Effects of Perilipin (PLIN) Gene Variation on Metabolic Syndrome Risk and Weight Loss in Obese Children and Adolescents

Context: Genetic polymorphisms at the perilipin (PLIN) locus have been investigated for their potential utility as markers for obesity and metabolic syndrome (MS). We examined in obese children and adolescents (OCA) aged 7-14 yr the association of single-nucleotide polymorphisms (SNP) at the PLIN locus with anthropometric, metabolic traits, and weight loss after 20-wk multi-disciplinary behavioral and nutritional treatment without medication. Design: A total of 234 OCA [body mass index (BMI = 30.4 +/- 4.4 kg/m(2); BMI Z-score = 2.31 +/- 0.4) were evaluated at baseline and after intervention. We genotyped four SNPs (PLIN1 6209T -> C, PLIN4 11482G -> A, PLIN5 13041A -> G, and PLIN6 14995A -> T). Results: Allele frequencies were similar to other populations, PLIN1 and PLIN4 were in linkage disequilibrium (D` = 0.999; P < 0.001). At baseline, no anthropometric differences were observed, but minor allele A at PLIN4 was associated with higher triglycerides (111 +/- 49 vs. 94 +/- 42 mg/dl; P = 0.003), lower high-density lipoprotein cholesterol (40 +/- 9 vs. 44 +/- 10 mg/dl; P = 0.003) and higher homeostasis model assessment for insulin resistance (4.0 +/- 2.3 vs. 3.5 +/- 2.1; P +/- 0.015). Minor allele A at PLIN4 was associated with MS risk (age and sex adjusted) hazard ratio 2.4 (95% confidence interval = 1.1-4.9) for genotype GA and 3.5 (95% confidence interval = 1.2-9.9) for AA. After intervention, subjects carrying minor allele T at PLIN6 had increased weight loss (3.3 +/- 3.7 vs. 1.9 +/- 3.4 kg; P = 0.002) and increased loss of the BMI Z-score (0.23 +/- 0.18 vs. 0.18 +/- 0.15; P +/- 0.003). Due to group size, risk of by-chance findings cannot be excluded. Conclusion: The minor A allele at PLIN4 was associated with higher risk of MS at baseline, whereas the PLIN6 SNP was associated with better weight loss, suggesting that these polymorphisms may predict outcome strategies based on multidisciplinary treatment for OCA. (J Clin Endocrinol Metab 93: 4933-4940, 2008)

Image reconstruction affects computer tomographic assessment of lung hyperinflation

Objectives: Lung hyperinflation may be assessed by computed tomography (CT). As shown for patients with emphysema, however, CT image reconstruction affects quantification of hyperinflation. We studied the impact of reconstruction parameters on hyperinflation measurements in mechanically ventilated (MV) patients. Design: Observational analysis. Setting: A University hospital-affiliated research Unit. Patients: The patients were MV patients with injured (n = 5) or normal lungs (n = 6), and spontaneously breathing patients (n = 5). Interventions: None. Measurements and results: Eight image series involving 3, 5, 7, and 10 mm slices and standard and sharp filters were reconstructed from identical CT raw data. Hyperinflated (V-hyper), normally (V-normal), poorly (V-poor), and nonaerated (V-non) volumes were calculated by densitometry as percentage of total lung volume (V-total). V-hyper obtained with the sharp filter systematically exceeded that with the standard filter showing a median (interquartile range) increment of 138 (62-272) ml corresponding to approximately 4% of V-total. In contrast, sharp filtering minimally affected the other subvolumes (V-normal, V-poor, V-non, and V-total). Decreasing slice thickness also increased V-hyper significantly. When changing from 10 to 3 mm thickness, V-hyper increased by a median value of 107 (49-252) ml in parallel with a small and inconsistent increment in V-non of 12 (7-16) ml. Conclusions: Reconstruction parameters significantly affect quantitative CT assessment of V-hyper in MV patients. Our observations suggest that sharp filters are inappropriate for this purpose. Thin slices combined with standard filters and more appropriate thresholds (e.g., -950 HU in normal lungs) might improve the detection of V-hyper. Different studies on V-hyper can only be compared if identical reconstruction parameters were used.

Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients

Background Mutations in the PTPN11 gene are the main cause of Noonan syndrome (NS). The presence of some NS features is a frequent finding in children with idiopathic short stature (ISS). These children can represent the milder end of the NS clinical spectrum and PTPN11 is a good candidate for involvement in the pathogenesis of ISS. Objective To evaluate the presence of mutations in PTPN11 in ISS children who presented NS-related signs and in well-characterized NS patients. Patients and methods We studied 50 ISS children who presented at least two NS-associated signs but did not fulfil the criteria for NS diagnosis. Forty-nine NS patients diagnosed by the criteria of van der Burgt et al. were used to assess the adequacy of these criteria to select patients for PTPN11 mutation screening. The coding region of PTPN11 was amplified by polymerase chain reaction (PCR), followed by direct sequencing. Results No mutations or polymorphisms were found in the coding region of the PTPN11 gene in ISS children. Nineteen of the 49 NS patients (39%) presented mutations in PTPN11. No single characteristic enabled us to distinguish between NS patients with or without PTPN11 mutations. Conclusion Considering that no mutations were found in the present cohort with NS-related signs, it is unlikely that mutations would be found in unselected ISS children. The van der Burgt et al. criteria are adequate in attaining NS diagnosis and selecting patients for molecular studies. Mutations in the PTPN11 gene are commonly involved in the pathogenesis of NS but are not a common cause of ISS.

Two novel mutations in the EIF2AK3 gene in children with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, epiphyseal dysplasia, and other multisystemic clinical manifestations. We described two novel mutations in the EIF2AK3 gene in two consanguineous families with WRS from Brazil and Morocco. We have observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398 (Gln398Stop). Both of his parents were found to be heterozygous for the mutation. We detected in both parents of case 2, a deceased Moroccan girl, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (p.Pro285AlafsX3). Both cases 1 and 2 had neonatal diabetes mellitus, multiple epiphyseal dysplasia, and growth delay, and presented episodes of acute hepatic dysfunction. Case 1 presented central hypothyroidism, developmental delay, and mild mental retardation. Case 2 presented a fatal episode of acute renal failure. The clinical phenotype associated with the syndrome can be variable, but a combination of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and hepatic and/or renal dysfunction is the mainstay of diagnosis.

Computed tomographic assessment of lung weights in trauma patients with early posttraumatic lung dysfunction

Introduction: Quantitative computed tomography (qCT)-based assessment of total lung weight (M(lung)) has the potential to differentiate atelectasis from consolidation and could thus provide valuable information for managing trauma patients fulfilling commonly used criteria for acute lung injury (ALI). We hypothesized that qCT would identify atelectasis as a frequent mimic of early posttraumatic ALI. Methods: In this prospective observational study, M(lung) was calculated by qCT in 78 mechanically ventilated trauma patients fulfilling the ALI criteria at admission. A reference interval for M(lung) was derived from 74 trauma patients with morphologically and functionally normal lungs (reference). Results are given as medians with interquartile ranges. Results: The ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen was 560 (506 to 616) mmHg in reference patients and 169 (95 to 240) mmHg in ALI patients. The median reference M(lung) value was 885 (771 to 973) g, and the reference interval for M(lung) was 584 to 1164 g, which matched that of previous reports. Despite the significantly greater median M(lung) value (1088 (862 to 1,342) g) in the ALI group, 46 (59%) ALI patients had M(lung) values within the reference interval and thus most likely had atelectasis. In only 17 patients (22%), Mlung was increased to the range previously reported for ALI patients and compatible with lung consolidation. Statistically significant differences between atelectasis and consolidation patients were found for age, Lung Injury Score, Glasgow Coma Scale score, total lung volume, mass of the nonaerated lung compartment, ventilator-free days and intensive care unit-free days. Conclusions: Atelectasis is a frequent cause of early posttraumatic lung dysfunction. Differentiation between atelectasis and consolidation from other causes of lung damage by using qCT may help to identify patients who could benefit from management strategies such as damage control surgery and lung-protective mechanical ventilation that focus on the prevention of pulmonary complications.

Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer

Mycosis fungoides (MF) and Sezary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin`s lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS. J Clin Oncol 29:2598-2607. (C) 2011 by American Society of Clinical Oncology

Rehabilitation of executive dysfunction: A controlled trial of an attention and problem solving treatment group

In this study, the effectiveness of a group-based attention and problem solving (APS) treatment approach to executive impairments in patients with frontal lobe lesions was investigated. Thirty participants with lesions in the frontal lobes, 16 with left frontal (LF) and 14 with right frontal (RF) lesions, were allocated into three groups, each with 10 participants. The APS treatment was initially compared to two other control conditions, an information/education (IE) approach and treatment-as-usual or traditional rehabilitation (TR), with each of the control groups subsequently receiving the APS intervention in a crossover design. This design allowed for an evaluation of the treatment through assessment before and after treatment and on follow up, six months later. There was an improvement on some executive and functional measures after the implementation of the APS programme in the three groups. Size, and to a lesser extent laterality, of lesion affected baseline performance on measures of executive function, but there was no apparent relationship between size, laterality or site of lesion and level of benefit from the treatment intervention. The results were discussed in terms of models of executive functioning and the effectiveness of domain specific interventions in the rehabilitation of executive dysfunction.

Dyslipidemia in women with polycystic ovary syndrome: incidence, pattern and predictors

One hundred forty-two women with polycystic ovary syndrome (PCOS) with an average body mass index (BMI) of 29.1 kg/m(2) and average age of 25.12 years were studied. By BMI, 30.2% were normal, 38.0% were overweight and 31.6% were obese. Thirty-one eumenorrheic women matched for BMI and age, with no evidence of hyperandrogenism, were recruited as controls. The incidence of dyslipidemia in the PCOS group was twice that of the Control group (76.1% versus 32.25%). The most frequent abnormalities were low high-density lipoprotein cholesterol (HDL-C; 57.6%) and high triglyceride (TG) (28.3%). HDL-C was significantly lower in all subgroups of women with PCOS when compared to the subgroups of normal women. No significant differences were seen in the total cholesterol (p = 0.307), low-density lipoprotein cholesterol (LDL-C; p = 0.283) and TGs (p = 0.113) levels among the subgroups. An independent effect on HDL-C was detected for glucose (p = 0.004) and fasting insulin (p = 0.01); on TG for age (p = 0.003) and homeostatic model assessment insulin resistance (p = 0.03) and on total cholesterol and LDL-C for age (p = 0.02 and p = 0.033, respectively). In conclusion, dyslipidemia is common in women with PCOS, mainly due to low HDL-C levels. BMI has a significant impact on this abnormality.

Metabolism of triglyceride-rich lipoproteins and lipid transfer to high-density lipoprotein in young obese and normal-weight patients with polycystic ovary syndrome

Objective: To clarify whether the metabolism of triglyceride-rich lipoproteins and lipid transfer to high-density lipoprotein (HDL) are altered in patients with polycystic ovary syndrome (PCOS). Design: Case control study. Setting: Endocrinology clinics. Patient(s): Eight normal-weight (NW) and 15 obese (013) patients with PCOS were compared with 10 NW and 10 Ob women without PCOS paired for age and body mass index. Intervention(s): Determination of triglyceride-rich lipoprotein metabolism and lipid transfer to HDL. Main Outcome Measure(s): Participants were injected triglyceride-rich emulsions labeled with (14)C-cholesteryl esters and (3)H-triglycerides and the fractional clearance rate (FCR, in min(-1)) of labels was determined. Lipid transfer from artificial nanoemulsions to HDL was performed by incubating radioactively labeled lipid nanoemulsions with plasma during 1 hour, followed by radioactive counting of HDL-containing supernatant after chemical precipitation. Result(s): Lipolysis estimated by triglyceride FCR was equal in PCOS groups (NW = 0.043 +/- 0.032, Ob = 0.033 +/- 0.009) and respective controls (NW = 0.039 +/- 0.015, Ob = 0.044 +/- 0.019). However, the remnant removal as estimated by cholesteryl ester FCR was reduced in both PCOS groups (NW = 0.005 +/- 0.006, Ob = 0.005 +/- 0.005) compared with controls (NW = 0.016 +/- 0.006, Ob = 0.011 +/- 0.072). Lipid transfer rates were not different among groups, but triglyceride transfer rates were positively correlated with homeostasis model assessment estimate of insulin resistance in PCOS. Conclusion(s): PCOS patients showed decreased removal of atherogenic remnants even when fasting glucose was <100 mg/dL. This reinforces the usefulness of the measures taken to prevent cardiovascular events in PCOS patients. (Fertil Steril (R) 2010;93:1948-56. (C)2010 by American Society for Reproductive Medicine.)

A new FOXL2 gene mutation in a woman with premature ovarian failure and sporadic blepharophimosis-ptosis-epicanthus inversus syndrome

Objective: To describe a new FOXL2 gene mutation in a woman with sporadic blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and hypergonadotropic hypogonadism. Design: Case report. Setting: University medical center. Patient(s): A 28-year-old woman. Intervention(s): Clinical evaluation, hormone assays, gene mutation research. Main Outcome Measure(s): FOXL2 gene mutation. Result(s): The patient with hypergonadotropic hypogonadism was diagnosed with BPES due to a new FOXL2 gene mutation. Conclusion(s): Blepharophimosis-ptosis-epicanthus inversus syndrome is a rare disorder associated with premature ovarian failure (POF). The syndrome is an autosomal dominant trait that causes eyelid malformations and POF in affected women. Mutations in FOXL2 gene, located in chromosome 3, are related to the development of BPES with POF (BPES type I) or without POF (BPES type II). This report demonstrates a previously undescribed de novo mutation in the FOXL2 gene-a thymidine deletion, c. 627delT (g. 864delT)-in a woman with a sporadic case of BPES and POF. This mutation leads to truncated protein production that is related to a BPES type I phenotype. This report shows the importance of family history and genetic analysis in the evaluation of patients with POF and corroborates the relationship between mutations on the FOXL2 gene and ovarian insufficiency. (Fertil Steril (R) 2010; 93: 1006.e3-e6. (C) 2010 by American Society for Reproductive Medicine.)

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines

Because of the advent of a new influenza A H1N1. strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barre syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21.5 cases of Guillain-Barre syndrome and 5.75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86.3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

TNF receptor-associated periodic syndrome (TRAPS): Description of a novel TNFRSF1A mutation and response to etanercept

TRAPS is the most common of the autosomal dominant periodic fever syndromes. It is caused by mutations in the TNFRSF1A gene, which encodes for the type 1 TNF-receptor (TNFR1). We describe here a Brazilian patient with TRAPS associated to a novel TNFRSF1A de novo mutation and the response to anti-TNF therapy. The patient is a 9-year-old girl with recurrent fevers since the age of 3 years, usually lasting 3 to 7 days, and recurring every other week. These episodes are associated with mild abdominal pain, nausea, vomiting and generalized myalgia. Recurrent conjunctivitis and erysipela-like skin lesions in the lower limbs also occur. Laboratory studies show persistent normocytic normochromic anemia, thrombocytosis, elevated erythrocyte sedimentation rate and C-reactive protein. IgD levels are normal. Mutational screening of TNFRSF1A revealed the association of a novel C30F mutation with the common R92Q low-penetrance mutation. The R92Q mutation is seen in 5% of the general population and is associated with an atypical inflammatory phenotype. The patient had a very good response to etanercept, with cessation of fever and normalization of inflammatory markers. Our report expands the spectrum of TNFRSF1A mutations associated with TRAPS, adding further evidence for possible additive effects of a low-penetration R92Q and cysteine residue mutations, and confirms etanercept as an efficacious treatment alternative.

Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): Description of a rare non-exon 3 and a novel CIAS1 missense mutation

We describe in this paper the phenotype-genotype analysis of a Brazilian cohort of patients with cryopyrin-associated periodic syndromes (CAPS). Patient 1 presented with an urticarial rash and recurrent fever exacerbated by cold weather, arthritis, and anterior uveitis, thus, receiving a clinical diagnosis of familial cold autoinflammatory syndrome. CIAS1 sequencing identified the T436I mutation, previously associated to a clinical phenotype of chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease. Patient 2 developed a papular exanthema with daily fever shortly after birth, frontal bossing, patellae enlargement, and cognitive and motor impairments. Sequencing identified the exceedingly rare G755R CIAS1 mutation in exon 4. Patient 3 developed skin rash and articular symptoms 6 h after birth, followed by aseptic meningitis. He was found to have the novel C148Y missense mutation in CIAS1. This report expands the spectrum of CIAS1 mutations associated to clinical disease, suggests that the same mutation can be associated with different clinical syndromes, and supports the evidence that CAPS patients should always be screened for mutations outside exon 3.

Optimizing the CAMCOG test in the screening for mild cognitive impairment and incipient dementia: saving time with relevant domains

Objective: To identify the CAMCOG sub-items that best contribute for the identification of patients with mild cognitive impairment (MCI) and incipient Alzheimer`s disease (AD) in clinical practice. Methods: Cross-sectional assessment of 272 older adults (98 MCI, 82 AD, and 92 controls) with a standardized neuropsychological battery and the CAMCOG schedule. Backward logistic regression analysis with diagnosis (MCI and controls) as dependent variable and the sub-items of the CAMCOG as independent variable was carried out to determine the CAMCOG sub-items that predicted the diagnosis of MCI. Results: Lower scores on Language, Memory, Praxis, and Calculation CAMCOG sub-items were significantly associated with the diagnosis of MCI. A composite score obtained by the sum of these scores significantly discriminated MCI patients from comparison groups. This reduced version of the CAMCOG showed similar diagnostic accuracy than the original schedule for the identification of patients with MCI as compared to controls (AUC = 0.80 +/- 0.03 for the reduced CAMCOG; AUC = 0.79 +/- 0.03 for the original CAMCOG). Conclusion: This reduced version of the CAMCOG had similar diagnostic properties as the original CAMCOG and was faster and easier to administer, rendering it more suitable for the screening of subtle cognitive deficits in general clinical practice. Copyright (C) 2010 John Wiley & Sons, Ltd.

Cognitive functioning in subjects with recent-onset psychosis from a low-middle-income environment: Multiple-domain deficits and longitudinal evaluation

Cognitive deficits are a key feature of recent-onset psychosis, but there is no consensus on whether such deficits are generalized or confined to specific domains. Besides, it is unclear whether cognitive deficits: a) are found in psychotic patients in samples from outside high-income countries; and b) whether they progress uniformly over time in schizophrenia and affective psychoses. We applied 12 tests organized into eight cognitive domains, comparing psychosis patients (n = 56, time from initial contact = 677.95+/-183.27 days) versus healthy controls (n = 70) recruited from the same area of Sao Paulo, Brazil. Longitudinal comparisons (digit span and verbal fluency) were conducted between a previous assessment of the subjects carried out at their psychosis onset, and the current follow-up evaluation. Psychosis patients differed significantly from controls on five domains, most prominently on verbal memory. Cognitive deficits remained detectable in separate comparisons of the schizophrenia subgroup and, to a lesser extent, the affective psychosis subjects against controls. Longitudinal comparisons indicated significant improvement in schizophrenia, affective psychoses, and control subjects, with no significant group-by-time interactions. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non-affective nature, which persist over time. (C) 2009 Elsevier Ireland Ltd. All rights reserved.