A Metabolic Enhancer Protects against Diet-Induced Obesity and Liver Steatosis and Corrects a Pro-Atherogenic Serum Profile in Mice.

OBJECTIVE: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect. METHODS: We explored the impact of a metabolic enhancer (ME), consisting of 7 naturally occurring antioxidants and mitochondrial enhancing agents, on diet-induced obesity, hepatic steatosis and atherogenic serum profile in mice. RESULTS: Here we show that a diet-based ME supplementation and exercise have similar beneficial effects on adiposity and hepatic steatosis in mice. Mechanistically, ME reduced hepatic ER stress, fibrosis, apoptosis, and inflammation, thereby improving overall liver health. Furthermore, we demonstrated that ME improved HFD-induced pro-atherogenic serum profile in mice, similar to exercise. The protective effects of ME were reduced in proprotein convertase subtilisin/kexin 9 (PCSK9) knock out mice, suggesting that ME exerts it protective effect partly in a PCSK9-dependent manner. CONCLUSIONS: Our findings suggest that components of the ME have a positive, protective effect on obesity, hepatic steatosis and cardiovascular risk and that they show similar effects as exercise training.

Diagnosis and management of intraparenchymal rhabdomyosarcoma.

BACKGROUND: Intracranial rhabdomyosarcomas represent a rare condition, posing a diagnostic challenge to physicians. Brain intraparenchymal rhabdomyosarcomas are exceptionally rare with poorly understood pathogenesis. METHODS: Here we report the first adult case of intraparenchymal rhabdomyosarcoma (RMS) with brainstem and cranial nerve involvement. We conducted a literature search using Embase, MEDLINE, and PubMed for published cases of patients with rhabdomyosarcoma of the brain. The keywords used were 'rhabdomyosarcoma' combined with 'intraparenchymal', 'parenchymal', 'cerebral' or 'brain' for title/abstract. Included cases were adult patients (>18 years of age). RESULTS: A 59-year-old man presents with multiple cranial nerve palsies. MRI revealed a solitary pontine lesion that was not responsive to steroids. No systemic lesions were identified with an extensive imaging workup. A wide range of serum and cerebrospinal fluid tests were non-diagnostic during a ten-month workup until, ultimately, the patient died as a result of aspiration pneumonia. At autopsy, pathological examination on whole-brain autopsy revealed RMS, centred in the left side of pons with extension to the left side of the midbrain and the right side of pons with multiple cranial nerve involvement. There are only 20 adult cases of primary intraparenchymal RMS reported in the literature. Our present case is the first reported adult RMS in this location, with novel molecular information, providing some insight into the pathogenesis of this rare diagnosis. CONCLUSIONS: Intraparenchymal rhabdomyosarcoma without evidence of systemic primary disease is extremely rare, resulting in delayed diagnosis in some cases, particularly those not amenable to biopsy. The diagnostic challenge posed by this complementary case highlights the importance of maintaining a differential of neoplasm in the face of non-diagnostic investigations to the contrary.

Correction: Lifelong aerobic exercise protects against inflammaging and cancer.

[This corrects the article DOI: 10.1371/journal.pone.0210863.].

Lifelong aerobic exercise protects against inflammaging and cancer.

Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model (C57BL/J6). Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the 'physiologic reserve' of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines (P < 0.05 O-SED vs. 2-month-old Y-CON), was potently mitigated by lifelong AET (P < 0.05 O-AET vs. O-SED), including master regulators of the cytokine cascade and cancer progression (IL-1ß, TNF-α, and IL-6). In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.

Maternal and pregnancy related predictors of cardiometabolic traits in newborns.

BACKGROUND: The influence of multiple maternal and pregnancy characteristics on offspring cardiometabolic traits at birth is not well understood and was evaluated in this study. METHODS AND FINDINGS: The Family Atherosclerosis Monitoring In earLY life (FAMILY) Study prospectively evaluated 11 cardiometabolic traits in 901 babies born to 857 mothers. The influence of maternal age, health (pre-pregnancy weight, blood pressure, glycemic status, lipids), health behaviors (diet, activity, smoking) and pregnancy characteristics (gestational age at birth, gestational weight gain and placental-fetal ratio) were examined. Greater gestational age influenced multiple newborn cardiometabolic traits including cord blood lipids, glucose and insulin, body fat and blood pressure. In a subset of 442 singleton mother/infant pairs, principal component analysis grouped 11 newborn cardiometabolic traits into 5 components (anthropometry/insulin, 2 lipid components, blood pressure and glycemia), accounting for 74% of the variance of the 11 outcome variables. Determinants of these components, corrected for sex and gestational age, were examined. Baby anthropometry/insulin was independently predicted by higher maternal pre-pregnancy weight (standardized estimate 0.30) and gestational weight gain (0.30; both p<0.0001) and was inversely related to smoking during pregnancy (-0.144; p = 0.01) and maternal polyunsaturated to saturated fat intake (-0.135;p = 0.01). Component 2 (HDL-C/Apo Apolipoprotein1) was inversely associated with maternal age. Component 3 (blood pressure) was not clustered with any other newborn cardiometabolic trait and no associations with maternal pregnancy characteristics were identified. Component 4 (triglycerides) was positively associated with maternal hypertension and triglycerides, and inversely associated with maternal HDL and age. Component 5 (glycemia) was inversely associated with placental/fetal ratio (-0.141; p = 0.005). LDL-C was a bridging variable between the lipid factors and glycemia. CONCLUSIONS: Maternal health, health behaviours and placenta to fetal weight ratio are associated with newborn cardiometabolic traits over and above gestational age. Future investigations are needed to determine if these factors remain important determinants of cardiometabolic health throughout childhood.

A blinded study of bone marrow examinations in patients with primary immune thrombocytopenia.

OBJECTIVE: The role of bone marrow examinations in patients with primary immune thrombocytopenia (ITP) is uncertain. The objectives of this study were to determine the inter-rater reliability of bone marrow examinations and to identify distinguishing morphological features of ITP bone marrows under controlled conditions. METHODS: Histological slides of bone marrow biopsy specimens and aspirates from 32 adult patients with severe primary ITP who had failed a median of two treatments, and 51 non-thrombocytopenic controls were retrieved from hospital archives. Slides were arranged in random order in a slide box and coded. Blinded to the diagnosis and platelet counts, three independent hematopathologists were asked to identify the ITP bone marrows and to evaluate megakaryocyte number, morphology, and distribution. RESULTS: Overall chance-corrected agreement on ITP classification among the three raters was poor [kappa (κ) = 0.30; 95% confidence interval 0.22-0.38]. Raters were generally unable to correctly identify the ITP bone marrows from controls. Increased number of megakaryocytes, while an uncommon finding, was more frequent among ITP patients compared with controls (6/32, 18.8%; vs. 2/51, 3.9%; P = 0.05), and abnormal megakaryocyte morphology often led individual raters to reach a diagnosis of ITP. Overall sensitivity and specificity of bone marrow examinations were 24% and 90%, respectively. CONCLUSIONS: This study confirms methodologically that bone marrow examinations are unreliable and frequently non-diagnostic in ITP. Thus, they are not useful for patients with typical disease. Rare subsets of patients with severe ITP demonstrated unique features such as increased number of megakaryocytes.

Diffusion tensor MRI to assess skeletal muscle disruption following eccentric exercise.

INTRODUCTION: Structural evidence of exercise-induced muscle disruption has traditionally involved histological analysis of muscle tissue obtained by needle biopsy, however, there are multiple limitations with this technique. Recently, diffusion tensor magnetic resonance imaging (DT-MRI) has been successfully demonstrated to noninvasively assess skeletal muscle abnormalities induced by traumatic injury. METHODS: To determine the potential for DT-MRI to detect musculoskeletal changes after a bout of eccentric exercise, 10 healthy men performed 300 eccentric actions on an isokinetic dynamometer. DT-MRI measurements and muscle biopsies from the vastus lateralis were obtained before and 24 h post-exercise. RESULTS: Z-band streaming was higher 24 h post-exercise compared with baseline (P < 0.05). The histological indices of damage coincided with changes in DT-MRI parameters of fractional anisotropy (FA) and apparent diffusion coefficient; reflecting altered skeletal muscle geometry (P < 0.05). Z-band streaming quantified per fiber correlated with FA (r = -0.512; P < 0.05). CONCLUSIONS: DT-MRI can detect changes in human skeletal muscle structure following eccentric exercise.

Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage.

Massage therapy is commonly used during physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. Although there is evidence that massage may relieve pain in injured muscle, how massage affects cellular function remains unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of 11 young male participants after exercise-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline, immediately after 10 min of massage treatment, and after a 2.5-hour period of recovery. We found that massage activated the mechanotransduction signaling pathways focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2), potentiated mitochondrial biogenesis signaling [nuclear peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)], and mitigated the rise in nuclear factor κB (NFκB) (p65) nuclear accumulation caused by exercise-induced muscle trauma. Moreover, despite having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and reduced heat shock protein 27 (HSP27) phosphorylation, thereby mitigating cellular stress resulting from myofiber injury. In summary, when administered to skeletal muscle that has been acutely damaged through exercise, massage therapy appears to be clinically beneficial by reducing inflammation and promoting mitochondrial biogenesis.

Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice.

A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.

The Family Atherosclerosis Monitoring In earLY life (FAMILY) study: rationale, design, and baseline data of a study examining the early determinants of atherosclerosis.

BACKGROUND: Complex interactions among genetic, epigenetic, and environmental exposures, further modified by a child's postnatal environment, underlie the relationship among maternal health, fetal growth, and the development of cardiovascular disease (CVD) risk factors in the child and disease in the adult. Few available studies consider the genetic and environmental influences of the family, beyond maternal health. The purpose of this study is to examine the fetal and early childhood family-based determinants for the development of adiposity, CVD risk factors, and atherosclerosis in childhood. METHOD: A cohort of 850 children and their families (mother, father, eldest sibling) are being recruited during pregnancy to a prospective longitudinal study to investigate the relative contribution of (a) prenatal and postnatal determinants and (b) individual and family (maternal/paternal) determinants for the development of adiposity and CVD risk factors at 3, 5, and 10 years of age and carotid intima media thickness at 10 years. IMPLICATIONS: The FAMILY study will advance understanding of the fetal and early childhood determinants for CVD development and will contribute to the design of primary prevention programs based on identification of the most important modifiable determinants for early childhood adiposity and CVD risk factor development.

Financial impact of coronary stenting in emergency for acute coronary syndromes.

BACKGROUND: Since the prospective payment system, health institutions have only specific payments for the emergency care in the emergency room. The direct urgent admissions in coronary care units for acute coronary syndrome (ACS) do not collect this complementary refund. For the patient's stay, hospital is remunerated with fixed national prices which are similar even in case of emergent or planed coronary revascularization when realized. AIMS: To analyze and compare the financial impact between emergent and planed coronary stenting in the setting of ACS. PATIENTS AND METHODS: This retrospective study was based on patients suffering from ACS who experienced emergent coronary stenting during the year 2005. On 154 patients, 127 were age-, sex- and diagnosis-related group (called "groupe homogène de malades" in the French Health Care system)-matched with 127 suffering from same ACS but with planed "ad hoc" coronary stenting. The overall charges (medical and paramedical team, pharmacy, biology, implantable coronary devices, radiology) were compared between the two groups. RESULTS: Mean stay duration was 6.7 days and did not differ between the two groups. Mean financial retributions were significantly higher in the emergent group (7338 euro [6831-7846] IC95 vs 6509 euro [5994-7023]; p=0,02) but with a much more raised consumption (6810 euro [6283-7336] vs 5223 euro [4632-5814]; p=0,001). This overcost was due especially to drugs and biological expenses. The hospitalization payments did not cover the overall expenses for 25% of the patients' stays (N=64) among whom 39 have had emergent coronary stenting (30.7%, p=0.04). Among the different GHM, the most important difference was observed in non-STEMI without complication with a negative receipts/costs ratio for 37.8% of the stay with coronary stenting in emergency. CONCLUSION: The application of the recent guidelines for coronary revascularization in the management of ACS represents a financial venture for hospital institutions. The engaged charges for emergent coronary stenting are covered with difficulties contrary to planed revascularization.

Antenatal MR imaging of pulmonary lymphangiectasia secondary to hypoplastic left heart syndrome.

We report a case of pulmonary lymphangiectasia detected antenatally with MRI in a fetus with hypoplastic left heart syndrome and a restrictive atrial septum.

Conjugated linoleic acid prevents growth attenuation induced by corticosteroid administration and increases bone mineral content in young rats.

Corticosteroids are a common therapy in many disease states, despite frequent and potentially serious side effects. Nutritional supplementation with conjugated linoleic acid (CLA) has been shown to increase fat-free mass, whereas supplementation with n-3 and n-6 fatty acids has been shown to increase bone mineral density (BMD). To determine whether CLA can attenuate the side effects of 8 weeks of corticosteroid administration, we randomized twenty-four 5-week-old male Sprague-Dawley rats into 1 of 4 groups: control; control + methylprednisolone (7 mg.kg-1.week-1); CLA diet (1% CLA w/w); or CLA plus methylprednisolone. Body composition, bone mineral content (BMC), and BMD were assessed with dual-energy X-ray absorptiometry at the onset and at the end of the 8-week intervention. The mechanical properties of bone were determined using 3-point femur bending at the end of the intervention. Methylprednisolone resulted in an attenuation of the increase in body mass and lean mass over the 8 weeks (p < 0.05). CLA prevented the methylprednisolone-induced attenuation of body mass and lean mass accumulation. CLA also resulted in a greater increase in BMC (p < 0.05) in the lumbar spine. The energy at failure of the isolated femurs was increased with CLA (p < 0.05). Dietary CLA prevents many of the growth- and bone-related side effects arising from 8 weeks of corticosteroid administration, results in greater increases in BMC and BMD, and can contribute to an improvement in some of the mechanical properties of bone.

Paraspinal synovial sarcoma as an unusual postradiation complication in pediatric abdominal neuroblastoma.

SUMMARY: The development of a soft-tissue sarcoma is an infrequent but well-known long-term complication of radiotherapy. Malignant fibrous histiocytomas, extraskeletal osteosarcomas, fibrosarcomas, malignant peripheral nerve sheath tumors, and angiosarcomas are most frequently encountered. Radiation-associated synovial sarcomas are uncommon and exceedingly rare in pediatric patients. We report an unusual case of paraspinal synovial sarcoma presenting in an adolescent female 13 years after radiation therapy for her neuroblastoma.

Creatine monohydrate attenuates body fat accumulation in children with acute lymphoblastic leukemia during maintenance chemotherapy.

BACKGROUND: Corticosteroids are an important component of the treatment of acute lymphoblastic leukemia (ALL), with known significantly negative effects on bone and muscle. Creatine monohydrate (CrM) supplementation may be an adjunctive therapeutic strategy to attenuate some of these adverse effects. PROCEDURE: Nine children with ALL in the maintenance phase of treatment on the Dana-Farber Cancer Institute (DFCI) protocol 2000-2001 were treated with CrM (0.1 g/kg/day) for two sequential periods of 16 weeks (16 weeks treat > 6 weeks wash-out > 16 weeks treat). A cohort of children (N = 50) who were receiving the same chemotherapy at the same time served as natural history controls. Measurements included height, weight, body mass index (BMI), and lumbar spine bone mineral density (LS-BMD), whole body bone mineral content (WB-BMC), fat-free mass (FFM), and percent body fat (%BF) using dual-energy X-ray absorptiometry. RESULTS: Despite the long course of corticosteroid treatment for ALL, children showed significant increases in height, LS-BMD, WB-BMC and FFM over approximately 38 weeks (P < 0.05) during the study. There was an increase in BMI over time, but children taking CrM had a reduction, while the natural history group showed an increase in % BF (P < 0.05 for interaction). CONCLUSIONS: Children with ALL treated with corticosteroids as part of a maintenance protocol of chemotherapy showed an increase in % BF that was attenuated by CrM supplementation.

Isolation of human foetal myoblasts and its application for microencapsulation.

Foetal cells secrete more growth factors, generate less immune response, grow and proliferate better than adult cells. These characteristics make them desirable for recombinant modification and use in microencapsulated cellular gene therapeutics. We have established a system in vitro to obtain a pure population of primary human foetal myoblasts under several rounds of selection with non-collagen coated plates and identified by desmin staining. These primary myoblasts presented good proliferation ability and better differentiation characteristics in monolayer and after microencapsulation compared to murine myoblast C2C12 cells based on creatine phosphokinase (CPK), major histocompatibility complex (MHC) and multi-nucleated myotubule determination. The lifespan of primary myoblasts was 70 population doublings before entering into senescent state, with a population time of 18-24 hrs. Hence, we have developed a protocol for isolating human foetal primary myoblasts with excellent differentiation potential and robust growth and longevity. They should be useful for cell-based therapy in human clinical applications with microencapsulation technology.

Encapsulated human primary myoblasts deliver functional hFIX in hemophilic mice.

BACKGROUND: Hemophilia B is a bleeding disorder caused by defective factor IX (FIX), currently treated by regular infusions of plasma-derived or recombinant FIX. We propose a gene therapy strategy based on the implantation of cells secreting FIX enclosed in alginate microcapsules as a highly desirable alternative treatment. We have reported sustained delivery of human factor IX (hFIX) in immunocompetent mice implanted with encapsulated primary mouse myoblasts engineered to secrete hFIX. As a step towards the treatment of human patients, in this study we report the implantation of encapsulated human primary myoblasts secreting hFIX in hemophilia B mice. METHODS: Human primary myoblasts were transfected with plasmids pKL4M-hFIX, pLNM-betaIXL, pMFG-hFIX, and transduced with retrovirus MFG-hFIX. Two human primary myoblast clones secreting approximately 1 microg hFIX/10(6) cells/day were enclosed in biocompatible alginate microcapsules and implanted intraperitoneally into SCID and hemophilic mice. RESULTS: Circulating hFIX (peak of approximately 120 ng/ml) was detected in hemophilia B mice on day 1 after implantation. Human FIX delivery was transient, however, becoming undetectable on day 14. Concurrently, anti-hFIX antibodies were detected. At the same time, activated partial thromboplastin time (APTT) was reduced from 94 s before treatment to 78-80 s. Tail bleeding time decreased from 15 min to 1.5-7 min after treatment, some mice being normalised. These findings indicate that the delivered hFIX is biologically active. Similarly treated NOD/SCID mice had circulating hFIX levels of 170 ng/ml on day 1 that remained detectable for 1 month, albeit at low levels. Cell viability of microcapsules retrieved on day 60 was below 5%. CONCLUSIONS: Our findings indicate that encapsulated human primary myoblasts secrete functional hFIX. Furthermore, implantation of encapsulated human primary myoblasts can partially correct the phenotype of hemophilia B mice, supporting the feasibility of this gene therapy approach for hemophilia B. However, the long-term viability of the encapsulated human myoblasts must first be improved.