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Genetics in Medicine : Official Journal... Feb 2023The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient...
The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration's regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.
Topics: United States; Humans; Progeria; Lamin Type A; Piperidines; Pyridines
PubMed: 36507973
DOI: 10.1016/j.gim.2022.11.003 -
Expert Opinion on Pharmacotherapy 2015Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary... (Review)
Review
INTRODUCTION
Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects.
AREAS COVERED
Although the existence of asthma in patients with asthma-COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation.
EXPERT OPINION
For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Disease Management; Drug Therapy, Combination; Glucocorticoids; Humans; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Syndrome
PubMed: 26194213
DOI: 10.1517/14656566.2015.1067682 -
Journal of the American Heart... Mar 2015Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary...
BACKGROUND
Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary hypertension and right ventricular dysfunction in humans remain unclear. We investigated the association of MetS and obesity with right ventricular structure and function in patients without cardiovascular disease.
METHODS AND RESULTS
A total of 156 patients with MetS (mean age 44 years, 71% women, mean body mass index 40 kg/m(2)), 45 similarly obese persons without MetS, and 45 nonobese controls underwent echocardiography, including pulsed wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time. Pulmonary artery systolic pressure was estimated from PAAT using validated equations. MetS was associated with lower tricuspid valve e' (right ventricular diastolic function parameter), shorter PAAT, shorter ejection time, and larger pulmonary artery diameter compared with controls (P<0.05 for all). Estimated pulmonary artery systolic pressure based on PAAT was 42±12 mm Hg in participants with MetS compared with 32±9 and 32±10 mm Hg in obese and nonobese controls (P for ANOVA <0.0001). After adjustment for age, sex, hypertension, diabetes, body mass index, and triglycerides, MetS remained associated with a 20-ms-shorter PAAT (β=-20.4, SE=6.5, P=0.002 versus obese). This association persisted after accounting for left ventricular structure and function and after exclusion of participants with obstructive sleep apnea.
CONCLUSIONS
MetS is associated with abnormal right ventricular and pulmonary artery hemodynamics, as shown by shorter PAAT and subclinical right ventricular diastolic dysfunction. Estimated pulmonary artery systolic pressures are higher in MetS and preclinical metabolic heart disease and raise the possibility that pulmonary hypertension contributes to the pathophysiology of metabolic heart disease.
Topics: Adult; Arterial Pressure; Case-Control Studies; Diastole; Echocardiography, Doppler, Pulsed; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Metabolic Syndrome; Middle Aged; Obesity; Predictive Value of Tests; Pulmonary Artery; Risk Factors; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right
PubMed: 25758604
DOI: 10.1161/JAHA.114.001597 -
BioMed Research International 2021Mutations in insulin receptor genes can cause severe insulin resistance syndrome. Compared with Rabson-Mendenhall Syndrome and Donohue's Syndrome, type A insulin...
BACKGROUND
Mutations in insulin receptor genes can cause severe insulin resistance syndrome. Compared with Rabson-Mendenhall Syndrome and Donohue's Syndrome, type A insulin resistance syndrome is generally not serious. The main manifestations in woman with type A insulin resistance syndrome are hyperinsulinemia, insulin resistance, acanthosis nigricans, hyperandrogenism, and polycystic ovary. . A 13-year-old girl (Han nationality) visited the hospital due to hairiness and acanthosis nigricans. Further examination revealed severe hyperinsulinemia, insulin resistance, elevated blood glucose, hyperandrogenism, and polycystic ovary. Analysis of the insulin receptor gene by sequencing showed the presence of a nucleotide change in intron 7 (c. 1610+1G > A). The mutation was a splicing mutation, which can obviously affect the mRNA splicing of the insulin receptor and cause its function loss. The patient was finally diagnosed with type A insulin resistance syndrome. After 2 months of metformin treatment, the patient had spontaneous menstrual cramps and significantly improved acanthosis nigricans and sex hormones.
CONCLUSION
We report for the first time a new splicing mutation on the insulin receptor gene at the 7th intron (c.1610+1G > A), which leads to type A insulin resistance syndrome. In clinically suspected patients with polycystic ovary syndrome, if there are extremely high blood levels of insulin in the blood, genetic testing should be performed to detect insulin receptor gene mutation of type A insulin resistance syndrome.
Topics: Adolescent; Antigens, CD; Female; Humans; Introns; Metabolic Syndrome; Metformin; Point Mutation; RNA Splicing; Receptor, Insulin; Severity of Illness Index
PubMed: 33728347
DOI: 10.1155/2021/8878149 -
Diabetologia Jul 2018Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic... (Comparative Study)
Comparative Study
AIMS/HYPOTHESIS
Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies.
METHODS
Ten naturally occurring mutant human INSRs with defects affecting different aspects of receptor function were modelled and assessed for response to insulin and anti-INSR antibodies. A novel 3T3-L1 adipocyte model of insulin receptoropathy was generated, permitting conditional knockdown of endogenous mouse Insr by lentiviral expression of species-specific short hairpin (sh)RNAs with simultaneous expression of human mutant INSR transgenes.
RESULTS
All expressed mutant INSR bound to all antibodies tested. Eight mutants showed antibody-induced autophosphorylation, while co-treatment with antibody and insulin increased maximal phosphorylation compared with insulin alone. After knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes, two antibodies (83-7 and 83-14) activated signalling via protein kinase B (Akt) preferentially over signalling via extracellular signal-regulated kinase 1/2 (ERK1/2) for seven mutants. These antibodies stimulated glucose uptake via P193L, S323L, F382V and D707A mutant INSRs, with antibody response greater than insulin response for D707A.
CONCLUSIONS/INTERPRETATION
Anti-INSR monoclonal antibodies can activate selected naturally occurring mutant human insulin receptors, bringing closer the prospect of novel therapy for severe insulin resistance caused by recessive mutations.
Topics: 3T3-L1 Cells; Adipocytes; Animals; Antibodies; Antigens, CD; CHO Cells; Cricetulus; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Mice; Mutation; Phosphorylation; Receptor, Insulin; Signal Transduction
PubMed: 29700562
DOI: 10.1007/s00125-018-4606-2 -
Journal of the American Heart... Apr 2019Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese...
Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese patients would help identify high-risk individuals for heart failure prevention strategies. We assessed the predictive value of GAL3 (galectin-3), FSTL3 (follistatin-like 3 peptide), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) to identify stage B MHD in young obese participants free of clinically evident cardiovascular disease. Methods and Results Asymptomatic obese patients (n=250) and non-obese controls (n=21) underwent echocardiographic cardiac phenotyping. Obese patients were classified as MHD positive ( MHD - POS ; n=94) if they had abnormal diastolic function or left ventricular hypertrophy and had estimated pulmonary artery systolic pressure ≥35 mm Hg. Obese patients without such abnormalities were classified as MHD negative (MHD-NEG; n=52). Serum biomarkers timed with echocardiography. MHD - POS and MHD-NEG individuals were similarly obese, but MHD - POS patients were older, with more diabetes mellitus and metabolic syndrome. Right ventricular coupling was worse in MHD - POS patients ( P<0.001). GAL 3 levels were higher in MHD - POS versus MHD -NEG patients (7.7±2.3 versus 6.3±1.9 ng/mL, respectively; P<0.001). Both GAL 3 and FSTL 3 levels correlated with diastolic dysfunction and increased pulmonary artery systolic pressure but not with left ventricular mass. In multivariate models including all 3 biomarkers, only GAL 3 remained associated with MHD (odds ratio: 1.30; 95% CI , 1.01-1.68; P=0.04). Conclusions In young obese individuals without known cardiovascular disease, GAL 3 is associated with the presence of preclinical MHD . GAL 3 may be useful in screening for preclinical MHD and identifying individuals with increased risk of progression to obesity-related heart failure with preserved ejection fraction.
Topics: Adult; Biomarkers; Blood Proteins; Case-Control Studies; Echocardiography; Female; Follistatin-Related Proteins; Galectin 3; Galectins; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Male; Metabolic Diseases; Middle Aged; Natriuretic Peptide, Brain; Obesity; Peptide Fragments
PubMed: 30929550
DOI: 10.1161/JAHA.118.011100 -
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 -
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 -
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 -
Cytometry. Part B, Clinical Cytometry Jul 2018Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder that has not been well-documented in children, particularly those with...
Standardized high-sensitivity flow cytometry testing for paroxysmal nocturnal hemoglobinuria in children with acquired bone marrow failure disorders: A single center US study.
BACKGROUND
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder that has not been well-documented in children, particularly those with acquired bone marrow failure disorders (ABMFD)-acquired aplastic anemia (AAA) and myelodysplastic syndrome (MDS). Therefore, we sought to determine the prevalence of PNH populations in children with ABMFD.
METHODS
PNH testing was performed in children with an ABMFD diagnosis using high sensitivity (≥0.01%) fluorescent aerolysin (FLAER)-based assay according to 2010 International Clinical Cytometry Society (ICCS) PNH Consensus Guidelines and 2012 Practical PNH Guidelines. FLAER/CD64/CD15/CD24/CD14/CD45 and CD235a/CD59 panels were used for white blood cell and red blood cell testing, respectively.
RESULTS
Thirty-seven patients with ABMFD (34 AAA, 3 MDS) were included (17M/20F, age 2-18 years, median 9 years). PNH populations were identified in 17 of 37 (46%) patients. Of the 17 patients with PNH populations identified, 7 were PNH clones (>1% PNH population), and 10 had minor PNH population or rare cells with PNH phenotype (≤1% PNH population).
CONCLUSIONS
This is the first study to use a standardized high-sensitivity FLAER-based flow cytometry assay and the recommended cutoff of 0.01% to identify cells with PNH phenotype in pediatric patients with ABMFD in the United States. The identification of a PNH population in 46% of ABMFD supports the recommendation for high sensitivity PNH testing in children with these disorders. As a less sensitive assay using a cutoff of ≥ 1% PNH population would have missed 10 (27%) patients with minor PNH population or rare cells with PNH phenotype. © 2017 International Clinical Cytometry Society.
Topics: Adolescent; Anemia, Aplastic; Child; Child, Preschool; Female; Flow Cytometry; Hemoglobinuria, Paroxysmal; Humans; Male; Myelodysplastic Syndromes; Prevalence; Retrospective Studies; Sensitivity and Specificity
PubMed: 28574201
DOI: 10.1002/cyto.b.21536