.

The Northwick Park Heart Study: evidence from the laboratory.

The Northwick Park Heart Study (NPHS) has shown associations of high plasma fibrinogen and factor VII (FVIIc) levels with the risk of death from coronary heart disease (CHD). The finding for fibrinogen has been confirmed in many other studies. Whereas one further study has found a similar prospective association for FVIIc, several have not. Experimental studies have demonstrated the impact that the coagulation activity of fibrinogen and FVIIc have on the progression and phenotype of atherosclerotic lesions. FVIIc-driven thrombin generation and fibrin formation within the vessel wall are important determinants of both plaque (in)stability and atherothrombosis. In blood, local concentrations of FVIIc and thrombin may be sufficient to allow interactions between these serine proteases and protease-activated receptors, to drive cellular inflammatory reactions that further promote these processes. Local fibrinogen concentrations dictate fibrin clot structure and resistance to fibrinolysis. Within the atherosclerotic plaque, coagulation reactions driven by proinflammatory stimuli may initially support lesion stability (as part of wound healing), but, with advanced inflammation, thrombin and fibrin generation diminish because of proteolytic activity contributing to plaque instability. The NPHS findings have proved controversial, but, in the light of current knowledge, a reappraisal of the importance of FVIIc and fibrinogen in atherosclerosis, atherothrombosis and CHD is justified. Hypercoagulability, reflected in turn by thrombin generation capacity, and local concentrations of coagulation proteins, including FVIIc and fibrinogen, is linked to plaque phenotype, and even minute local concentrations of fibrinogen and proteases such as FVIIc may affect thrombin generation capacity.

Optimization of pulsed DEER measurements for Gd-based labels: choice of operational frequencies, pulse durations and positions, and temperature.

In this work, the experimental conditions and parameters necessary to optimize the long-distance (≥ 60 Å) Double Electron-Electron Resonance (DEER) measurements of biomacromolecules labeled with Gd(III) tags are analyzed. The specific parameters discussed are the temperature, microwave band, the separation between the pumping and observation frequencies, pulse train repetition rate, pulse durations and pulse positioning in the electron paramagnetic resonance spectrum. It was found that: (i) in optimized DEER measurements, the observation pulses have to be applied at the maximum of the EPR spectrum; (ii) the optimal temperature range for Ka-band measurements is 14-17 K, while in W-band the optimal temperatures are between 6-9 K; (iii) W-band is preferable to Ka-band for DEER measurements. Recent achievements and the conditions necessary for short-distance measurements (<15 Å) are also briefly discussed.

Navigating motherhood choices in the context of rheumatoid arthritis: women's stories.

OBJECTIVE: Planning a family is a complex decision. For women with chronic conditions such as rheumatoid arthritis (RA), there are additional concerns about their own and their baby's health. This qualitative study examined women's experiences of negotiating their family decisions in the context of RA. METHODS: A qualitative study was conducted in 14 women who provided a written account of their motherhood decisions and experiences. Those 'stories' were then thematically analysed. RESULTS: RA was found to affect women's motherhood decisions and experiences. Three key themes were identified for both the process of decision making and the experience of that decision: capacity, uncertainty and acceptance. Only two of the women decided not to have children, while for others the decision centred on changing expectations from the number of children they planned to have, to parenting within the restrictions of their physical abilities. CONCLUSION: While many women struggled through the negotiations of their motherhood choices, those who chose to have children reported great joy in that experience. The challenges faced by women with RA contemplating motherhood, however, highlight the need for understanding and support from health professionals and the provision of resources so that women can make informed choices.

Measuring perinatal mental health risk.

The purpose of this review was to critically analyse existing tools to measure perinatal mental health risk and report on the psychometric properties of the various approaches using defined criteria. An initial literature search revealed 379 papers, from which 21 papers relating to ten instruments were included in the final review. A further four papers were identified from experts (one excluded) in the field. The psychometric properties of six multidimensional tools and/or criteria were assessed. None of the instruments met all of the requirements of the psychometric properties defined. Some had used large sample sizes but reported low positive predictive values (Antenatal Risk Questionnaire (ANRQ)) or insufficient information regarding their clinical performance (Antenatal Routine Psychosocial Assessment (ARPA)), while others had insufficient sample sizes (Antenatal Psychosocial Health Assessment Tool, Camberwell Assessment of Need-Mothers and Contextual Assessment of Maternity Experience). The ANRQ has fulfilled the requirements of this analysis more comprehensively than any other instrument examined based on the defined rating criteria. While it is desirable to recommend a tool for clinical practice, it is important that clinicians are made aware of their limitations. The ANRQ and ARPA represent multidimensional instruments commonly used within Australia, developed within large samples with either cutoff scores or numbers of risk factors related to service outcomes. Clinicians can use these tools, within the limitations presented here, to determine the need for further intervention or to refer women to mental health services. However, the effectiveness of routine perinatal psychosocial assessment continues to be debated, with further research required.

Dielectric Resonator for Ka-Band Pulsed EPR Measurements at Cryogenic Temperatures: Probehead Construction and Applications.

The construction and performance of a Ka-band pulsed electron paramagnetic resonance (EPR) cryogenic probehead that incorporates dielectric resonator (DR) is presented. We demonstrate that the use of DR allows one to optimize pulsed double electron-electron resonance (DEER) measurements utilizing large resonator bandwidth and large amplitude of the microwave field B1 . In DEER measurements of Gd-based spin labels, use of this probe finally allows one to implement the potentials of Gd-based labels in distance measurements. Evidently, this DR is well suited to any applications requiring large B1-fields and resonator bandwidths, such as electron spin echo envelope modulation spectroscopy of nuclei having low magnetic moments and strong hyperfine interactions and double quantum coherence dipolar spectroscopy as was recently demonstrated in the application of a similar probe based on an loop-gap resonator and reported by Forrer et al. (J Magn Reson 190:280, 2008).

Pulsed dipolar spectroscopy distance measurements in biomacromolecules labeled with Gd(III) markers.

This work demonstrates the feasibility of using Gd(III) tags for long-range Double Electron Electron Resonance (DEER) distance measurements in biomacromolecules. Double-stranded 14- base pair Gd(III)-DNA conjugates were synthesized and investigated at K(a) band. For the longest Gd(III) tag the average distance and average deviation between Gd(III) ions determined from the DEER time domains was about 59±12Å. This result demonstrates that DEER measurements with Gd(III) tags can be routinely carried out for distances of at least 60Å, and analysis indicates that distance measurements up to 100Å are possible. Compared with commonly used nitroxide labels, Gd(III)-based labels will be most beneficial for the detection of distance variations in large biomacromolecules, with an emphasis on large scale changes in shape or distance. Tracking the folding/unfolding and domain interactions of proteins and the conformational changes in DNA are examples of such applications.

Distance measurements in model bis-Gd(III) complexes with flexible "bridge". Emulation of biological molecules having flexible structure with Gd(III) labels attached.

In this work, we continue to explore Gd(III) as a possible spin label for high-field Double Electron-Electron Resonance (DEER) based distance measurements in biological molecules with flexible geometry. For this purpose, a bis-Gd(III) complex with a flexible "bridge" was used as a model. The distances in the model were expected to be distributed in the range of 5-26 A, allowing us to probe the shortest limits of accessible distances which were found to be as small as 13 A. The upper distance limit for these labels was also evaluated and was found to be about 60 A. Various pulse duration setups can result in apparent differences in the distribution function derived from DEER kinetics due to short distance limit variations. The advantages, such as the ability to perform measurements at cryogenic temperatures and high repetition rates simultaneously, the use of very short pumping and observation pulses without mutual interference, the lack of orientational selectivity, as well as the shortcomings, such as the limited mw operational frequency range and intrinsically smaller amplitude of oscillation related to dipolar interaction as compared with nitroxide spin labels are discussed. Most probably the use of nitroxide and Gd-based labels for distance measurements will be complementary depending on the particulars of the problem and the availability of instrumentation.

Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case-control study.

PURPOSE: The aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis. METHODS: A hospital-based case-control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol. RESULTS: After adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD. CONCLUSIONS: This study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation.

A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke.

Non-invasive identification of transplanted neural stem cells in vivo by pre-labelling with contrast agents may play an important role in the translation of cell therapy to the clinic. Understanding the impact of these labels on the cells' ability to repair is therefore vital. In rats with middle cerebral artery occlusion (MCAo), a model of stroke, the transhemispheric migration of MHP36 cells labelled with the bimodal contrast agent GRID was detected on magnetic resonance images (MRI) up to 4 weeks following transplantation. However, compared to MHP36 cells labelled with the red fluorescent dye PKH26, GRID-labelled transplants did not significantly improve behaviour, and performance was akin to non-treated animals. Likewise, the evolution of anatomical damage as assessed by serial, T(2)-weighted MRI over 1 year indicated that GRID-labelled transplants resulted in a slight increase in lesion size compared to MCAo-only animals, whereas the same, PKH26-labelled cells significantly decreased lesion size by 35%. Although GRID labelling allows the in vivo identification of transplanted cells up to 1 month after transplantation, it is likely that some is gradually degraded inside cells. The translation of cellular imaging therefore does not only require the in vitro assessment of contrast agents on cellular functions, but also requires the chronic, in vivo assessment of the label on the stem cells' ability to repair in preclinical models of neurological disease.

Assessing the contribution of fibrinogen in predicting risk of death in men with peripheral arterial disease.

BACKGROUND: Although fibrinogen is known to be an independent population-level risk factor for cardiovascular disease in healthy individuals, less is known about its value for individual-level risk prediction. OBJECTIVES: To assess the independent contribution of plasma fibrinogen to risk prediction in men with peripheral arterial disease. PATIENTS AND METHODS: We used data from the 785 men randomized to placebo in the Lower Extremity Arterial Disease Event Reduction (LEADER) trial. Men were followed at 6-monthly intervals up to 3 years, during which 116 patients died. Multivariable standard and pooled logistic regression were used to model odds of death in the next 3 years or in a 6-month interval. The c-statistic and predictiveness curves were used to assess improvement in predictive ability. RESULTS: Fibrinogen measured at baseline was an independent predictor of all-cause mortality risk (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02-1.94, for a 1 g L(-1) increase). Adding baseline fibrinogen to a set of other risk factors did not, however, substantially improve predictive ability. Similarly, fibrinogen measured at the start of a 6-month interval was independently associated with odds of death in the next 6 months (adjusted OR 1.65; 95% CI 0.96-2.73). Again, predictiveness curves with and without fibrinogen did not substantially differ, although the c-statistic increased by 0.011. CONCLUSIONS: Although fibrinogen was independently associated with both 6-month and 3-year mortality risk, individual-level risk prediction was not substantially improved by including fibrinogen in risk models.

Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I).

BACKGROUND: The long-term associations of established risk factors for coronary heart disease (CHD), for example cholesterol, are well known, but not for the less familiar hemostatic variables. OBJECTIVES: To establish whether associations between hemostatic variables and CHD first identified nearly three decades ago have persisted long-term. METHODS: The first Northwick Park Heart Study (NPHS-I) recruited 2167 white men and 941 white women, average age at entry 48 years, on whom measures of factor (F) VII activity (VIIc) and plasma fibrinogen were carried out, both at entry and at follow-up approximately 6 years later. RESULTS: During a median follow-up of 29 years, 231 male and 36 female CHD deaths were recorded from notifications by the Office for National Statistics. VIIc at recruitment was significantly related to CHD mortality, corrected rate ratio, RR, per 1 SD increase 1.56 (95% CI 1.29, 1.88) in men and RR 1.78 (95% CI 1.17, 2.72) in women. Recruitment fibrinogen was also strongly related to CHD mortality in men, RR 1.63 (95% CI 1.33, 1.99) but not in women, RR 0.75 (95% CI 0.40, 1.43). The associations persisted after controlling for confounders and were confirmed using 6-year follow-up measurements and in analyses omitting deaths within 10 years of recruitment. CONCLUSIONS: The hemostatic system contributes to CHD mortality, and its effect is stable over time. For VIIc, the effect was similar in men and women, while for fibrinogen it appeared to be present only in men.

Associations of plasma fibrinogen and factor VII clotting activity with coronary heart disease and stroke: prospective cohort study from the screening phase of the Thrombosis Prevention Trial.

BACKGROUND: As with 'conventional' risk factors such as cholesterol and smoking, there is a need for large, long-term prospective studies on hemostatic factors. OBJECTIVES: To investigate the prospective relationship of fibrinogen and factor VII clotting activity (FVIIc) with risk of coronary heart disease (CHD) and stroke in a study with a large number of outcomes over a period of 15 years. PATIENTS/METHODS: A cohort of 22 715 men aged 45-69 years was screened for participation in the Thrombosis Prevention Trial. Men were followed up for fatal and non-fatal CHD and stroke events. There were 1515 CHD events (933 CHD deaths) and 391 strokes (180 stroke deaths). Hazard ratios (HRs) and 95% confidence intervals are expressed per standardized increase in log fibrinogen and log FVIIc, adjusting for age, trial treatment group, conventional CHD risk factors and regression dilution bias. RESULTS: Hazard ratios for fibrinogen were 1.52 (1.37-1.70) for all CHD events, and 1.36 (1.09-1.69) for all strokes. Exclusion of events within the first 10 years showed a persistent association between CHD and fibrinogen, with an adjusted HR of 1.93 (1.42-2.64). The HRs for FVIIc, adjusting for age and trial treatment, were 1.07 (1.01-1.12) for all CHD events and 1.07 (0.97-1.20) for all strokes, and the fully adjusted HRs were, respectively, 0.97 (0.84-1.05) and 1.07 (0.85-1.33). CONCLUSIONS: The persisting association between fibrinogen and CHD beyond 10 years may imply a causal effect. There is a small effect of FVIIc on CHD, after adjustment for age and trial treatment, but no association independent of other risk factors.