-
Molecules and Cells Jan 2010Although mutations in the insulin receptor have been causally implicated with leprechaunism, the full pathophysiology of the syndrome cannot be accounted for by...
Although mutations in the insulin receptor have been causally implicated with leprechaunism, the full pathophysiology of the syndrome cannot be accounted for by malfunction of this gene alone. We sought to characterize a connection between Wnt-mediated cell signaling and the production of reactive oxygen species (ROS) which revealed a novel mechanistic basis for understanding the pathogenesis of leprechaunism. To identify candidate genes involved in this process, a PCR-based subtractive hybridization was performed. Candidate genes were examined for interaction with the Wnt signaling pathway and ROS generation. We found that Dickkopf 1 (Dkk1), a Wnt inhibitor, is overexpressed in skin fibroblast cells derived from three leprechaunism patients and that the cells showed an impaired response to Wnt2 in terms of beta-catenin-Tcf activation. Knockdown of Dkk1 in the patient cell lines rescued Wnt2-mediated Tcf activation. Concerted action of Wnt2 and knockdown of Dkk1 resulted in enhanced Nox4 expression and PDGF-induced ROS generation compared to parental patient cells. Furthermore, we found that NFATc2 was activated in response to Wnt2 stimulation and directly activates Nox4 expression. These data show a crosstalk between Wnt and ROS pathways which in turn provides new mechanistic insights at the molecular level into the pathogenesis of leprechaunism.
Topics: Cell Culture Techniques; Cells, Cultured; Donohue Syndrome; Fibroblasts; Gene Expression Profiling; Humans; Intercellular Signaling Peptides and Proteins; NADPH Oxidase 4; NADPH Oxidases; NFATC Transcription Factors; Platelet-Derived Growth Factor; RNA, Small Interfering; Reactive Oxygen Species; Signal Transduction; Skin; T Cell Transcription Factor 1; Transcriptional Activation; Wnt2 Protein; beta Catenin
PubMed: 20033851
DOI: 10.1007/s10059-010-0017-z -
The Annals of Thoracic Surgery Aug 2016Understanding the seminal complications leading to death after pediatric cardiac surgical procedures may provide opportunities to reduce mortality. This study analyzed...
BACKGROUND
Understanding the seminal complications leading to death after pediatric cardiac surgical procedures may provide opportunities to reduce mortality. This study analyzed all deaths at two pediatric cardiac surgical programs and developed a method to identify the seminal complications and modes of death.
METHODS
Trained nurses abstracted all cases of in-hospital mortality meeting inclusion criteria from each site over 5 years (2008 to 2012). Complication definitions were consistent with those of a multicenter clinical registry. An adjudication committee assigned a seminal complication in each case (the complication initiating the cascade of events leading to death). Seminal complications were grouped into categories to designate "mode of death." The epidemiology of seminal complications and of mode of death was described.
RESULTS
In 191 subjects, low cardiac output syndrome (71% of all subjects), cardiac arrest (52%), and arrhythmia (48%) were the most common complications. The committee assigned low cardiac output syndrome (30%), failure to separate from bypass (16%), and cardiac arrest (12%) most frequently as seminal complications. Seminal complications occurred a median 2 hours (interquartile range [IQR], 0 to 35 hours) postoperatively. Patients experienced a median of seven (IQR, 3 to 12) additional complications before death at a median of 15 days (IQR, 4 to 46). Systemic circulatory failure was the most common mode of death (51%), followed by inadequate pulmonary blood flow (13%) and cardiac arrest (12%).
CONCLUSIONS
Seminal complications occurred early postoperatively, and systemic circulatory failure was the most common mode of death. Our classification system is likely scalable for subsequent multicenter analysis to understand cause-specific mortality variation across hospitals and to drive quality improvement.
Topics: Cardiac Surgical Procedures; Cause of Death; Female; Heart Defects, Congenital; Hospital Mortality; Humans; Infant; Infant, Newborn; Male; Postoperative Complications; Registries; Survival Rate; United States
PubMed: 27154145
DOI: 10.1016/j.athoracsur.2016.02.043 -
Biology of Blood and Marrow... Jun 2020While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is...
While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is still a high risk of relapse or transplant-related complications. We collected data on all patients who had undergone allo-HCT at our center (Copenhagen University Hospital) between 2000 and 2018. In total, 215 patients with MDS (n = 196) or chronic myelomonocytic leukemia (n = 19) were included. Estimated 1-year overall survival (OS) was 70.3% (95% confidence interval [CI], 64.2% to 77.0%), and the median survival was 7.7 years (95% CI, 4.7 to indeterminable). There was a significant improvement in OS over time (P = .011, comparing 2000 to 2010, 2010 to 2014, and 2014 to 2018). Treatment was standardized throughout the study period, allowing comparison between patients receiving nonmyeloablative (NMA, n = 124), standard myeloablative (SMA, n = 36), and fludarabine and treosulfan (FluTreo, n = 55) conditioning. FluTreo has myeloablative properties but lower toxicity and replaced standard myeloablative conditioning at our center in 2014. The FluTreo group was significantly older and had more comorbidities than the SMA group but similar disease severity. One-year OS was 84.0% (95% CI, 74.3% to 94.9%), 58.3% (95% CI, 44.3% to 76.9%), and 68.3% (95% CI, 60.2% to 77.5%) for FluTreo, SMA, and NMA, respectively (P = .04). In univariate analysis, Revised International Scoring System (IPSS-R) (high versus low), donor sex mismatch, and cytomegalovirus status mismatch were significant factors for OS. In multivariate analysis of OS including age, IPSS-R, and HCT specific comorbidity index, NMA was borderline inferior to FluTreo (P = .073) while SMA was significantly inferior to FluTreo with a hazard ratio of 6.89 (95% CI, 2.53 to 18.77, P < .001). The introduction of FluTreo allowed us to administer a myeloablative regimen to a broader patient group and shows promising results.
Topics: Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine
PubMed: 32088368
DOI: 10.1016/j.bbmt.2020.02.010 -
Journal of Clinical Research in... Dec 2017Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized...
Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized by acanthosis nigricans, generalized lanugo, tooth and nail dysplasia, high nasal bridge, and growth retardation. A 5-year-old female patient was referred due to acanthosis nigricans and generalized lanugo. On her physical examination, severe acanthosis nigricans of the neck, axillae, the external genitalia and antecubital regions, generalized lanugo, mildly decreased subcutaneous fat, dysmorphic facial features, and polydactyly on her left hand were noted. Insulin resistance and impaired glucose tolerance were found. Sequence analysis of the INSR in the patient revealed c.3529+5G>A mutation in homozygous state. RMS should be suspected in a patient with characteristic physical features and insulin resistance.
Topics: Acanthosis Nigricans; Antigens, CD; Child, Preschool; Donohue Syndrome; Female; Humans; Mutation, Missense; Receptor, Insulin; Severity of Illness Index
PubMed: 28663160
DOI: 10.4274/jcrpe.4577 -
Endocrine Journal 2013Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a...
Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism.
Topics: Child, Preschool; Donohue Syndrome; Humans; Hypoglycemic Agents; Infant; Insulin, Short-Acting; Insulin-Like Growth Factor I; Male; Mutation; Receptor, Insulin; Recombinant Proteins
PubMed: 22972224
DOI: 10.1507/endocrj.ej12-0289 -
American Journal of Physiology.... Aug 2009Muscle wasting is a critical feature of patients afflicted by acquired immune deficiency syndrome (AIDS), cancer, or chronic inflammatory diseases. In a mouse model of...
Muscle wasting is a critical feature of patients afflicted by acquired immune deficiency syndrome (AIDS), cancer, or chronic inflammatory diseases. In a mouse model of muscle wasting, TNF-alpha induces oxidative stress and nitric oxide synthase-2 (NOS2) and decreases myogenin, Jun-D, and creatinine kinase muscle isoform (CKM) expression. Here, we studied 12 patients with muscle wasting due to cancer (N = 10) or AIDS (N = 2) and 4 control subjects. We show that in skeletal muscle of cachectic patients there is 1) increased expression and activity of the TNF-alpha signaling, including TNF-alpha mRNA, activation of TNFR1, and TNF-alpha-associated to TNFR1; 2) increased oxidative stress, as determined by the presence of malondialdehyde-lysine adducts; 3) increased NOS2 mRNA and protein; 4) decreased expression of Jun-D, myogenin, myosin, and CKM mRNA and protein; 5) impaired CKM-E box binding activities, associated with decreased Jun-D/myogenin activities; and 6) oxidative modification and ubiquitination of Jun-D. These studies show that these molecular pathways are modulated in association with muscle wasting in patients with cancer or AIDS, and whether or not they cause muscle wasting remains to be determined.
Topics: Adult; Aged; Cachexia; Creatine Kinase, MM Form; Down-Regulation; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Myogenin; Nitric Oxide Synthase Type II; Oxidative Stress; Protein Binding; Proto-Oncogene Proteins c-jun; Receptors, Tumor Necrosis Factor; Response Elements; Tumor Necrosis Factor-alpha; Wasting Syndrome
PubMed: 19470832
DOI: 10.1152/ajpendo.90529.2008 -
Pediatric Critical Care Medicine : a... Feb 2019To develop a postoperative mortality case-mix adjustment model to facilitate assessment of cardiac ICU quality of care, and to describe variation in adjusted cardiac ICU... (Observational Study)
Observational Study
OBJECTIVE
To develop a postoperative mortality case-mix adjustment model to facilitate assessment of cardiac ICU quality of care, and to describe variation in adjusted cardiac ICU mortality across hospitals within the Pediatric Cardiac Critical Care Consortium.
DESIGN
Observational analysis.
SETTING
Multicenter Pediatric Cardiac Critical Care Consortium clinical registry.
PARTICIPANTS
All surgical cardiac ICU admissions between August 2014 and May 2016. The analysis included 8,543 admissions from 23 dedicated cardiac ICUs.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
We developed a novel case-mix adjustment model to measure postoperative cardiac ICU mortality after congenital heart surgery. Multivariable logistic regression was performed to assess preoperative, intraoperative, and immediate postoperative severity of illness variables as candidate predictors. We used generalized estimating equations to account for clustering of patients within hospital and obtain robust SEs. Bootstrap resampling (1,000 samples) was used to derive bias-corrected 95% CIs around each predictor and validate the model. The final model was used to calculate expected mortality at each hospital. We calculated a standardized mortality ratio (observed-to-expected mortality) for each hospital and derived 95% CIs around the standardized mortality ratio estimate. Hospital standardized mortality ratio was considered a statistically significant outlier if the 95% CI did not include 1. Significant preoperative predictors of mortality in the final model included age, chromosomal abnormality/syndrome, previous cardiac surgeries, preoperative mechanical ventilation, and surgical complexity. Significant early postoperative risk factors included open sternum, mechanical ventilation, maximum vasoactive inotropic score, and extracorporeal membrane oxygenation. The model demonstrated excellent discrimination (C statistic, 0.92) and adequate calibration. Comparison across Pediatric Cardiac Critical Care Consortium hospitals revealed five-fold difference in standardized mortality ratio (0.4-1.9). Two hospitals had significantly better-than-expected and two had significantly worse-than-expected mortality.
CONCLUSIONS
For the first time, we have demonstrated that variation in mortality as a quality metric exists across dedicated cardiac ICUs. These findings can guide efforts to reduce mortality after cardiac surgery.
Topics: Age Factors; Cardiac Surgical Procedures; Child, Preschool; Critical Care; Extracorporeal Membrane Oxygenation; Female; Heart Defects, Congenital; Hospital Mortality; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Logistic Models; Male; Respiration, Artificial; Retrospective Studies; Risk Adjustment; Risk Factors; Severity of Illness Index
PubMed: 30489488
DOI: 10.1097/PCC.0000000000001776 -
SAGE Open Medicine 2023We sought to determine predictors, incidence, and interventions required for patients who developed barotrauma. Pneumothorax, subcutaneous emphysema, and...
OBJECTIVE
We sought to determine predictors, incidence, and interventions required for patients who developed barotrauma. Pneumothorax, subcutaneous emphysema, and pneumomediastinum have all been reported as complications related to COVID-19-positive patients requiring invasive mechanical ventilation.
METHODS
In this retrospective study, clinical and imaging data from COVID-19 patients were collected and reviewed by two independent intensivists between January 4, 2020 and January 10, 2020. Data were used to identify COVID-19-positive patients requiring invasive mechanical ventilation and the incidence of barotrauma. Two separate cohorts were created as non-injured (no barotrauma) and injured (barotrauma present). We then sought to identify the risk factors for barotrauma in the non-injured cohort on Days 0, 7, 10, and 14 after intubation and day of injury in the injured cohort.
RESULTS
Of the 264 patients with COVID-19, 55.8% were African American. The non-injured group was older (60 ± 15 versus 49 ± 16, 0.006), with male predominance in the injured group versus non-injured group (75% versus 55%). A total of 16 (6.5%) patients developed one or more complications of barotrauma, defined as subcutaneous emphysema, pneumothorax, or pneumomediastinum. Length of stay was longer for the injured group versus non-injured group (47 versus 25 days). Plateau pressure ( 0.024), fraction of inspired oxygen ( < 0.001), and driving pressure ( = 0.001) were statistically significant in injured cohort. Mortality rate in non-injured versus injured was 49.4% versus 69%. Using random effect model, fraction of inspired oxygen ( = 0.003) and mean airway pressure ( 0.010) were significant at the time of injury. When comparing alive versus deceased in the injured cohort, thoracostomy placement in alive versus deceased was 80% versus 54.5%.
CONCLUSION
COVID acute respiratory distress syndrome patients requiring invasive mechanical ventilation had a higher rate of barotrauma and were younger than those who did not develop barotrauma. Possible interventions to be considered to decrease barotrauma are decreased driving pressure goal and universal use of esophageal balloon manometry.
PubMed: 36941897
DOI: 10.1177/20503121231159479 -
The Journal of Clinical Investigation Mar 2021The effectiveness of virus-specific strategies, including administered HIV-specific mAbs, to target cells that persistently harbor latent, rebound-competent HIV genomes...
The effectiveness of virus-specific strategies, including administered HIV-specific mAbs, to target cells that persistently harbor latent, rebound-competent HIV genomes during combination antiretroviral therapy (cART) has been limited by inefficient induction of viral protein expression. To examine antibody-mediated viral reservoir targeting without a need for viral induction, we used an anti-CD4 mAb to deplete both infected and uninfected CD4+ T cells. Ten rhesus macaques infected with barcoded SIVmac239M received cART for 93 weeks starting 4 days after infection. During cART, 5 animals received 5 to 6 anti-CD4 antibody administrations and CD4+ T cell populations were then allowed 1 year on cART to recover. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not significantly delayed in anti-CD4-treated animals compared with controls. Viral reactivation rates, determined based on rebounding SIVmac239M clonotype proportions, also were not significantly different in CD4-depleted animals. Notably, antibody-mediated depletion was limited in rectal tissue and negligible in lymphoid follicles. These results suggest that, even if robust viral reactivation can be achieved, antibody-mediated viral reservoir depletion may be limited in key tissue sites.
Topics: Animals; Anti-HIV Agents; Anti-Retroviral Agents; Antibodies, Monoclonal; Antibodies, Viral; CD4 Antigens; CD4-Positive T-Lymphocytes; Female; HIV Infections; HIV-1; Humans; Lymphocyte Depletion; Lymphoid Tissue; Macaca mulatta; Male; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Viral Load; Virus Activation; Virus Replication
PubMed: 33465055
DOI: 10.1172/JCI142421 -
Acta Diabetologica Mar 2023
Topics: Female; Humans; Donohue Syndrome; Insulin Resistance; Receptor, Insulin; Mutation
PubMed: 36331627
DOI: 10.1007/s00592-022-01971-3