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PubMed2006

Nanostructure of the neurocentral growth plate: Insight from scanning small angle X-ray scattering, atomic force microscopy and scanning electron microscopy.

In this study, the experimental techniques scanning electron microscopy (SEM) including energy-dispersive X-ray analysis, atomic force microscopy (AFM) and scanning small angle X-ray scattering (SAXS) have been exploited to characterize the organization of large molecules and nanocrystallites in and around the neurocentral growth plate (NGP) of a pig vertebrae L4. The techniques offer unique complementary information on the nano- to micrometer length scale and provide new insight in the changes in the matrix structure during endochondral bone formation. AFM and SEM imaging of the NGP reveal a fibrous network likely to consist of collagen type II and proteoglycans. High-resolution AFM imaging shows that the fibers have a diameter of approximately 100 nm and periodic features along the fibers with a periodicity of 50-70 nm. This is consistent with the SAXS analysis that yields a cross-sectional diameter of the fibers in the range of 90 to 112 nm and a predominant orientation in the longitudinal direction of the NGP. Furthermore, we find inhomogeneities around 7 nm in the NGP by SAXS analysis. Moving towards the bone in the direction perpendicular to the growth plate, a systematic change in apparent thickness is observed, while the large-scale structural features remain constant. In the region of bone, the apparent thickness equals the mean mineral thickness and increases from 2 nm to approximately 3.5 nm as a function distance from the NGP. The mineral particles are organized as plates in a rather compact network structure. We have demonstrated that SEM, AFM and SAXS are valuable tools for the investigation of the organization of large molecules and nanocrystallites in the NGP and adjacent trabecular bone. Our findings will be an important basis for future work into identifying the defects on nanometer length scale responsible for idiopathic scoliosis and other growth-plate-related diseases.

Animals↗
PubMed2006

Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans.

Epilepsy is estimated to affect 1-2% of the world population, yet remains poorly understood at a molecular level. We have previously established the roundworm Caenorhabditis elegans as a model for investigating genetic susceptibilities to seizure-like convulsions in vivo. Here we investigate the behavioral consequences of decreasing the activity of nematode gene homologs within the LIS1 pathway that are associated with a human cortical malformation termed lissencephaly. Bioinformatic analysis revealed the nud-2 gene, encoding the worm homolog of mammalian effectors of LIS1, termed NDE1 and NDEL1. Phenotypic analysis of animals targeted by RNA interference (RNAi) was performed using a pentylenetetrazole (PTZ) exposure paradigm to induce convulsions. Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5, and CDKA-1) exhibited significant convulsions following PTZ and RNAi treatment. Strains harboring fluorescent markers for GABAergic neuronal architecture and synaptic vesicle trafficking were employed to discern putative mechanisms accounting for observed convulsion behaviors. We found that depletion of LIS1 pathway components resulted in defective GABA synaptic vesicle trafficking. We also utilized combinations of specific genetic backgrounds to create a sensitized state for convulsion susceptibility and discovered that convulsion effects were significantly enhanced when LIS-1 and other pathway components were compromised within the same animals. Thus, interactions among gene products with LIS-1 may mediate intrinsic thresholds of neuronal synchrony.

Animals↗
PubMed2024

Comprehensive analyses of a large human gut Bacteroidales culture collection reveal species- and strain-level diversity and evolution.

Species of the Bacteroidales order are among the most abundant and stable bacterial members of the human gut microbiome, with diverse impacts on human health. We cultured and sequenced the genomes of 408 Bacteroidales isolates from healthy human donors representing nine genera and 35 species and performed comparative genomic, gene-specific, metabolomic, and horizontal gene transfer analyses. Families, genera, and species could be grouped based on many distinctive features. We also observed extensive DNA transfer between diverse families, allowing for shared traits and strain evolution. Inter- and intra-species diversity is also apparent in the metabolomic profiling studies. This highly characterized and diverse Bacteroidales culture collection with strain-resolved genomic and metabolomic analyses represents a valuable resource to facilitate informed selection of strains for microbiome reconstitution.

Humans↗
PubMed2004

Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells.

Epidemiological studies have associated coxsackie B virus (CBV) with the development of insulin-dependent diabetes mellitus (IDDM) in humans. Infections of genetically susceptible mice with CBV strain 4 (CB4) induce autoimmune diabetes. Herein, we demonstrate that in mice, CB4 infection of insulin-producing pancreatic beta cells does not directly cause beta cell death. Instead, we observed the phagocytosis of beta cells by macrophages following infection. Further, antigen-presenting cells isolated from CB4-infected mice induced diabetes upon adoptive transfer. Therefore, the specificity of CB4 for infection of beta cells leads indirectly to the development of IDDM. This generalized mechanism suggests that macrophages are the initiating pathogenic cell type during virus-mediated autoimmune diabetes and that multiple environmental agents specific for beta cells could cause IDDM.

Animals↗
PubMed2022

FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit.

Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.

Alcohol Drinking↗
PubMed2005

Using cyclodextrin complexation to enhance secondary photoprotection of topically applied ibuprofen.

Each year millions of people are overexposed to the sun resulting in photodamage of the skin. Secondary photoprotection is the application of medicinal agents to the body after sun exposure to reduce this damage. The objective of this study was to determine the affects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the secondary photoprotective properties of topically applied ibuprofen. Complexation of ibuprofen by HPCD was demonstrated by differential scanning calorimetry, while solubilities were determined using HPLC. A linear (r2>0.999) relationship was found between ibuprofen solubility and HPCD concentration. For subsequent experiments, the concentration of ibuprofen was held constant at the solubility in 10% HPCD (10.6 mg/ml), while the HPCD concentration varied from 0 to 20% (w/w). In vitro transdermal permeation experiments demonstrated a parabolic relationship between transdermal kinetic parameters and HPCD concentration, with maximum values for both flux and skin accumulation occurring with the 10% HPCD formulation. In vivo experiments were performed by exposing hairless mice to UV radiation and applying ibuprofen-HPCD formulations topically at various times following UV exposure. Edema and epidermal lipid damage data demonstrated that application of ibuprofen-HPCD formulations within 1h of UV exposure provided significant photoprotection.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2007

An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension.

OBJECTIVES: To assess perioperative outcomes and blood pressure (BP) responses to an implantable carotid sinus baroreflex activating system being investigated for the treatment of resistant hypertension. METHODS: We report on the first seventeen patients enrolled in a multicenter study. Bilateral perivascular carotid sinus electrodes (CSL) and a pulse generator (IPG) are permanently implanted. Optimal placement of the CSL is determined by intraoperative BP responses to test activations. Acute BP responses were tested postoperatively and during the first four months of follow-up. RESULTS: Prior to implant, BP was 189.6+/-27.5/110.7+/-15.3 mmHg despite stable therapy (5.2+/-1.8 antihypertensive drugs). The mean procedure time was 202+/-43 minutes. No perioperative strokes or deaths occurred. System tests performed 1 or up to 3 days postoperatively resulted in significant (all p < or = 0.0001) mean maximum reduction, with standard deviations and 95% confidence limits for systolic BP, diastolic BP and heart rate of 28+/-22 (17, 39) mmHg, 16+/-11 (10, 22) mmHg and 8+/-4 (6, 11) BPM, respectively. Repeated testing during 3 months of therapeutic electrical activation demonstrated a durable response. CONCLUSIONS: These preliminary data suggest an acceptable safety of the procedure with a low rate of adverse events and support further clinical development of baroreflex activation as a new concept to treat resistant hypertension.

Adult↗
PubMed2005

Proliferation dynamics in cultured skin fibroblasts from Down syndrome subjects.

With a view to better understanding the role of oxidant/antioxidant variables in proliferation dynamics of somatic cells, we explored the relationships among superoxide dismutase (SOD) activity, glutathione peroxidase (Gpx) activity, reactive oxygen intermediates (ROI), and indices of cellular proliferation and senescence in cultured fibroblasts from Down syndrome and normal donors. We found that Down syndrome cells had a significantly slower proliferative rate, but attain replicative senescence at similar population doubling (PD) as control cells. Irrespective of donor origin, the number of PD until replicative senescence was positively correlated with Gpx activity (r = 0.784, P = 0.007). In addition, the presence of exogenous catalase in the growth medium significantly extended the number of PD until replicative senescence (P = 0.011). The loss of telomere repeats per PD was not different between Down syndrome cells and controls. However, SOD activity was inversely correlated with the loss of telomere repeats per PD. Collectively, these findings suggest that replicative senescence ultimately relates to mechanisms downstream to SOD (i.e., Gpx and catalase) and confirmed previous observations about inverse relationships between SOD activity and telomere repeat loss per cellular replication.

Cell Proliferation↗
PubMed2016

The impact of metagenomic interplay on the mosquito redox homeostasis.

Mosquitoes are exposed to oxidative challenges throughout their life cycle. The primary challenge comes from a blood meal. The blood digestion turns the midgut into an oxidative environment, which imposes pressure not only on mosquito fecundity and other physiological traits but also on the microbiota in the midgut. During evolution, mosquitoes have developed numerous oxidative defense mechanisms to maintain redox homeostasis in the midgut. In addition to antioxidants, SOD, catalase, and glutathione system, sufficient supply of the reducing agent, NADPH, is vital for a successful defense against oxidative stress. Increasing evidence indicates that in response to oxidative stress, cells reconfigure metabolic pathways to increase the generation of NADPH through NADP-reducing networks including the pentose phosphate pathway and others. The microbial homeostasis is critical for the functional contributions to various host phenotypes. The symbiotic microbiota is regulated largely by the Duox-ROS pathway in Drosophila. In mosquitoes, Duox-ROS pathway, heme-mediated signaling, antimicrobial peptide production and C-type lectins work in concert to maintain the dynamic microbial community in the midgut. Microbial mechanisms against oxidative stress in this context are not well understood. Emerging evidence that microbial metabolites trigger host oxidative response warrants further study on the metagenomic interplay in an oxidative environment like mosquito gut ecosystem. Besides the classical Drosophila model, hematophagous insects like mosquitoes provide an alternative model system to study redox homeostasis in a symbiotic metagenomic context.

Animals↗
PubMed2004

Resistance training for chronic heart failure patients on beta blocker medications.

BACKGROUND: Resistance training increases the skeletal muscle strength and functional ability of chronic heart failure patients. However, there is limited data regarding the effect of resistance training on the hemodynamic responses and peak oxygen consumption (peak VO(2)) of chronic heart failure patients treated with beta-blocker. This study examined the effect of resistance training on hemodynamics, peak aerobic capacity, muscle strength and quality of life of chronic heart failure patients on beta-blockers medication. METHODS: Fifteen men diagnosed with chronic heart failure were matched to either a resistance training program or non-training control group. At baseline and after 8 weeks of resistance training patients performed both Balke incremental and maximal strength tests and completed quality of life questionnaires. RESULTS: The resistance training group demonstrated a significant increase of walking time and peak VO(2) by 11.7% (p=0.002) and approximately 19% (p<0.05), respectively. Peak VO(2) was significantly correlated with both walking time (r=0.54, p=0.038) and change in total weight lifted (r=0.55, p=0.034). Quality of life significantly increased by 87% (p=0.030). The improvement in quality of life was correlated with post training peak VO(2) (r=0.58, p=0.025) and total weight lifted during the post maximal strength test (r=-0.52, p=0.047). CONCLUSIONS: The benefits from resistance training for chronic heart failure patients on beta-blocker medication included an increased aerobic and exercise capacity, skeletal muscle strength and most importantly, an improvement in the quality of life, which is the main goal of cardiac rehabilitation programs. Furthermore, with appropriate supervision, it is recommended that resistance exercise be added to the exercise rehabilitation program of these patients when possible.

Adaptation, Physiological↗
PubMed2005

The effect of resistance training on left ventricular function and structure of patients with chronic heart failure.

INTRODUCTION: Resistance training (RT) has been shown to improve chronic heart failure (CHF) patients' functional ability and quality of life. Despite these benefits RT has not always been recommend as a form of exercise principally because of a concern for acceleration of the left ventricular (LV) remodeling process. This study investigated the effects of 8 weeks RT on the LV structure and function of patients with CHF. METHOD: Fifteen men who suffered from CHF were divided into either a RT program or non-training control group. Before and after 8 weeks of training patients underwent resting echocardiography to assess their end-diastolic and end-systolic dimensions (EDD and ESD, respectively), ejection fraction (EF), fractional shortening (FS) and stroke volume (SV). RESULTS: A repeated measured ANOVA showed that 8 weeks of RT had no significant effect on the LV measurements (group x time, p>0.05). Post training comparison, however, revealed that the EF and FS of the training group was significantly higher than in the control group (40.9+/-10.5% vs. 30.3+/-4.6%, p=0.029 and 25.0+/-7.0% vs. 17.4+/-3.1%, p=0.020 respectively). CONCLUSION: RT is a suitable method of training for CHF patients since it does not cause a reduction of LV contractility function or enhance myocardial deterioration as measured by EF and FS.

Echocardiography↗
PubMed2005

Exposure to community violence and upper respiratory illness in older adolescents.

PURPOSE: To examine the relationship between exposure to chronic community violence and upper respiratory illness (URI) symptoms among urban adolescents of color; and to test the generality of a model of the relationship between social stress and URI. METHOD: The research used a cross-sectional correlational design. The sample was 769 first-semester first-year students in an urban nonresidential 4-year college from the academic years 1999-2002. Data were collected by a group-administered questionnaire in academic classes. The research used three multi-item additive scales (each with high reliability and validity): exposure to community violence, psychological distress, and URI symptoms. Multiple regression procedures were used to analyze the data. RESULTS: Positive correlations were obtained between: exposure to community violence and reporting of URI (r = .19), exposure and psychological distress (r = .22), and psychological distress and URI (r = .51). The relationship between exposure to community violence and URI is greatly reduced when level of psychological distress is statistically controlled. CONCLUSIONS: Exposure to community violence is related to experiencing URI symptoms among older urban adolescents of color; the effect size of the relationship is small-medium. Psychological distress mediates the impact of exposure to community violence on URI. The findings expand the range of social stressors that are empirically related to URI, and populations in which a relationship between social stressors and URI may be found.

Adolescent↗
PubMed2003

Obesity influences outcome of sentinel lymph node biopsy in early-stage breast cancer.

BACKGROUND: Sentinel lymph node biopsy is a rapidly emerging standard of care for staging the axilla in invasive breast cancer. Factors influencing success must be identified to understand the procedure's limitations and challenges. Increasing body mass with age has an inverse relationship to success. A proportion of SLN biopsy patients are both senior and overweight, so measurement of the body mass to age relationship is essential. STUDY DESIGN: We reviewed mapping successes and failures in 2,495 SLN biopsy procedures performed between September 1996 and June 2001. Clinical stage T1 N0 to T3 N0 breast cancer cases were included. We used a combined technique (radioisotope and blue dye) to detect SLNs. Failure was defined as the inability to identify any nodes with either blue dye or by in vivo counts. Body- mass index (BMI) for each patient was measured by height and weight data (kg/m(2)), and cases were stratified by BMI and age. RESULTS: Among 2,495 cases, there were 62 failed and 2,433 successful mappings (failure rate = 2.48%). Mean age, weight, and BMI were significantly higher in the failure group. The success of SLN biopsy was inversely related to BMI (r = -0.98, p = 0.002). When stratified by patient age (< 50 versus > or =50 years), this relationship was more pronounced in the > or = 50 group. Multivariate analysis of age, weight, and BMI found age (p = 0.011) and BMI (p = 0.00001) to be predictive of SLN mapping success, with weight alone not significant. CONCLUSIONS: Increasing age and BMI do not appear to be contraindications for SLN biopsy. Rather, surgeons should be aware that increasing body mass and age are potential risk factors for a failed procedure, in which case a completion axillary node dissection for staging is required.

Adult↗
PubMed2005

Is the clinically positive axilla in breast cancer really a contraindication to sentinel lymph node biopsy?

BACKGROUND: Clinically positive axillary nodes are widely considered a contraindication to sentinel lymph node (SLN) biopsy in breast cancer, yet no data support this mandate. In fact, data from the era of axillary lymph node dissection (ALND) suggest that clinical examination of the axilla is falsely positive in as many as 30% of cases. Here we report the results of SLN biopsy in a selected group of breast cancer patients with palpable axillary nodes classified as either moderately or highly suspicious for metastasis. STUDY DESIGN: Among 2,027 consecutive SLN biopsy procedures performed by two experienced surgeons, clinically suspicious axillary nodes were identified in 106, and categorized as group 1 (asymmetric enlargement of the ipsilateral axillary nodes moderately suspicious for metastasis, n = 62) and group 2 (clinically positive axillary nodes highly suspicious for metastasis, n = 44). RESULTS: Clinical examination of the axilla was inaccurate in 41% of patients (43 of 106) overall, and was falsely positive in 53% of patients (33 of 62) with moderately suspicious nodes and 23% of patients (10 of 44) with highly suspicious nodes. False-positive results were less frequent with larger tumor size (p = 0.002) and higher histologic grade (p = 0.002), but were not associated with age, body mass index, or a previous surgical biopsy. CONCLUSIONS: Clinical axillary examination in breast cancer is subject to false-positive results, and is by itself insufficient justification for axillary lymph node dissection. If other means of preoperative assessment such as palpation- or image-guided fine needle aspiration are negative or indeterminate, then SLN biopsy deserves wider consideration as an alternative to routine axillary lymph node dissection in the clinically node-positive setting.

Adult↗
PubMed2005

Induction of antigen specific peripheral humoral tolerance to cardiac myosin does not prevent CB3-mediated autoimmune myocarditis.

Chronic myocarditis often progresses to dilated cardiomyopathy resulting in heart failure or cardiac transplantation. Viral infection is the most common cause of myocarditis and coxsackie B viruses (CBV) are the most frequently cited etiologic agents associated with myocarditis and cardiomyopathy. Additionally, CBV infections of genetically susceptible mice induce autoimmune myocarditis resembling human disease, including the development of autoantibodies to cardiac myosin. Herein, we describe experiments in which peripheral tolerance to cardiac myosin was induced by administration of antigen-coupled antigen presenting cells. While the antibody response to cardiac myosin following CB3 infection was reduced, the viral induction of clinical autoimmune myocarditis was not affected. Additionally, viral replication was unaffected by the reduced humoral response to cardiac myosin. Therefore, the humoral response to cardiac myosin is not required for the development of autoimmunity following infection of NOD mice. This work demonstrates the difficulty in using antigen specific tolerance as a course of treatment to prevent multivalent autoimmune disorders.

Animals↗
PubMed2005

Inhibition of prostate cancer-meditated osteoblastic bone lesions by the low-calcemic analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D3.

Prostate cancer metastasizes almost exclusively into the bone whereby it induces primarily an osteoblastic response. Non-calcemic vitamin D analogs have been shown to inhibit proliferation of prostate cancer cells in culture and inhibit their growth as subcutaneous xenografts in mice. However, their effect on prostate cancer cell growth in the bone has not been examined. In the present study, we inoculated the osteoblastic prostate cancer cell line MDA-PCa 2b into the bone of male SCID mice and examined the effect of the low-calcemic hybrid analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D(3) (JK-1626-2) on their ability to induce bone lesions. We found that 7 weeks after inoculation of MDA-PCa 2b cells, 90% of the mice in the vehicle-treated group had significant bone lesions that were detectable by micro-computed tomography and characterized by thickening of the cortical bone and ossification of the epiphysis. Only 30% of the mice in the analog-treated group (daily injections of 4microg/kg, 5 days/week for up to 7 weeks) had detectable bone lesions. Histological examination of the decalcified tumor-bearing bones has shown that tumor cells completely replaced the bone marrow in the diaphysis, and destroyed the trabecular bone in the metaphysis in 90% of the vehicle-treated mice. In contrast, the metaphysis of 60% of analog-treated mice appeared normal, although tumor cells were still found in the diaphysis of 70% of the bones in the analog-treated group. There was no evidence of hypercalcemia in any of the analog-treated mice. In a co-culture, MDA-PCa 2b cells induced a profound mitogenic response in osteoblasts followed by enhanced differentiation. However, in the presence of the analog the mitogenic response of the osteoblasts to the malignant cells was significantly attenuated. These experiments led to the hypothesis that, in vivo, JK-1626-2 prevented the metastatic bone lesions by inhibiting the mitogenic response of osteoblasts to growth factors produced by MDA-PCa 2b cells.

Animals↗