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.

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.

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.

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.

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.

Correction: Lifelong aerobic exercise protects against inflammaging and cancer.

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

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.

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.

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.

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.

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 increases bone mineral density in young Sprague-Dawley rats.

INTRODUCTION: Creatine kinase, found in osteoblasts, is an enzyme that is upregulated in response to interventions that enhance bone mass accretion. Creatine monohydrate supplementation can increase fat-free mass in young healthy men and women and can reduce markers of bone breakdown in boys with Duchenne muscular dystrophy. PURPOSE: The objective of this study was to determine the influence of supplementation with creatine monohydrate on bone structure and function in growing rats, to establish a therapeutic model. MATERIALS AND METHODS: Creatine monohydrate (2% w.w.) (CR; N = 16) or standard rat chow (CON; N = 16) was fed to Sprague-Dawley rats beginning at 5 wk of age, for 8 wk. Bone mineral density (BMD) and content (BMC) were assessed using dual-energy x-ray absorptiometry at the beginning and end of the protocol. The rats were sacrificed, and one femur was removed for the determination of mechanical properties. RESULTS: The CR-treated rats showed greater lumbar BMD and femoral bending load at failure compared with the CON rats (P < 0.05). CONCLUSIONS: Together, these data suggest that creatine monohydrate potentially has a beneficial influence on bone function and structure; further investigation is warranted into its effect on bone functional properties and its effects in disorders associated with bone loss.

Antiangiogenic cancer therapy with microencapsulated cells.

Inhibition of angiogenesis has led to tumor suppression in several cancer models. Although administering purified recombinant antiangiogenic product is effective, alternative approaches through genetic manipulation may be more cost-effective. We propose to implant nonautologous recombinant cells secreting angiostatin for systemic delivery of angiostatin in cancer treatment. These cells are protected from graft rejection in alginate microcapsules to function as "micro-organs" to deliver angiostatin in vivo. This approach was tested by implanting encapsulated mouse myoblast C2C12 cells genetically modified to secrete angiostatin into mice bearing solid tumor. Angiostatin was detected in sera of the treated mice. Efficacy was demonstrated by suppression of palpable tumor growth and improved survival. At autopsy, angiostatin localized to residual tumors and high levels of angiostatic activity were detected in tumor extracts. Tumor tissues showed increased apoptosis and necrosis compared with those from untreated or mock-treated mice. Immunohistochemical staining against von Willebrand factor, an endothelial cell marker, showed that within tumors from the treated mice, the neovasculature was poorly defined by endothelial cells, many of which were undergoing apoptosis. However, the tumors eventually developed neovasculature independent of endothelial cells. Such vascular mimicry would account for the lack of long-term efficacy despite persistent angiostatin delivery. In conclusion, implantation with nonautologous microencapsulated cells is feasible for systemic delivery of angiostatin, resulting in localization of angiostatin to tumors and targeted apoptosis of the endothelial cells. Clinical efficacy was demonstrated by suppression of tumor growth and extension of life span. Although the potential of this cell-based approach for angiostatin-mediated cancer therapy is confirmed, long-term efficacy must take into account the possible escape by some tumors from angiogenesis inhibition.

Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.

A novel approach to tumor suppression with microencapsulated recombinant cells.

A novel approach to cancer gene therapy is to implant microcapsules containing nonautologous cells engineered to secrete molecules with antineoplastic properties. The efficacy of this treatment is now tested in a mouse model bearing HER-2/neu-positive tumors. Nonautologous mouse myoblasts (C(2)C(12)) were genetically modified to secrete interleukin-2 linked to the Fv region of a humanized antibody with affinity to HER-2/neu. The resulting fusion protein, sFvIL-2, would encompass immune-stimulatory cytokine activity now targeted to the HER-2/neu-expressing tumor. These recombinant cells were then immunoprotected with alginate-poly-L-lysine-alginate microcapsules before implantation into tumor-bearing mice. Treatment with these encapsulated cells led to a delay in tumor progression and prolonged survival of the animals. The long-term efficacy was limited by an inflammatory reaction against the implanted microcapsules probably because of the secreted cytokine and antigenic response against the xenogeneic fusion protein itself. However, over the short term (initial 2 weeks), efficacy was confirmed when a significant amount of biologically active interleukin-2 was detected systemically, and targeting of the fusion protein to the HER-2/neu-expressing tumor was shown immunohistochemically. The tumor suppression in the treated animals was associated with increased apoptosis and necrosis in the tumor tissue, thus demonstrating successful targeting of the antiproliferative effect to the tumors by this delivery paradigm. In conclusion, this new approach to systemic cancer gene therapy needs to be modified to provide long-term delivery, but has demonstrated short-term efficacy and potential to become a cost-effective, benign, and non-viral-based adjunct to the current armory of anticancer strategies.

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.

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.

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.