Impact of Mental Health Services on Resilience in Youth with First Episode Psychosis: A Qualitative Study.

The purpose of this qualitative study is to understand how mental health and related services support and hinder resilience in young people diagnosed with first-episode psychosis. Seventeen youth between the ages of 18-24 were recruited and 31 in-depth interviews were conducted. Findings illustrated that informational and meaning making, instrumental, and emotional supports were experienced positively (i.e., resilience-enhancing); whereas services with ghettoizing, engulfing, regulating, and out of tune practices were experienced negatively (i.e., resilience-hindering). These results demonstrate how various types of service-related practices influence resilience in youth and can inform future planning of services for psychosis.

Alendronate does not prevent long bone fragility in an inactive rat model.

The lack of estrogen and inactivity are both important in the pathogenesis of osteoporosis in elderly women, and there have been no appropriate rodent studies to examine the effects of common bisphosphonates on these two components separately. We compared the efficacy of alendronate (ALN) on the long bones of aged female rats, which were sedentary, estrogen deficient, or both. The rats were either forced to remain in a sitting position or allowed to walk in standard cages with or without ALN administration. The 8-week experimental period began 5 weeks after ovariectomy or sham surgery. Parameters of the hindlimb bones were determined by a three-point bending test, peripheral quantitative computed tomography, microfocus computed tomography, confocal laser Raman microspectroscopy, and dynamic histomorphometry. Regardless of ovariectomy, ALN was ineffective against the deterioration of breaking stress caused by sitting even though the trabecular bone mineral density was significantly higher in the sitting-ALN groups. Toughness was significantly deficient in the ovariectomy sitting-ALN group. This was in agreement with the bone geometry with a greater marrow space. Sitting also increased the mineral-to-matrix ratio and the carbonate-to-phosphate ratio, both indicative of aged bone. A greater loss of proteinaceous amide intensity compared with mineral intensity resulted in an increased mineral-to-matrix ratio in the presence of ALN. Sitting resulted in deficits in the quality and the geometry of cortical bone, resulting in fragility. The use of bisphosphonates, such as ALN, may provide a therapy best suited for osteoporotic individuals whose daily activity is not limited.

High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides.

The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.

Expected possible selves and coping skills among young and middle-aged adults with bipolar disorder.

OBJECTIVES: This qualitative study explored expected possible selves and coping skills among young and middle-aged adults with bipolar disorder in Hong Kong. Disruptive or positive experiences associated with bipolar disorder can shape the development of the sense of possible selves. METHODS: Guided by narrative inquiry methodology, 14 Chinese participants (8 women; age range, 22-65 years), recruited from community mental health services and the public, were interviewed. RESULTS: Young participants (18-40 years) elaborated on their expected possible selves as they related to health, work, and family, whereas middle-aged participants (41-65 years) talked about independent possible selves. The participants used problem-focused, emotion-focused, and cultural coping methods to deal with their bipolar disorder and achieve their expected possible selves. Furthermore, the young participants expressed ambivalence towards self-help strategies to manage high mood episodes. CONCLUSIONS: This study not only improves our understanding of possible selves among young and middle-aged adults with bipolar disorder, but also provides information for designing self-help interventions. Limitations of the study along with directions for future research are discussed.

Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury.

Cisplatin (CDDP), a major chemotherapeutic agent used to treat solid tumors, is known to induce acute renal failure (ARF). The progression of tissue injury involves the coordination of inflammatory and repair responses. Interleukin-6 (IL-6) has been suggested to modulate inflammatory and repair processes in various tissue injuries. In this study, we analyzed IL-6 regulation during CDDP-induced ARF in wild-type (WT) mice and determined the pathological role of IL-6 using IL-6 knockout ((-/-)) mice. A correlation between increase in serum IL-6 level and blood urea nitrogen level was found in WT mice. Renal IL-6 expression in most proximal tubular cells and suppressor of cytokine signaling 3 (SOCS3) gene expression significantly increased in WT mice after administration of CDDP, suggesting active IL-6 signaling during CDDP-induced ARF development. Interestingly, renal dysfunction occurred soon after administration of CDDP and became more severe in IL-6(-/-) mice than that in WT mice. In contrast, the survival rate of IL-6(-/-) mice (50% at 8 days) was better than that of WT mice (10%). Induction levels of proapoptotic Bcl-2 associated X protein (Bax) in renal proximal tubular cells was significantly higher in IL-6(-/-) mice than in WT mice at 24h after CDDP injection. Levels of antiapoptotic proteins, Bcl-2 and Bcl-extra large (Bcl-x(L)), in IL-6(-/-) groups were significantly higher than those in CDDP-treated WT groups throughout the experimental period. Bax might contribute to the development of CDDP-induced ARF at 24h; however, high expression levels of Bcl-x(L) and Bcl-2 might overcome the proapoptosis signaling at 72 h in IL-6(-/-) mice. These results indicated that local and systemic elevation of IL-6 contributes to the development of CDDP-induced ARF and that IL-6 produced in renal tubular cells prevents progression of ARF at the early stage. IL-6 deficiency accelerates CDDP-induced ARF but not development of systemic injury.

Successful treatment of patients with rheumatic disorders and acquired factor VIII inhibitors with cyclophosphamide and prednisolone combination therapy: two case reports.

Acquired haemophilia associated with autoimmune disorders can be fatal and has been reported to be refractory to steroid therapy alone. We report two cases of female patients, aged 24 years and 54 years, with acquired haemophilia caused by factor VIII inhibitors. Underlying diseases were systemic lupus erythematosus in the 24-year-old patient and rheumatoid arthritis in the 54-year-old patient. Both conditions were nearly quiescent when the patients manifested haemorrhagic diathesis. In response to combination therapy with prednisolone and cyclophosphamide, coagulation abnormalities were resolved together with complete elimination of factor VIII inhibitors in both patients. Thus, combination therapy with alkylating agents may be recommended as initial therapy for the management of autoimmune patients with factor VIII inhibitors.

Acquired hemophilia A in a patient with systemic lupus erythematosus.

A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical.

Induction and catabolite repression mechanisms of cellulase in fungi.

Cellulases are induced in most of fungi only when cellulose or an inducer exists. In Hypocrea jecorina and Penicillium purpurogenum, the respective inducers are sophorose and gentiobiose, which do not have beta-1,4 linkages though cellobiose, which has this linkage, is an inducer in other fungi. beta-Glucosidase, which catalyzes transglucosylation, is the key enzyme in converting cello-oligosaccharides to the inducers for cellulase induction in H. jecorina and P. purpurogenum. There are three states in the regulation of cellulase at the transcriptional level in fungi: expression at a basal level, mass secretion of cellulases induced by inducers, and glucose or catabolite repression. Expression at a basal level allows a small amount of cellulase to hydrolyze cellulose to soluble oligosaccharides or to an inducer if cellulose exists near the mycelia. Once the inducer enters the cell, it triggers full-scale transcription of the cellulase gene mediated by activator proteins and activating elements. After cellulose is degraded a large amount of glucose is liberated, which causes catabolite repression.

Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].

We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.

Novel inhibitors of AP-1 and NF-kappaB mediated gene expression: structure-activity relationship studies of ethyl 4-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-2-(trifluoromethyl)++ +pyrimidi ne-5-carboxylate.

In an effort to identify novel inhibitors of AP-1 and NF-kappaB mediated transcriptional activation, several analogues of ethyl 4-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-2-(trifluoromethyl)pyr imidine-5-carboxylate (1) were synthesized and tested in two in vitro assays. The 2-(2'-thienyl) substituted compound (11) was identified as the most potent in this series.

Factor VII R110C: a novel missense mutation (Arg110Cys) in the second epidermal growth factor-like domain causing factor VII deficiency in members of a Japanese family.

This report describes the findings of a genetic analysis of the factor VII (FVII) gene in a Japanese, male patient with FVII deficiency. The proband showed FVII activity level of 25% and FVII antigen level of 28% of the normal value, but he had no severe bleeding episodes. We identified the mutation by direct sequencing of polymerase chain reaction products representing all exons except 1b and their flanking intronic regions of his FVII gene. We detected a single point mutation, a C-->T substitution at nucleotide position 7863 in exon 5, which results in an amino acid replacement of Arg (CGC) to Cys (TGC) at codon 110 in the second epidermal growth factor-like domain. Homozygosity was confirmed in the propositus by loss of a site for the restriction endonuclease Eco47III. Furthermore, his parents, who had moderately reduced levels of factor VII activity and antigen, carried this mutation site as a heterozygote. Although the Arg11O residue is located distal to the tissue factor (TF) in the soluble TF-FVIIa crystal structure, we infer that the replacement of the positively charged and larger Arg residue with a neutral Cys residue may be likely to impair proper folding, resulting in destabilization of the protein structure.

Hyoid position, pharyngeal airway and head posture in relation to relapse after the mandibular setback in skeletal Class III.

This study evaluates the process of relapse after mandibular setback surgery by an analysis of the role of craniofacial morphology, hyoid position, pharyngeal airway and head posture. Subjects examined were 62 patients who received the sagittal split ramus osteotomies (SSRO). Changes of the craniofacial and related structures were evaluated from the serial cephalograms up to 3 years after the surgery. Results indicated that mandibular relapse represented by Pg occurred mostly within 6 months after the surgery. A net setback of the mandible was 9.1 mm and the superior move was 1.7 mm, with a reduction of 7.2 mm in mandibular length, 4.2 mm in ramus height, 3.7 mm in posterior face height, 2.6 degrees in gonial angle, an increase of 2.9 degrees in mandibular plane angle (MPA) by the last examination. Hyoid bone moved backward and downward and head posture was raised. The forward relapse of Pg was correlated with the changes of ANB, MPA, ramus height and hyoid position. Only hyoid position was predictably correlated with mandibular morphology and head posture. These findings suggest that mandibular setback alters the relationship among the hyoid position, pharyngeal airway and the head posture. It might be critical, therefore, relapse is closely monitored and controlled before the full healing of fragments and new muscular balance is established.

Hyoid position, pharyngeal airway and head posture in relation to relapse after the mandibular setback in skeletal Class III.

This study evaluates the process of relapse after mandibular setback surgery by an analysis of the role of craniofacial morphology, hyoid position, pharyngeal airway and head posture. Subjects examined were 62 patients who received the sagittal split ramus osteotomies (SSRO). Changes of the craniofacial and related structures were evaluated from the serial cephalograms up to 3 years after the surgery. Results indicated that mandibular relapse represented by Pg occurred mostly within 6 months after the surgery. A net setback of the mandible was 9.1 mm and the superior move was 1.7 mm, with a reduction of 7.2 mm in mandibular length, 4.2 mm in ramus height, 3.7 mm in posterior face height, 2.6 degrees in gonial angle, an increase of 2.9 degrees in mandibular plane angle (MPA) by the last examination. Hyoid bone moved backward and downward and head posture was raised. The forward relapse of Pg was correlated with the changes of ANB, MPA, ramus height and hyoid position. Only hyoid position was predictably correlated with mandibular morphology and head posture. These findings suggest that mandibular setback alters the relationship among the hyoid position, pharyngeal airway and the head posture. It might be critical, therefore, relapse is closely monitored and controlled before the full healing of fragments and new muscular balance is established.

Developments in solution-phase combinatorial chemistry.

The use of solution-phase parallel synthesis as a means of producing libraries of compounds for lead discovery and optimization has increased steadily. More emphasis has been placed on the development of techniques that are applicable across a range of structures and chemistries. In addition, the techniques have been developed with a medicinal chemistry focus and therefore, can be used by a wide range of chemists in standard laboratory settings. This review highlights some of the developments over the last 12 to 18 months, including the use of multi-component reactions and high-throughput purification. New chemistry that may be applicable to parallel synthesis, useful scavenging techniques, and the combination of several polymer-bound reagents or applications.

2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3',5'- bis(trifluoromethyl)phenyl)-carboxamide: a potent inhibitor of NF-kappa B- and AP-1-mediated gene expression identified using solution-phase combinatorial chemistry.

Described is the identification of a novel series of compounds that blocks the activation of two key transcription factors, AP-1 and NF-kappa B. These transcription factors regulate the expression of several critical proinflammatory proteins and cytokines and represent attractive targets for drug discovery. Through the use of high throughput screening and solution-phase parallel synthesis, inhibitors of both NF-kappa B and AP-1 were identified. In subsequent testing, these compounds were also shown to block both IL-2 and IL-8 levels in the same cells. One of the most potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the importance of AP-1 and NF-kappa B as potential therapeutic targets. The synthesis and preliminary structure-activity relationships of these compounds is addressed.