Functional status and all-cause mortality in serious mental illness

Background

Serious mental illness can affect many aspects of an individual’s ability to function in daily life. The aim of this investigation was to determine if the environmental and functional status of people with serious mental illness contribute to the high mortality risk observed in this patient group.

Methods

We identified cases of schizophrenia, schizoaffective and bipolar disorder aged ≥15 years in a large secondary mental healthcare case register linked to national mortality tracing. We modelled the effect of activities of daily living (ADLs), living conditions, occupational and recreational activities and relationship factors (Health of the Nation Outcome Scale [HoNOS] subscales) on all-cause mortality over a 4-year observation period (2007–10) using Cox regression.

Results

We identified 6,880 SMI cases (242 deaths) in the observation period. ADL impairment was associated with an increased risk of all-cause mortality (adjusted HR 1.9; 95% CI 1.3–2.8; p = 0.001, p for trend across ADL categories = 0.001) after controlling for a broad range of covariates (including demographic factors, physical health, mental health symptoms and behaviours, socio-economic status and mental health service contact). No associations were found for the other three exposures. Stratification by age indicated that ADLs were most strongly associated with mortality in the youngest (15 to <35 years) and oldest (≥55 years) groups.

Conclusions

Functional impairment in people with serious mental illness diagnoses is a marker of increased mortality risk, possibly in younger age groups as a marker of negative symptomatology.     

Phosphodiesterase 3A (PDE3A) deletion suppresses proliferation of cultured murine vascular smooth muscle cells (VSMCs) via inhibition of mitogen-activated protein kinase (MAPK) signaling and alterations in critical cell cycle regulatory proteins

Cyclic nucleotide phosphodiesterase 3 (PDE3) is an important regulator of cyclic adenosine monophosphate (cAMP) signaling within the cardiovascular system. In this study, we examined the role of PDE3A and PDE3B isoforms in regulation of growth of cultured vascular smooth muscle cells (VSMCs) and the mechanisms by which they may affect signaling pathways that mediate mitogen-induced VSMC proliferation. Serum- and PDGF-induced DNA synthesis in VSMCs grown from aortas of PDE3A-deficient (3A-KO) mice was markedly less than that in VSMCs from PDE3A wild type (3A-WT) and PDE3B-deficient (3B-KO) mice. The reduced growth response was accompanied by significantly less phosphorylation of extracellular signal-regulated kinase (ERK) in 3A-KO VSMCs, most likely due to a combination of greater site-specific inhibitory phosphorylation of Raf-1^Ser-259 by protein kinase A (PKA) and enhanced dephosphorylation of ERKs due to elevated mitogen-activated protein kinase phosphatase 1 (MKP-1). Furthermore, 3A-KO VSMCs, compared with 3A-WT, exhibited higher basal PKA activity and cAMP response element-binding protein (CREB) phosphorylation, higher levels of p53 and p53 phosphorylation, and elevated p21 protein together with lower levels of Cyclin-D1 and retinoblastoma (Rb) protein and Rb phosphorylation. Adenoviral overexpression of inactive CREB partially restored growth effects of serum in 3A-KO VSMCs. In contrast, exposure of 3A-WT VSMCs to VP16 CREB (active CREB) was associated with inhibition of serum-induced DNA synthesis similar to that in untreated 3A-KO VSMCs. Transfection of 3A-KO VSMCs with p53 siRNA reduced p21 and MKP-1 levels and completely restored growth without affecting amounts of Cyclin-D1 and Rb phosphorylation. We conclude that PDE3A regulates VSMC growth via two complementary pathways, i.e. PKA-catalyzed inhibitory phosphorylation of Raf-1 with resulting inhibition of MAPK signaling and PKA/CREB-mediated induction of p21, leading to G₀/G₁ cell cycle arrest, as well as by increased accumulation of p53, which induces MKP-1, p21, and WIP1, leading to inhibition of G₁ to S cell cycle progression.     

Structural and mechanistic studies of chloride induced activation of human pancreatic alpha-amylase

The mechanism of allosteric activation of alpha-amylase by chloride has been studied through structural and kinetic experiments focusing on the chloride-dependent N298S variant of human pancreatic alpha-amylase (HPA) and a chloride-independent TAKA-amylase. Kinetic analysis of the HPA variant clearly demonstrates the pronounced activating effect of chloride ion binding on reaction rates and its effect on the pH-dependence of catalysis. Structural alterations observed in the N298S variant upon chloride ion binding suggest that the chloride ion plays a variety of roles that serve to promote catalysis. One of these is having a strong influence on the positioning of the acid/base catalyst residue E233. Absence of chloride ion results in multiple conformations for this residue and unexpected enzymatic products. Chloride ion and N298 also appear to stabilize a helical region of polypeptide chain from which projects the flexible substrate binding loop unique to chloride-dependent alpha-amylases. This structural feature also serves to properly orient the catalytically essential residue D300. Comparative analyses show that the chloride-independent alpha-amylases compensate for the absence of bound chloride by substituting a hydrophobic core, altering the manner in which substrate interactions are made and shifting the placement of N298. These evolutionary differences presumably arise in response to alternative operating environments or the advantage gained in a particular product profile. Attempts to engineer chloride-dependence into the chloride-independent TAKA-amylase point out the complexity of this system, and the fact that a multitude of factors play a role in binding chloride ion in the chloride-dependent alpha-amylases.     

Host-pathogen interactions during apoptosis

Host pathogen interaction results in a variety of responses, which include phagocytosis of the pathogen, release of cytokines, secretion of toxins, as well as production of reactive oxygen species (ROS). Recent studies have shown that many pathogens exert control on the processes that regulate apoptosis in the host. The induction of apoptosis upon infection results from a complex interaction of parasite proteins with cellular host proteins. Abrogation of host cell apoptosis is often beneficial for the pathogen and results in a successful host invasion. However, in some cases, it has been shown that induction of apoptosis in the infected cells significantly imparts protection to the host from the pathogen. There is a strong correlation between apoptosis and the host protein translation machinery: the pathogen makes all possible efforts to modify this process so as to inhibit cell suicide and ensure that it can survive and, in some cases, establish latent infection. This review discusses the significance of various pathways/steps during virus-mediated modulation of host cell apoptosis.     

Cambial sensitivity to rising temperatures by natural condition and artificial heating from late winter to early spring in the evergreen conifer Cryptomeria japonica

Differences in the timing of cambial reactivation and the initiation of xylem differentiation in response to the sum of daily maximum temperatures were studied in two Cryptomeria japonica trees with cambium of different ages under natural and locally heated conditions. In addition, we observed the effects of low temperature on cambial activity. The timing of cambial reactivation and of the initiation of xylem differentiation differed between 55- and 80-year-old cambium under natural conditions. In the 55-year-old cambium, cambial reactivation occurred when the cambial reactivation index (CRI), calculated on the basis of daily maximum temperatures in excess of 10°C, was 94 and 97°C in 2007 and 2008, respectively. In 80-year-old cambium, cambial reactivation occurred when the CRI, calculated on the basis of daily maximum temperatures in excess of 11°C, was 69 and 71°C in 2007 and 2008, respectively. After cambial reactivation in 2007, normal cell division was evident in the cambium even though the minimum temperature had fallen between −2 and −3°C. Under natural conditions, xylem differentiation started 38–44 days after cambial reactivation. In heated stems, the time between cambial reactivation and the initiation of xylem differentiation ranged from 14 to 16 days, a much shorter time than under natural conditions, indicating that continuous exposure to an elevated temperature had induced earlier xylem differentiation. Our observations indicate that the sensitivity to reactivation inducing stimuli of the cambium depends on both the stage of dormancy and tree age of the cambium.     

The NMDA receptor antagonist MK-801 inhibits vitellogenesis in the flesh fly Neobellieria bullata and in the desert locust Schistocerca gregaria

We found that in the flesh fly Neobellieria bullata, vitellogenesis can be inhibited in a dose-dependent way by two injections of 60 microg MK-801/g body mass. In the desert locust Schistocerca gregaria, vitellogenesis can also be fully inhibited but only by repeated injections of 200-400 microg/g body mass. In this species, the inhibition can be overruled by coapplication of juvenile hormone. Vitellogenin bands remained visible in electropherograms of hemolymph of MK-801-treated female locusts, but vitellogenin did not accumulate as might be expected when only its uptake by the oocytes, and not its synthesis by the fat body, would be affected. Whether MK-801 acts by inhibiting juvenile hormone synthesis by the corpora allata remains to be investigated.     

Expression profiling of lymphocyte plasma membrane proteins

The physicochemical properties of plasma membrane proteins of mammalian cells render them refractory to systematic analysis by two-dimensional electrophoresis. We have therefore used in vivo cell surface labeling with a water-soluble biotinylation reagent, followed by cell lysis and membrane purification, prior to affinity capture of biotinylated proteins. Purified membrane proteins were then separated by solution-phase isoelectric focusing and SDS-PAGE and identified by high-pressure liquid chromatography electrospray/tandem mass spectrometry. Using this approach, we identified 42 plasma membrane proteins from a murine T cell hybridoma and 46 from unfractionated primary murine splenocytes. These included three unexpected proteins; nicastrin, osteoclast inhibitory lectin, and a transmembrane domain-containing hypothetical protein of 11.4 kDa. Following stimulation of murine splenocytes with phorbol ester and calcium ionophore, we observed differences in expression of CD69, major histocompatibility complex class II molecules, the glucocorticoid-induced TNF receptor family-related gene product, and surface immunoglobulin M and D that were subsequently confirmed by Western blot or flow cytometric analysis. This approach offers a generic and powerful strategy for investigating differential expression of surface proteins in many cell types under varying environmental and pathophysiological conditions.     

Antinociceptive activity of methanolic extract of leaves of Achyranthes aspera Linn. (Amaranthaceae) in animal models of nociception

Antinociceptive activity of methanolic extract of leaves of A. aspera was studied by peripheral/non-narcotic model of nociception like acetic acid induced writhing syndrome test and central/narcotic models like hot plate and tail flick tests. The methanolic extract of the plant, administered orally (@ 300, 600 and 900 mg/kg, body weight) and the standard drug (piroxicam; 10 mg/kg body weight, po) produced significant analgesic activity in acetic acid induced writhing syndrome as compared to the vehicle treated control group. In the hot plate analgesic test, in A. aspera at the above doses and the standard drug treated group (morphine sulphate @ 1.5 mg/kg, ip), the duration of reaction time (sec) increased dose dependently and significantly compared to the control group. In the tail flick test, the plant extract produced dose dependant increase in reaction time which was significantly higher in the test and standard group compared to the control group. The plant possesses significant antinociceptive property as evidenced in all the animal models of nociception. It might possibly exert its effect through diverse mechanism that may involve both central and peripheral pathways. The preliminary phytochemical investigation revealed the presence of steroids, alkaloids and triterpene in the methanolic extract of leaves of A. aspera which may be responsible for its antinociceptive activity.     

Acyclovir Therapy Reduces the CD4+ T Cell Response against the Immunodominant pp65 Protein from Cytomegalovirus in Immune Competent Individuals

Cytomegalovirus (CMV) infects the majority of the global population and leads to the development of a strong virus-specific immune response. The CMV-specific CD4+ and CD8+ T cell immune response can comprise between 10 and 50% of the T cell pool within peripheral blood and there is concern that this may impair immunity to other pathogens. Elderly individuals with the highest magnitude of CMV-specific immune response have been demonstrated to be at increased risk of mortality and there is increasing interest in interventions that may serve to moderate this. Acyclovir is an anti-viral drug with activity against a range of herpes viruses and is used as long term treatment to suppress reactivation of herpes simplex virus. We studied the immune response to CMV in patients who were taking acyclovir to assess if therapy could be used to suppress the CMV-specific immune response. The T cell reactivity against the immunodominant late viral protein pp65 was reduced by 53% in people who were taking acyclovir. This effect was seen within one year of therapy and was observed primarily within the CD4+ response. Acyclovir treatment only modestly influenced the immune response to the IE-1 target protein. These data show that low dose acyclovir treatment has the potential to modulate components of the T cell response to CMV antigen proteins and indicate that anti-viral drugs should be further investigated as a means to reduce the magnitude of CMV-specific immune response and potentially improve overall immune function.