Intragraft B cell differentiation during the development of tolerance to kidney allografts is associated with a regulatory B cell signature revealed by single cell transcriptomics.

Mouse kidney allografts are spontaneously accepted in select, fully mismatched donor-recipient strain combinations, like DBA/2J to C57BL/6 (B6), by natural tolerance. We previously showed accepted renal grafts form aggregates containing various immune cells within 2 weeks posttransplant, referred to as regulatory T cell-rich organized lymphoid structures, which are a novel regulatory tertiary lymphoid organ. To characterize the cells within T cell-rich organized lymphoid structures, we performed single-cell RNA sequencing on CD45+ sorted cells from accepted and rejected renal grafts from 1-week to 6-months posttransplant. Analysis of single-cell RNA sequencing data revealed a shifting from a T cell-dominant to a B cell-rich population by 6 months with an increased regulatory B cell signature. Furthermore, B cells were a greater proportion of the early infiltrating cells in accepted vs rejecting grafts. Flow cytometry of B cells at 20 weeks posttransplant revealed T cell, immunoglobulin domain and mucin domain-1+ B cells, potentially implicating a regulatory role in the maintenance of allograft tolerance. Lastly, B cell trajectory analysis revealed intragraft differentiation from precursor B cells to memory B cells in accepted allografts. In summary, we show a shifting T cell- to B cell-rich environment and a differential cellular pattern among accepted vs rejecting kidney allografts, possibly implicating B cells in the maintenance of kidney allograft acceptance.

Novel intragraft regulatory lymphoid structures in kidney allograft tolerance.

Intragraft events thought to be relevant to the development of tolerance are here subjected to a comprehensive mechanistic study during long-term spontaneous tolerance that occurs in C57BL/6 mice that receive life sustaining DBA/2 kidneys. These allografts rapidly develop periarterial Treg-rich organized lymphoid structures (TOLS) that form in response to class II but not to class I MHC disparity and form independently of lymphotoxin α and lymphotoxin ß receptor pathways. TOLS form in situ in the absence of lymph nodes, spleen, and thymus. Distinctive transcript patterns are maintained over time in TOLS including transcripts associated with Treg differentiation, T cell checkpoint signaling, and Th2 differentiation. Pathway transcripts related to inflammation are expressed in early stages of accepted grafts but diminish with time, while B cell transcripts increase. Intragraft transcript patterns at one week posttransplant distinguish those from kidneys destined to be rejected, that is, C57BL/6 allografts into DBA/2 recipients, from those that will be accepted. In contrast to inflammatory tertiary lymphoid organs (iTLOs) that form in response to chronic viral infection and transgenic Lta expression, TOLS lack high endothelial venules and germinal centers. TOLS represent a novel, pathogenetically important type of TLO that are in situ markers of regulatory tolerance.

Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance.

Tolerance of mouse kidney allografts arises in grafts that develop regulatory Tertiary Lymphoid Organs (rTLOs). scRNAseq data and adoptive transfer of alloreactive T cells post-transplant showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required since adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance since renal allotransplantation into CD8 KO recipients resulted in acceptance and not rejection. Analysis of scRNAseq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters and trajectory analysis showed that cytotoxic CD8+ T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call "defensive tolerance." This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.

Atypical antipsychotics for psychosis in adolescents.

BACKGROUND: Schizophrenia often presents in adolescence, but current treatment guidelines are based largely on studies of adults with psychosis. Over the past decade, the number of studies on treatment of adolescent-onset psychosis has increased. The current systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis. OBJECTIVES: To investigate the effects of atypical antipsychotic medications in adolescents with psychosis. We reviewed in separate analyses various comparisons of atypical antipsychotic medications with placebo or a typical antipsychotic medication or another atypical antipsychotic medication or the same atypical antipsychotic medication but at a lower dose. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Register (October 2011), which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies and contacted study authors and relevant pharmaceutical companies to ask for more information. SELECTION CRITERIA: We included all relevant randomised controlled trials (RCTs) that compared atypical antipsychotic medication with placebo or another pharmacological intervention or with psychosocial interventions, standard psychiatric treatment or no intervention in children and young people aged 13 to 18 years with a diagnosis of schizophrenia, schizoaffective disorder, acute and transient psychoses or unspecified psychosis. We included studies published in English and in other languages that were available in standardised databases. DATA COLLECTION AND ANALYSIS: Review authors AK and SSD selected the studies, rated the quality of the studies and performed data extraction. For dichotomous data, we estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model. When possible, for binary data presented in the 'Summary of findings' table, we calculated illustrative comparative risks. We summated continuous data using the mean difference (MD). Risk of bias was assessed for included studies. MAIN RESULTS: We included 13 RCTs, with a total of 1112 participants. We found no data on service utilisation, economic outcomes, behaviour or cognitive response. Trials were classified into the following groups. 1. Atypical antipsychotics versus placebo: Only two studies compared one atypical antipsychotic medication with placebo. In one study, the number of non-responders treated with olanzapine was not different from the number treated with placebo (1 RCT, n = 107, RR 0.84, 95% CI 0.65 to 1.10); however, significantly more (57% vs 32%) people left the study early (1 RCT, n = 107, RR 0.56, 95% CI 0.36 to 0.87) from the placebo group compared with the olanzapine group. With regard to adverse effects, young people treated with aripiprazole had significantly lower serum cholesterol compared with those given placebo (1 RCT, n = 302, RR 3.77, 95% CI 1.88 to 7.58). 2. Atypical antipsychotics versus typical antipsychotics: When the findings of all five trials comparing atypical antipsychotic medications with a typical antipsychotic medication were collated, no difference in the mean end point Brief Psychiatric Rating Scale (BPRS) score was noted between the two arms (5 RCTs, n = 236, MD -1.08, 95% CI -3.08 to 0.93). With regard to adverse effects, the mean end point serum prolactin concentration was much higher than the reference range for treatment with risperidone, olanzapine and molindone in one of the studies. However, fewer adolescents who were receiving atypical antipsychotic medications left the study because of adverse effects (3 RCTs, n = 187, RR 0.65, 95% CI 0.36 to 1.15) or for any reason (3 RCTs, n = 187, RR 0.62, 95% CI 0.39 to 0.97).3. One atypical antipsychotic versus another atypical antipsychotic: The mean end point BPRS score was not significantly different for people who received risperidone compared with those who received olanzapine; however, the above data were highly skewed. Overall no difference was noted in the number of people leaving the studies early because of any adverse effects between each study arm in the three studies comparing olanzapine and risperidone (3 RCTs, n = 130, RR 1.15, 95% CI 0.44 to 3.04). Specific adverse events were not reported uniformly across the six different studies included in this section of the review; therefore it was difficult to do a head-to-head comparison of adverse events for different atypical antipsychotic medications.4. Lower-dose atypical antipsychotic versus standard/higher-dose atypical antipsychotic: Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/higher doses of the same medication. One study reported better symptom reduction with a standard dose of risperidone as compared with a low dose (1 RCT, n = 257, RR -8.00, 95% CI -13.75 to -2.25). In another study, no difference was reported in the number of participants not achieving remission between the group receiving 10 mg/d and those who received 30 mg/d of aripiprazole (1 RCT, n = 196, RR 0.84, 95% CI 0.48 to 1.48). Similarly in the other study, authors reported no statistically significant difference in clinical response between the two groups receiving lower-dose (80 mg/d) and higher-dose (160 mg/d) ziprasidone, as reflected by the mean end point BPRS score (1 RCT, n = 17, MD -4.40, 95% CI -19.20 to 10.40). AUTHORS' CONCLUSIONS: No convincing evidence suggests that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis. However, atypical antipsychotic medications may be more acceptable to young people because fewer symptomatic adverse effects are seen in the short term. Little evidence is available to support the superiority of one atypical antipsychotic medication over another, but side effect profiles are different for different medications. Treatment with olanzapine, risperidone and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidaemia. Adolescents may respond better to standard-dose as opposed to lower-dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trials should ensure uniform ways of reporting.

Adolescent suicide: characterizing the need and identifying the predictive factors for preventive consultation or hospitalization in a rural community setting.

BACKGROUND: Studies from India consistently document the highest suicide rates in the world, and the majority of completed suicides had been within adolescents. OBJECTIVE: To characterize the need and identify the predictive factors for preventive consultation or hospitalization for adolescent suicide in a community setting. SUBJECTS: We prospectively collected data from 500 adolescents in a rural South Indian community with independent, trained raters. METHODS: The need for suicide prevention was measured with the SAD PERSONS scale, socio-economic status with the Modified Kuppusamy Scale, depression and anxiety disorders with the Beck Depression Inventory and the Screen for Child Anxiety Related Emotional Disorders, respectively. The relationship between predictors and the need for preventive action was analyzed with univariate and multivariate regression analyses and a predictive model was built. RESULTS: Of those investigated, 2% and 0.6% required emergency consultation and hospitalization, respectively. Males needed more preventive action (p=0.04). Age (OR=3.40, p=0.07), gender (OR=3.13, p=0.05), presence of anxiety (OR=16.35, p=0.001), or depressive (OR=42.59, p=0.001) disorder independently predicted a need for protective action and, together, contributed to a parsimonious predictive model. CONCLUSIONS: The majority of adolescents in the community do not require preventive steps to address suicide risk. These predictors could identify the high-risk adolescents for suicide prevention and reduce the burden of care in the community.

Feeding Difficulties Among Children With Special Needs: A Cross-Sectional Study From India.

Deficits in feeding can lead to impairments in occupational performance for children with special needs. This correlational study assessed the relationship between oromotor deficits, behavior problems related to feeding, and caregiver perception of the behavior in children with special needs. We included children with neurodevelopmental disorders (n=79), between 2 and 12 years of chronological age, and their caregivers. Those fulfilling the selection criteria were administered the Behavioral Pediatric Feeding Assessment Scale (BPFAS) and Schedule for Oromotor Assessment (SOMA). More than half the sample had skill deficits and behavioral problems related to feeding. There was a statistically significant correlation of oromotor deficits with specific food consistencies and feeding-related behavior problems. Children with special needs have impaired participation in feeding. Deficits at the body system level are associated with parental and cultural factors, which would have to be mitigated to optimize performance.

Early acceptance of renal allografts in mice is dependent on foxp3(+) cells.

Mouse renal allografts have a remarkable ability to promote acceptance across full major histocompatibility complex incompatibilities in certain strain combinations without immunosuppression. The mechanism is unknown but is believed to involve immunoregulation. This study tests whether Foxp3(+) T-regulatory cells are responsible in the early phase of graft acceptance, using B6.Foxp3(DTR) mice that express diphtheria toxin receptor (DTR) in Foxp3(+) cells. The administration of DT to B6.Foxp3(DTR) recipients with accepted DBA/2 kidneys, 3 weeks to 3 months after transplantation, caused a marked depletion of Foxp3 cells and triggered acute cellular rejection, manifested by a sudden increase in blood urea nitrogen within a week. None of the controls showed an increase in blood urea nitrogen, including DT-treated B6 wild-type recipients of DBA/2 kidneys or B6.Foxp3(DTR) recipients of isografts. Accepted DBA/2 allografts showed prominent lymphoid sheaths around arteries containing numerous CD3(+)Foxp3(+) cells, CD4(+) cells, dedritic cells, and B cells, which was independent of CCR4. The lymphoid sheaths disintegrate after Foxp3 depletion, accompanied by widespread CD8 interstitial mononuclear inflammation, tubulitis, and endarteritis. The Foxp3 depletion caused an increased frequency of donor-reactive cells in the spleen by interferon (IFN) γ enzyme-linked immunosorbent spot (ELISPOT) assays and increased expression of the maturation markers, CD86 and IA(b), on dendritic cells in the spleen and kidney. We conclude that Foxp3(+) cells are needed to maintain acceptance of major histocompatibility complex-incompatible renal allografts in the first 3 months after transplantation and may act by inhibiting DC maturation.

Kidney-induced systemic tolerance of heart allografts in mice.

In swine and nonhuman primates, kidney allografts can induce tolerance of heart allografts, leading to their long-term, immunosuppression-free survival. We refer to this phenomenon as kidney-induced cardiac allograft tolerance (KICAT). In this study, we have developed a murine model for KICAT to determine the underlining cellular/molecular mechanisms. Here, we show that spontaneously accepted DBA/2J kidneys in C57BL/6 recipients induce systemic tolerance that results in the long-term acceptance of DBA/2J heart allografts but not third-party cardiac allografts. The state of systemic tolerance of hearts was established 2 weeks after transplantation of the kidney, after which time, the kidney allograft is no longer required. Depletion of Foxp3+ T cells from these mice precipitated rejection of the heart allografts, indicating that KICAT is dependent on Treg function. Acceptance of kidney allografts and cotransplanted heart allografts did not require the thymus. In conclusion, these data show that kidney allografts induce systemic, donor-specific tolerance of cardiac allografts via Foxp3 cells, and that tolerance is independent of the thymus and continued presence of the kidney allograft. This experimental system should promote increased understanding of the tolerogenic mechanisms of the kidney.

Plasmacytoid Dendritic Cell-driven Induction of Treg Is Strain Specific and Correlates With Spontaneous Acceptance of Kidney Allografts.

BACKGROUND: DBA/2J kidney allografts, but not heart allografts, are spontaneously accepted indefinitely in C57BL/6 (B6) mice, through regulatory tolerance mechanism dependent on Foxp3 cells. In contrast, B6 kidneys are rejected within a week in DBA/2J recipients. We hypothesized that the tolerogenic difference of the kidneys might be due to differences in number or function of plasmacytoid dendritic cells (pDCs), because these cells are potent inducers of Foxp3 cells. METHODS: pDCs from murine bone marrow, native kidneys, and spontaneously accepted kidney allografts were analyzed using flow cytometry and immunohistochemical staining. Naive T cells were cocultured with pDCs in specific strain combinations and analyzed for FoxP3 induction and functionality. MEK/ERK and NFκB inhibitors were used to assess the regulatory T-cell induction pathways. pDCs and T-cell cultures were adoptively transferred before heterotopic heart transplantation to assess allograft survival. RESULTS: DBA/2J pDCs were more potent in inducing Foxp3 in B6 T cells than the reverse combination, correlating with survival of the kidney allografts. Foxp3 induction by pDCs in vitro was dependent on pDC viability, immaturity, and class II MHC mismatch and blocked by MEK/ERK and NFκB inhibition. pDC-induced Foxp3 T cells suppressed proliferation of B6 T cells in vitro, and adoptive transfer into B6 recipients 2 weeks before heterotopic DBA/2J heart transplantation resulted in prolonged allograft survival. CONCLUSIONS: These data suggest that pDC-induced regulatory T cells are dependent on downstream signaling effects and on strain-dependent, MHC class II disparity with naive T cells, which may explain organ- and strain-specific differences in spontaneous tolerance.

Predictive components in the structure of an intensive, parent mediated, early intervention for children with autism spectrum disorders in India.

INTRODUCTION: The predictive factors of parent mediated, Early Intervention (EI) for children with Autism Spectrum Disorders (ASD) have not been studied in India; we document the structural therapeutic factors, which predict the EI outcome. METHODS: Data of 77 children with an ICD 10 diagnosis of Pervasive Developmental Disorder (ASD in DSM 5), and completed a 12-week EI with proven effectiveness was collected from the database of a teaching hospital. We studied the structural therapeutic factors associated with EI outcome, as measured by Psycho-Educational Profile-Revised (PEP-R), while controlling the confounders with multiple linear regression analyses. RESULTS: The Fine-motor skills improved in residential patients (t = 2.54, P = 0.02; 15 units). As the duration of intervention decreased at home per day, there was a significant decrease in Gross-motor skills (t = -2.67, P = 0.02; -15 units). With increase in duration of intervention in hospital per day, there was a significant increase (t = 2.86, P = 0.01; 30 units) in the Eye-hand integration. Cognitive-verbal skills acquisition decreased (t = -2.90, P = 0.01; 33 units) as the duration of intervention decreased at hospital. The use of medication did not predict any of the outcome factors. CONCLUSION: The above mentioned predictive factors should be monitored and titrated in the family context when children with ASD undergo parent mediated, EI programme. It is important to that the multidisciplinary family medicine teams reinforce these parents, who are the main column of support in primary-care settings for children with neuro-developmental disabilities in India.

The clinical usefulness of three depression screens for adolescents in India: A need in primary-care settings.

INTRODUCTION: Adolescent Depression (AD) although is widely prevalent and is a prioritized disorder, it is under-diagnosed and under reported in primary-care. We document the post-test probability of three measures and select the best measure for identifying AD in primary-care settings in India based on the clinical utility. MATERIALS AND METHODS: Three measures have been validated in India for AD and thus can be further evaluated for primary-care use; we calculated the positive (+PTP) and negative (-PTP) post-test probability from the prevalence of AD in India for Beck Depression Inventory-21 item version (BDI-21), Patient Health Questionnaire-9 item version (PHQ-9), and Children's Depression Rating Scale-Revised version (CDRS-R) using the Bayes theorem. The usefulness of the measure was defined a priori based on the odds ratio (OR) of +PTP (OR > 3) and -PTP (OR < 0.1). RESULTS: The +PTP and -PTP for BDI-21 was 43% (95%CI = 40, 45%; OR = 0.7) and 25% (95%CI = 13, 43%; OR = 0.3) respectively. Similarly, the +PTP and - PTP for PHQ-9 was 74% (95%CI = 66, 81%; OR = 2.9) and 10% (95%CI = 6, 17%; OR = 0.1). Finally, +PTP and - PTP for CDRS-R was 78% (95%CI = 69, 84%; OR = 3.5) and 12% (95%CI = 7, 18%; OR = 0.1). Only CDRS-R achieved the useful decided a priori as can be seen in the Fagan's Nomograms. CONCLUSION: This research provides the evidence base for selecting CDRS-R as the screening measure, for Adolescent Depression, for clinical use in Primary-care settings in India.

The changing role of natural killer cells in solid organ rejection and tolerance.

Natural killer (NK) cells have emerged as a particular focus of interest in transplantation due to their ability to distinguish allogeneic major histocompatibility complex (MHC) antigens and their potent cytolytic effector mechanisms. Once relegated to the field of bone marrow transplantation, NK cells have recently been shown to participate in the immune response against solid organ allo- and xenografts. These new findings suggest that the role of NK cells in solid organ rejection and tolerance needs to be reexamined.

Predictive factors for polypharmacy among child and adolescent psychiatry inpatients.

BACKGROUND: Aim was to determine the predictive factors for polypharmacy among inpatient children and adolescents with psychiatric disorders. METHODS: Blinded, case-note review of children and adolescents with ICD 10 diagnosis of psychiatric disorders on psychotropic medication was conducted. Data on demography, illness, and treatment was analyzed with univariate and multivariate techniques. RESULTS: Proscribing non-pharmacological interventions (OR = 4.7) and pro re nata medication (OR = 3.3), increased the risk of polypharmacy. Prescribing physical restraint reduced the risk of receiving multiple medications (OR = 0.3). CONCLUSION: Proscribing non-pharmacological interventions, pro re nata medication and physical restraints increased polypharmacy.

Evidence base for using atypical antipsychotics for psychosis in adolescents.

Atypical antipsychotic medications have been the first line of treatment for adolescents with psychosis in the past couple of decades. Till the late 90s, there were very few randomized controlled trials (RCTs) on the treatment of adolescents with psychosis, although a fifth of schizophrenia starts during adolescence. Most of the treatment guidelines for adolescents with psychosis were derived from data on adults. In the past 10 years, there has been increasing number of studies on adolescents with psychosis. The current paper summarizes the findings of trials on adolescents with psychosis in 4 groups: (a) atypical antipsychotic medications vs placebo, (b) atypical antipsychotic medication vs typical antipsychotic medications, (c) one atypical antipsychotic medication vs another atypical antipsychotic medication, and (d) Low dose vs standard dose of atypical antipsychotic medication. We included 13 RCTs, with a total of 1112 participants. Although our review suggest that atypical antipsychotic medications are as effective as typical antipsychotic medications as regards clinical efficacy, atypical antipsychotic medications have a preferred side effect profile and lesser drop-out rate from trials. Obviously, this is extremely important as treatment adherence is key to successful remission of psychotic symptoms and also in some case prevent relapse of illness. Treatment with olanzapine, risperidone, and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidemia. Adolescents may respond better to standard-dose as opposed to lower dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trial should be longer term and have uniform ways of reporting side effects.

Depletion of T regulatory cells promotes natural killer cell-mediated cardiac allograft vasculopathy.

BACKGROUND: A role for natural killer (NK) cells in cardiac allograft vasculopathy (CAV) was suggested by our earlier observation that CAV arises even in the absence of detectable antidonor T-cell or B-cell reactivity in parental to F1 mouse heart grafts. However, prevention of CAV in this setting required the depletion of both NK and CD4 T cells. METHODS: To clarify the interrelationship between NK and CD4 cells, we analyzed early events and selective depletion of T regulatory cells (Tregs). Hearts from C57BL/6 (B6) donors were transplanted heterotopically into BALB/c x C57BL/6 (CB6F1) recipients and NK cells, CD4 T cells, and Tregs were depleted with anti-NK1.1 (PK136), anti-CD4 (GK1.5), or anti-CD25 (PC61), respectively. RESULTS: In contrast to prior studies in which the prevention of CAV at 8 weeks required the codepletion of NK and CD4 T cells, NK cells depletion alone eliminated CAV at 3 weeks. Furthermore, depletion of CD25 cells accelerated the onset and maturation of CAV at both 2 and 3 weeks (P<0.02 and P<0.001, respectively). However, anti-NK1.1 treatment prevented lesions in CD25-depleted recipients. Finally, CD4 T cell depletion alone did not prevent or accelerate development of CAV but inhibited the effect of CD25 T cell depletion. CONCLUSION: These data suggest that NK cells can play an important role in the early pathogenesis of CAV but that their ability to mediate early CAV can be modulated by Tregs.

INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD): development and validation.

OBJECTIVE: To develop and validate INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD). DESIGN: Diagnostic test evaluation by cross sectional design. SETTING: Four tertiary pediatric neurology centers in Delhi and Thiruvanthapuram, India. METHODS: Children aged 2-9 years were enrolled in the study. INDT-ASD and Childhood Autism Rating Scale (CARS) were administered in a randomly decided sequence by trained psychologist, followed by an expert evaluation by DSM-IV TR diagnostic criteria (gold standard). MAIN OUTCOME MEASURES: Psychometric parameters of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. RESULTS: 154 children (110 boys, mean age 64.2 mo) were enrolled. The overall diagnostic accuracy (AUC=0.97, 95% CI 0.93, 0.99; P<0.001) and validity (sensitivity 98%, specificity 95%, positive predictive value 91%, negative predictive value 99%) of INDT-ASD for Autism spectrum disorder were high, taking expert diagnosis using DSM-IV-TR as gold standard. The concordance rate between the INDT-ASD and expert diagnosis for 'ASD group' was 82.52% [Cohen's k=0.89; 95% CI (0.82, 0.97); P=0.001]. The internal consistency of INDT-ASD was 0.96. The convergent validity with CARS (r = 0.73, P= 0.001) and divergent validity with Binet-Kamat Test of intelligence (r = -0.37; P=0.004) were significantly high. INDT-ASD has a 4-factor structure explaining 85.3% of the variance. CONCLUSIONS: INDT-ASD has high diagnostic accuracy, adequate content validity, good internal consistency high criterion validity and high to moderate convergent validity and 4-factor construct validity for diagnosis of Autistm spectrum disorder.

INCLEN diagnostic tool for attention deficit hyperactivity disorder (INDT-ADHD): development and validation.

OBJECTIVE: To develop and validate INCLEN Diagnostic Tool for Attention Deficit Hyperactivity Disorder (INDT-ADHD). DESIGN: Diagnostic test evaluation by cross sectional design. SETTING: Tertiary care pediatric centers. PARTICIPANTS: 156 children aged 65-117 months. METHODS: After randomization, INDT-ADHD and Connors 3 Parent Rating Scale (C3PS) were administered, followed by an expert evaluation by DSM-IV-TR diagnostic criteria. MAIN OUTCOME MEASURES: Psychometric evaluation of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. RESULTS: INDT-ADHD had 18 items that quantified symptoms and impairment. Attention deficit hyperactivity disorder was identified in 57, 87 and 116 children by expert evaluation, INDT-ADHD and C3PS, respectively. Psychometric parameters of INDT-ADHD for differentiating attention deficit hyperactivity disorder and normal children were: sensitivity 87.7%, specificity 97.2%, positive predictive value 98.0% and negative predictive value 83.3%, whereas for differentiating from other neuro-developmental disorders were 87.7%, 42.9%, 58.1% and 79.4%, respectively. Internal consistency was 0.91. INDT-ADHD has a 4-factor structure explaining 60.4% of the variance. Convergent validity with Conner's Parents Rating Scale was moderate (r =0.73, P= 0.001). CONCLUSIONS: INDT-ADHD is suitable for diagnosing attention deficit hyperactivity disorder in Indian children between the ages of 6 to 9 years.

Menstrual irregularity and poly cystic ovarian syndrome among adolescent girls--a 2 year follow-up study.

OBJECTIVE: To study the clinical outcome after a gap of 2 years, among adolescent girls with confirmed menstrual irregularity and with or without ultrasound diagnosed polycystic ovaries. METHODS: 136 adolescent girls from a cohort of 301 girls between 15 and 17 years of age with confirmed menstrual irregularity, with or without ultrasound diagnosed polycystic ovaries, were assessed in detail after a gap of 2 years. Present menstrual history and symptoms as well as signs of polycystic ovary syndrome (PCOS) were recorded, apart from ultrasound scanning of abdomen. PCOS was diagnosed using Rotterdam's consensus criteria and a comparative analysis was done among cases with and without PCOS. RESULTS: In the phase-II study done after a gap of 2 years, there was a statistically significant lower percentage of irregularities in menses, acne and enlarged thyroid, but a statistically significant increase in hirsuitism as compared to Phase-I study. Of the 136 cases reported, 36.0% cases were found to have PCOS and 63.9% cases were normal. Comparison of the two groups showed a statistically significant higher percentage difference in prevalence of irregular menses (59.9%), hirsuitism (56.3%), acne (17.8%), obesity (17.3%), polycystic ovaries on ultrasound (47.8%) and clinical hyperandrogenism (56.1%) among those with PCOS as against those without PCOS. CONCLUSIONS: The results of this study support screening for menstrual irregularity, obesity and signs of clinical hyperandrogenism for early diagnosis of PCOS in an effort to improve the reproductive health of adolescent girls.

Role of complement and NK cells in antibody mediated rejection.

Despite extensive research on T cells and potent immunosuppressive regimens that target cellular mediated rejection, few regimens have been proved to be effective on antibody-mediated rejection (AMR), particularly in the chronic setting. C4d deposition in the graft has been proved to be a useful marker for AMR; however, there is an imperfect association between C4d and AMR. While complement has been considered as the main player in acute AMR, the effector mechanisms in chronic AMR are still debated. Recent studies support the role of NK cells and direct effects of antibody on endothelium cells in a mechanism suggesting the presence of a complement-independent pathway. Here, we review the history, currently available systems and progress in experimental animal research. Although there are consistent findings from human and animal research, transposing the experimental results from rodent to human has been hampered by the differences in endothelial functions between species. We briefly describe the findings from patients and compare them with results from animals, to propose a combined perspective.