Cardiac hemodynamics in fetuses with transposition of the great arteries and intact ventricular septum from diagnosis to end of pregnancy: longitudinal follow-up.

OBJECTIVES: Little is known about cardiac hemodynamics in the fetus with transposition of the great arteries and intact ventricular septum (TGA-IVS). Better understanding of the fetal physiology in TGA-IVS would help to provide insights into specific clinical complications observed after birth, in particular neonatal hypoxia and pulmonary hypertension. The aim of this study was to assess cardiac hemodynamics in fetuses with TGA-IVS by performing systematic longitudinal echocardiographic follow-up from diagnosis to delivery. METHODS: This was a longitudinal retrospective study of fetuses referred between 2010 and 2018 to the Sainte-Justine University Hospital Centre. Complete assessment of cardiac hemodynamics was performed in fetuses with TGA-IVS at 18-22, 28-32 and 35-38 weeks' gestation, which were compared with normal fetuses matched for gestational age. The maximum diameter of the foramen ovale was measured using two-dimensional echocardiography under the guidance of color Doppler echocardiography. Fetal cardiac hemodynamics were analyzed according to postnatal preductal transcutaneous oxygen saturation (TcSO2 ) < 65% or ≥ 65%, as a neonatal outcome, in fetuses with TGA-IVS. RESULTS: In total, 59 fetuses with TGA-IVS and 160 normal fetuses were included. Global cardiac output was significantly higher in fetuses with TGA-IVS than in controls, mainly owing to higher global pulmonary output, while global systemic cardiac output did not differ between TGA-IVS fetuses and controls throughout pregnancy. Aortic flow (right ventricular output in fetuses with TGA-IVS, left ventricular output in controls) was significantly higher in fetuses with TGA-IVS than in normal fetuses. Ductal flow was significantly lower in fetuses with TGA-IVS at every timepoint, and this difference increased considerably after 28-32 weeks. In parallel, the diameter of the foramen ovale was significantly smaller in fetuses with TGA-IVS at 28-32 and 35-38 weeks, with a stagnation in growth after 28 weeks, compared with continuous growth in normal fetuses. Most of these cardiac hemodynamic anomalies in fetuses with TGA-IVS were already present at 18-22 weeks, and the differences became greater at 28-32 weeks' gestation. TGA-IVS neonates with TcSO2 < 65% had lower fetal left ventricular output, higher diastolic ductal retrograde flow and smaller foramen ovale at 28-32 weeks, compared with fetal values in those with postnatal TcSO2 ≥ 65%. CONCLUSIONS: Compared with normal fetuses, those with TGA-IVS undergo a complex redistribution of blood flow during the second half of pregnancy, with higher global pulmonary flow, lower ductal flow (with negative diastolic flow at the end of pregnancy) and a smaller foramen ovale. In addition, fetal cardiac hemodynamic anomalies observed at 28-32 weeks' gestation were associated with lower postnatal TcSO2 . These observations may provide a better understanding of premature closure of the foramen ovale and postnatal hypoxia that are specific to TGA-IVS physiology. © 2019 International Society of Ultrasound in Obstetrics and Gynecology.

Poor adherence to population-based vaccination in two counties after meningococcal B:14:P1.7,16 outbreak: an illustration of the growing vaccine hesitancy in France.

BACKGROUND: Neisseria meningitidis is a virulent bacteria provoking outbreaks of invasive meningococcal disease (IMD) that authorities may try to control with population-based vaccinations. Such campaigns are most often thoroughly followed. We assess the response of poor adherence during a population-based vaccination after a meningococcal B:14:P1.7,16 outbreak. METHODS: Between July, 2012, and April, 2013, six cases including one fatality of invasive meningococcal disease related to N. meningitidis B:14:P1.7,16/ST32 were reported in two neighboring counties. A vaccination campaign with MenBVac® targeting 6911 inhabitants was implemented. People entering the vaccination schedule from January 2014 received 4CMenB. RESULTS: The number of immunized patients proved to be low, with 1721 (24.1%) receiving at least one dose out of 5069 doses administered. However, the incidence of IMD in the zone dramatically fell, with only one purpura fulminans case in June 2014 with a good outcome. The campaign was stopped after 1 year and a 2-year monitoring period was implemented until June, 2016, with no new cases. CONCLUSIONS: This outbreak probably self-terminated in a context of a low incidence of serogroup B IMD during 2014 in France. Poor adherence illustrates the growing vaccine hesitancy in France. Similar campaigns will have to be thoroughly planned and implemented in terms of timing, modalities of injections, and mass communication.

Pilot study on 18 F-FDG PET/CT for detection of inflammatory changes in blood-induced knee arthropathy in a rabbit model.

RATIONALE: 18 F-FDG-PET/CT has a potential role in the early detection of haemophilic arthritis, at a time when treatment may still avoid further joint degeneration. The purposes of this pilot study were to determine the ability of 18 F-FDG-PET/CT to detect inflammatory changes associated with blood-induced arthropathy in knees of a rabbit model. METHODS: Ten juvenile rabbits were imaged at baseline and weeks 5 and 17 post intraarticular autologous blood injections (ABI). Five rabbits in group 1 (G1) had ABI into the same knee joint every 2 weeks (total, eight injections). Five rabbits in group 2 (G2) had only two injections into the same knee, at weeks 5 and 17. Images were assessed visually and semi-quantitatively by measuring maximal standardized uptake values (SUVmax) and standardized uptake ratio (SUR = SUVmax in affected knee/SUVmax in non-affected knee). RESULTS: More rabbits in G1 than G2 presented with positive chronic inflammatory synovial scores at week 17. Mean iron staining scores in injected knees were greater for G1 than for G2 (P = 0.049). No increased uptake was identified in the injected knees in any of the rabbits at baseline or at week 5. At week 17, all G1 rabbits demonstrated increased uptake in their affected knees with higher mean SUVmax (1.5) than normal knees (1.0) (P < 0.02). None of the G2 rabbits showed asymmetric increased uptake. The SUR of G1 was higher at week 17 compared to baseline (P < 0.01) and week 5 (P < 0.01). The SUR at week 17 was higher for G1 than for G2 (1.13) rabbits (P < 0.01). CONCLUSION: 18 F-FDG-PET is able to detect the inflammatory changes associated with haemophilic arthropathy in this experimental model.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts.

BACKGROUND: CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS: Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS: At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS: ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

Histology of solid lateral cervical masses biopsied in children.

INTRODUCTION: Solid cervical lateral neck masses in children may require surgical biopsy to confirm appropriate diagnostic and begin a directed therapeutic treatment. We aimed to describe the contribution of pathological results and compare them with the clinical diagnosis and the paraclinical tools. METHODS: A retrospective review of surgical biopsies for solid lateral neck masses in children over a ten year period in a pediatric tertiary center was conducted. Demographic, imaging, laboratory analysis, surgical and pathological data were collected and analyzed using descriptive statistics with SPSS 17.0. RESULTS: 44 biopsies were done between 2002 and 2012. Inflammatory masses were found in 26/44 biopsies with half of them (13/26) being nontuberculous mycobacterial (NTM) lymphadenitis. Non-inflammatory/benign masses represented 9/44 biopsies and 5/44 masses were of malignant etiology. Malignant masses imaging had a sensitivity and specificity of 33% and 75%, respectively, for ultrasound, whereas Neck CT scan had 33% and 77%, respectively. The contribution of pathological results to the clinical management was questionable in 39% (17/44) of biopsies. CONCLUSION: Inflammatory masses with NTM lymphadenitis were the most common diagnosis. Imaging was not helpful in establishing the diagnosis. Heterogeneity in the management of solid lateral neck masses between clinicians was important and indicates the need for guideline approach.

Shopper cards data and storage practices for the investigation of an outbreak of Shiga-toxin producing Escherichia coli O157 infections.

INTRODUCTION: An outbreak of shiga-toxin producing Escherichia coli infections occurred in southwest France in June 2012. The outbreak was investigated to identify the source of infection, and guide control measures. METHODS: Confirmed outbreak cases were patients who developed bloody diarrhoea or haemolytic uremic syndrome (HUS) between 28 May and 6 July 2012, with E. coli O157 isolates showing indistinguishable patterns on pulse field gel electrophoresis (PFGE). A standardized questionnaire was administered to patients to document food consumption and other risk exposures. Their purchase was checked through their supermarket shopper card data. RESULTS: Six patients (four with HUS and two with bloody diarrhea) were confirmed outbreak cases. Fresh ground beef burgers from one supermarket were the only common food exposure, identified by interviews and shopper card data. The PFGE profile of shiga toxin-producing E. coli O157 isolated from the suspected beef burgers was identical to those from the human cases. The suspected beef burgers were no longer on sale at the time of investigation but three patients confirmed as outbreak cases had deep-frozen some at home. CONCLUSION: Shopper card data was particularly useful to obtain precise and reliable information on the traceability of consumed food. Despite the expired use-by date, a recall was issued for the beef burgers. This contributed to preventing other cases among consumers who had deep-frozen the beef burgers.

Contemporary approach to diagnosis and treatment of neuroblastoma.

The diagnostic value of Metaiodobenzylguanidine (MIBG) scintigraphy in the management of neuroblastoma is well established. The specificity of MIBG is virtually 100% and remains the most specific imaging modality. Numerous semi-quantitative scores and guidelines have emerged in the last decade that illustrate standardization of the procedure. Other pharmaceuticals such as norcholesterol derivatives, [111In]pentetreotide and [68Ga]somatostatin analogs, [18F]fluorodeoxyglucose, [18F]fluorodopa, [18F]fluorodopamine, [11C]meta hydroxyephedrine, and [11C] /[18F] /[123I]Metomidate (MTO) have been or are being evaluated currently (including development of new analogues labeled with positron emitting radionuclides such as [124I], [18F], and [76Br]. Radiopharmaceutical therapy of neuroblastoma, initiated over 30 years ago, demonstrates that a significant fraction of patients enter partial remission but complete remission is rare and relapse is frequent. With the combination of chemotherapy, radiosensitizers, and autologous stem cell support, some centers have seen overall response rates of up to 30% in refractory or recurrent diseases. Topoisomerase I inhibitor topotecan may improve upon existing [131I]MIBG therapy. Areas of future development may be in vitro cultures and animal models, proper instrumentation to acquire sub-centimeter resolution and human clinical trials to evaluate treatment at earlier times or stages of disease, evaluation with concomitant immunotherapy with monoclonal antibodies targeting the GD2 ganglioside or inhibitors of anaplastic lymphoma kinase. Because of the complexity of those trials, progress remains extremely slow as well designed multicenter studies are required. Nonetheless, the future has never been so hopeful.

[Detection of Aspergillus antigen galactomannan using ELISA method: validation of the performances of the method for accreditation]. / Validation d'une méthode Elisa pour la recherche de l'antigène aspergillaire galactomannane en vue de l'accréditation.

Diagnosis of invasive aspergillosis for patients with high risk of infection is based on the monitoring of Aspergillus antigenemia assessed by the detection of galactomannan in serum by a sandwich-type ELISA (Biorad(®)). The validation of the method was displayed according to the guide COFRAC SH GTA 04. The internal quality control system settled, involves two quality control samples made of pools of sera (negative and positive). The repeatability of the measurements, as estimated by the coefficients of variation (CV), obtained by two different technicians was found from 9 to 13.7% for the positive control. The CV of the negative control, for which the provider indicates it is not useful in the analytical process, was found from 7.1 to 30%. In our experience it could be an indicator of environmental contamination. The evaluation of the intermediary fidelity was 15.7% for the positive control and 22.5% for the negative one. In the lack of reference material (International Standard) and recommendation from scientific societies, performances obtained will be discussed according to the results reported in the technical form of the supplier and those obtained by 39 laboratories participating in the only available external quality assessment program organized in France by ProBioQual(®) where the CV of reproducibility are 44.7% of unit (mean index 0.131) for the negative control and 18% (mean index 1.089) for the positive one in 2011.

Anatomical distribution of vertebral fractures: comparison of pediatric and adult spines.

SUMMARY: We compared the distribution of vertebral fractures in adults and children and found that fractures occurred in different locations in the two age groups. This likely relates to the different shape of the immature spine. INTRODUCTION: We hypothesized that the anatomical distribution of vertebral fractures (VF) would be different in children compared to adults. METHODS: We compared the distribution of VF defined using the Genant semi-quantitative method (GSQ method) in adults (N = 221; 545 fractures) and in children early in the course of glucocorticoid therapy (N = 44; 94 fractures). RESULTS: The average age in the adult cohort was 62.9 years (standard deviation (SD), 13.4 years), 26% was male, the mean lumbar spine Z-score was -1.0 (SD, 1.5), and the corresponding T-score was -2.4 (SD, 1.4). The pediatric cohort median age was 7.7 years (range, 2.1-16.6 years), the mean lumbar spine Z-score was -1.7 (SD, 1.5), 52% was male, and disease categories were acute lymphoblastic leukemia (66%), rheumatological conditions (21%), and nephrotic syndrome (14%). The VF distribution was biphasic in both populations, but the peaks differed in location. In adults, the peaks were at T7/T8 and at T12/L1. In children, the focus was higher in the thoracic spine, at T6/T7, and lower in the lumbar spine, at L1/L2. When children were assessed in two age-defined sub-groups, a biphasic VF distribution was seen in both, but the upward shift of the thoracic focus to T6 was observed only in the older group, with the highest rates of fracture present between ages 7 and 10 years. CONCLUSIONS: These results suggest that the anatomical distribution of VF differs between children and adults, perhaps relating to the different shape of the immature spine, notably the changing ratio of kyphosis to lordosis.

Household transmission of haemolytic uraemic syndrome associated with Escherichia coli O104:H4, south-western France, June 2011.

Following the outbreak of haemolytic uraemic syndrome (HUS) on June 2011 in south-western France, household transmission due to Escherichia coli O104:H4 was suspected for two cases who developed symptoms 9 and 10 days after onset of symptoms of the index case. The analysis of exposures and of the incubation period is in favour of a secondary transmission within the family. Recommendations should be reinforced to prevent person-to-person transmission within households.

Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models.

Using knockout and transgenic technology, genetically modified animal models allowed us to understand the role of glucagon signalling in metabolism. Mice with a global deletion of the glucagon receptor gene (Gcgr) were designed using gene targeting. The phenotype of Gcgr(-/-) mouse provided important clues about the role of Gcgr in foetal growth, pancreatic development and glucose and lipid homeostasis. The lack of Gcgr activation was associated with: (i) hypoglycaemic pregnancies, poor foetal growth and increased foetal-neonatal demise; (ii) altered cytoarchitecture of pancreatic islets; (iii) altered glucose, lipid and hormonal milieu; (iv) reduced gastric emptying; (v) altered body composition and protection from diet-induced obesity; (vi) altered energy state; (vii) impaired hepatocyte survival; (viii) altered metabolic response to prolonged fasting and exercise and (ix) prevented development of diabetes in insulin-deficient mice. In contrast, mice overexpressing the Gcgr on pancreatic ß-cells displayed an increase insulin secretion, pancreatic insulin content and ß-cell mass, and partially protected against hyperglycaemia and impaired glucose tolerance when fed a high-fat diet. These findings suggest that glucagon signalling plays a significant role in the regulation of glucose and lipid homeostasis. Treatment options designed to block Gcgr activation may have negative implications in the treatment of diabetes.

Assessing the impact of non-dilating the eye on full-field electroretinogram and standard flash response.

We investigated the possibility of performing electroretinography (ERG) in non-pharmacologically dilated eyes using brighter flash (time-integrated) luminance. Photopic (N = 26; background 25.5 cd·m(-2), white LED flashes) and scotopic ERG (N = 23, green LED flashes) luminance response functions were obtained simultaneously in a dilated (DE) and non-dilated eye (NDE). In the NDE, photopic V (max) b-wave amplitude was reduced by 14% (P < 0.0001), implicit time prolonged (P < 0.0001), and retinal sensitivity (log K) decreased by 0.38 log units (P < 0.0001) with no effect on a-wave. Using a xenon strobe light (N = 6) to increase flash luminance, V (max) remained lower by about 12% in the NDE (P = 0.02). V (max) with LED and xenon was achieved at 3.9 ± 1.0 cd·s·m(-2) and 3.3 ± 0.81 cd·s·m(-2) in the DE and 10.6 ± 1.2 cd·s·m(-2) and 12.3 ± 1.90 cd·s·m(-2) in the NDE, that is an increase of 0.43 and 0.57 log unit (P < 0.0001), respectively. Increasing background luminance by 0.50 log units (80 cd·m(-2), N = 4) resulted in implicit time normalization but not V (max) amplitude. Rod V (max) was decreased by 7% in NDE (P < 0.05) and sensitivity reduced by 0.40 log units (P < 0.0001), but our data suggest that the luminance may have not been sufficient to reach V (max) in all participants in the NDE and that the sensitivity change may have been due to an inadequate inter-stimulus interval. For the photopic ERG, increasing flash luminance is not sufficient to compensate for the smaller pupil size, whereas for the scotopic ERG, more data are needed to establish proper inter-stimulus interval to perform recordings in a non-pharmacologically dilated.

Circadian variation in the electroretinogram and the presence of central melatonin.

The light/dark cycle is the most important circadian clock synchronizer for mammals and humans. Circadian rhythms of dopamine and melatonin production in the retina have been reported to follow the light and dark cycle, but their impact on rod and cone functioning is not clear. The purpose of this study was to assess diurnal variations (morning vs. evening) in retinal function as measured with the photopic and scotopic electroretinogram (ERG). We also tried to correlate our results with the presence or absence of melatonin secretion in the saliva. Photopic and scotopic luminance-response functions were obtained in 29 participants at 11:00 (when melatonin should not be present) and 23:00 (when melatonin should be present). From the luminance-response function, Vmax, log K and slope parameters were derived. In scotopic condition, a significant increase of 6% in Vmax amplitude was observed in evening compared to morning (P = 0.03) along with a prolonged b-wave implicit time of 8% (P = 0.01) and an increase in rod sensitivity in evening compared to morning (P = 0.02). As expected, these changes in rod function were accompanied by a higher concentration of melatonin in saliva samples in the evening (P = 0.01). In photopic condition, only a prolonged a-wave implicit time of 5% was observed in evening when compared to morning (P = 0.02). Our findings suggest that the rod system is favored during night time, when circulating melatonin is present. Although statistically significant changes were observed, the day vs. night difference observed in the present study appears to be too small to impact significantly upon clinical assessment of retinal function.

A pitfall of radioisotope quantification of the ratio of pulmonary blood flow to systemic blood flow (Qp/Qs) in a patient with severe postoperative pulmonary venous obstruction.

PURPOSE: We report a case with initial misinterpretation of the radionuclide angiocardiographic study that was obtained in a child with persistent tachypnea and concern for residual left to right shunt after prior repair of total anomalous pulmonary veins and an atrial septal defect. MATERIALS AND METHODS: Ultrasound, radionuclide angiocardiogram, and magnetic resonance imaging studies were obtained. RESULTS: The radionuclide study was ordered after an unremarkable ultrasound. Unsuspected severely reduced left pulmonary arterial flow associated with high-grade ipsilateral pulmonary venous obstruction led to misinterpretation of the radionuclide study as a large residual shunt. Later replotting of the graphic data using each lung separately corrected the error. Magnetic resonance played a key role in making the correct diagnosis. CONCLUSIONS: Significant asymmetric pulmonary flow due to vascular obstruction is an important additional potential pitfall to recognize in interpreting radionuclide angiocardiographic studies.

Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates.

Patients on a statin regimen have a decreased risk of death due to bacterial sepsis. We have found that protection by simvastatin includes the inhibition of host cell invasion by Staphylococcus aureus, the most common etiologic agent of sepsis. Inhibition was due in part to depletion of isoprenoid intermediates within the cholesterol biosynthesis pathway and led to the cytosolic accumulation of the small GTPases CDC42, Rac, and RhoB. Actin stress fiber disassembly required for host invasion was attenuated by simvastatin and by the inhibition of phosphoinositide 3-kinase (PI3K) activity. PI3K relies on coupling to prenylated proteins, such as this subset of small GTPases, for access to membrane-bound phosphoinositide to mediate stress fiber disassembly. Therefore, we examined whether simvastatin restricts PI3K cellular localization. In response to simvastatin, the PI3K isoform p85, coupled to these small-GTPases, was sequestered within the cytosol. From these findings, we propose a mechanism whereby simvastatin restricts p85 localization, inhibiting the actin dynamics required for bacterial endocytosis. This approach may provide the basis for protection at the level of the host in invasive infections by S. aureus.

Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia.

AIMS/HYPOTHESIS: Under normal physiological conditions, glucagon signalling is important in glucose homeostasis. Hyperglucagonaemia or altered insulin:glucagon ratio plays a role in maintaining hyperglycaemia in subjects with type 2 diabetes. It has been reported that glucagon receptor knockout (Gcgr (-/-)) mice develop normally and have lower plasma glucose on a normal diet. The goal of the current research was to further investigate the role of glucagon signalling in metabolic control and glucose homeostasis. METHODS: Gcgr (-/-) mice were challenged with a high-fat diet (HFD) and with streptozotocin, which induces beta cell damage. They were then analysed for whole-body and serum metabolic phenotypes as well as pancreatic islet morphology. RESULTS: In comparison with wild-type mice, Gcgr (-/-) mice exhibited decreased body weight and food intake, reduced plasma glucose levels, and improved oral and intraperitoneal glucose tolerance. Elevated glucagon-like peptide-1 levels and reduced gastric emptying were also observed in Gcgr (-/-) mice, which also had reduced HFD-induced hyperinsulinaemia and hyperleptinaemia, and were resistant to the development of hepatic steatosis. In addition, Gcgr (-/-) mice were resistant to STZ-induced hyperglycaemia and pancreatic beta cell destruction. CONCLUSIONS/INTERPRETATION: This study demonstrates that blocking glucagon signalling by targeted Gcgr gene deletion leads to an improvement in metabolic control in this mouse model.

Hypoglycemia leads to age-related loss of vision.

The retina is among the most metabolically active tissues in the body, requiring a constant supply of blood glucose to sustain function. We assessed the impact of low blood glucose on the vision of C57BL/6J mice rendered hypoglycemic by a null mutation of the glucagon receptor gene, Gcgr. Metabolic stress from moderate hypoglycemia led to late-onset loss of retinal function in Gcgr(-/-) mice, loss of visual acuity, and eventual death of retinal cells. Retinal function measured by the electroretinogram b-wave threshold declined >100-fold from age 9 to 13 months, whereas decreases in photoreceptor function measured by the ERG a-wave were delayed by 3 months. At 10 months of age Gcgr(-/-) mice began to lose visual acuity and exhibit changes in retinal anatomy, including an increase in cell death that was initially more pronounced in the inner retina. Decreases in retinal function and visual acuity correlated directly with the degree of hypoglycemia. This work demonstrates a metabolic-stress-induced loss of vision in mammals, which has not been described previously. Linkage between low blood glucose and loss of vision in mice may highlight the importance for glycemic control in diabetics and retinal diseases related to metabolic stress as macular degeneration.

Evidence-based review of treatment and follow up of pediatric patients with differentiated thyroid carcinoma.

Childhood onset differentiated thyroid cancer (DTC) is distinct from the adult-onset disease being more aggressive at the time of initial evaluation with a higher risk category for disease recurrence; however, it is ultimately less lethal. International groups have outlined consensus statements detailing follow up and management guidelines for adult DTC, but since disease progression and markers are significantly different in childhood DTC compared to adults, management protocols may differ. Unfortunately, there is no consensus regarding the means of follow up, timing and management strategy regarding pediatric DTC. We performed an evidence-based review of DTC in children targeted to address the following questions: What is the most appropriate initial treatment? What is the goal of thyroid hormone replacement management? What is the approach to follow-up of childhood DTC? and, How should tumor recurrence/persistence be assessed and treated? We conducted a literature search using PubMed, Cochrane databases, guidelines from various international groups, and studies pertaining to pediatric DTC management and outcome in order to answer these questions. We suggest a pre-set algorithm and approach for the management of children with DTC according to our review.

Genetic modification of the heart: transgenic modification of cardiac lipid and carbohydrate utilization.

Many recent advances in cardiovascular research have been made possible by the use of transgenic technology. This review will discuss a number of mouse models where transgenic technology has been utilized to alter expression of genes involved in cardiac uptake and metabolism of either lipid or carbohydrate. Particular attention will be paid to the proteins which regulate (1) carbohydrate and lipid transport into cardiomyocytes and (2) the subsequent metabolic process which occur within the cytosol. These steps are important in determining substrate availability for mitochondrial oxidative metabolism. The heart relies predominantly on fatty acids as its major fuel supply, while glucose and lactate provide a small percentage. Under certain conditions, this balance becomes altered such that the heart relies more on glucose, as seen in pathological hypertrophy or may rely almost solely on fatty acids, as observed in cardiac tissue of animal models of diabetes. Initially this switch in metabolic substrate provides adequate energy to maintain normal cardiac function however with time diastolic dysfunction and cardiac failure often occur associated with depletion in high-energy phosphates. The creation of transgenic mice with altered expression of genes involved in carbohydrate and lipid metabolism have provided a unique insight into the fine balance which exits in the mouse heart to maintain energy status and cardiac function. The models discussed in this review define both transport and cytosolic metabolism of lipid and carbohydrate as key cellular processes in the regulation of cardiac function and the pathogenesis of cardiac disease.