Showing papers by "Boston Children's Hospital published in 2002"
TL;DR: In view of its rapid development in genetically stable populations, the childhood obesity epidemic can be primarily attributed to adverse environmental factors for which straightforward, if politically difficult, solutions exist.
3,117 citations
TL;DR: The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily.
Abstract: Methods In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening. Results At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening. Conclusions The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension. (N Engl J Med
2,443 citations
Emory University1, Research Triangle Park2, Case Western Reserve University3, National Institutes of Health4, University of Alabama at Birmingham5, Yale University6, Indiana University7, University of Cincinnati8, Boston Children's Hospital9, University of Texas Health Science Center at Houston10, Brown University11, University of Miami12, University of Tennessee Health Science Center13, Wayne State University14, University of Texas Southwestern Medical Center15, Stanford University16, University of New Mexico17
TL;DR: Infants who developed late-onset sepsis had a significantly prolonged hospital stay and were significantly more likely to die than those who were uninfected, especially if they were infected with Gram-negative organisms or fungi.
Abstract: Objective. Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401–1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998–2000). Methods. The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998. Results. Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%). Conclusions. Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.
2,102 citations
TL;DR: This study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta- catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.
1,849 citations
TL;DR: It is shown that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells, indicating that the equilibrium established between effector and regulatory T Cells in sites of chronic infection might reflect both parasite and host survival strategies.
Abstract: The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation1,2,3. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5–10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens4. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress—by both interleukin-10-dependent and interleukin-10-independent mechanisms—the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.
1,730 citations
TL;DR: The physiological effects of the glycemic index and the relevance of these effects in preventing and treating obesity, diabetes, and cardiovascular disease are examined.
Abstract: The glycemic index was proposed in 1981 as an alternative system for classifying carbohydrate-containing food. Since then, several hundred scientific articles and numerous popular diet books have been published on the topic. However, the clinical significance of the glycemic index remains the subject of debate. The purpose of this review is to examine the physiological effects of the glycemic index and the relevance of these effects in preventing and treating obesity, diabetes, and cardiovascular disease.
1,682 citations
TL;DR: As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases.
Abstract: While originally characterized as a collection of related syndromes, cystic fibrosis (CF) is now recognized as a single disease whose diverse symptoms stem from the wide tissue distribution of the gene product that is defective in CF, the ion channel and regulator, cystic fibrosis transmembrane conductance regulator (CFTR). Defective CFTR protein impacts the function of the pancreas and alters the consistency of mucosal secretions. The latter of these effects probably plays an important role in the defective resistance of CF patients to many pathogens. As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases. These factors have led to the successful management of many CF-related infections with the notable exception of chronic lung infection with the gram-negative bacterium Pseudomonas aeruginosa. The virulence of P. aeruginosa stems from multiple bacterial attributes, including antibiotic resistance, the ability to utilize quorum-sensing signals to form biofilms, the destructive potential of a multitude of its microbial toxins, and the ability to acquire a mucoid phenotype, which renders this microbe resistant to both the innate and acquired immunologic defenses of the host.
1,584 citations
TL;DR: The RACHS-1 method should adjust for baseline risk differences and allow meaningful comparisons of in-hospital mortality for groups of children undergoing surgery for congenital heart disease.
1,217 citations
TL;DR: The Pediatric Quality of Life Inventory (PedsQL) is a modular instrument designed to measure health‐related quality of life (HRQOL) in children and adolescents ages 2–18 years.
Abstract: BACKGROUND
The Pediatric Quality of Life Inventory (PedsQL) is a modular instrument designed to measure health-related quality of life (HRQOL) in children and adolescents ages 2–18 years. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and parent proxy-report scales developed as the generic core measure to be integrated with the PedsQL disease specific modules. The PedsQL Multidimensional Fatigue Scale was designed to measure fatigue in pediatric patients. The PedsQL 3.0 Cancer Module was designed to measure pediatric cancer specific HRQOL.
METHODS
The PedsQL Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module were administered to 339 families (220 child self-reports; 337 parent proxy-reports).
RESULTS
Internal consistency reliability for the PedsQL Generic Core Total Scale Score (α = 0.88 child, 0.93 parent report), Multidimensional Fatigue Total Scale Score (α = 0.89 child, 0.92 parent report) and most Cancer Module Scales (average α = 0.72 child, 0.87 parent report) demonstrated reliability acceptable for group comparisons. Validity was demonstrated using the known-groups method. The PedsQL distinguished between healthy children and children with cancer as a group, and among children on-treatment versus off-treatment. The validity of the PedsQL Multidimensional Fatigue Scale was further demonstrated through hypothesized intercorrelations with dimensions of generic and cancer specific HRQOL.
CONCLUSIONS
The results demonstrate the reliability and validity of the PedsQL Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module in pediatric cancer. The PedsQL may be utilized as an outcome measure in clinical trials, research, and clinical practice. Cancer 2002;94:2090–106. © 2002 American Cancer Society.
DOI 10.1002/cncr.10427
1,211 citations
National Institutes of Health1, University of Washington2, Centers for Disease Control and Prevention3, University of Massachusetts Medical School4, University of Wisconsin-Madison5, Brown University6, Harvard University7, University of Texas Southwestern Medical Center8, Sharp Memorial Hospital9, Columbia University10, University of Minnesota11, University of North Carolina at Chapel Hill12, Boston Children's Hospital13
TL;DR: The recommended preventive strategies with the strongest supportive evidence are education and training of healthcare providers who insert and maintain catheters, and maximal sterile barrier precautions during central venous catheter insertion, which can reduce the risk for serious catheter-related infection.
Abstract: Background:Although many catheter-related blood-stream infections (CRBSIs) are preventable, measures to reduce these infections are not uniformly implementedObjective:To update an existing evidenced-based guideline that promotes strategies to prevent CRBSIsData Sources:The MEDLINE database, conference proceedings, and bibliographies of review articles and book chapters were searched for relevant articlesStudies Included:Laboratory-based studies, controlled clinical trials, prospective interventional trials, and epidemiologic investigationsOutcome Measures:Reduction in CRBSI, catheter colonization, or catheter-related infectionSynthesis:The recommended preventive strategies with the strongest supportive evidence are education and training of healthcare providers who insert and maintain catheters; maximal sterile barrier precautions during central venous catheter insertion; use of a 2% chlorhexidine preparation for skin antisepsis; no routine replacement of central venous catheters for prevention of infection; and use of antiseptic/antibiotic-impregnated short-term central venous catheters if the rate of infection is high despite adherence to other strategies (ie, education and training, maximal sterile barrier precautions, and 2% chlorhexidine for skin antisepsis)Conclusion:Successful implementation of these evidence-based interventions can reduce the risk for serious catheter-related infection
985 citations
TL;DR: A registry‐based study to determine prognostic indicators of 8‐year mortality and morbidity in young children with cystic fibrosis (CF) and clinical outcomes in 1998 is conducted.
Abstract: We conducted a registry-based study to determine prognostic indicators of 8-year mortality and morbidity in young children with cystic fibrosis (CF). Patients ages 1-5 years from the 1990 U.S. Cystic Fibrosis Foundation (CFF) National Patient Registry served as the study cohort (N = 3,323). Registry data provided information on baseline characteristics in 1990, 8-year mortality, and clinical outcomes in 1998.P. aeruginosa respiratory infection was found to be a major predictor of morbidity and mortality. The 8-year risk of death was 2.6 times higher in patients who had respiratory cultures positive for P. aeruginosa in 1990 (95% confidence interval 1.6, 4.1) than in children without P. aeruginosa in their respiratory cultures. Culture-positive patients in 1990 also had a significantly lower percent predicted forced expiratory volume in 1 sec (FEV(1)) and weight percentile at follow-up, and they had an increased risk of continued P. aeruginosa respiratory infection and hospitalization for acute respiratory exacerbation in 1998. Among the other predictors of increased morbidity and mortality were lower baseline weight percentiles and number of CF-related hospitalizations during the baseline year.These findings confirm reports from previous smaller studies of outcomes among young children with CF, and highlight the potential to decrease the morbidity and mortality of young patients with CF through early intervention.
TL;DR: Multiple methicillin-resistant Staphylococcus aureus clones carrying type IV staphylitiscal cassette chromosome mec were identified in the community-acquired MRSA strains of both the United States and Australia.
Abstract: Multiple methicillin-resistant Staphylococcus aureus (MRSA) clones carrying type IV staphylococcal cassette chromosome mec were identified in the community-acquired MRSA strains of both the United States and Australia. They multiplied much faster than health-care-associated MRSA and were resistant to fewer non-beta-lactam antibiotics. They seem to have been derived from more diverse S. aureus populations than health-care-associated MRSA strains.
TL;DR: Depressed adolescents are at increased risk for the development and persistence of obesity during adolescence, and the shared biological and social determinants linking depressed mood and obesity may inform the prevention and treatment of both disorders.
Abstract: Background. Adolescent obesity is a strong predictor of adult obesity, and adult obesity has been associated with depression, especially in women. Studies have also suggested an association between depression in adolescence and higher body mass index (BMI) in adulthood. Whether depression leads to obesity or obesity causes depression is unclear. Objective. To determine in longitudinal analyses whether depressed mood predicts the development and persistence of obesity in adolescents. Methods. A prospective cohort study of 9374 adolescents in grades 7 through 12 who completed in-home interviews for the National Longitudinal Study of Adolescent Health. Assessments were made at baseline (1995) and at follow-up 1 year later. Depressed mood was assessed with the Center for Epidemiologic Studies Depression Scale. BMI (kg/m2) was calculated from self-reported height and weight. BMI percentiles and z scores were computed using the 2000 Centers for Disease Control and Prevention growth charts. Obesity was defined as BMI ≥95th percentile, overweight as BMI ≥85th percentile and Results. At baseline, 12.9% were overweight, 9.7% were obese, and 8.8% had depressed mood. Baseline depression was not significantly correlated with baseline obesity. Among the 9.7% who were obese at follow-up, 79.6% were obese at baseline, 18.6% were overweight at baseline, and 1.8% were normal weight at baseline. Having depressed mood at baseline independently predicted obesity at follow-up (odds ratio: 2.05; 95% confidence interval: 1.18, 3.56) after controlling for BMI z score at baseline, age, race, gender, parental obesity, number of parents in the home, and family socioeconomic status. This finding persisted after controlling further for the adolescents’ report of smoking, self-esteem, delinquent behavior (conduct disorder), and physical activity. After controlling for all these same factors, depressed mood at baseline also predicted obesity at follow-up among those not obese at baseline (odds ratio: 2.05; 95% confidence interval: 1.04, 4.06) and follow-up BMI z score among those obese at baseline (β = 0.11; standard error β = 0.05). In contrast, baseline obesity did not predict follow-up depression. Conclusions. Depressed adolescents are at increased risk for the development and persistence of obesity during adolescence. Understanding the shared biological and social determinants linking depressed mood and obesity may inform the prevention and treatment of both disorders.
TL;DR: The mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
Abstract: CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
TL;DR: A causal model by which to understand psychological effects among OSA patients is outlined, proposing that sleep disruption and blood gas abnormalities prevent sleep‐related restorative processes, and further induce chemical and structural central nervous system cellular injury.
Abstract: Obstructive sleep apnea (OSA) is accompanied by significant daytime cognitive and behavioral deficits that extend beyond the effects of sleepiness. This article outlines a causal model by which to understand these psychological effects among OSA patients. The model proposes that sleep disruption and blood gas abnormalities prevent sleep-related restorative processes, and further induce chemical and structural central nervous system cellular injury. This, in turn, leads to dysfunction of prefrontal regions of the brain cortex (PFC), manifested behaviorally in what neuropsychologists have termed 'executive dysfunction'. Executive dysfunction is proposed to markedly affect the functional application of cognitive abilities, resulting in maladaptive daytime behaviors. The proposed model (1) accounts for the specific psychological phenotype associated with OSA, (2) accommodates developmental components in this phenotype, (3) bridges between physical and psychological phenomena, (4) suggests mechanisms by which the nocturnal disorder might have effects on daytime functioning, (5) is empirically testable, (6) generates unique research hypotheses, and (7) has practical implications. The model is intended to act as a catalyst for future research and as a preliminary guide for clinicians.
TL;DR: Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies by enhancing the antitumor activity of Apo-2L/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo.
Abstract: Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo
TL;DR: It is shown that accumulation of α-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species.
Abstract: The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54 83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.
TL;DR: Findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease, and are associated with autosomal-recessive hypomagnesemia with secondary hypocalcemia.
Abstract: Magnesium is an essential ion involved in many biochemical and physiological processes. Homeostasis of magnesium levels is tightly regulated and depends on the balance between intestinal absorption and renal excretion. However, little is known about specific proteins mediating transepithelial magnesium transport. Using a positional candidate gene approach, we identified mutations in TRPM6 (also known as CHAK2), encoding TRPM6, in autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH, OMIM 602014), previously mapped to chromosome 9q22 (ref. 3). The TRPM6 protein is a new member of the long transient receptor potential channel (TRPM) family and is highly similar to TRPM7 (also known as TRP-PLIK), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity. TRPM6 is expressed in intestinal epithelia and kidney tubules. These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease.
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TL;DR: There is an increased but variable risk of epilepsy in autism and the prevalence is highest in studies that have included adolescents and young adults, individuals with moderate to severe mental retardation and those with motor deficits, and individuals with severe receptive language deficits.
Abstract: Summary There is an increased but variable risk of epilepsy in autism. Three main factors—age, cognitive level, and type of language disorder—account for variability in the reported prevalence of epilepsy. The prevalence is highest in studies that have included adolescents and young adults, individuals with moderate to severe mental retardation and those with motor deficits, and individuals with severe receptive language deficits. The association of autism with clinical or subclinical epilepsy might denote common genetic factors in some cases. Whether subclinical epilepsy has adverse effects on cognition, language, and behaviour is debated, as is the relation of autistic regression with an epileptiform electroencephalogram to Landau-Kleffner syndrome. There is no evidence-based treatment recommendation for individuals with autism, regression, and subclinical epilepsy. Double-blind studies with sufficient power to resolve this issue are urgently needed.
TL;DR: The possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo is discussed, and it is reported two children who were conceived by intracytoplasmic sperm injection and who developed Angelman syndrome are reported.
Abstract: In germ cells and the early embryo, the mammalian genome undergoes widespread epigenetic reprogramming. Animal studies suggest that this process is vulnerable to external factors. We report two children who were conceived by intracytoplasmic sperm injection (ICSI) and who developed Angelman syndrome. Molecular studies, including DNA methylation and microsatellite and quantitative Southern blot analysis, revealed a sporadic imprinting defect in both patients. We discuss the possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo.
TL;DR: It is suggested that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response.
TL;DR: Although VEGF alone did not improve bone regeneration, it acted synergistically with BMP4 to increase recruitment of mesenchymal stem cells, to enhance cell survival, and to augment cartilage formation in the early stages of endochondral bone formation.
Abstract: We investigated the interaction between angiogenic and osteogenic factors in bone formation and bone healing with ex vivo gene therapy using muscle-derived stem cells genetically engineered to express human bone morphogenetic protein-4 (BMP4), VEGF, or VEGF-specific antagonist (soluble Flt1). Our results show that although VEGF alone did not improve bone regeneration, it acted synergistically with BMP4 to increase recruitment of mesenchymal stem cells, to enhance cell survival, and to augment cartilage formation in the early stages of endochondral bone formation. These early effects, coupled with accelerated cartilage resorption, eventually led to a significant enhancement of bone formation and bone healing. The beneficial effect of VEGF on bone healing elicited by BMP4 depends critically on the ratio of VEGF to BMP4, with an improper ratio leading to detrimental effects on bone healing. Finally, we show that soluble Flt1 inhibits bone formation elicited by BMP4. Thus, VEGF plays an important role in bone formation elicited by BMP4, and it can significantly enhance BMP4-elicited bone formation and regeneration through multiple mechanisms. This study has important implications for the formulation of new strategies to improve bone healing through increasing mesenchymal stem cell recruitment and survival, in combination with muscle-derived stem cell–based gene therapy.
TL;DR: It is revealed that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans.
Abstract: Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. β-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.
TL;DR: Young adults with childhood-onset CRF have a high prevalence of arteriopathy associated with indicators of microinflammation, hyperparathyroidism, calcium-phosphate overload, and hyperhomocysteinemia but not traditional atherogenic risk factors.
Abstract: Background— Cardiovascular mortality is excessive in young adults with end-stage renal disease (ESRD). The factors contributing to ESRD-related vascular disease are incompletely understood. Young adults with childhood-onset chronic renal failure (CRF) are uniquely suited for risk factor assessment because of their long-term exposure at an age when vascular pathology in the general population is still minimal. Methods and Results— We used novel noninvasive technologies to screen for coronary and carotid artery disease in 39 patients with ESRD aged 19 to 39 years with childhood-onset CRF presently treated by dialysis or renal transplantation. Coronary artery calcification burden was assessed by CT scan with ECG gating and the intima-media thickness (IMT) of the carotid arteries by high-resolution ultrasound. Coronary artery calcifications were present in 92% of patients; calcium scores exceeded the 95th age- and sex-specific percentiles >10-fold on average. Carotid IMT was significantly increased compared w...
TL;DR: Significant alterations in the upper and lower intestinal flora of children with late-onset autism are demonstrated and may provide insights into the nature of this disorder.
Abstract: Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.
TL;DR: This data indicates that the statistical use of pediatric ABPM reference values has been compromised by the non-Gaussian distribution of 24-h blood pressure values.
Abstract: Background Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is an essential tool in the diagnosis and therapeutic monitoring of arterial hypertension in children. The statistical use of pediatric ABPM reference values has been compromised by the non-Gaussian distribution of 24-h blood pr
TL;DR: It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.
Abstract: Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25-dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and tumor-induced osteomalacia. Although the involvement of a newly identified factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical evidence indicating the role of FGF-23 has been lacking. We have previously shown that FGF-23 is cleaved between Arg(179) and Ser(180), and this processing abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore, sandwich ELISA for biologically active intact human FGF-23 was developed using two kinds of monoclonal antibodies that requires the simultaneous presence of both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23 in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast, those in a patient with TIO were over 200 ng/L. After the resection of the responsible tumor, the elevated FGF-23 level returned to normal level within 1 h. The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate, and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23. In addition, the elevated serum FGF-23 levels were demonstrated in most patients with XLH. It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.
TL;DR: The structure and histological organization of skeletal muscle is outlined and the basic physiology of skeletal skeletal muscle contraction is described and the clinical treatments currently available for injured skeletal muscle are presented.
Abstract: After injury, muscle healing occurs through different phases, including (1) degeneration and inflammation, (2) muscle regeneration, and (3) development of fibrosis.
The severity and type of muscle injury influence the healing process.
Enhancement of muscle regeneration and prevention of muscle fibrosis can improve muscle healing.
Growth factors, including basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and nerve growth factor (NGF), can improve muscle regeneration, but the post-injury healing process remains incomplete.
The use of anti-fibrosis agents that antagonize the effect of transforming growth factor-β1 (TGF-β1) can prevent fibrosis and improve muscle healing, resulting in nearly complete recovery.
Optimal muscle recovery may require the use of novel technologies, such as gene therapy and tissue engineering, to achieve both high levels and long-term persistence of these growth factors and cytokines within the injured muscle.
Muscle injury presents a challenging problem in traumatology, as injured muscles heal very slowly and often with incomplete functional recovery. It has been observed that injured muscles can initiate regeneration promptly, but the healing process is often inefficient and hindered by the formation of scar tissue, which may contribute to the tendency for muscle injury to recur. The enhancement of muscle regeneration and the prevention of muscle fibrosis through the use of biological approaches are being investigated in an effort to improve muscle healing after injury. In this Current Concepts Review, we will outline the structure and histological organization of skeletal muscle and describe the basic physiology of skeletal muscle contraction. We will subsequently summarize the biological and pathological processes that occur in skeletal muscle after injury (i.e., degeneration, inflammation, regeneration, and fibrosis) and present the clinical treatments currently available for injured skeletal muscle. Finally, we will discuss current trends in research, which include the improvement of regeneration and the inhibition of fibrosis in injured skeletal …
TL;DR: In this article, the levels of production of interleukin-6 (IL-6), IL-8, and prostaglandin E2 (PGE2) were found in disc tissue from patients undergoing discectomy for sciatica (63) with patients undergoing fusion for discogenic low back pain (20) using an enzyme-linked immunoabsorbent assay.
Abstract: Herniated intervertebral disc tissue has been shown to produce a number of proinflammatory mediators and cytokines, but there have been no similar studies using discs from patients with discogenic low back pain. We have compared the levels of production of interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E2 (PGE2) in disc tissue from patients undergoing discectomy for sciatica (63) with that from patients undergoing fusion for discogenic low back pain (20) using an enzyme-linked immunoabsorbent assay. There was a statistically significant difference between levels of production of IL-6 and IL-8 in the sciatica and low back pain groups (p < 0.006 and p < 0.003, respectively). The high levels of proinflammatory mediator found in disc tissue from patients undergoing fusion suggest that production of proinflammatory mediators within the nucleus pulposus may be a major factor in the genesis of a painful lumbar disc.
Johns Hopkins University1, National Institutes of Health2, Saarland University3, Radboud University Nijmegen4, University College London5, Johns Hopkins University School of Medicine6, Harvard University7, Free University of Berlin8, University of California, San Francisco9, Gunma University10, University of Hawaii at Manoa11, Boston Children's Hospital12, University of Washington13, Keio University14, Ohio State University15
TL;DR: The current effort to unify the TRP nomenclature focuses on three subfamilies that bear significant similarities to the founding member of this superfamily, Drosophila TRP, and which include highly related members in worms, flies, mice, and humans.