ABSTRACT
BACKGROUND: Sebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3-5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials. METHODS: We recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed. RESULTS: Analyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective. CONCLUSION: 5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the 'trough' periods before the next dosing, even with this intensive regimen.
Subject(s)
Sterol Esterase , Wolman Disease , Humans , Infant , Sterol Esterase/administration & dosage , Sterol Esterase/therapeutic use , Wolman Disease/drug therapyABSTRACT
BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.
Subject(s)
Bone Diseases , Gaucher Disease , Adult , Humans , Male , Female , Gaucher Disease/drug therapy , Gaucher Disease/diagnosis , Chitinase-3-Like Protein 1 , Lipocalin-2 , Follow-Up Studies , Quality of Life , Biomarkers , PainABSTRACT
It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechanisms through which cancer cells manipulate non-cancerous cell metabolism, and the subsequent impact on their survival and proliferation remains limited. Additionally, the variations in these processes across different cancer types and progression stages, and their implications for therapy, also remain largely unexplored. This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellular in-silico model that facilitates the qualitative and quantitative analysis of the metabolic network spawned by an in-vitro co-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE & Metabotools algorithms, the novel redHuman algorithm, along with 13C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating our in-silico model against the in-vitro model, we found that the in-silico model successfully reproduces vital metabolic behaviours of its in-vitro counterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells.
Subject(s)
Cancer Vaccines , Multiple Myeloma , Humans , Metabolic Networks and Pathways , Algorithms , Cell CycleABSTRACT
Cassava brown streak disease (CBSD), dubbed the "Ebola of plants", is a serious threat to food security in Africa caused by two viruses of the family Potyviridae: cassava brown streak virus (CBSV) and Ugandan (U)CBSV. Intriguingly, U/CBSV, along with another member of this family and one secoviridae, are the only known RNA viruses encoding a protein of the Maf/ham1-like family, a group of widespread pyrophosphatase of non-canonical nucleotides (ITPase) expressed by all living organisms. Despite the socio-economic impact of CDSD, the relevance and role of this atypical viral factor has not been yet established. Here, using an infectious cDNA clone and reverse genetics, we demonstrate that UCBSV requires the ITPase activity for infectivity in cassava, but not in the model plant Nicotiana benthamiana. HPLC-MS/MS experiments showed that, quite likely, this host-specific constraint is due to an unexpected high concentration of non-canonical nucleotides in cassava. Finally, protein analyses and experimental evolution of mutant viruses indicated that keeping a fraction of the yielded UCBSV ITPase covalently bound to the viral RNA-dependent RNA polymerase (RdRP) optimizes viral fitness, and this seems to be a feature shared by the other members of the Potyviridae family expressing Maf/ham1-like proteins. All in all, our work (i) reveals that the over-accumulation of non-canonical nucleotides in the host might have a key role in antiviral defense, and (ii) provides the first example of an RdRP-ITPase partnership, reinforcing the idea that RNA viruses are incredibly versatile at adaptation to different host setups.
Subject(s)
Manihot , Potyviridae , Manihot/genetics , Nucleotides , Plant Diseases , Potyviridae/genetics , Pyrophosphatases , RNA, Viral/analysis , RNA, Viral/genetics , RNA-Dependent RNA Polymerase , Tandem Mass SpectrometryABSTRACT
BACKGROUND & AIMS: COVID-19 patients present a high hospitalization rate with a high mortality risk for those requiring intensive care. When these patients have other comorbid conditions and older age, the risk for severe disease and poor outcomes after ICU admission are increased. The present work aims to describe the preliminary results of the ongoing NUTRICOVID study about the nutritional and functional status and the quality of life of adult COVID-19 survivors after ICU discharge, emphasizing the in-hospital and discharge situation of this population. METHODS: A multicenter, ambispective, observational cohort study was conducted in 16 public hospitals of the Community of Madrid with COVID-19 survivors who were admitted to the ICU during the first outbreak. Preliminary results of this study include data retrospectively collected. Malnutrition and sarcopenia were screened at discharge using MUST and SARC-F; the use of healthcare resources was measured as the length of hospital stay and requirement of respiratory support and tracheostomy during hospitalization; other study variables were the need for medical nutrition therapy (MNT); and patients' functional status (Barthel index) and health-related quality of life (EQ-5D-5L). RESULTS: A total of 176 patients were included in this preliminary analysis. Most patients were male and older than 60 years, who suffered an average (SD) weight loss of 16.6% (8.3%) during the hospital stay, with a median length of stay of 53 (27-89.5) days and a median ICU stay of 24.5 (11-43.5) days. At discharge, 83.5% and 86.9% of the patients were at risk of malnutrition and sarcopenia, respectively, but only 38% were prescribed MNT. In addition, more than 70% of patients had significant impairment of their mobility and to conduct their usual activities at hospital discharge. CONCLUSIONS: This preliminary analysis evidences the high nutritional and functional impairment of COVID-19 survivors at hospital discharge and highlights the need for guidelines and systematic protocols, together with appropriate rehabilitation programs, to optimize the nutritional management of these patients after discharge.
Subject(s)
COVID-19 , Malnutrition , Sarcopenia , Adult , Humans , Male , Female , Quality of Life , COVID-19/epidemiology , Sarcopenia/epidemiology , Functional Status , Retrospective Studies , Intensive Care Units , Hospitalization , Survivors , Malnutrition/epidemiology , Disease Outbreaks , Nutritional StatusABSTRACT
Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.
Subject(s)
Cytoskeletal Proteins/genetics , Exons/genetics , Neurodevelopmental Disorders/genetics , Sequence Deletion , Transcription Factors/genetics , Transcription Initiation Site , Child, Preschool , Cytoskeletal Proteins/biosynthesis , Cytoskeletal Proteins/deficiency , Dwarfism/genetics , Gene Expression Regulation , Genetic Association Studies , Humans , Male , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Syndrome , Transcription Factors/biosynthesis , Transcription Factors/deficiency , Transcription, GeneticABSTRACT
BACKGROUND: Since enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients' characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied. RESULTS: A total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications. CONCLUSIONS: Our work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications.
Subject(s)
Gaucher Disease , Machine Learning , Risk Factors , Adult , Enzyme Replacement Therapy , Female , Gaucher Disease/complications , Gaucher Disease/drug therapy , Gaucher Disease/genetics , Glucosylceramidase/therapeutic use , Humans , Incidence , Male , RegistriesABSTRACT
OBJECTIVE: An analysis of the SARS-CoV-2 pandemic impact in the Spanish Gaucher Disease (GD) community is presented here. PATIENTS & METHODS: The Spanish GD foundation (FEETEF) surveyed 113 GD patients from March 30 to April 27; all patients provided a verbal consent. RESULTS: 110 surveys were analyzed. The median age was 47 years old (y.o.), 31 patients were ≥ 60 y.o.; and 34% of patients reported comorbidities. 46% (51/110) of patients were treated by enzyme replacement therapy (ERT), 48 of them at hospitals; 45.1% (45/110) were on substrate reduction therapy (SRT) and 9% (10/110) receive no therapy. 25% (11/48) of ERT-hospital-based patients reported therapy interruptions, while SRT-patients did not report missing doses. No bone crises were reported. However, 50% (55/110) of patients reported being worried about their predisposition to a severe SARS-COV-2 infection and 29% (16/55) of them took anxiolytics or antidepressants for this. While 6 patients reported to have contact with an infected person, another two confirmed SARS-CoV-2 infections were reported in splenectomyzed patients, one of them (a 79-year-old diabetic) died. CONCLUSIONS: One quarter of the patients treated at hospitals reported dose interruptions. Home-based therapy may need to be considered in order to minimize the impact of the COVID-19 pandemic.
Subject(s)
Betacoronavirus , Continuity of Patient Care , Coronavirus Infections , Enzyme Replacement Therapy , Gaucher Disease/drug therapy , Glucosylceramidase/therapeutic use , Home Care Services, Hospital-Based , Pandemics , Pneumonia, Viral , Adult , Aged , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Anxiety/drug therapy , Anxiety/etiology , COVID-19 , Combined Modality Therapy , Comorbidity , Depression/drug therapy , Depression/etiology , Diabetes Mellitus/epidemiology , Disease Susceptibility , Enzyme Replacement Therapy/methods , Female , Gaucher Disease/psychology , Gaucher Disease/surgery , Glucosylceramidase/supply & distribution , Humans , Immunocompromised Host , Male , Middle Aged , SARS-CoV-2 , Spain/epidemiology , Splenectomy/adverse effects , Young AdultABSTRACT
El corioangioma es el tumor benigno de la placenta más frecuente. Cuando esta lesión es mayor de 5cm puede causar diversas complicaciones maternofetales, por lo que es importante realizar su diagnóstico prenatal. Presentamos el caso de un coriangioma placentario gigante de 12 x 8cm(AU)
The chorioangioma is the most common benign tumour of the placenta. Lesions larger than 5cm may cause various foetal and maternal complications. Prenatal diagnosis is very important. We report a case of a giant placental chorioangioma measuring 12 x 8cm(AU)
Subject(s)
Humans , Male , Female , Pregnancy , Adult , Hemangioma/complications , Hemangioma/diagnosis , Prenatal Diagnosis/instrumentation , Prenatal Diagnosis/methods , Prenatal Diagnosis , Hemangioma/physiopathology , Hemangioma , Biometry/instrumentation , Biometry/methodsABSTRACT
Los gemelos siameses o gemelos unidos son gemelos monocigóticos, monoamnióticos, monocoriales, unidos entre sí por alguna región de su anatomía, como resultado de una división incompleta del disco embrionario que ocurre después del día 13 de la concepción. Presentamos el caso de unos siameses parapagus tetrabrachius dipus, diagnosticados de forma temprana mediante ecografía a la 11+5 semanas de gestación(AU)
Conjoined twins are defined as monozygotic, monochorionic and monoamniotic twins fused at any portion of their body as a result of an incomplete division of the embryonic disk, which occurs after the 13th day of conception. We present a case report describing the first trimester ultrasound diagnosis of Parapagus Tetrabrachius Dipus twins(AU)
Subject(s)
Humans , Male , Female , Twins, Conjoined/embryology , Twins, Conjoined/physiopathology , Prenatal Diagnosis/instrumentation , Prenatal Diagnosis/methods , Prenatal Diagnosis , Diagnostic Techniques, Obstetrical and Gynecological/trends , Prenatal Diagnosis/trendsABSTRACT
La aplasia cutis congénita es un rara alteración caracterizada por ausencia localizada de epidermis y dermis, y según su profundidad en ocasiones compromete tejidos subyacentes. El pronóstico está determinado por el tamaño, la presencia de malformaciones asociadas y la localización del defecto, siendo el cuero cabelludo la forma más frecuente (AU)
Aplasia cutis congenita is a rare condition characterized by localized absence of epidermis, dermis and in some cases the underlying tissues. The prognosis is determined by the presence of associated malformations and the size and location of the defect, the scalp being the most frequently affected area (AU)
Subject(s)
Humans , Female , Pregnancy , Adult , Prenatal Diagnosis/methods , Skin Diseases, Genetic/diagnosis , Amenorrhea/complications , Amenorrhea/diagnosis , Amniocentesis/methods , Prenatal Diagnosis/trends , Epidermis/pathology , Dermis/pathology , Longitudinal Studies , Cross-Sectional Studies , Spine , Diagnosis, DifferentialABSTRACT
La tuberculosis (TB) genital es una entidad decurso insidioso que, en el caso de ser sintomática,se manifiesta con infertilidad, sangrado uterinoanormal, amenorrea, metrorragia posmenopáusica,dolor y/o masa pélvica. El diagnóstico definitivo sehace con cultivo de flujo menstrual o biopsiaendometrial para Mycobacterium tuberculosis. Sepresenta el caso de una paciente de 78 años, conpiometra, cuyo diagnóstico final fue de TBendometrial
Genital tuberculosis follows an insidious course.Symptomatic disease usually presents withinfertility, menstrual abnormalities, amenorrhea,postmenopausal bleeding, abdominal pain and/orpelvic mass. The definitive diagnosis should beconfirmed by culture of menstrual blood orendometrial biopsy tissue for Mycobacteriumtuberculosis. We report the case of a 78-year-oldpatient with pyometra in whom endometrialtuberculosis was confirmed by culture findings
Subject(s)
Humans , Female , Aged , Tuberculosis, Female Genital/diagnosis , Endometritis/microbiology , Tuberculosis, Female Genital/drug therapy , Mycobacterium tuberculosis/isolation & purificationABSTRACT
The aim of this study is to assess whether gender and body mass index (BMI) should be considered in developing thresholds to define GH deficiency, using GH responses to GHRH + arginine (ARG) stimulation and insulin tolerance test (ITT). Thirty-nine healthy subjects (19 males, 20 females; ages 21-50 yr) underwent GHRH + ARG, and another 27 subjects (19 males, 8 females; ages 20-49 yr) underwent ITT. Peak GH response was significantly higher (P = 0.005) after GHRH + ARG than with ITT, and this difference could not be explained by age, gender, or BMI. Peak GH response was negatively correlated with BMI in both tests (GHRH + ARG, r = -0.76; and ITT, r = -0.65). Peak GH response to GHRH + ARG was higher in females than males (P = 0.004; ratio = 2.4), but it was attenuated after eliminating the influence of BMI (P = 0.13; ratio = 1.6). No significant gender differences were found in peak GH responses to ITT, which could be due to the smaller number of female subjects studied. GH response to GHRH + ARG and ITT stimulation is sensitive to BMI differences and less so to gender differences. A higher BMI is associated with a depressed GH response to both stimulation tests. BMI should therefore be considered as a factor when defining the diagnostic cut-off points in the assessment of GH deficiency, whereas whether gender should be likewise used is inconclusive from this study.
Subject(s)
Arginine , Body Mass Index , Human Growth Hormone/deficiency , Metabolic Diseases/diagnosis , Oligopeptides , Adult , Diagnostic Techniques, Endocrine , Female , Human Growth Hormone/blood , Humans , Insulin/metabolism , Insulin Resistance , Male , Middle Aged , Sex CharacteristicsABSTRACT
The cyclooxygenase (COX)-2 enzyme has been implicated in the pathogenesis of several inflammatory diseases. However, its role in diabetic vascular disease is unclear. In this study, we evaluated the hypothesis that diabetic conditions can induce COX-2 in monocytes. High glucose treatment of THP-1 monocytic cells led to a significant three- to fivefold induction of COX-2 mRNA and protein expression but not COX-1 mRNA. High glucose-induced COX-2 mRNA was blocked by inhibitors of nuclear factor-kappaB (NF-kappaB), protein kinase C, and p38 mitogen-activated protein kinase. In addition, an antioxidant and inhibitors of mitochondrial superoxide, NADPH oxidase, and glucose metabolism to glucosamine also blocked high glucose-induced COX-2 expression to varying degrees. High glucose significantly increased transcription from a human COX-2 promoter-luciferase construct (twofold, P < 0.001). Promoter deletion analyses and inhibition of transcription by NF-kappaB superrepressor and cAMP-responsive element binding (CREB) mutants confirmed the involvement of NF-kappaB and CREB transcription factors in high glucose-induced COX-2 regulation. In addition, isolated peripheral blood monocytes from type 1 and type 2 diabetic patients had high levels of COX-2 mRNA, whereas those from normal volunteers showed no expression. These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications.
Subject(s)
Gene Expression Regulation, Enzymologic/drug effects , Glucose/pharmacology , Isoenzymes/genetics , Monocytes/enzymology , Prostaglandin-Endoperoxide Synthases/genetics , Transcription, Genetic/drug effects , Base Sequence , Cell Line , Cycloheximide/pharmacology , Cyclooxygenase 1 , Cyclooxygenase 2 , DNA Primers , Dactinomycin/pharmacology , Humans , Membrane Proteins , Monocytes/drug effects , RNA, Messenger/geneticsABSTRACT
The transcription factor NF-kappaB (NF-kappaB) plays a pivotal role in regulating inflammatory gene expression. Its effects are optimized by various coactivators including histone acetyltransferases (HATs) such as CBP/p300 and p/CAF. Evidence shows that high glucose (HG) conditions mimicking diabetes can activate the transcription of NF-kappaB-regulated inflammatory genes. However, the underlying in vivo transcription and nuclear chromatin remodeling events are unknown. We therefore carried out chromatin immunoprecipitation (ChIP) assays in monocytes to identify 1) chromatin factors bound to the promoters of tumor necrosis factor-alpha (TNF-alpha) and related NF-kappaB-regulated genes under HG or diabetic conditions, 2) specific lysine (Lys (K)) residues on histone H3 (HH3) and HH4 acetylated in this process. HG treatment of THP-1 monocytes increased the transcriptional activity of NF-kappaB p65, which was augmented by CBP/p300 and p/CAF. ChIP assays showed that HG increased the recruitment of NF-kappaB p65, CPB, and p/CAF to the TNF-alpha and COX-2 promoters. Interestingly, ChIP assays also demonstrated concomitant acetylation of HH3 at Lys(9) and Lys(14), and HH4 at Lys(5), Lys(8), and Lys(12) at the TNF-alpha and COX-2 promoters. Overexpression of histone deacetylase (HDAC) isoforms inhibited p65-mediated TNF-alpha transcription. In contrast, a HDAC inhibitor stimulated gene transcription and histone acetylation. Finally, we demonstrated increased HH3 acetylation at TNF-alpha and COX-2 promoters in human blood monocytes from type 1 and type 2 diabetic subjects relative to nondiabetic. These results show for the first time that diabetic conditions can increase in vivo recruitment of NF-kappaB and HATs, as well as histone acetylation at the promoters of inflammatory genes, leading to chromatin remodeling and transcription.
Subject(s)
Chromatin/chemistry , Diabetes Mellitus/metabolism , Transcription, Genetic , Acetylation , Acetyltransferases/metabolism , Cell Line , Cell Nucleus/metabolism , Cells, Cultured , Chromatin/metabolism , Glucose/metabolism , Histone Acetyltransferases , Histone Deacetylases/chemistry , Histones/chemistry , Humans , Inflammation , Luciferases/metabolism , Lysine/chemistry , Monocytes/metabolism , NF-kappa B/metabolism , Precipitin Tests , Promoter Regions, Genetic , Protein Binding , Protein Isoforms , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transfection , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Klinefelter syndrome (KS) is a sex chromosome abnormality associated with male infertility and mild cognitive deficits. Individuals with KS have been reported to have impaired verbal ability, as well as deficits in executive function. To further understand the nature of their deficits, we assessed specific elements of frontal lobe function such as working memory and relational reasoning. Men with KS exhibited a deficit in a transitive inference task in which participants ordered a set of names based on a list of propositions about the relative heights of the people named. This deficit was present even for items in which the propositions were given in order, so a chaining strategy could be used. Men with KS are also impaired on the n-back task, which uses letters as stimuli. In contrast, these men performed as well as controls in nonverbal reasoning (Raven's Progressive Matrices). These results suggest that men with KS have intact nonverbal reasoning abilities, but that a difficulty in encoding verbal information into working memory may underlie their executive and linguistic impairments.
Subject(s)
Intelligence/physiology , Klinefelter Syndrome/physiopathology , Memory, Short-Term/physiology , Adult , Case-Control Studies , Humans , Intelligence Tests , Male , Neuropsychological Tests , Problem Solving , Semantics , Verbal LearningABSTRACT
This study aimed to characterize cerebral perfusion in men with Klinefelter's syndrome, known to present specific deficits in language, using (99m)Tc- hexamethylpropylene-amine-oxime scintigraphy and Talairach normalization. While a perfusion asymmetry toward the left hemisphere was found in controls, perfusion was mostly symmetrical in Klinefelter patients in the upper temporal and lower parietal areas. Scores on verbal tests were inversely correlated with perfusion changes, providing neurobiological substrate of anomalous cerebral laterality.
Subject(s)
Brain/blood supply , Functional Laterality , Klinefelter Syndrome/diagnostic imaging , Klinefelter Syndrome/physiopathology , Tomography, Emission-Computed, Single-Photon , Adolescent , Adult , Brain/pathology , Cerebrovascular Circulation , Cognition , Humans , Image Processing, Computer-Assisted , Klinefelter Syndrome/pathology , Male , Neuropsychological Tests , RadiographyABSTRACT
OBJECTIVE: To evaluate the feasibility of using [(18)F]fluorodeoxyglucose ((18)FDG) triple-head coincidence imaging as a potential cost-effective alternative to positron emission tomography in the setting of suspected recurrence of papillary thyroid carcinoma. METHODS: We retrospectively studied 10 patients with suspected recurrence of papillary carcinoma of the thyroid, who underwent (18)FDG coincidence imaging,(131)I scanning, and a reference anatomic scan (computed tomography, magnetic resonance imaging, or both) within 1 year in most cases. RESULTS: The (131)I scan detected the recurrence in five patients (62.5%) and failed to reveal recurrent cancer in three patients (37.5%); in contrast,(18)FDG imaging detected the recurrence in eight patients (100%) and was true negative in two patients in whom the scans were performed more than 1 year after effective therapy for the recurrence. The sensitivity of detection was unrelated to lesion size. The (18)FDG imaging results led to additional radiotherapy in all (131)I-negative patients, two of whom had high thyroglobulin levels and one of whom had a low thyroglobulin concentration but the presence of antithy-roglobulin antibodies. CONCLUSION: We conclude that (18)FDG triple-head coincidence imaging is useful for routine management of patients with thyroid cancer who have no abnormalities detected on (131)I scans but have high serum thyroglobulin levels. This technique, however, may not be as sensitive as a dedicated positron emission tomographic device, particularly for the assessment of small tumors.