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1.
Front Surg ; 9: 868483, 2022.
Article in English | MEDLINE | ID: mdl-35529908

ABSTRACT

Neonatal and pediatric surgical emergencies in Low and Low Middle Income countries remain a significant challenge in combatting the burden and inequities of global health. IPSAC-Vietnam is a small Non-Governmental Organization that has been engaged in a 12-year multi-pronged partnership with several children's hospitals in Vietnam VN to enhance pediatric surgery capacity. We describe the health care, medical training and emergency system in VN as the background for IPSAC activities and development of Pediatric Acute Surgical Support (PASS) course. The course goal is to prepare health care personnel in the immediate management of neonatal/pediatric life-threatening surgical conditions and road injuries at their first point of entry into Vietnam hospitals. PASS is a horizontal outreach initiative that adopts an interprofessional, multidisciplinary, team-training, train-the-trainers, and outcome-based training approach. PASS can be used as a tool for sustainable horizontal capacity-building by champion leaders at the teaching children's hospitals and medical universities in developing countries, to strengthen training for pediatric surgical emergencies, to integrate pediatric and pediatric surgical care and to advocate for a comprehensive approach to emergency care of the critically ill child.

2.
J Biomed Mater Res B Appl Biomater ; 107(2): 253-268, 2019 02.
Article in English | MEDLINE | ID: mdl-29603873

ABSTRACT

Artificial tissue-engineered grafts offer a potential alternative to autologous tissue grafts for patients, which can be traumatic. After decellularizing Papio hamadryas esophagus and studying the morphology and physical properties of the extracellular matrix (ECM), we generated electrospun polyamide-6 based scaffolds to mimic it. The scaffolds supported a greater mechanical load than the native ECM and demonstrated similar 3D microstructure, with randomly aligned fibers, 90% porosity, 29 µm maximal pore size, and average fiber diameter of 2.87 ± 0.95 µm. Biocompatibility studies showed that human adipose- and bone marrow-derived mesenchymal stromal cells (AD-MSC and BMD-MSC) adhered to the scaffold surface and showed some proliferation: scaffold cell coverage was 25% after 72 h of incubation when seeded with 1000 cells/mm2 ; cells elongated processes along the polyamide-6, although they flattened 1.67-4 times less than on cell culture plastic. Human umbilical vein endothelial cells, however, showed poor adherence and proliferation. We thus provide in vitro evidence that polyamide-6 scaffolds approximating the esophageal biomechanics and 3D topography of nonhuman primates may provide a biocompatible substrate for both AD-MSC and BMD-MSCs, supporting their adhesion and survival to some degree. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 253-268, 2019.


Subject(s)
Caprolactam/analogs & derivatives , Esophagus/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Materials Testing , Mesenchymal Stem Cells/metabolism , Polymers/chemistry , Tissue Engineering , Tissue Scaffolds/chemistry , Animals , Caprolactam/chemistry , Esophagus/cytology , Human Umbilical Vein Endothelial Cells/cytology , Humans , Male , Mesenchymal Stem Cells/cytology , Papio hamadryas
3.
Exp Neurol ; 304: 14-20, 2018 06.
Article in English | MEDLINE | ID: mdl-29453977

ABSTRACT

We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II+) CD11b+Ly-6G+ neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II+, CD11b+Ly-6C+ mature monocytes increased modestly throughout the disease course. Amelioration of the clinical disease by TSA treatment was accompanied by diminished abundance of CD11b+Ly-6Gdim activated neutrophils in secondary lymphoid organs and their influx into the spinal cord without affecting monocytes. Interestingly, the co-inhibitory ligand CD274+ (PD-L1+) but not CD275+ (ICOS-L+), CD39+ or CD11c+ dendritic cells were decreased in the peripheral lymphoid compartment of drug treated mice. Thus, in addition to myelin-specific T cell tolerance induction observed previously, selective repression of mature neutrophils and PD-L1+ cells is critically involved in the epigenetic regulation of P-EAE.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Epigenesis, Genetic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Neutrophils/drug effects , Animals , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Mice , Mice, Inbred NOD , Neutrophils/immunology
4.
Neurobiol Dis ; 108: 1-12, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28736194

ABSTRACT

Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Protection was accompanied by histone hyperacetylation, and reduced inflammation and axonal damage in the spinal cord. Drug treatment diminished the generation of CD4+ memory T cells and induced tolerance in CD4+ T cells recognizing the immunizing myelin peptide. During the early immunization period, CD4+ T cells producing GM-CSF+IFN-γ, GM-CSF+IL-17A, as well as those expressing both IL-17A+IFN-γ (double-producers) were detected in the secondary lymphoid organs followed by the appearance of cells producing IFN-γ and GM-CSF. On the other hand, IFN-γ producing Th1 cells appear first in the spinal cord followed by cells producing IL-17A and GM-CSF. Treatment with Trichostatin A substantially reduced the frequencies of all T cells secreting various lymphokines both in the periphery and in the spinal cord. These data indicate that epigenetic modifications induced by histone hyperacetylation facilitates T cell tolerance induction in the periphery leading to reduced migration of T cells to the spinal cord and mitigation of neuronal damage and improved clinical outcome. These results suggest that epigenetic modulation of the genome may similarly offer benefits to multiple sclerosis patients via abrogating the function of encephalitogenic T lymphocytes without exerting severe side effects associated with currently used disease-modifying therapies.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Hydroxamic Acids/pharmacology , Neuroprotective Agents/pharmacology , Spinal Cord/drug effects , T-Lymphocyte Subsets/drug effects , Animals , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Epigenesis, Genetic/drug effects , Female , Histones/drug effects , Histones/metabolism , Lymphoid Tissue/drug effects , Lymphoid Tissue/metabolism , Mice, Inbred NOD , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments , Random Allocation , Spinal Cord/pathology , Spinal Cord/physiopathology , T-Lymphocyte Subsets/pathology , T-Lymphocyte Subsets/physiology
5.
J Pediatr Surg ; 52(9): 1438-1441, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28069270

ABSTRACT

PURPOSE: The aim of this study was to expand on our previous report of 115 patients after more than a decade-long experience using incision and loop drainage for pediatric subcutaneous abscess management. This report comprises the largest consecutive series of pediatric abscess patients from a single institution ever recorded. METHODS: A retrospective study was performed of all pediatric patients who underwent incision and loop drainage of subcutaneous abscesses at our institution between January 2002 and December 2014. TECHNIQUE: Two sub 5mm incisions were made at the periphery on the abscess. The abscess cavity was probed to break down loculations and drain pus. The abscess cavity was irrigated with normal saline. A loop drain was passed through one incision and brought out through the other. A simple absorbent dressing was applied over the drain. RESULTS: Five hundred seventy-six consecutive patients underwent loop drainage procedures. Mean values are as follows: age, 3.84years; duration of symptoms, 6.17days; postoperative length of stay (with 4 outliers excluded), 0.69days; drain duration, 8.38days; and number of postoperative visits, 1.28. Twenty-six patients had reoperations (4.5%), 2 of which were planned staged excisions of pilonidal cysts and 1 because of accidental home removal. CONCLUSIONS: Micro-incisions and loop drainage is a safe and effective treatment modality for subcutaneous abscesses in children. The findings eliminate the need for repetitive wound packing and simplify postoperative wound care. Loop drainage offers shorter time to discharge, lower recurrence rates, and minimal scarring. Additionally, there is expected cost reduction. We recommend this minimally invasive procedure to be the standard of care for subcutaneous abscesses in children. TYPE OF STUDY: Treatment study - retrospective review. LEVEL OF EVIDENCE: Level IV - case series with no comparison group.


Subject(s)
Abscess/surgery , Drainage/methods , Minimally Invasive Surgical Procedures/methods , Subcutaneous Tissue/surgery , Abscess/diagnosis , Bandages , Child , Child, Preschool , Female , Humans , Male , Retrospective Studies , Treatment Outcome
6.
J Pediatr Surg ; 52(4): 544-548, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27637140

ABSTRACT

BACKGROUND: The increasing prevalence of obesity has necessitated the increasing use of bariatric surgery in the adolescent population. Outcomes following laparoscopic sleeve gastrectomy (LSG) among adolescents, however, have not been well-studied. We report outcomes following LSG as a first-line surgical therapy in patients under 21years of age. METHODS: All patients who underwent LSG as a primary surgical option for morbid obesity were identified at the University of Illinois at Chicago between 2006 and 2014. Standard clinicopathologic and outcomes data were recorded. RESULTS: We identified 18 patients (13 females, 5 males) who underwent LSG. Mean patient age was 17.8±1.7years. Mean BMI among all patients was 48.6±7.2kg/m2 and did not differ by gender (P=0.68). One patient (5.6%) experienced a 30-day perioperative complication (pulmonary embolism). Median LOS following LSG was 3days (IQR: 2, 3). 2 patients (11.1%) were readmitted within 30-days because of feeding intolerance that resolved without invasive intervention. At a median follow-up of 10.6 (range: 0-38) months, percent excess weight loss (%EWL) among all patients was 35.6%. Among patients with at least 2years follow-up (n=3), %EWL was 50.2%. CONCLUSIONS: Laparoscopic sleeve gastrectomy in morbidly obese adolescents is a safe and feasible option. Short- and long-term weight loss appears to be successful following LSG. As such, LSG should be strongly considered as a primary surgical treatment option for all morbidly obese adolescents. LEVEL OF EVIDENCE: Level IV.


Subject(s)
Bariatric Surgery/methods , Gastrectomy/methods , Laparoscopy , Obesity, Morbid/surgery , Weight Loss , Adolescent , Bariatric Surgery/adverse effects , Body Mass Index , Female , Follow-Up Studies , Gastrectomy/adverse effects , Humans , Male , Perioperative Period , Treatment Outcome , Young Adult
7.
Biomaterials ; 77: 320-35, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26618750

ABSTRACT

The currently available surgical options to repair the diaphragm are associated with significant risks of defect recurrence, lack of growth potential and restored functionality. A tissue engineered diaphragm has the potential to improve surgical outcomes for patients with congenital or acquired disorders. Here we show that decellularized diaphragmatic tissue reseeded with bone marrow mesenchymal stromal cells (BM-MSCs) facilitates in situ regeneration of functional tissue. A novel bioreactor, using simultaneous perfusion and agitation, was used to rapidly decellularize rat diaphragms. The scaffolds retained architecture and mechanical properties and supported cell adhesion, proliferation and differentiation. Biocompatibility was further confirmed in vitro and in vivo. We replaced 80% of the left hemidiaphragm with reseeded diaphragmatic scaffolds. After three weeks, transplanted animals gained 32% weight, showed myography, spirometry parameters, and histological evaluations similar to native rats. In conclusion, our study suggested that reseeded decellularized diaphragmatic tissue appears to be a promising option for patients in need of diaphragmatic reconstruction.


Subject(s)
Diaphragm/transplantation , Mesenchymal Stem Cell Transplantation/methods , Tissue Engineering/methods , Tissue Scaffolds , Absorbable Implants , Allografts , Animals , Bioreactors , Cell Adhesion , Cell Differentiation , Diaphragm/blood supply , Diaphragm/diagnostic imaging , Diaphragm/immunology , Electromyography , Graft Survival , Hernias, Diaphragmatic, Congenital , Macrophages/immunology , Male , Neovascularization, Physiologic , Radiography , Rats , Rats, Inbred Lew , Tissue Engineering/instrumentation , Transplantation, Heterotopic , Transplants/blood supply , Transplants/immunology , Transplants/physiology , Wound Healing
8.
J Interferon Cytokine Res ; 35(8): 585-99, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25803788

ABSTRACT

Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti-inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them "tolerogenic," which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro-inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility.


Subject(s)
Cytokines/physiology , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Inflammation Mediators/physiology , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmunity , Cytokines/pharmacology , Cytokines/therapeutic use , Drug Evaluation, Preclinical , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Immune Tolerance , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Immunotherapy , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Inflammation Mediators/pharmacology , Inflammation Mediators/therapeutic use
9.
Obesity (Silver Spring) ; 21(3): 591-7, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23592668

ABSTRACT

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is increasingly an indication for liver transplantation in adults. While severe obesity (SO, BMI ≥40 kg m(-2) ) in adults is long standing, it is recent in duration in adolescents. With adolescent obesity on the rise, NAFLD is becoming the most frequent liver disease in adolescents. The hypothesis that SO adolescents and adults have different severity of NAFLD because of longer duration of obesity in SO adults was tested. DESIGN AND METHODS: Preoperative clinical data, NAFLD activity and NASH (Nonalcoholic steatohepatitis) scores from intraoperative liver biopsies were extracted from a prospective database of consecutively operated SO adolescents and adults (n = 24 each). Fasting preoperative serum inflammatory mediators were evaluated by ELISA. RESULTS: Other than age, baseline BMI, ethnicity and gender distribution, the incidence and extent of dyslipidemia, hypertension, and metabolic syndrome were comparable between groups. Histologic scores for steatosis and inflammation were similar. Adolescents have significantly higher NASH incidence, hepatocyte injury scores and fibrosis. This was associated with higher serum C-reactive protein and sCD14 levels. CONCLUSION: For comparable BMI and metabolic profile, SO adolescents have more advanced liver damage, more severe systemic inflammation, suggesting differences in NAFLD etiologies and more aggressive disease progression in the young obese population.


Subject(s)
Fatty Liver/epidemiology , Obesity, Morbid/epidemiology , Adolescent , Adult , Biomarkers/blood , Biopsy , Body Mass Index , C-Reactive Protein/analysis , Cross-Sectional Studies , Disease Progression , Enzyme-Linked Immunosorbent Assay , Fatty Liver/etiology , Female , Hepatocytes/pathology , Humans , Inflammation Mediators/blood , Liver/pathology , Liver/surgery , Liver Transplantation , Male , Middle Aged , Non-alcoholic Fatty Liver Disease , Obesity, Morbid/complications , Prospective Studies , Risk Factors
10.
PLoS One ; 8(1): e55074, 2013.
Article in English | MEDLINE | ID: mdl-23383062

ABSTRACT

Classic genetic studies implicated several genes including immune response genes in the risk of developing type 1 diabetes in humans. However, recent evidence including discordant diabetes incidence among monozygotic twins suggested a role for epigenetics in disease manifestation. NOD mice spontaneously develop type 1 diabetes like humans and serve as an excellent model system to study the mechanisms of type 1 diabetes as well as the efficacy of maneuvers to manipulate the disease. Using this preclinical model, we have recently demonstrated that pharmacological inhibition of histone deacetylases can lead to histone hyperacetylation, selective up-regulation of interferon-γ and its transactivator Tbx21/Tbet, and amelioration of autoimmune diabetes. In the current study, we show that chromatin remodeling can render splenocytes incapable of transferring diabetes into immunodeficient NOD.scid mice. To elucidate the underlying mechanisms of drug-mediated protection against type 1 diabetes, we performed global gene expression profiling of splenocytes using high throughput microarray technology. This unbiased transcriptome analysis unraveled the exaggerated expression of a novel set of closely related inflammatory genes in splenocytes of acutely diabetic mice and their repression in mice cured of diabetes by chromatin remodeling. Analysis of gene expression by qRT-PCR using RNA derived from spleens and pancreata of cured mice validated the suppression of most of these genes, indicating an inverse correlation between the high levels of these inflammatory genes and protection against diabetes in NOD mice. In addition, higher-level expression of genes involved in insulin sensitivity, erythropoiesis, hemangioblast generation, and cellular redox control was evident in spleens of cured mice, indicating their possible contribution to protection against type 1 diabetes. Taken together, these results are consistent with the involvement of epistatic mechanisms in the manifestation of autoimmune diabetes and further indicate the utility of chromatin remodeling in curing this complex autoimmune disorder.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/prevention & control , Epigenesis, Genetic/genetics , Gene Expression Profiling , Genomics , Animals , Chromatin Assembly and Disassembly/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Down-Regulation/genetics , Female , Inflammation/genetics , Mice , Mice, Inbred NOD , T-Lymphocytes/immunology
11.
J Pediatr Surg ; 47(9): 1633-9, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22974598

ABSTRACT

PURPOSE: The aim of the study was to compare the baseline and the 18-month follow-up for weight and metabolic characteristics of superobese (SO) (body mass index [BMI] ≥50 kg/m(2)) and morbidly obese (MO) (BMI <50 kg/m(2)) adolescents who participated in a prospective longitudinal study of gastric banding delivered in an adolescent multidisciplinary treatment program. METHODS: Clinical information was extracted from an institutional review board-approved database of bariatric adolescents. Fasting cytokine and acute phase protein serum levels were analyzed by enzyme-linked immunosorbent assay. Liver histopathologies were assessed using the Kleiner's classification score. RESULTS: Other than BMI, MO (n = 11) and SO (n = 7) patients have similar degree of insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. Serum C-reactive protein (10.2 ± 5.6 SO vs 4 ± 3.9 µg/mL MO [P < .02]) and leptin (71 ± 31 SO vs 45 ± 28 MO ng/mL [P = .04]) were more elevated in SO patients. Although weight loss is similar (30 ± 19 kg MO vs 28 ± 12 kg SO, P = .8 at 18 months; mean percent change in BMI, 22.8% ± 11.6% vs 20.5% ± 10.3% SO, P = .2), SO patients has less resolution of insulin resistance and dyslipidemia but experienced significantly improved health-related quality of life. CONCLUSIONS: The SO adolescents demonstrate equivalent short-term weight loss and improved quality of life but delayed metabolic response to a gastric banding-based weight loss treatment program compared with MO patients, illustrating the importance of early referral for timely intervention of MO patients.


Subject(s)
Gastroplasty , Metabolic Syndrome/surgery , Obesity, Morbid/surgery , Weight Loss , Acute-Phase Proteins/metabolism , Adolescent , Biomarkers/blood , Body Mass Index , Cross-Sectional Studies , Cytokines/blood , Dyslipidemias/complications , Enzyme-Linked Immunosorbent Assay , Fatty Liver/complications , Follow-Up Studies , Gastroplasty/methods , Humans , Insulin Resistance , Laparoscopy , Leptin/blood , Metabolic Syndrome/blood , Metabolic Syndrome/complications , Non-alcoholic Fatty Liver Disease , Obesity, Morbid/blood , Obesity, Morbid/complications , Prospective Studies , Treatment Outcome , Weight Reduction Programs
12.
Surg Clin North Am ; 92(3): 559-82, viii, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22595709

ABSTRACT

Childhood obesity is a tremendous burden for children, their families, and society. Obesity prevention remains the ultimate goal but rapid development and deployment of effective nonsurgical treatment options is not currently achievable given the complexity of this disease. Surgical options for adolescent obesity have been proven to be safe and effective and should be offered. The development of stratified protocols of increasing intensity should be individualized for patients based on their disease severity and risk factors. These protocols should be offered in multidisciplinary, cooperative clinical trials to critically evaluate and develop optimal treatment strategies for morbid obesity.


Subject(s)
Bariatric Surgery , Obesity/surgery , Adolescent , Anti-Obesity Agents/therapeutic use , Bariatric Surgery/instrumentation , Bariatric Surgery/methods , Child , Clinical Protocols , Combined Modality Therapy , Comorbidity , Humans , Obesity/epidemiology , Obesity/etiology , Obesity/therapy , Practice Guidelines as Topic , United States/epidemiology , Weight Reduction Programs
13.
BMC Med ; 10: 3, 2012 Jan 10.
Article in English | MEDLINE | ID: mdl-22233865

ABSTRACT

BACKGROUND: Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet ß cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D. METHODS: We developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n=15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21). RESULTS: Stem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual ß cell function (n=6) and patients with no residual pancreatic islet ß cell function (n=6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n=3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance. CONCLUSIONS: Stem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet ß cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01350219.


Subject(s)
Diabetes Mellitus, Type 1/therapy , Immunomodulation , Insulin-Secreting Cells/physiology , Multipotent Stem Cells/immunology , Multipotent Stem Cells/transplantation , Regeneration , Adolescent , Adult , C-Peptide/blood , Cell Communication , Cells, Cultured , Diabetes Mellitus, Type 1/immunology , Female , Fetal Blood/cytology , Follow-Up Studies , Humans , Insulin-Secreting Cells/metabolism , Male , Recovery of Function , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology
14.
Biochem Biophys Res Commun ; 399(4): 629-36, 2010 Sep 03.
Article in English | MEDLINE | ID: mdl-20691153

ABSTRACT

Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing beta cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2rgamma(null) mice. The selective destruction of pancreatic islet beta cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total beta-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the beta cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet beta cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4(+) T cell infiltration and clonal expansion, and the mouse islet beta-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet beta cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.


Subject(s)
Diabetes Mellitus, Type 1/immunology , Disease Models, Animal , Insulin-Secreting Cells/immunology , Mice , T-Lymphocytes/immunology , Animals , Cell Movement , Chemokine CXCL12/metabolism , Diabetes Mellitus, Type 1/pathology , Humans , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/radiation effects , Leukocytes, Mononuclear/transplantation , Mice, Inbred NOD , Mice, SCID , Spleen/cytology , Spleen/immunology , Spleen/radiation effects , T-Lymphocytes/transplantation , Translational Research, Biomedical
15.
J Immunol ; 184(12): 6695-708, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20483724

ABSTRACT

The levels of expression of alternatively spliced variants of CTLA-4 and insufficient CTLA-4 signaling have been implicated in type 1 diabetes. Hence, we hypothesized that increasing CTLA-4-specific ligand strength on autoantigen-presenting dendritic cells (DCs) can enhance ligation of CTLA-4 on T cells and lead to modulation of autoreactive T cell response. In this study, we show that DC-directed enhanced CTLA-4 engagement upon pancreatic beta cell Ag presentation results in the suppression of autoreactive T cell response in NOD mice. The T cells from prediabetic NOD mice treated with an agonistic anti-CTLA-4 Ab-coated DC (anti-CTLA-4-Ab DC) showed significantly less proliferative response and enhanced IL-10 and TGF-beta1 production upon exposure to beta cell Ags. Furthermore, these mice showed increased frequency of Foxp3+ and IL-10+ T cells, less severe insulitis, and a significant delay in the onset of hyperglycemia compared with mice treated with control Ab-coated DCs. Further analyses showed that diabetogenic T cell function was modulated primarily through the induction of Foxp3 and IL-10 expression upon Ag presentation by anti-CTLA-4-Ab DCs. The induction of Foxp3 and IL-10 expression appeared to be a consequence of increased TGF-beta1 production by T cells activated using anti-CTLA-4-Ab DCs, and this effect could be enhanced by the addition of exogenous IL-2 or TGF-beta1. Collectively, this study demonstrates the potential of a DC-directed CTLA-4 engagement approach not only in treating autoimmunity in type 1 diabetes, but also in altering diabetogenic T cell function ex vivo for therapy.


Subject(s)
Antigen Presentation/immunology , Antigens, CD/metabolism , Dendritic Cells/metabolism , Diabetes Mellitus, Type 1/metabolism , Insulin-Secreting Cells/metabolism , Animals , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen , Cell Separation , Cytokines/biosynthesis , Cytokines/immunology , Dendritic Cells/immunology , Diabetes Mellitus, Type 1/immunology , Flow Cytometry , Insulin-Secreting Cells/immunology , Lymphocyte Activation/immunology , Mice , Mice, Inbred NOD
16.
Transl Res ; 155(5): 211-6, 2010 May.
Article in English | MEDLINE | ID: mdl-20403575

ABSTRACT

Type 1 diabetes (T1D) is an autoimmune disease caused by an autoimmune destruction of pancreatic islet insulin-producing cells. Autoimmunity and shortage of insulin-producing cells are 2 key issues for the treatment of T1D. To cure T1D in a comprehensive manner, both issues need to be addressed simultaneously. Not only must the islet cells be replaced, the patient's immune system also must be dealt with. Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and self-tolerance through their inhibitory impacts on autoreactive effector T cells. We identified a novel type of stem cells from human umbilical cord blood, designated cord blood stem cells (CB-SC), which may be able to address immune modulation of the autoimmune process and allow for beta-cell replacement. We are the first group using CB-SC to correct functional defects of CD4(+)CD62L(+) Tregs, leading to a reversal of overt diabetes in an autoimmune-caused diabetic NOD mouse model. Notably, treatment with CB-SC-modulated CD4(+)CD62L(+) Tregs (mCD4CD62L Tregs) simultaneously can overcome the autoimmunity via systemic and local immune modulations and the shortage of insulin-producing cells via stimulating the beta-cell regeneration. These new stem cells will offer a promising avenue for the development of powerful autologous therapeutic products for prevention and reversal of T1D.


Subject(s)
Cord Blood Stem Cell Transplantation , Diabetes Mellitus, Type 1/therapy , Stem Cells/cytology , Animals , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/prevention & control , Humans , Islets of Langerhans/metabolism , Mice , T-Lymphocytes, Regulatory/immunology
17.
J Immunol ; 184(6): 3008-15, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20164427

ABSTRACT

Although allogeneic bone marrow transplantation has been shown to prevent autoimmune diabetes in heavily irradiated nonobese diabetic (NOD) mice, a similar procedure is not suitable for the treatment of patients with type 1 diabetes because of associated severe side effects. Therefore, we evaluated whether mouse newborn blood (NBB), equivalent to human umbilical cord blood, could be used for diabetes prevention without recipient preconditioning. To test this hypothesis, unconditioned, prediabetic female NOD mice were given a single injection of whole NBB derived from the allogeneic diabetes-resistant mouse strain C57BL/6. Transfusion of allogeneic NBB but not adult blood prevented diabetes incidence in a majority of treated mice for a prolonged period of time. This was accompanied by the release of insulin in response to a challenge with glucose. Invasive cellular infiltration of islets was also substantially reduced in these mice. Although NBB transfusion induced a low level of hematopoietic microchimerism, it did not strictly correlate with amelioration of diabetes. Induction of genes implicated in diabetes, such as Il18, Tnfa, and Inos but not Il4, Il17 or Ifng, was repressed in splenocytes derived from protected mice. Notably, expression of the transcription factor Tbet/Tbx21 but not Gata3 or Rorgt was upregulated in protected mice. These data indicate that allogeneic NBB transfusion can prevent diabetes in NOD mice associated with modulation of selected cytokine genes implicated in diabetes manifestation. The data presented in this study provide the proof of principle for the utility of allogeneic umbilical cord blood transfusion to treat patients with autoimmune diabetes.


Subject(s)
Cytokines/biosynthesis , Cytokines/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/prevention & control , Fetal Blood/transplantation , Animals , Animals, Newborn , Antigens, Ly/biosynthesis , Antigens, Ly/genetics , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Autoimmune Diseases/prevention & control , Cytokines/antagonists & inhibitors , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , Female , Fetal Blood/cytology , Fetal Blood/immunology , Genetic Predisposition to Disease , Hematopoietic Stem Cell Transplantation/methods , Immunity, Innate/genetics , Immunity, Innate/immunology , Immunophenotyping , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Prediabetic State/genetics , Prediabetic State/immunology , Prediabetic State/pathology
18.
J Pediatr Surg ; 45(1): 74-8; discussion 78-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20105583

ABSTRACT

UNLABELLED: BACKGROUND AND MATERIALS AND METHODS: The outcome of patients completing 12 months of follow-up in a prospective longitudinal trial of the safety/efficacy of laparoscopic adjustable gastric banding (LAGB) for morbidly obese adolescents aged 14 to 17 years using a Food and Drug Administration Institutional Device Exemption for the use of the LAPBAND was analyzed. Baseline and outcome data were abstracted from a prospective database. RESULTS: Baseline (mean +/- SD) body mass index was 50 +/- 10 kg/m(2), and excess weight was 178 +/- 53 lb in 20 patients. Comorbidities included hypertension (45%), dyslipidemia (80%), insulin resistance (90%), metabolic syndrome (95%), and biopsy-proven nonalcoholic steatohepatitis (88%). At mean (SD) follow-up of 26 (9) months, % excess weight loss was 34% +/- 22% (n = 20) and 41% +/- 27% (n = 12), and the metabolic syndrome was resolved in 63% and 82% of the patients at 12 and 18 months, respectively. Hypertension normalized in all patients, along with improvement in lipid abnormalities and quality of life scores (P < .05). At 12 months, of the 5 patients with less than 20% excess weight loss, dyslipidemia and metabolic syndrome were resolved in 2 patients. CONCLUSION: At intermediate follow-up of a LAGB-based obesity treatment program, weight loss led to resolution or improvement of major obesity-related comorbidities in most patients, supporting the efficacy of LAGB as a surgical adjunct to a comprehensive obesity treatment program and its long-term evaluation.


Subject(s)
Gastroplasty/methods , Metabolic Syndrome/therapy , Obesity, Morbid/surgery , Quality of Life , Weight Loss , Adolescent , Body Mass Index , Comorbidity , Electronics, Medical/instrumentation , Equipment Design/methods , Female , Follow-Up Studies , Gastroplasty/instrumentation , Health Status , Humans , Laparoscopy , Male , Metabolic Syndrome/epidemiology , Obesity, Morbid/epidemiology , Outcome Assessment, Health Care , Prospective Studies , Surveys and Questionnaires , Treatment Outcome , United States , United States Food and Drug Administration
19.
J Pediatr Surg ; 44(4): E13-6, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19361617

ABSTRACT

Leucine-hypersensitive hypoglycemia is a rare clinical entity that is usually diagnosed after an exhaustive search for other causes of hypoglycemia. In nonsurgical patients, an imbalance between metabolic demands and gluconeogenesis are most frequently responsible for recurrent symptomatic hypoglycemia. In the postoperative patient, hypoglycemia more commonly results from inadequate energy intake or malabsorption from functional or anatomical abnormalities. Presented here is an unusual case of a child who was initially diagnosed with postoperative gastrocolic fistula and dumping syndrome as the cause of hypoglycemia but later found to have leucine-hypersensitive hypoglycemia.


Subject(s)
Colonic Diseases/diagnosis , Gastric Fistula/diagnosis , Hypoglycemia/diagnosis , Intestinal Fistula/diagnosis , Leucine , Blood Glucose/analysis , Child , Chronic Disease , Colonic Diseases/complications , Fluoroscopy/methods , Follow-Up Studies , Gastric Fistula/complications , Humans , Hypersensitivity/complications , Hypersensitivity/diagnosis , Hypoglycemia/etiology , Incidental Findings , Intestinal Fistula/complications , Leucine/immunology , Male , Risk Assessment , Severity of Illness Index
20.
J Pediatr Surg ; 44(1): e29-32, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19159707

ABSTRACT

Poland's syndrome is a constellation of rare congenital anomalies that include hypoplasia of breast and underlying subcutaneous tissue, absence of the costosternal portion of the pectoralis major muscle, deformity or absence of ribs, absence of axillary hair, and syndactyly. Various surgical techniques have been described to repair such chest wall defects. We report a case of simultaneous Fonkalsrud procedure (costal cartilage-sparing version of the modified Ravitch procedure) and latissimus dorsi transfer in a 15-year-old boy with Poland's syndrome. The Fonkalsrud procedure has been used in the repair of pectus excavatum and pectus carinatum, and latissimus dorsi muscle transfer has been used in the repair of Poland's syndrome. In this report, we describe their combined use in an adolescent with severe pectus excavatum associated with Poland's syndrome. This combination of established operations resulted in a successful outcome.


Subject(s)
Muscle, Skeletal/transplantation , Poland Syndrome/surgery , Thoracic Wall/abnormalities , Thoracic Wall/surgery , Thoracoplasty/methods , Adolescent , Humans , Male , Surgical Flaps
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