Therapeutic plasma exchange normalizes insulin-mediated response in a child with type 1 diabetes and insulin autoimmune syndrome.

BACKGROUND: Insulin autoimmune syndrome (IAS), characterized by glycemic dysregulation and life-threatening hypoglycemia, can occur in patients with type 1 diabetes (T1D). Diagnostic confirmation is complex but important in order to ensure timely initiation of definitive therapy. AIMS: We aimed to quantitate the degree of immunoglobulin-insulin complex (IIC) formation and its effects on glycemic control in a patient with T1D and IAS compared with T1D and non-T1D controls and before and after therapeutic plasma exchange (TPE). MATERIALS & METHODS: The prospective descriptive study was conducted between June 2015 and December 2015 in a quaternary children's hospital in Brisbane, Australia. Percent Free "Immunoreactive" Insulin (%FII) as assessed by polyethylene glycol precipitation studies and its relationship to plasma glucose and serum insulin concentration. RESULTS: Samples from the patient with T1D and IAS demonstrated lower mean %FII compared to T1D (23.8 ± 2.0 vs 52.0 ± 6.7; P < .0001) and non-T1D (23.8 ± 2.0 vs 102.9 ± 2.7; P < .0001) controls. This was associated with loss of glycemic predictability and frequent severe hypoglycemia. TPE increased %FII (23.8 ± 2.0 before TPE vs 83.6 ± 2.5 after TPE, P < .0001) and reestablished plasma glucose responsiveness to exogenous insulin. DISCUSSION: IAS should be considered in T1D patients with unexplained glycemic instability and hypoglycemia. The laboratory plays an integral diagnostic role. CONCLUSION: TPE is an effective method for removing IICs and normalizing insulin-mediated glucose responses.

Comparison of weight- vs body surface area-based growth hormone dosing for children: implications for response.

OBJECTIVE: To compare weight (per kg)- vs body surface area (BSA, per m(2) )-based growth hormone (GH) dosing formats in children and to derive a useful conversion formula between the two formats. PATIENTS AND DESIGN: Growth hormone doses (>33,000) from 1874 children were obtained from the national Australian database (OZGROW) and used to derive conversion formulae and to confirm the accuracy of a conversion formula based on a weight-only BSA estimate. A further 27,000 doses were used to test the accuracy of all formulae. The best conversion formula was used to compare weight- and surface area-based GH dosing, which included an analysis of first year response (∆SDS height or growth velocity, GV). MEASUREMENTS: Growth hormone doses in mg/m(2) /wk and mg/kg/wk, dose estimates, residuals, first year ∆SDS, first year GV. RESULTS: The formula, [Formula: see text] based on a weight-only BSA estimate, provides accurate dose conversion (mean residual, 0·005 mg/kg/week). A constant mg/m(2) /week dose expressed in terms of mg/kg/week declines quickly with increasing body weight to approximately 15 kg after which the decline continues although less dramatically. For Australian patients, despite an increase in mean per m(2) dose with increased starting weight/age, the per kg dose decreased. This was associated with a greater decline in first year GV than estimated if a per kg dose had been maintained. CONCLUSIONS: Growth hormone doses can be accurately converted between formats. Surface area-based GH dosing is likely to result in a reduced height response as children become heavier when compared with weight-based GH dosing.

Smell and taste of milk during tube feeding of preterm infants: neurodevelopmental follow-up of the randomized TASTE trial, study protocol.

BACKGROUND: The Taste And Smell To Enhance nutrition (TASTE) trial investigated the effects of smell and taste of milk with tube feeding compared to routine care on the growth of preterm infants. There was no difference between groups in growth (weight, head circumference, length) z-scores at discharge from the hospital. Infants in the intervention group had higher head circumference and length z-scores at 36 weeks postmenstrual age, both secondary outcomes. The objective of this follow-up study is to assess 2-year neurodevelopmental and growth outcomes after exposure of preterm infants to the smell and taste of milk with tube feeding compared to routine care. METHODS: This is a neurodevelopmental follow-up study of a two-center, placebo-controlled randomized trial. Infants born before 29 weeks postmenstrual age and/or with a birth weight of less than 1250 g were randomized to smell and taste of milk with each tube feed or routine care. The current follow-up assessed the 2-year neurodevelopmental and growth outcomes of participants of the TASTE trial discharged from the hospital (n = 334). The primary outcome is survival free of any major neurodevelopmental impairment comprising any moderate/severe cerebral palsy (Gross Motor Function Classification System score II-V), Bayley Scales of Infant and Toddler Development, Third/Fourth Edition (Bayley-III/Bayley-4) motor, cognitive, or language scores < -2SD, blindness, or deafness at 2 years of age. Other outcomes include death, breastfeeding within the first year, and respiratory support, oral feeding, and anthropometric parameters at 2 years of age. The Human Research Ethics Committees of Mater Misericordiae Limited and the Royal Women's Hospital approved the TASTE trial including the neurodevelopmental follow-up described in this protocol. DISCUSSION: For patients and their families, the neurodevelopmental outcomes of preterm infants are of utmost importance. Consequently, they should be investigated following any interventional study performed during the newborn period. Furthermore, improved weight gain and head growth in the hospital are associated with better long-term neurodevelopmental outcomes. Smelling and tasting of milk is an uncomplicated and cost-effective intervention that may improve the growth and neurodevelopmental outcomes of preterm infants. Potential limitations affecting this follow-up study, caused by the COVID-19 pandemic, are anticipated and discussed in this protocol. TRIAL REGISTRATION: Name of the registry: Australian and New Zealand Clinical Trials Registry; Registration number: ACTRN12617000583347 ; Registration date: 26 April 2017.

Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature.

OBJECTIVE: To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. CONTEXT: Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). DESIGN: Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. PATIENTS: Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. MEASUREMENTS: Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). RESULTS: First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. CONCLUSIONS: The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious.

DRD2 C957T and TaqIA genotyping reveals gender effects and unique low-risk and high-risk genotypes in alcohol dependence.

AIMS: As recent conflicting reports describe a genetic association between both the C- and the T-alleles of the dopamine D2 receptor (DRD2) C957T polymorphism (rs6277) in alcohol-dependent subjects, our aim was to examine this polymorphism and TaqIA (rs1800497) in Australian alcohol-dependent subjects. METHODS: The C957T polymorphism was genotyped in 228 patients with alcohol dependence (72 females and 156 males) and 228 healthy controls. RESULTS: The C-allele and C/C genotype of C957T was associated with alcohol dependence, whereas the TaqIA polymorphism was not. When analysed separately for C957T, males showed an even stronger association with the C-allele and females showed no association. The C957T and TaqIA haplotyping revealed a strong association with alcohol dependence and a double-genotype analysis (combining C957T and TaqIA genotypes) revealed that the relative risk of different genotypes varied by up to 27-fold with the TT/A1A2 having an 8.5-fold lower risk of alcohol dependence than other genotypes. CONCLUSION: Decreased DRD2 binding associated with the C-allele of the DRD2 C957T polymorphism is likely to be important in the underlying pathophysiology of at least some forms of alcohol dependence, and this effect appears to be limited to males only.

Growth hormone treatment for Turner syndrome in Australia reveals that younger age and increased dose interact to improve response.

OBJECTIVE: To investigate response to growth hormone (GH) in the first, second and third years of treatment in the total clinical cohort of Turner syndrome (TS) patients in Australia. CONTEXT: Short stature is the most common clinical manifestation of TS. GH treatment improves growth. DESIGN: Response was measured for each year of treatment. Stepwise multiple regression analyses were used to identify factors that significantly influenced response. PATIENTS: Prepubertal TS patients who completed 1 year (n=176), 2 years (n=148), or 3 years (n=117) of treatment and were currently receiving GH. MEASUREMENTS: Change in TS specific Height Standard Deviation Score (ΔTSZ) was the main response variable used. Major influencing variables considered included dose, starting age and height, BMI, bone age delay, karyotype, parental height, and interactions between dose and starting age or height. RESULTS: Response was greatest in first year and declined thereafter (median ΔTSZ: 1st year= +0·705, 2nd year= +0·439, 3rd year= +0·377) despite the median dose increasing [1st year= 5·5 mg/m(2) /week (0·23 mg/kg/week), 2nd year= 6·4(0·24), 3rd year= 7·2(0·26)]. An Age*Dose interaction was identified influencing first, second year, and total ΔTSZ. The ΔTSZ over 3 years was significantly influenced by first-year dose. Dose increments only attenuated the general decline in response. An acceptable first-year response (ΔTSZ>1·01) was achieved by only 17·6% of patients. CONCLUSIONS: Growth response is greatest and most influenced by dose in the first year. Dose in first year is a major factor contributing to total response. A starting Age*Dose interaction effect was observed such that young girls on a high dose respond disproportionately better. Optimal GH treatment of short stature in TS thus requires early initiation with the highest safe dose in the first year.

A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study.

BACKGROUND: It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. METHODS: To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. RESULTS: The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. CONCLUSIONS: Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

Effects on Growth of Smell and Taste of Milk During Tube Feeding of Preterm Infants: A Randomized Clinical Trial.

Importance: Smell and taste of food increase food anticipation, activate gut motility, and stimulate digestion and metabolism. Despite poor growth of many preterm infants in neonatal intensive care units, the smell and taste of milk with tube feeding are not generally considered a regular component of care. Objective: To determine the effect of smell and taste of milk with tube feeding on weight z scores at discharge from the hospital. Design, Setting, and Participants: A randomized, controlled, nonblinded, superiority trial was conducted at 2 perinatal centers between May 9, 2017, and February 1, 2020. Eligible infants (n = 659) were born at less than 29 weeks' postmenstrual age (PMA) and/or with a birth weight of less than 1250 g. Interventions: Infants were randomly assigned to receive either the smell and taste of milk with each tube feeding or routine care without the provision of smell and taste of milk. Main Outcomes and Measures: The primary outcome was weight z score at discharge from any hospital. Secondary outcomes included anthropometric measures at predefined time points, time to full enteral feeds, and other health outcomes associated with prematurity. Results: Of the 658 infants, a total of 396 infants were randomized; some parents had not been approached for consent (n = 144) or declined participation (n = 117), and 1 infant with consent was not randomized. Of the 396 infants, 196 were assigned to the treatment group (51% male; mean [SD] PMA at birth, 27.5 [2.2] weeks) and 200 were assigned to the control group (52% male; mean [SD] PMA at birth, 27.6 (2.3) weeks). Mean weight z scores at discharge were -0.87 (95% CI, -1.02 to -0.72) for the treatment group and -0.97 (95% CI, -1.11 to -0.83) for the control group (P = .40). The mean difference in z scores between the treatment and control groups at 36 weeks' PMA was 0.21 (95% CI, 0.01 to 0.4; P = .04) for head circumference and 0.26 (95% CI, 0.05 to 0.51; P = .04) for length. There were no clinically notable differences between the study groups for any other anthropometric, feeding, or health outcomes. Conclusions and Relevance: In this randomized clinical trial, regular smell and taste of milk included with tube feeding did not improve weight at discharge in preterm infants. Secondary outcomes suggest exposure to smell and taste may improve head circumference and length at 36 weeks' PMA, but not at discharge. Regular exposure to the smell and taste of milk is a simple and inexpensive intervention with potential benefits and no apparent adverse effects. Trial Registration: anzctr.org.au Identifier: ACTRN12617000583347.

The influence of secular trend for height on ascertainment and eligibility for growth hormone treatment.

OBJECTIVE: Assessment of short stature in many instances is based on a comparison with the Centers for Disease Control's (CDC) growth curves. The secular trend for height may limit the utility of CDC data for contemporary populations. We investigate the effect of the secular trend on Australian and US populations. DESIGN: Describe CDC-defined height SDS distributions of contemporary populations for different ages and genders. Compare observed means and standard deviations (SDs) to expected values of 0 and 1. Compare frequency of individuals shorter than the CDC-1st centile to those shorter than 1st centile defined empirically from the contemporary population. SUBJECTS: Healthy Kids Queensland Survey 2006: 1686 boys, 1822 girls. Australian National Children's Nutrition and Physical Activity Survey 2007: 2415 boys, 2379 girls. US National Health and Nutrition Examination Survey 2005-2006: 2160 boys, 2118 girls. MEASUREMENTS: Means, SDs and normality of CDC-defined height SDS distributions. Frequency of individuals shorter than the CDC-1st centile and shorter than an empirically defined 1st centile. RESULTS: In Australia, means of CDC-defined height SDS distributions are always greater than 0 and the CDC-1st centile identifies only the shortest 0·5% of children. Means may vary with age and occasionally between genders in contemporary populations. Normality and SDs of 1 are retained. CONCLUSIONS: The secular trend has resulted in an underestimate of the number of Australian children eligible for GH treatment using the CDC-1st centile cut-off. Contemporary, local data should be used to construct standards. Using the 2nd CDC centile would approximate the 1st local centile until new standards are constructed. The secular trend does not account for the gender bias in GH therapy.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia.

BACKGROUND: A number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. METHODS: To investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. RESULTS: The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. CONCLUSIONS: This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

In vitro differentiation of human calvarial suture derived cells with and without dexamethasone does not induce in vivo-like expression.

Osteogenic supplements are a requirement for osteoblastic cell differentiation during in vitro culture of human calvarial suture-derived cell populations. We investigated the ability of ascorbic acid and beta-glycerophosphate with and without the addition of dexamethasone to stimulate in vivo-like osteoblastic differentiation. Cells were isolated from unfused and prematurely fused suture tissue from patients with syndromic and non-syndromic craniosynostosis and cultured in each osteogenic medium for varying lengths of time. The effect of media supplementation was investigated with respect to the ability of cells to form mineralised bone nodules and the expression of five osteodifferentiation marker genes (COL1A1, ALP, BSP, OC and RUNX2), and five genes that are differentially expressed during human premature suture fusion (GPC3, RBP4, C1QTNF3, WIF1 and FGF2). Cells from unfused sutures responded more slowly to osteogenic media but formed comparable bone nodules to fused suture-derived cells after 16 days of culture in either osteogenic media. However, gene expression differed between unfused and fused suture-derived cells, as did expression in each osteogenic medium. When compared to expression in the explant tissue of origin, neither medium induced a level or profile of gene expression similar to that seen in vivo. Overall, our results demonstrate that cells from the same suture that are isolated during different stages of morphogenesis in vivo, despite being de-differentiated to a similar level in vitro, respond uniquely and differently to each osteogenic medium. Further, we suggest that neither cell culture medium recapitulates differentiation via activation of the same genetic cascades as occurs in vivo.

The DRD2 gene 957C>T polymorphism is associated with posttraumatic stress disorder in war veterans.

BACKGROUND: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (-141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. METHODS: To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD. RESULTS: No significant association was found between PTSD and the Taq1A or -141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021). CONCLUSIONS: Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD.

Identification of genes differentially expressed by prematurely fused human sutures using a novel in vivo - in vitro approach.

Craniosynostosis is the premature fusion of calvarial sutures. It results from abnormal differentiation or proliferation of cells within the osteogenic fronts of growing calvarial bones. To date, research has focused on animal models and in vitro organ and tissue culture to determine the molecular mechanisms controlling calvarial suture morphogenesis. Here, we test a new, in vivo-in vitro approach based on the hypothesis that calvarial suture cells passaged in minimal medium exhibit a stable gene expression profile similar to undifferentiated osteoblastic cells that can provide a benchmark for comparison with in vivo expression of differentiated tissue. We show that tissue-specific expression is lost after the first passage and, using cDNA microarrays, compare expression between fused suture tissue from craniosynostosis patients and in vitro de-differentiated explant cells. A large number of differentially expressed genes were identified, including novel genes WIF1, LEF1, SATB2, RARRES1, DEFA1, DMP1, PTPRZ1, and PTPRC, as well as those commonly associated with human suture morphogenesis, e.g., FGF2, MSX2, and BMP2. Two differentially expressed genes, WIF1 and FGF2, were further examined in an in vivo-in vivo comparison between unfused and prematurely fused tissue. The same pattern of differential expression was observed in each case, further validating the ability of our in vivo-in vitro approach to identify genes involved in in vivo human calvarial tissue differentiation.

Proposed new target height equations for use in Australian growth clinics.

Equations for target height estimation designed for easy use in the Australian growth clinics are presented that are based on the standard deviation score method of Hermanussen and Cole. These equations are superior to the commonly used corrected midparental height method as they account for assortative mating and regression to the mean. Simulations using different mating types were performed to compare different methods of target height estimation. While the equations relate directly to growth charts used in Australia, it is noted that neither account for the secular increase in height observed from generation to generation.

Unravelling the molecular control of calvarial suture fusion in children with craniosynostosis.

BACKGROUND: Craniosynostosis, the premature fusion of calvarial sutures, is a common craniofacial abnormality. Causative mutations in more than 10 genes have been identified, involving fibroblast growth factor, transforming growth factor beta, and Eph/ephrin signalling pathways. Mutations affect each human calvarial suture (coronal, sagittal, metopic, and lambdoid) differently, suggesting different gene expression patterns exist in each human suture. To better understand the molecular control of human suture morphogenesis we used microarray analysis to identify genes differentially expressed during suture fusion in children with craniosynostosis. Expression differences were also analysed between each unfused suture type, between sutures from syndromic and non-syndromic craniosynostosis patients, and between unfused sutures from individuals with and without craniosynostosis. RESULTS: We identified genes with increased expression in unfused sutures compared to fusing/fused sutures that may be pivotal to the maintenance of suture patency or in controlling early osteoblast differentiation (i.e. RBP4, GPC3, C1QTNF3, IL11RA, PTN, POSTN). In addition, we have identified genes with increased expression in fusing/fused suture tissue that we suggest could have a role in premature suture fusion (i.e. WIF1, ANXA3, CYFIP2). Proteins of two of these genes, glypican 3 and retinol binding protein 4, were investigated by immunohistochemistry and localised to the suture mesenchyme and osteogenic fronts of developing human calvaria, respectively, suggesting novel roles for these proteins in the maintenance of suture patency or in controlling early osteoblast differentiation. We show that there is limited difference in whole genome expression between sutures isolated from patients with syndromic and non-syndromic craniosynostosis and confirmed this by quantitative RT-PCR. Furthermore, distinct expression profiles for each unfused suture type were noted, with the metopic suture being most disparate. Finally, although calvarial bones are generally thought to grow without a cartilage precursor, we show histologically and by identification of cartilage-specific gene expression that cartilage may be involved in the morphogenesis of lambdoid and posterior sagittal sutures. CONCLUSION: This study has provided further insight into the complex signalling network which controls human calvarial suture morphogenesis and craniosynostosis. Identified genes are candidates for targeted therapeutic development and to screen for craniosynostosis-causing mutations.

Early cessation and non-response are important and possibly related problems in growth hormone therapy: An OZGROW analysis.

OBJECTIVE: To investigate growth hormone (GH) treatment and treatment cessation with respect to efficacy and efficiency. To identify factors that best classify or predict cessation type: completed treatment (CT), early cessation (EC), or non-response (NR). DESIGN: Observational study (1990-2013) of the Australian GH Program comparing CT, EC, and NR groups with respect to demographic, clinical, and response criteria. All patients treated for GH deficiency (GHD; 909), short stature and slow growth (SSSG; 2144), and Turner Syndrome (TS; 626) were included. Information was retrieved from the OZGROW database. RESULTS: 51.9% of patients were EC, 40.7% CT and 7.4% NR.Median treatment durations for NR patients were often longer than patients who completed treatment. EC and NR groups were both associated with poor growth response with males overrepresented.Socioeconomic status differentiated NR (higher) and EC (lower) groups. CONCLUSIONS: EC was observed at very high rates and appears, generally, to be a little-recognised but frequent problem in GH therapy.EC and delayed recognition of NR may be interrelated being differentiated by the decision to cease or continue treatment following poor response.Poor treatment compliance is likely a major causal factor in EC.Strategies to address poor response and compliance have been developed, however, given the scale of these problems, it may be that long acting GH formulations or individualized treatment need consideration.

NOS1AP is associated with increased severity of PTSD and depression in untreated combat veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-d-aspartate (NMDA) activity, was investigated in combat veterans. METHODS: A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control individuals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). RESULTS: The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p=0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p=0.002 F=6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p=0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p=0.001). LIMITATIONS: The sample sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. CONCLUSIONS: This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide.

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset: HapMap tag-single-nucleotide polymorphism analysis.

BACKGROUND: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain, which is known to be important in the etiology of schizophrenia. It is, therefore, not surprising that most antipsychotic medication acts on DRD2. DRD2 is widely expressed in the brain; levels are reduced in the brains of patients with schizophrenia, and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. METHODS: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single-nucleotide polymorphisms (SNPs) in DRD2 by using a multiplex mass spectrometry method. SNPs were chosen by using a haplotype block-based gene-tagging approach; so, the entire DRD2 gene was represented. RESULTS: One polymorphism, rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared with controls. CONCLUSIONS: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor of age of onset.