Laboratory-based measures of executive function and daily living skills in young children with Down syndrome: informing future interventions.

BACKGROUND: Adaptive behaviour refers to the practical skills necessary for independence and is considered a high-priority intervention target for children with neurogenetic conditions associated with intellectual disability, like Down syndrome (DS). Daily living skills (DLS) are a critical aspect of adaptive behaviour, but they have received little intervention attention, possibly because they involve a wide variety of skills across many settings. The present study aimed to advance DLS intervention science by examining the concurrent and longitudinal association between DLS performances and a cognitive skillset hypothesised to support DLS skill acquisition, executive function (EF). METHODS: Participants were 71 children with DS between the ages of 2.5 and 8.7 years (M = 5.23 years; standard deviation = 1.65) who completed a battery of adapted EF tasks and a primary caregiver who completed the Vineland Adaptive Behavior Scales 3rd Edition Parent/Caregiver Comprehensive Report Form. A subset of caregivers also provided 6- and 12-month follow-up adaptive behaviour information. RESULTS: Results demonstrated a positive association between EF task performance and DLS standard scores and v-scores both concurrently and longitudinally. CONCLUSIONS: The findings have implications for potential future intervention approaches that aim to strengthen DLS performances by advancing EF skills in this population.

Evaluating an adapted reverse categorisation task to assess cognitive flexibility in young children with Down syndrome.

BACKGROUND: Accurate measurement of cognitive skills is necessary to advance both developmental and intervention science for individuals with Down syndrome (DS). This study evaluated the feasibility, developmental sensitivity and preliminary reliability of a reverse categorisation measure designed to assess cognitive flexibility in young children with DS. METHODS: Seventy-two children with DS ages 2.5-8 years completed an adapted version of a reverse categorisation task. Twenty-eight of the participants were assessed again 2 weeks later for retest reliability. RESULTS: This adapted measure demonstrated adequate feasibility and developmental sensitivity, and preliminary evidence for test-retest reliability when administered to children with DS in this age range. CONCLUSIONS: This adapted reverse categorisation measure may be useful for future developmental and treatment studies that target early foundations of cognitive flexibility in young children with DS. Additional recommendations for use of this measure are discussed.

Occupational asbestos exposure and ovarian cancer: updated systematic review.

BACKGROUND: The association between asbestos exposure and ovarian cancer has been questioned given the possible misdiagnosis of peritoneal mesothelioma as ovarian cancer. AIMS: To update a systematic review on ovarian cancer risk in women occupationally exposed to asbestos, exploring the association with the time since first exposure and the duration of exposure. METHODS: We searched PubMed from 2008 onwards, screened previous systematic reviews, combined standardized mortality ratios (SMR) using random effect models and quantified heterogeneity using the I2 statistic. To assess tumour misclassification, we compared the distribution of observed excess ovarian cancers (OEOC) to that expected (EEOC) from the distribution of peritoneal cancers in strata of latency and exposure duration. RESULTS: Eighteen publications (20 populations), including a pooled analysis of 21 cohorts, were included. The pooled SMR was 1.79 (95% confidence interval 1.38-2.31), with moderate heterogeneity between studies (I2 = 42%), based on 144 ovarian cancer deaths/cases. The risk was increased for women with indirect indicators of higher exposure, longer duration and latency, and lower for chrysotile than for crocidolite exposure. The effect of duration and latency could not be completely disentangled, since no multivariate analysis was available for time-related variables. The dissimilarity index between OEOC and EEOC for the time since first exposure was small suggesting a similar pattern of risk. CONCLUSIONS: While some misclassification between ovarian and peritoneal cancers cannot be excluded, the observed excess risk of ovarian cancer should be added to the overall disease burden of asbestos.

Latent profiles of autism symptoms in children and adolescents with Down syndrome.

BACKGROUND: Down syndrome (DS) is associated with elevated rates of autism spectrum disorder (ASD) and autism symptomatology. To better characterise heterogeneity in ASD symptomatology in DS, profiles of caregiver-reported ASD symptoms were modelled for children and adolescents with DS. METHODS: Participants (n = 125) were recruited through several multi-site research studies on cognition and language in DS. Using the Social Responsiveness Scale-2 (SRS-2; Constantino and Gruber 2012), two latent profile analyses (LPA) were performed, one on the broad composite scores of social communication and interaction and restricted interests and repetitive behaviour, and a second on the four social dimensions of social communication, social motivation, social awareness, and social cognition. RESULTS: A three-profile model was the best fit for both analyses, with each analysis yielding a low ASD symptom profile, an elevated or mixed ASD symptom profile and a high ASD symptom profile. Associations were observed between profile probability scores and IQ, the number of co-occurring biomedical conditions reported, sex, and SRS-2 form. CONCLUSIONS: Characterising heterogeneity in ASD symptom profiles can inform more personalised supports in this population, and implications for potential therapeutic approaches for individuals with DS are discussed.

Theranostic efficiency of biosurfactants against COVID-19 and similar viruses - A review.

The world has witnessed an extreme vulnerability of a pandemic during 2020; originated from China. The coronavirus disease 2019 (COVID-19) is infecting and beginning deaths in thousands to millions, creating of the global economic crisis. Biosurfactants (BSs) can carry the prevention, control and management of pandemic out through diverse approaches, such as pharmaceutical, therapeutic, hygienic and environmental. The microbiotas having virulent intrinsic properties towards starting as easily as spreading of diseases (huge morbidity and mortality) could be inhibited via BSs. Such elements could be recognised for their antimicrobial activity, capability to interact with the immune system via micelles formation and in nanoparticulate synthesis. However, they can be used for developing novel and more effective therapeutics, pharmaceuticals, non-toxic formulations, vaccines, and effective cleaning agents. Such approaches can be utilized for product development and implemented for managing and combating the pandemic conditions. This review emphasized on the potentiality of BSs as key components with several ways for protecting against unknown and known pathogens, including COVID-19.

Feasibility of a syndrome-informed micro-intervention for infants with Down syndrome.

BACKGROUND: Infants with Down syndrome (DS) are at risk for a range of phenotypic outcomes, including delays in the onset of reaching behaviour, a critical skill that facilitates early learning. This parallel-group feasibility and pilot study presents findings from a parent-mediated micro-intervention that aimed to support the development of reaching behaviour in a sample of infants with DS. METHODS: Participants were 73 infants with DS and their caregivers. Infants who qualified for the home-based intervention (based on manual skill performance on Bayley Scales of Infant and Toddler Development, Third Edition items) were randomly assigned individually or by geographical region to a treatment or an alternative treatment condition that involved toy-based interactions with caregivers. Infants in the treatment condition experienced facilitated reaching during the toy-based interactions through the use of Velcro-affixed mittens and toys. RESULTS: Forty-two infants met criteria to participate in the intervention, and 37 participated in both baseline and post-treatment visits. At post-treatment, infants in the treatment condition demonstrated shorter latencies to make contact with objects and showed higher frequencies of reach attempts and swats at objects than infants in the alternative treatment group. These findings were more pronounced when examining a chronological age-restricted subgroup of infants 5 to 10 months. CONCLUSIONS: Findings suggest that a syndrome-informed approach to targeted intervention may be a promising application of phenotyping science in DS and other neurogenetic conditions associated with intellectual disability.

Acute metronidazole-induced neurotoxicity: an update on MRI findings.

AIM: To describe a series of 10 cases of metronidazole-induced neurotoxicity (MIN) and review the established literature to better define its clinical and imaging findings. MATERIALS AND METHODS: The clinical presentations and magnetic resonance imaging (MRI) images of 10 patients with clinically diagnosed MIN were reviewed retrospectively. A review of an additional 31 cases from prior published case series was performed. RESULTS: The median age of patients from the authors' institutions with MIN was 54 (range 8-84) years. The median cumulative dose of metronidazole received was 64.5 g (range 7.5-1,380 g). Common presenting neurological symptoms were ataxia (n=6) and altered mental status (n=3). All of the patients (n=10) had symmetric T2 hyperintense lesions in the dentate nuclei at presentation. Other involved structures included the midbrain, corpus callosum, pons, medulla, basal ganglia, and supratentorial white matter. True restricted diffusion was seen in the corpus callosum (n=6). Symptoms resolved in all patients except for one. For the patients with available follow up MRI (n=4), the observed lesions resolved. CONCLUSION: MIN affects both adult and paediatric patients. Symptoms typically occur after prolonged exposure to the antibiotic, but can occur at low cumulative doses. Most frequently involved structures are the dentate nucleus, midbrain, and splenium corpus callosum. Restricted diffusion within the corpus callosum is likely due to cytotoxic oedema. Symptoms typically resolve after cessation of metronidazole, and lesions typically resolve on follow-up imaging.

Correlates of early cognition in infants with Down syndrome.

BACKGROUND: While delays in cognitive development are detectable during early development in Down syndrome, the neuropsychological and biomedical underpinnings of cognitive skill acquisition in this population remain poorly understood. METHOD: To explore this issue, 38 infants with Down syndrome [mean chronological age = 9.65 months; SD = 3.64] completed the Bayley Scales of Infant Development-III and a set of laboratory tasks that measured sustained attention (duration of visual attention during a 1-min object exploration task), attention shifting (mean latency to shift attention on an alternating object presentation task) and visual short-term memory (dishabituation to a novel object on a change preference task). RESULTS: Latency to shift attention was negatively associated with Bayley Cognitive Scale raw scores, even when controlling for the effects of chronological age, r (33) = -.41, P = .02. In addition, prematurity status was associated with latency to shift attention. CONCLUSIONS: Early attention shifting may be an important factor that facilitates overall cognitive skill acquisition in infants with Down syndrome, and premature birth may be a risk factor for difficulties on this dimension.

Reliability of parent report measures of behaviour in children with Down syndrome.

BACKGROUND: Behavioural problems are common among children with Down syndrome (DS). Tools to detect and evaluate maladaptive behaviours have been developed for typically developing children and have been evaluated for use among children with intellectual and developmental disabilities. However, these measures have not been evaluated for use specifically in children with DS. This psychometric evaluation is important given that some clinically observed behaviours are not addressed in currently available rating scales. The current study evaluates the psychometric properties of the Child Behavior Checklist (CBCL), a commonly used screening tool developed for typically developing children and commonly used with children with intellectual and developmental disabilities. METHODS: The study investigated the psychometric properties of the CBCL among school-aged children with DS, including an assessment of the rate of detecting behaviour problems, concerns with distribution, internal consistency, inter-rater reliability and convergent and discriminant validity with the Aberrant Behavior Checklist and Nisonger Child Behavior Rating Form. Caregivers of 88 children with DS aged 6-18 years rated their child's behaviour with the CBCL, Aberrant Behavior Checklist and Nisonger Child Behavior Rating Form. Teachers completed the Teacher Report Form. RESULTS: About one-third of children with DS were reported to exhibit behaviours of clinical concern on the total score of the CBCL. Internal consistency for CBCL sub-scales was poor to excellent, and inter-rater reliability was generally acceptable. The sub-scales of the CBCL performed best when evaluating convergent validity, with variable discriminant validity. Normative data conversions controlled for age and gender differences in this sample. CONCLUSIONS: The study findings suggest that, among children with DS, some CBCL sub-scales generally performed in a psychometrically sound and theoretically appropriate manner in relation to other measures of behaviour. Caution is warranted when interpreting specific sub-scales (Anxious/Depressed, Somatic Complaints and Thought Problems). The CBCL can continue to be used as a screening measure when evaluating behavioural concerns among children with DS, acknowledging poor discriminant validity and the possibility that key behaviour concerns in DS may not be captured by the CBCL screen.

Insights into the pathophysiology of catch-up compared with non-catch-up growth in children born small for gestational age: an integrated analysis of metabolic and transcriptomic data.

Small for gestational age (SGA) children exhibiting catch-up (CU) growth have a greater risk of cardiometabolic diseases in later life compared with non-catch-up (NCU) SGA children. The aim of this study was to establish differences in metabolism and gene expression profiles between CU and NCU at age 4-9 years. CU children (n=22) had greater height, weight and body mass index standard deviation scores along with insulin-like growth factor-I (IGF-I) and fasting glucose levels but lower adiponectin values than NCU children (n=11; all P<0.05). Metabolic profiling demonstrated a fourfold decrease of urine myo-inositol in CU compared with NCU (P<0.05). There were 1558 genes differentially expressed in peripheral blood mononuclear cells between the groups (P<0.05). Integrated analysis of data identified myo-inositol related to gene clusters associated with an increase in insulin, growth factor and IGF-I signalling in CU children (P<0.05). Metabolic and transcriptomic profiles in CU SGA children showed changes that may relate to cardiometabolic risk.

PET/MR Imaging in Evaluating Treatment Failure of Head and Neck Malignancies: A Neck Imaging Reporting and Data System-Based Study.

BACKGROUND AND PURPOSE: PET/MR imaging is a relatively new hybrid technology that holds great promise for the evaluation of head and neck cancer. The aim of this study was to assess the performance of simultaneous PET/MR imaging versus MR imaging in the evaluation of posttreatment head and neck malignancies, as determined by its ability to predict locoregional recurrence or progression after imaging. MATERIALS AND METHODS: The electronic medical records of patients who had posttreatment PET/MR imaging studies were reviewed, and after applying the exclusion criteria, we retrospectively included 46 studies. PET/MR imaging studies were independently reviewed by 2 neuroradiologists, who recorded scores based on the Neck Imaging Reporting and Data System (using CT/PET-CT criteria) for the diagnostic MR imaging sequences alone and the combined PET/MR imaging. Treatment failure was determined with either biopsy pathology or initiation of new treatment. Statistical analyses including univariate association, interobserver agreement, and receiver operating characteristic analysis were performed. RESULTS: There was substantial interreader agreement among PET/MR imaging scores (κ = 0.634; 95% CI, 0.605-0.663). PET/MR imaging scores showed a strong association with treatment failure by univariate association analysis, with P < .001 for the primary site, neck lymph nodes, and combined sites. Receiver operating characteristic curves of PET/MR imaging scores versus treatment failure indicated statistically significant diagnostic accuracy (area under curve range, 0.864-0.987; P < .001). CONCLUSIONS: Simultaneous PET/MR imaging has excellent discriminatory performance for treatment outcomes of head and neck malignancy when the Neck Imaging Reporting and Data System is applied. PET/MR imaging could play an important role in surveillance imaging for head and neck cancer.

Diagnosis, prevention, and treatment of coronavirus disease: a review.

INTRODUCTION: Coronavirus disease (COVID-19) was first reported in Wuhan, China, in late December 2019 and subsequently, declared a pandemic. As of 3 June 2021, 172,493,290 individuals have acquired COVID-19 and 3,708,334 patients have died worldwide, according to the World Health Organization. AREAS COVERED: This review explores epidemiology; virology; pathogenesis; genomic variations; mode of transmission; clinical occurrence; diagnosis; and treatment with antiviral agents, antibiotics, and supportive therapies. It covers a nanotechnology-based treatment approach and emphasizes the importance of herbal and marine antiviral drugs. The review attempts to explain current advances in research, prevention, and control of COVID-19 spread through artificial intelligence and vaccine development status under cosmopolitan consideration. EXPERT OPINION: While COVID-19 research is advancing at full capacity, the discovery of drugs or vaccines that can fight the pandemic is necessary. Human survival in such a critical situation will be possible only with the development of strong immunity by opting for exercise, yoga, and consumption of hygienic food and beverages. Therefore, education about COVID-19 lethality and its impact on livelihood is important. The pandemic has also shown positive effects on the environment, such as a significant reduction in environmental pollution and global warming and improvement in river water quality.

Low dose (0.05 units/kg/h) is comparable with standard dose (0.1 units/kg/h) intravenous insulin infusion for the initial treatment of diabetic ketoacidosis in children with type 1 diabetes-an observational study.

OBJECTIVE: To compare low dose (0.05 units/kg/h) with standard dose (0.1 units/kg/h) intravenous insulin infusion for the treatment of diabetic ketoacidosis (DKA) in children with type 1 diabetes. STUDY DESIGN: Data from five paediatric centres were compared in children who received 0.05 (41 episodes) or 0.1 units/kg/h (52 episodes). RESULTS: In the low vs. standard dose group, at 6 h following admission, the fall in blood glucose levels [11.3 (95% confidence interval 8.6 to 13.9) vs. 11.8 (8.4 to 15.2) mmol/L, p = 0.86] and rise in pH [0.13 (0.09 to 0.18) vs. 0.11 (0.07 to 0.15), p = 0.78] were similar. These changes were comparable between doses in relation to: severity of initial acidosis, children newly diagnosed with diabetes or aged less than 5 years. After adjustment for other clinical and biochemical covariates, insulin dose was unrelated to the change in pH and blood glucose levels at 6 h following admission. Comparisons of safety data, particularly in relation to abnormal Glasgow Coma Score, were inconclusive. CONCLUSION: In this observational study, low dose was as effective as standard dose intravenous insulin infusion in the initial treatment (less than 6 h) of DKA in children with type 1 diabetes. A randomised controlled trial is required to show true equivalence between doses and to evaluate potential safety benefits.

Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland.

OBJECTIVES: The presence of an ectopic posterior pituitary gland (EPP) in childhood is associated with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency. GHD in late adolescence has been defined as a peak GH level <5 microg/l. The aim of this study was to identify the likelihood of persistent GHD in late adolescence in patients with an EPP compared with those with a normally sited posterior pituitary (NPP). METHODS: In 18 patients with an EPP and 15 patients with an NPP, clinical, biochemical and radiographic data were collected. RESULTS: In the EPP vs. the NPP group, the change in peak GH levels at the end of growth was less (+0.4[95% confidence interval (CI) - 0.8 to 2.7] vs. +4.1[95%CI + 0.4 to +10.5] microg/l, P-value for ancova = 0.03, after adjustment for age and sex). Using a peak GH level of <5 microg/l as a cut-off for GHD, 66% of EPP subjects compared with 40% of NPP subjects had GHD (P = 0.3). Hundred per cent of EPP subjects had a peak GH level on retesting <10 microg/l, compared with 40% of NPP subjects (P < 0.001). CONCLUSION: It is important to document GH status at the end of growth, even if there is a structural abnormality of the hypothalamic-pituitary axis. The presence of an EPP compared to an NPP increases the likelihood of persistent GHD by 26%. As all EPP patients had a peak GH level of <10 microg/l, the cut-off for persistent GHD in late adolescence may need to be revised.

p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.

Nitric oxide is a chemical messenger implicated in neuronal damage associated with ischemia, neurodegenerative disease, and excitotoxicity. Excitotoxic injury leads to increased NO formation, as well as stimulation of the p38 mitogen-activated protein (MAP) kinase in neurons. In the present study, we determined if NO-induced cell death in neurons was dependent on p38 MAP kinase activity. Sodium nitroprusside (SNP), an NO donor, elevated caspase activity and induced death in human SH-SY5Y neuroblastoma cells and primary cultures of cortical neurons. Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection. A role for p38 MAP kinase was further substantiated by the observation that SB203580 blocked translocation of the cell death activator, Bax, from the cytosol to the mitochondria after treatment with SNP. Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP. Bax-deficient cortical neurons were resistant to SNP, further demonstrating the necessity of Bax in this mode of cell death. These results demonstrate that p38 MAP kinase activity plays a critical role in NO-mediated cell death in neurons by stimulating Bax translocation to the mitochondria, thereby activating the cell death pathway.

Redox regulation of fos and jun DNA-binding activity in vitro.

The proto-oncogenes c-fos and c-jun function cooperatively as inducible transcription factors in signal transduction processes. Their protein products, Fos and Jun, form a heterodimeric complex that interacts with the DNA regulatory element known as the activator protein-1 (AP-1) binding site. Dimerization occurs via interaction between leucine zipper domains and serves to bring into proper juxtaposition a region in each protein that is rich in basic amino acids and that forms a DNA-binding domain. DNA binding of the Fos-Jun heterodimer was modulated by reduction-oxidation (redox) of a single conserved cysteine residue in the DNA-binding domains of the two proteins. Furthermore, a nuclear protein was identified that reduced Fos and Jun and stimulated DNA-binding activity in vitro. These results suggest that transcriptional activity mediated by AP-1 binding factors may be regulated by a redox mechanism.

Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland.

INTRODUCTION: The presence of an ectopic posterior pituitary gland (EPP) on magnetic resonance imaging (MRI) is associated with hypopituitarism with one or more hormone deficiencies. We aimed to identify risk factors for having multiple pituitary hormone deficiency (MPHD) compared to isolated growth hormone deficiency (IGHD) in patients with an EPP. METHODS: In 67 patients (45 male) with an EPP on MRI, the site (hypothalamic vs. stalk) and surface area (SA) [ x (maximum diameter/2) x (maximum height/2), mm(2)] of the EPP were recorded and compared in patients with IGHD and MPHD in relation to clinical characteristics. RESULTS: In MPHD (n = 32) compared to IGHD (n = 35) patients: age of presentation was younger (1.4 [0.1-10.7]vs. 4.0 [0.1-11.3] years, P = 0.005), major incidents during pregnancy were increased (47%vs. 20%, P = 0.02) as were admissions to a neonatal intensive care unit (NICU) (60%vs. 26%, P = 0.04), whilst EPP SA was lower (12.3 [2.4-34.6]vs. 25.7 [6.9-48.2] mm(2), P < 0.001). In patients with a hypothalamic (n = 56) compared to a stalk sited EPP (n = 11): prevalence of MPHD was greater (55%vs. 9%,P = 0.05) and EPP surface area was smaller (17.3 [2.4-48.2]vs. 25.3 [11.8-38.5] mm(2), P < 0.001). In regression analysis, after adjusting for age, presence of MPHD was associated with: major incidents during pregnancy (RR 6.8 [95%CI 1.2-37.7]), hypothalamic EPP site (RR 10.9 [1.0-123.9]) and small EPP SA (RR 2.5 [1.0-5.0] for tertiles of SA). CONCLUSION: In patients with an EPP, adverse antenatal events, size (small) and position (hypothalamic) of the posterior pituitary gland on MRI were associated with MPHD. These findings suggest that adverse factors during pregnancy may be important for the development of an EPP.

Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN.

The PTEN tumor suppressor gene modulates several cellular functions, including cell migration, survival, and proliferation [1] by antagonizing phosphatidylinositol 3-kinase (PI 3-kinase)-mediated signaling cascades. Mechanisms by which the expression of PTEN is regulated are, however, unclear. The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) [2] has been shown to regulate differentiation and/or cell growth in a number of cell types [3, 4, 5], which has led to the suggestion that PPARgamma, like PTEN [1, 6], could act as a tumor suppressor. PPARgamma has also been implicated in anti-inflammatory responses [7, 8], although downstream mediators of these effects are not well defined. Here, we show that the activation of PPARgamma by its selective ligand, rosiglitazone, upregulates PTEN expression in human macrophages, Caco2 colorectal cancer cells, and MCF7 breast cancer cells. This upregulation correlated with decreased PI 3-kinase activity as measured by reduced phosphorylation of protein kinase B. One consequence of this was that rosiglitazone treatment reduced the proliferation rate of Caco2 and MCF7 cells. Antisense-mediated disruption of PPARgamma expression prevented the upregulation of PTEN that normally accompanies monocyte differentiation and reduced the proportion of macrophages undergoing apoptosis, while electrophoretic mobility shift assays showed that PPARgamma is able to bind two response elements in the genomic sequence upstream of PTEN. Our results demonstrate a role for PPARgamma in regulating PI 3-kinase signaling by modulating PTEN expression in inflammatory and tumor-derived cells.

Efficacy of a monthly compared to 3-monthly depot GnRH analogue (goserelin) in the treatment of children with central precocious puberty.

AIMS: To compare the efficacy of goserelin 10.8 mg (Zoladex LA-ZLA) administered 9-12 weekly with 3.6 mg (Zoladex-Z) given monthly in suppressing pubertal development, and effect on body mass index (BMI). METHODS: Children with central precocious puberty (CPP) treated with Z (n = 34) or ZLA (n = 28) were studied retrospectively. Pubertal scores and BMI SDS during 24 months' treatment were compared. RESULTS: To attain adequate pubertal suppression, more patients on ZLA than Z required increase in injection frequency (p = 0.02) and this was so for 7/8 patients with a structural aetiology for CPP on ZLA and 2/8 on Z. A greater proportion of patients on ZLA had BMI >+2 SDS before (p = 0.05), and at 18 and 24 months (p = 0.02 and 0.04). BMI SDS transiently increased during the first 6 months on ZLA (p = 0.04). CONCLUSION: Both Z and ZLA were effective in suppressing puberty. To achieve adequate suppression, increased injection frequency was more likely with ZLA than Z, and particularly in patients with structural defects. Children with CPP had an elevated BMI at the onset of therapy and ZLA had a transient positive influence on BMI.