Interleukin-6 blockade with tocilizumab increases Tregs and reduces T effector cytokines in renal graft inflammation: A randomized controlled trial.

Interleukin-6 (IL-6) is a proinflammatory cytokine and key regulator of Treg: T effector cell (Teff) balance. We hypothesized that IL-6 blockade with tocilizumab, a monoclonal antibody to IL-6R, would increase Tregs, dampen Teff function, and control graft inflammation. We conducted a randomized controlled clinical trial (2014-2018) of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first year posttransplant. Subjects received tocilizumab (8 mg/kg IV every 4 weeks; 6 doses; n = 16) or no treatment (controls; n = 14) on top of usual maintenance immunosuppression. Kidney biopsies pre- and post-treatment were analyzed using Banff criteria. Blood was analyzed for serum cytokines, Treg frequencies, and T cell effector molecule expression (IFN-γ, IL-17, granzyme B) post-stimulation ex vivo. Tocilizumab-treated subjects were more likely to show improved Banff ti-score (62.5% vs. 21.4%, p = .03), increased Treg frequency (7.1% ± 5.55% vs. 3.6% ± 1.7%, p = .0168), and a blunted Teff cytokine response compared to controls. Changes in Banff i- and t-scores were not significantly different. The treatment was relatively well tolerated with no patient deaths or graft loss. Blockade of IL-6 is a novel and promising treatment option to regulate the T cell alloimmune response in kidney transplant recipients. NCT02108600.

Identifying a potential biomarker for primary focal segmental glomerulosclerosis and its association with recurrence after transplantation.

BACKGROUND: We investigated circulating levels of individual soluble urokinase plasminogen activation receptor (suPAR) forms to determine if specific circulating fragments of suPAR (II-III) and (I) can better serve as clinical biomarkers for focal segmental glomerulosclerosis (FSGS) and the risk of recurrence after transplantation. MATERIALS AND METHODS: Serum levels of intact suPAR and its cleaved forms were measured with two assays, ELISA and TR-FIA. RESULTS: suPAR levels in healthy controls were significantly lower than those who had glomerular diseases but were not significantly different between FSGS patients and glomerular controls. Intact suPAR (I-II-III) levels were noted to be elevated in glomerular diseases including FSGS. uPAR fragment (I) levels measured with the TR-FIA 4 assay were significantly higher in FSGS (695.4 + 91.29 pMol/L) than glomerular controls (239.1 + 40.45 pMol/L, P = 0.001). However, suPAR(I) levels were not significantly different between recurrent FSGS and nonrecurrent FSGS patients. CONCLUSION: Our analysis of suPAR using the ELISA assay used in all previous studies does not appear to be a useful marker for FSGS nor serve as a predictor for its recurrence after transplantation. The TR-FIA assay results suggest that uPAR(I) is a potential biomarker for FSGS but not of its recurrence.

Altered balance between effector T cells and FOXP3+ HELIOS+ regulatory T cells after thymoglobulin induction in kidney transplant recipients.

This study examined the effect of thymoglobulin induction therapy on leukocyte population dynamics in kidney transplant patients. Patients receiving standard immunosuppression were compared with those who received additional thymoglobulin at the time of kidney transplantation. Thymoglobulin induction led to an immediate and significant decrease of all T cells and NK cells, but not B cells or monocytes. CD8(+) T cells recovered to near pretransplant level by 4 weeks post-transplant. CD4(+) T cells remained at less than 30% of pretransplant level for the entire study period of 78 weeks. Both CD4(+) and CD8(+) T cells showed reduced cytokine production after recovery. Deletion of CD4(+) FOXP3(+) HELIOS(+) regulatory T cells (Tregs) was less profound than that of CD4(+) FOXP3(-) cells, thus the relative percentage of Tregs elevated significantly when compared with pretransplant levels in thymoglobulin-treated patients. In contrast, the percentages of Tregs and their expression of FOXP3 in the standard immunosuppression group decreased steadily and by 12 weeks after transplant the average percentage of Tregs was 56% of the pretransplant level. Thus, thymoglobulin-induced deletion of T cells led to significant and long-lasting alterations of the T-cell compartment characterized by a preservation of Tregs and long-lasting reduction in CD4(+) , and potentially pathogenic, T cells.

Positive psychotherapy for psychosis in Hong Kong: A randomized controlled trial.

Recovery-oriented practice has been advocated in mental health services in Hong Kong since 2009. Well-being has become an important area of focus for mental health services. Positive Psychotherapy for Psychosis (PPP) is a well-being-focused intervention for use in psychosis, with preliminary evidence from a randomized controlled trial in the United Kingdom of impact on well-being and symptomatology. The aim of this study was to test the effectiveness of PPP on the well-being of people with psychosis in Hong Kong. The study was a randomized controlled trial with two-arm parallel groups. Both groups received treatments as usual, and in addition the intervention group received a 13-session intervention based on a Cantonese Chinese translation of the PPP manual. Intention-to-treat analysis was used. The trial was registered (ANZCTR: ACTRN12620000464965). A total of 154 participants (78 intervention, 76 control) were recruited. As compared to control group, intervention group participants showed significant changes over time on the primary outcome of well-being assessed using the Chinese Short Warwick-Edinburgh Mental Well-being Scale (p = 0.001) and on secondary outcomes of hope (Agency subscale: p = 0.029) and self-efficacy (p = 0.001). Positive Psychotherapy for Psychosis was found to be an effective treatment in improving the well-being and other mental health outcomes for people with psychosis. It can be recommended for use in mental health services to promote recovery.

Lung transplant recipients with idiopathic pulmonary fibrosis have impaired alloreactive immune responses.

BACKGROUND: Telomere dysfunction is associated with idiopathic pulmonary fibrosis (IPF) and worse outcomes following lung transplantation. Telomere dysfunction may impair immunity by upregulating p53 and arresting proliferation, but its influence on allograft-specific immune responses is unknown. We hypothesized that subjects undergoing lung transplantation for IPF would have impaired T cell proliferation to donor antigens. METHODS: We analyzed peripheral blood mononuclear cells (PBMC) from 14 IPF lung transplant recipients and 12 age-matched non-IPF subjects, before and 2 years after transplantation, as well as PBMC from 9 non-transplant controls. We quantified T cell proliferation and cytokine secretion to donor antigens. Associations between PBMC telomere length, measured by quantitative PCR, and T cell proliferation to alloantigens were evaluated with generalized estimating equation models. RESULTS: IPF subjects demonstrated impaired CD8+ T cell proliferation to donor antigens pre-transplant (p < 0.05). IL-2, IL-7, and IL-15 cytokine stimulation restored T cell proliferation, while p53 upregulation blocked proliferation. IPF subjects had shorter PBMC telomere lengths than non-IPF subjects (p < 0.001), and short PBMC telomere length was associated with impaired CD8+ T cell proliferation to alloantigens (p = 0.002). CONCLUSIONS: IPF as an indication for lung transplant is associated with short PBMC telomere length and impaired T cell responses to donor antigens. However, the rescue of proliferation following cytokine exposure suggests that alloimmune anergy could be overcome. Telomere length may inform immunosuppression strategies for IPF recipients.

Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans.

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

Facial emotion recognition in Chinese with schizophrenia at early and chronic stages of illness.

Deficits in facial emotion recognition have been recognised in Chinese patients diagnosed with schizophrenia. This study examined the relationship between chronicity of illness and performance of facial emotion recognition in Chinese with schizophrenia. There were altogether four groups of subjects matched for age and gender composition. The first and second groups comprised medically stable outpatients with first-episode schizophrenia (n=50) and their healthy controls (n=26). The third and fourth groups were patients with chronic schizophrenic illness (n=51) and their controls (n=28). The ability to recognise the six prototypical facial emotions was examined using locally validated coloured photographs from the Japanese and Caucasian Facial Expressions of Emotion. Chinese patients with schizophrenia, in both the first-episode and chronic stages, performed significantly worse than their control counterparts on overall facial emotion recognition, (P<0.001), with specific impairment in identifying surprise, fear and disgust. The level of deficit was similar at the two stages of illness. Findings suggest that impaired recognition of facial emotion did not appear to have worsened over the course of disease progression, suggesting that recognition of facial emotion is a rather stable trait of the illness. The emotion-specific deficit may have implications for understanding the social difficulties in schizophrenia.

Nuclear Factor of Activated T Cell-regulated Cytokine Gene Expression for Adjustment of Tacrolimus in Kidney Transplant Recipients: A Randomized Controlled Pilot Trial.

BACKGROUND: The aim of this pilot study was to assess the feasibility of a pharmacodynamics assay that measures Nuclear Factor of Activated T Cell-dependent cytokines expressed as % mean residual expression (MRE) to adjust tacrolimus (tac) dose (intervention [INT] arm) in comparison with the standard of care of tac trough levels (control [CTL] arm). METHODS: We conducted a single-center randomized controlled trial involving 40 stable kidney transplant recipients over 1 year. In the INT arm, the dose of tac was reduced by 15% if the MRE was less than 20% and was increased by 15% if the MRE was greater than 60%. Controls were adjusted based on tac trough levels. RESULTS: There was a median of 2 tac dose changes per arm. Ten subjects had 1 or more infections in the INT arm and 6 subjects had 1 or more infection in the CTL arm. Rates for hospitalizations, rejections, malignancies and death were similar in both arms. In subjects whose tac dose was not adjusted in the first 6 months, those with infections had a lower MRE at enrollment compared with those without infections (P = 0.049). This was not true for tac trough levels (P = 0.80). There was no correlation between MRE and rejection. CONCLUSIONS: Our study suggests that adjusting tac based on this pharmacodynamics assay is feasible. Quantitative analysis of nuclear factor of activated T-regulated gene expression may serve as a reliable assay to lower tac dosing. Further studies with larger populations are needed.

Lifetime Prevalence and Correlates of Schizophrenia-Spectrum, Affective, and Other Non-affective Psychotic Disorders in the Chinese Adult Population.

Lifetime prevalence of psychotic disorders varies widely across studies. Epidemiological surveys have rarely examined prevalences of specific psychotic disorders other than schizophrenia, and the majority used a single-phase design without employing clinical reappraisal interview for diagnostic verification. The current study investigated lifetime prevalence, correlates and service utilization of schizophrenia-spectrum, affective, and other non-affective psychotic disorders in a representative sample of community-dwelling Chinese adult population aged 16-75 years (N = 5719) based on a territory-wide, population-based household survey for mental disorders in Hong Kong. The survey adopted a 2-phase design comprising first-phase psychosis screening and second-phase diagnostic verification incorporating clinical information from psychiatrist-administered semi-structured interview and medical record review to ascertain DSM-IV lifetime diagnosis for psychotic disorders. Data on sociodemographics, psychosocial characteristics and service utilization were collected. Our results showed that lifetime prevalence was 2.47% for psychotic disorder overall, 1.25% for schizophrenia, 0.15% for delusional disorder, 0.38% for psychotic disorder not otherwise specified, 0.31% for bipolar disorder with psychosis, and 0.33% for depressive disorder with psychosis. Schizophrenia-spectrum disorder was associated with family history of psychosis, cigarette smoking and variables indicating socioeconomic disadvantage. Victimization experiences were significantly related to affective psychoses and other non-affective psychoses. Around 80% of participants with any psychotic disorder sought some kind of professional help for mental health problems in the past year. Using comprehensive diagnostic assessment involving interview and record data, our results indicate that approximately 2.5% of Chinese adult population had lifetime psychotic disorder which represents a major public health concern.

From deinstitutionalization to recovery-oriented assertive community treatment in Hong Kong: What we have achieved.

This paper explored the effectiveness of Assertive Community Treatment (ACT) for severely ill mental patients during a period of rapid deinstitutionalization in Hong Kong. We employed a flanking historical control design. The treatment group comprised 70 participants with 3 or more admissions to psychiatric hospitals within the preceding 12 months, and received ACT. Two historical control groups (C1 and C2), each 70 participants, with similar inclusion criteria flanking the recruitment period of treatment group, were identified and received Treatment as Usual (TAU). Outcome data were measured at baseline, 6, 12 and 18 months of intervention. Readmission rates, bed-days, emergency room visits and days of missing medical appointments improved with time during the deinstitutionalization process, irrespective of treatment modality. In addition, ACT had superior effect in most of these outcome parameters, compared to the control groups. We reported that the current model of ACT, with a relatively small case load per case manager, round the clock services, multidisciplinary team approach, with psychiatrists integrated in the services and case managers responsible for health and social care, is an effective intervention for helping people with mental illness who pursue their chosen independent living in the community.

Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K(+). The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.

Distinct gene expression programs function in progenitor and mature islet cells.

Homeodomain transcription factor Nkx2.2 is required for the final differentiation of the beta-cells in the pancreas and for the production of insulin. Nkx2.2 is expressed in islet cell precursors during pancreatic development and persists in a subset of mature islet cells including all beta-cells. To understand the mechanisms regulating the expression of Nkx2.2 in these different cell populations, we outlined the structure of the mouse nkx2.2 gene and identified regions that direct cell type-specific expression. The nkx2.2 gene has two noncoding alternative first exons (exons 1a and 1b). In transgenic mice, sequences upstream from exon 1a directed expression predominantly in mature islet cells. Within this exon 1a promoter, cooperative interactions between HNF3 and basic helix-loop-helix factors neurogenin-3 or NeuroD1 binding to adjacent sites played key roles in its islet cell-specific expression. In contrast, sequences upstream from exon 1b restricted expression specifically to islet cell precursors. These studies reveal distinct mechanisms for directing the expression of a key differentiation factor in precursors versus mature islet cells.

Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome.

Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha (PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe-PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.