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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 -
Journal of Clinical Research in... Feb 2020Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as “type A insulin resistance syndrome”....
Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as “type A insulin resistance syndrome”. Patients with severe disorders usually harbor homozygous or compound heterozygous mutations. In contrast, type A insulin resistance syndrome has been associated with heterozygous mutations; homozygous mutations are rarely responsible for this condition. We report a novel, homozygous mutation, p.Leu260Arg in exon 3, of the gene in a female adolescent patient with type A insulin resistance syndrome together with clinical details of her medical follow-up. Different mutations in the gene cause different phenotype and vary depending on the inheritance pattern. This report adds to the literature, increases understanding of the disease mechanism and aids in genetic counseling.
PubMed: 32018348
DOI: 10.4274/jcrpe.galenos.2020.2019.0213 -
Open Forum Infectious Diseases Nov 2022SARS-CoV-2 nucleocapsid antigen can be detected in plasma, but little is known about its performance as a diagnostic test for acute SARS-CoV-2 infection or infectious...
BACKGROUND
SARS-CoV-2 nucleocapsid antigen can be detected in plasma, but little is known about its performance as a diagnostic test for acute SARS-CoV-2 infection or infectious viral shedding among nonhospitalized individuals.
METHODS
We used data generated from anterior nasal and blood samples collected in a longitudinal household cohort of SARS-CoV-2 cases and contacts. Participants were classified as true positives if polymerase chain reaction (PCR) positive for SARS-CoV-2 and as true negatives if PCR negative and seronegative. Infectious viral shedding was determined by the cytopathic effect from viral culture. Stratified by 7 days after symptom onset, we constructed receiver operating characteristic (ROC) curves to describe optimized accuracy (Youden index), optimized sensitivity, and specificity.
RESULTS
Of 80 participants, 58 (73%) were true positives while 22 (27%) were true negatives. Using the manufacturer's cutoff of 1.25 pg/mL for evaluating infection, sensitivity was higher from 0 to 7 days (77.6% [95% confidence interval {CI}, 64%-88.2%]) than from 8 to 14 days (43.2% [95% CI, 31.1%-54.5%]) after symptom onset; specificity was unchanged at 100% (95% CI, 88.1%-100%). This test had higher sensitivity (100% [95% CI, 88.4%-100%]) and lower specificity (65% [95% CI, 40.8%-84.6%]) for infectious viral shedding as compared with infection, particularly within the first week of symptom onset. Although the presence of N-antigen correlated with infectious viral shedding ( = 0.63; < .01), sensitivity still declined over time. Additional cutoffs from ROC curves were identified to optimize sensitivity and specificity.
CONCLUSIONS
We found that this SARS-CoV-2 N-antigen test was highly sensitive for detecting early but not late infectious viral shedding, making it a viable screening test for community-dwelling individuals to inform isolation practices.
PubMed: 36381627
DOI: 10.1093/ofid/ofac563 -
Molecular Syndromology Nov 2020Donohue syndrome (leprechaunism; OMIM *246200) is a rare and often lethal autosomal recessive disease caused by mutations in the gene. We report the case of a...
Donohue syndrome (leprechaunism; OMIM *246200) is a rare and often lethal autosomal recessive disease caused by mutations in the gene. We report the case of a 29-year-old pregnant woman, primigravida, who was referred at 33 weeks of gestation for severe intrauterine growth restriction (IUGR). Ultrasound examination found severe IUGR associated with an obstructive hypertrophic cardiomyopathy (HCM), confirmed postnatally. The newborn's blood glucose level fluctuated from fasting hypoglycemia to postprandial hyperglycemia. The infant was found to be homozygous for a novel missense pathogenic variant, c.632C>T (p.T211l), in exon 2 of the gene, predicted to result in an abnormal insulin receptor. To our knowledge, this is the first report of leprechaunism being revealed by IUGR and HCM during the prenatal period. Clinicians should keep in mind that the association of these prenatal signs could indicate leprechaunism and specific early neonatal management could be proposed, in particular with recombinant human insulin-like growth factor-I.
PubMed: 33224016
DOI: 10.1159/000509837 -
Radiology Case Reports Jul 2021The extent, severity, and radiological findings of ovarian growth in infants with genetic syndromes of insulin resistance have not been fully described. We report a rare...
The extent, severity, and radiological findings of ovarian growth in infants with genetic syndromes of insulin resistance have not been fully described. We report a rare case of reversible massive ovarian enlargement in a female infant with a congenital insulin resistance syndrome, likely Rabson-Mendenhall syndrome given the less clinically severe course. The patient presented with neonatal diabetes with hyperinsulinemia and hyperglycemia due to congenital insulin resistance. She developed increasing severe bilateral ovarian enlargement which peaked at 4 months of age, followed by gradual decrease in size of the ovaries following treatment with insulin-sensitizing drugs and improved hyperinsulinemia. The ovarian enlargement is postulated to be secondary to the trophic effects of insulin acting in a gonadotropin-independent mechanism. Hyperinsulinemia in congenital insulin resistance can also result in hypertrophy of other organs. Understanding the pathophysiology behind massive ovarian enlargement in the setting of congenital insulin resistance syndromes can help guide appropriate therapy.
PubMed: 34007398
DOI: 10.1016/j.radcr.2021.03.067 -
CPT: Pharmacometrics & Systems... Jun 2024Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in... (Randomized Controlled Trial)
Randomized Controlled Trial
Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.
Topics: Humans; Male; Electrocardiography; Adult; Female; Healthy Volunteers; Nasal Sprays; Heart Rate; Double-Blind Method; Young Adult; Dose-Response Relationship, Drug; Middle Aged; Azepines; Administration, Intranasal; Long QT Syndrome; Adolescent
PubMed: 38812357
DOI: 10.1002/psp4.13140 -
Euro Surveillance : Bulletin Europeen... Oct 2020BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and... (Comparative Study)
Comparative Study
BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.
Topics: Adult; Antibodies, Neutralizing; Antibodies, Viral; Betacoronavirus; Blood Donors; COVID-19; Cluster Analysis; Coronavirus Infections; Enzyme-Linked Immunosorbent Assay; Female; Geography, Medical; Humans; Inhibitory Concentration 50; Male; Models, Immunological; Neutralization Tests; Pandemics; Pneumonia, Viral; Population Surveillance; Prevalence; SARS-CoV-2; Scotland; Sensitivity and Specificity; Seroepidemiologic Studies; Urban Population
PubMed: 33094713
DOI: 10.2807/1560-7917.ES.2020.25.42.2000685 -
Experimental and Clinical... Oct 2020Wiskott-Aldrich syndrome is a rare primary immuno-deficiency disorder that is characterized by a triad of microthrombocytopenia, eczema, and recurrent infections....
Wiskott-Aldrich syndrome is a rare primary immuno-deficiency disorder that is characterized by a triad of microthrombocytopenia, eczema, and recurrent infections. Progression to end-stage renal failure is common in survivors due to immunoglobulin A nephropathy. We describe the case of a 24-year-old male with Wiskott-Aldrich syndrome. The patient had previous hematopoietic stem cell transplant and was on hemodialysis due to end-stage renal failure. He subsequently underwent living-donor renal transplant from his mother as the donor. This is only the fifth case of renal transplant in a patient with Wiskott-Aldrich syndrome in the world. In all cases, the perioperative management of hemostatic function has been crucial. We used thromboelastography to guide our hemostatic decisions rather than platelet count, thus reducing exposure to unnecessary platelet transfusions and without increased bleeding risk. Our patient had an uneventful course after living-donor kidney transplant.
Topics: Clinical Decision-Making; Glomerulonephritis, IGA; Humans; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Platelet Transfusion; Point-of-Care Testing; Predictive Value of Tests; Risk Factors; Thrombelastography; Treatment Outcome; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 32281533
DOI: 10.6002/ect.2019.0347 -
International Journal of Molecular... Mar 2024Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder characterized by severe insulin resistance, resulting in early-onset diabetes mellitus. We report...
Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder characterized by severe insulin resistance, resulting in early-onset diabetes mellitus. We report the first case of RMS in a Paraguayan patient. The patient is a 6-year-old girl who presented with hypertrichosis, acanthosis nigricans, nephrocalcinosis, and elevated levels of glucose and insulin that served as diagnostic indicators for RMS. Genetic testing by next-generation sequencing (NGS) revealed two pathogenic variants in exons 2 and 19 of the gene: c.332G>T (p.Gly111Val) and c.3485C>T (p.Ala1162Val), in combined heterozygosis. The novel c. 332G>T variant leads to the substitution of glycine to valine at position 111 in the protein, and multiple in silico software programs predicted it as pathogenic. The c.3485C>T variant leads to the substitution of alanine to valine at position 1162 in the protein previously described for insulin resistance and RMS. The management of RMS is particularly challenging in children, and the use of metformin is often limited by its side effects. The patient was managed with nutritional measures due to the early age of onset. This report expands the knowledge of RMS to the Paraguayan population and adds a novel pathogenic variant to the existing literature.
Topics: Child; Female; Humans; Donohue Syndrome; Insulin Resistance; Receptor, Insulin; Mutation; Valine; Antigens, CD
PubMed: 38542117
DOI: 10.3390/ijms25063143