Physical healthcare of people with severe mental illness: everybody's business!

Aim People with severe mental illness are at higher risk of physical health problems. Guidelines recommend annual monitoring. An audit cycle was completed on individuals with severe mental illness under the care of an early interventions in psychosis (EIP) service to evaluate and improve physical health monitoring practice.Methods The number of patients who had undergone a physical health check in the previous year, and those having a record of it in their EIP notes, was examined. Interventions made between baseline audit and re-audit included improving awareness within the multidisciplinary EIP mental health team about the importance of physical health monitoring of people with severe mental illness and liaison with primary care health services.Results The number of patients undergoing at least one annual physical health check increased from 20% to 58%. Among patients who had undergone a physical health check at re-audit, a record of some or all the checks was available in the notes for 75% of patients.Clinical implications There is a need to improve awareness among mental health professionals about the importance of the physical health of people with severe mental illness and to make appropriate organisational changes.     

Butea monosperma and chemomodulation: Protective role against thioacetamide-mediated hepatic alterations in Wistar rats

The present study was carried out to study the effect of Butea monosperma, a known liver acting drug on the tumor promotion related events of carcinogenesis in rat liver. Thioacetamide (TAA) was used to induce tumor promotion response and oxidative stress and caused significant depletion in the detoxification and antioxidant enzyme armory with concomitant elevation in malondialdehyde (MDA) formation, hydrogen peroxide (H(2)O(2)) generation, ornithine decarboxylase (ODC) activity and unscheduled DNA synthesis. However, B. monosperma pretreatment at two different doses restored the levels of the above-said parameters (p < 0.001) in a dose-dependent manner. The alcoholic extract of B. monosperma used in the present study seems to offer dose-dependent protection and maintain the structural integrity of hepatic cells. This was evident from the significant reduction in TAA-induced serum GOT, GPT, Lactate dehydrogenase (LDH) and gamma-Glutamyl transpeptidase activity (GGT) activities (p < 0.001). These investigations validate the use of B. monosperma in liver disorders by Ayurvedic physicians. Overall results indicate that the methanolic extract of B. monosperma possesses hepatoprotective effects and also it might suppress the promotion stage via inhibition of oxidative stress and polyamine biosynthetic pathway.     

Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Introduction  

Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4⁺ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4⁺ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.     

Synergistic effect between apolipoprotein E and apolipoprotein A1 gene polymorphisms in the risk for coronary artery disease

Alterations in lipid metabolism and genetic predisposition are major risk factors for coronary artery disease (CAD). Variations in genes involved in lipid metabolism may act synergistically to confer risk or protection against CAD. The objective of the present study was to determine such interactions in variants of apolipoprotein E and apolipoprotein A1 genes. One hundred and forty subjects with clinically confirmed CAD and 100 unrelated normal subjects participated in the study. Multiple regression analysis was used to relate lipid and apolipoprotein profiles with genotypes. Odd ratios were calculated for various combinations of ApoE and ApoA1 genotypes. Prevalence of ApoE 'E4' and ApoA1 'A' and 'T' alleles was significantly higher in patients than controls. Serum apolipoprotein E and apolipoprotein A1 levels were significantly lower in CAD patients than controls. When lipid parameters were related to genotypes, the polymorphisms associated to various markers were in agreement with previous reports. ApoE 2/4 genotype in combination with either ApoA1 heterozygous GA or CT genotype conferred higher risk of CAD. E3 allele in homozygous or heterozygous state in combination with ApoA1+83 CC genotype conferred highest protection (P < 0.05). Thus, it appears that ApoE and ApoA1 gene variants may act synergistically to associate with risk and protection against CAD.     

Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators

FTY720 has been used to control inflammatory lesions, but the mechanisms by which the drug acts in vivo are poorly understood. Such mechanisms may result primarily from effects on lymphocyte and dendritic cell homing to lymphoid and inflammatory sites. We demonstrate that FTY720 may also act by causing the conversion of TCR-stimulated nonregulatory CD4(+) T cells to Foxp3(+)CD4(+) regulatory T cells and by enhancing their suppressive activity. In a model in which mice were ocularly infected with HSV, daily treatment with FTY720 resulted in significantly diminished ocular lesions. The treated animals showed increased frequencies of Foxp3(+) T cells in lymphoid organs and at two inflammatory sites, namely cornea and trigeminal ganglia. In a second series of experiments, immunized DO11.10RAG2(-/-) animals, normally lacking endogenous Foxp3(+) T cells, that were given FTY720 treatment developed high frequencies of Foxp3(+) regulatory T cells in lymph nodes. Some converted cells persisted in treated animals for several weeks after drug administration was discontinued. Finally, FTY720 could effectively induce Foxp3-expressing cells from Foxp3(-) cells in vitro, an effect inhibited by anti-TGF-beta or the proinflammatory cytokine IL-6. Accordingly, the anti-inflammatory effects of FTY720 could be mediated at least in part by its ability to cause the conversion of Ag-stimulated conventional T cells to become Foxp3(+) regulators. The use of FTY720 along with Ag administration could represent a useful therapeutic means to selectively expand Ag-specific regulators, which could be valuable in many clinical situations such as allotransplants, some autoimmunities, as well as with some chronic infections.     

USP14 regulates DNA damage repair by targeting RNF168-dependent ubiquitination

Recent reports have made important revelations, uncovering direct regulation of DNA damage response (DDR)-associated proteins and chromatin ubiquitination (Ubn) by macroautophagy/autophagy. Here, we report a previously unexplored connection between autophagy and DDR, via a deubiquitnase (DUB), USP14. Loss of autophagy in prostate cancer cells led to unrepaired DNA double-strand breaks (DSBs) as indicated by persistent ionizing radiation (IR)-induced foci (IRIF) formation for γH2AFX, and decreased protein levels and IRIF formation for RNF168, an E3-ubiquitin ligase essential for chromatin Ubn and recruitment of critical DDR effector proteins in response to DSBs, including TP53BP1. Consistently, RNF168-associated Ubn signaling and TP53BP1 IRIF formation were reduced in autophagy-deficient cells. An activity assay identified several DUBs, including USP14, which showed higher activity in autophagy-deficient cells. Importantly, inhibiting USP14 could overcome DDR defects in autophagy-deficient cells. USP14 IRIF formation and protein stability were increased in autophagy-deficient cells. Co-immunoprecipitation and colocalization of USP14 with MAP1LC3B and the UBA-domain of SQSTM1 identified USP14 as a substrate of autophagy and SQSTM1. Additionally, USP14 directly interacted with RNF168, which depended on the MIU1 domain of RNF168. These findings identify USP14 as a novel substrate of autophagy and regulation of RNF168-dependent Ubn and TP53BP1 recruitment by USP14 as a critical link between DDR and autophagy. Given the role of Ubn signaling in non-homologous end joining (NHEJ), the major pathway for repair of IR-induced DNA damage, these findings provide unique insights into the link between autophagy, DDR-associated Ubn signaling and NHEJ DNA repair.

Abbreviations: ATG7: autophagy related 7; CQ: chloroquine; DDR: DNA damage response; DUB: deubiquitinase; HR: homologous recombination; IR: ionizing radiation; IRIF: ionizing radiation-induced foci; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MIU1: motif interacting with ubiquitin; NHEJ: non homologous end-joining; PCa: prostate cancer; TP53BP1/53BP1: tumor protein p53 binding protein 1; RNF168: ring finger protein 168; SQSTM1/p62 sequestosome 1; γH2AFX/γH2AX: H2A histone family member X: phosphorylated, UBA: ubiquitin-associated; Ub: ubiquitin; Ubn: ubiquitination; USP14: ubiquitin specific peptidase 14.     

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity

Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.     

Strain improvement of Aspergillus niger for enhanced lipase production

The enhancement of lipase production from Aspergillus niger was attempted by ultraviolet (UV) and nitrous acid mutagenesis, and the mutants were selected on media containing bile salts. Nitrous acid mutants exhibited increased efficiency for lipase production when compared with UV mutants in submerged fermentation. The hyperproducing UV and nitrous acid mutants were further subjected to a second step of mutagenesis to devise an economical and ecofriendly technique for lipase production by the effective use of hydrocarbons. One percent kerosene was found to be optimal for lipase production, and one of the mutant strains NAII exhibited 2.53 times more increased lipase activity than the parental strain did. This investigation indicates a possible role for the A. niger mutant strains in the biodegradation of oil-polluted environments for the development of ecofriendly technologies.     

Physico-chemical and antigenic characterization of unconventional heavy chain antibodies of Indian desert camel (Camelus dromedarius L.)

Heavy chain antibodies (HCAbs) of IgG2 and IgG3 subtypes were purified from the sera of Indian desert camel (Camelus dromedarius L.) by ammonium sulphate precipitation, followed by ion-exchange chromatography on DEAE-cellulose and affinity chromatography on protein A-sepharose and protein G-sepharose, and characterized by SDS-polyacrylamide gel electrophoresis, agar gel immunodiffusion (AGID), counter-immunoelectrophoresis (CIEP), immunoelectrophoresis (IEP), ELISA and immunoblotting. IgG2 and IgG3 were found to have molecular mass 46.77 kDa and 43.65 kDa, respectively by SDS-PAGE under reducing conditions. They migrated in beta-region in IEP and could be detected in CIEP, because of being more negatively charged and smaller size. Anti-camel IgG3 cross-reacted in AGID, ELISA and immunoblotting with IgGs of pig and ruminants (cattle, buffalo, sheep and goat), but not with immunoglobulins from horse, dog, guinea pigs, mice, fish, poultry and human. The present findings suggest close antigenic relationship of camels with pigs and ruminants.     

Cutinase-Like Enzyme from the Yeast Cryptococcus sp. Strain S-2 Hydrolyzes Polylactic Acid and Other Biodegradable Plastics

A purified lipase from the yeast Cryptococcus sp. strain S-2 exhibited remote homology to proteins belonging to the cutinase family rather than to lipases. This enzyme could effectively degrade the high-molecular-weight compound polylactic acid, as well as other biodegradable plastics, including polybutylene succinate, poly (-caprolactone), and poly(3-hydroxybutyrate).