Properties of small molecular drug loading and diffusion in a fluorinated PEG hydrogel studied by ^1H molecular diffusion NMR and ^(19)F spin diffusion NMR

R_f-PEG (fluoroalkyl double-ended poly(ethylene glycol)) hydrogel is potentially useful as a drug delivery depot due to its advanced properties of sol–gel two-phase coexistence and low surface erosion. In this study, ^1H molecular diffusion nuclear magnetic resonance (NMR) and ^(19)F spin diffusion NMR were used to probe the drug loading and diffusion properties of the R_f-PEG hydrogel for small anticancer drugs, 5-fluorouracil (FU) and its hydrophobic analog, 1,3-dimethyl-5-fluorouracil (DMFU). It was found that FU has a larger apparent diffusion coefficient than that of DMFU, and the diffusion of the latter was more hindered. The result of ^(19)F spin diffusion NMR for the corresponding freeze-dried samples indicates that a larger portion of DMFU resided in the R_f core/IPDU intermediate-layer region (where IPDU refers to isophorone diurethane, as a linker to interconnect the R_f group and the PEG chain) than that of FU while the opposite is true in the PEG–water phase. To understand the experimental data, a diffusion model was proposed to include: (1) hindered diffusion of the drug molecules in the R_f core/IPDU-intermediate-layer region; (2) relatively free diffusion of the drug molecules in the PEG-water phase (or region); and (3) diffusive exchange of the probe molecules between the above two regions. This study also shows that molecular diffusion NMR combined with spin diffusion NMR is useful in studying the drug loading and diffusion properties in hydrogels for the purpose of drug delivery applications

Symptoms associated with victimization in patients with schizophrenia and related disorders

Background: Patients with psychoses have an increased risk of becoming victims of violence. Previous studies have suggested that higher symptom levels are associated with a raised risk of becoming a victim of physical violence. There has been, however, no evidence on the type of symptoms that are linked with an increased risk of recent victimization. Methods: Data was taken from two studies on involuntarily admitted patients, one national study in England and an international one in six other European countries. In the week following admission, trained interviewers asked patients whether they had been victims of physical violence in the year prior to admission, and assessed symptoms on the Brief Psychiatric Rating Scale (BPRS). Only patients with a diagnosis of schizophrenia or related disorders (ICD-10 F20–29) were included in the analysis which was conducted separately for the two samples. Symptom levels assessed on the BPRS subscales were tested as predictors of victimization. Univariable and multivariable logistic regression models were fitted to estimate adjusted odds ratios. Results: Data from 383 patients in the English sample and 543 patients in the European sample was analysed. Rates of victimization were 37.8% and 28.0% respectively. In multivariable models, the BPRS manic subscale was significantly associated with victimization in both samples. Conclusions: Higher levels of manic symptoms indicate a raised risk of being a victim of violence in involuntary patients with schizophrenia and related disorders. This might be explained by higher activity levels, impaired judgement or poorer self-control in patients with manic symptoms. Such symptoms should be specifically considered in risk assessments

The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression

BACKGROUND: The COMT gene is located on chromosome 22q11, a region strongly implicated in the aetiology of several psychiatric disorders, in particular schizophrenia. Previous research has suggested that activity and expression of COMT is altered in schizophrenia, and is mediated by one or more polymorphisms within the gene, including the functional Val(158)Met polymorphism. METHOD: In this study we examined the expression levels of COMT mRNA using quantitative RT-PCR in 60 post mortem cerebellum samples derived from individuals with schizophrenia, bipolar disorder, depression, and no history of psychopathology. Furthermore, we have examined the methylation status of two CpG sites in the promoter region of the gene. RESULTS: We found no evidence of altered COMT expression or methylation in any of the psychiatric diagnoses examined. We did, however, find evidence to suggest that genotype is related to COMT gene expression, replicating the findings of two previous studies. Specifically, val(158)met (rs165688; Val allele) rs737865 (G allele) and rs165599 (G allele) all showed reduced expression (P < 0.05). Finally, we observe a strong sexual dimorphism in COMT expression, with females exhibiting significantly greater levels of COMT mRNA. CONCLUSION: The expression of COMT does not appear to be altered in the cerebellum of individuals suffering from schizophrenia, bipolar disorder or depression, but does appear to be influenced by single nucleotide polymorphisms within the gene

Planetary Rings

Planetary rings are the only nearby astrophysical disks, and the only disks that have been investigated by spacecraft. Although there are significant differences between rings and other disks, chiefly the large planet/ring mass ratio that greatly enhances the flatness of rings (aspect ratios as small as 1e-7), understanding of disks in general can be enhanced by understanding the dynamical processes observed at close-range and in real-time in planetary rings. We review the known ring systems of the four giant planets, as well as the prospects for ring systems yet to be discovered. We then review planetary rings by type. The main rings of Saturn comprise our system's only dense broad disk and host many phenomena of general application to disks including spiral waves, gap formation, self-gravity wakes, viscous overstability and normal modes, impact clouds, and orbital evolution of embedded moons. Dense narrow rings are the primary natural laboratory for understanding shepherding and self-stability. Narrow dusty rings, likely generated by embedded source bodies, are surprisingly found to sport azimuthally-confined arcs. Finally, every known ring system includes a substantial component of diffuse dusty rings. Planetary rings have shown themselves to be useful as detectors of planetary processes around them, including the planetary magnetic field and interplanetary impactors as well as the gravity of nearby perturbing moons. Experimental rings science has made great progress in recent decades, especially numerical simulations of self-gravity wakes and other processes but also laboratory investigations of coefficient of restitution and spectroscopic ground truth. The age of self-sustained ring systems is a matter of debate; formation scenarios are most plausible in the context of the early solar system, while signs of youthfulness indicate at least that rings have never been static phenomena.Comment: 82 pages, 34 figures. Final revision of general review to be published in "Planets, Stars and Stellar Systems", P. Kalas and L. French (eds.), Springer (http://refworks.springer.com/sss

Comorbid substance abuse and brain morphology in recent-onset psychosis

The aim of the presented study was to compare schizophrenia and schizoaffective patients early in the course of the disease with and without comorbid substance abuse disorder (SUD vs. NSUD) with regard to brain morphology. In a prospective design 41 patients (20 SUD vs. 21 NSUD) diagnosed as recent-onset schizophrenia or schizoaffective disorder consecutively admitted to hospital received standardized psychopathological evaluation (BPRS, SANS, MADRS, CGI, GAF) and MRI scanning with volumetric measurement of superior temporal gyrus (STG), amygdala-hippocampal complex, and cingulum. Patients with SUD (primarily cannabis) were significantly younger, predominantly male and had a lower socioeconomic status. Despite less attentional impairment (SANS subscore) and elevated anxiety/depression (BPRS subscore) in patients with SUD compared to NSUD, no other psychopathological differences could be detected. There were no differences in the assessed temporolimbic brain morphology between the two subgroups. In conclusion, in this study substance abuse in recent-onset psychosis had no effect on brain morphology and the earlier onset of psychosis in patients with comorbid SUD could not be explained by supposed accentuated brain abnormalities in temporolimbic regions

Motivation and treatment engagement intervention trial (MotivaTe-IT): The effects of motivation feedback to clinicians on treatment engagement in patients with severe mental illness

Background: Treatment disengagement and non-completion poses a major problem for the successful treatment of patients with severe mental illness. Motivation for treatment has long been proposed as a major determinant of treatment engagement, but exact mechanisms remain unclear. This current study serves three purposes: 1) to determine whether a feedback intervention based on the patients' motivation for treatment is effective at improving treatment engagement (TE) of severe mentally ill patients in outpatient psychiatric treatment, 2) to gather insight into motivational processes and pos

Comparing population health in the United States and Canada

<p>Abstract</p> <p>Background</p> <p>The objective of the paper is to compare population health in the United States (US) and Canada. Although the two countries are very similar in many ways, there are potentially important differences in the levels of social and economic inequality and the organization and financing of and access to health care in the two countries.</p> <p>Methods</p> <p>Data are from the Joint Canada/United States Survey of Health 2002/03. The Health Utilities Index Mark 3 (HUI3) was used to measure overall health-related quality of life (HRQL). Mean HUI3 scores were compared, adjusting for major determinants of health, including body mass index, smoking, education, gender, race, and income. In addition, estimates of life expectancy were compared. Finally, mean HUI3 scores by age and gender and Canadian and US life tables were used to estimate health-adjusted life expectancy (HALE).</p> <p>Results</p> <p>Life expectancy in Canada is higher than in the US. For those < 40 years, there were no differences in HRQL between the US and Canada. For the 40+ group, HRQL appears to be higher in Canada. The results comparing the white-only population in both countries were very similar. For a 19-year-old, HALE was 52.0 years in Canada and 49.3 in the US.</p> <p>Conclusions</p> <p>The population of Canada appears to be substantially healthier than the US population with respect to life expectancy, HRQL, and HALE. Factors that account for the difference may include access to health care over the full life span (universal health insurance) and lower levels of social and economic inequality, especially among the elderly.</p

Neuroanatomical Pattern of Mitochondrial Complex I Pathology Varies between Schizophrenia, Bipolar Disorder and Major Depression

BACKGROUND:Mitochondrial dysfunction was reported in schizophrenia, bipolar disorderand major depression. The present study investigated whether mitochondrial complex I abnormalities show disease-specific characteristics. METHODOLOGY/PRINCIPAL FINDINGS:mRNA and protein levels of complex I subunits NDUFV1, NDUFV2 and NADUFS1, were assessed in striatal and lateral cerebellar hemisphere postmortem specimens and analyzed together with our previous data from prefrontal and parieto-occipital cortices specimens of patients with schizophrenia, bipolar disorder, major depression and healthy subjects. A disease-specific anatomical pattern in complex I subunits alterations was found. Schizophrenia-specific reductions were observed in the prefrontal cortex and in the striatum. The depressed group showed consistent reductions in all three subunits in the cerebellum. The bipolar group, however, showed increased expression in the parieto-occipital cortex, similar to those observed in schizophrenia, and reductions in the cerebellum, yet less consistent than the depressed group. CONCLUSIONS/SIGNIFICANCE:These results suggest that the neuroanatomical pattern of complex I pathology parallels the diversity and similarities in clinical symptoms of these mental disorders

Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

<p>Abstract</p> <p>Background</p> <p>The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC).</p> <p>Results</p> <p>This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged.</p> <p>Conclusion</p> <p>The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.</p