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1.
Undersea Hyperb Med ; 47(4): 621-624, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33227838

RESUMO

Arterial gas embolism is a well-described and frequently seen injury encountered in both civilian and military diving operations. It is becoming increasingly reported and potentially increasingly more common in the hospital environment as a complication of more frequent gastroenterology procedures. We present a case of a 49-year-old, active-duty female who developed significant left-sided neurological deficits manifesting as diffuse left-sided weakness, subjective confusion, and severe headache following esophagogastroduodenoscopy. With increased clinical suspicion for arterial gas embolism, the patient was evaluated by the hyperbaric medicine team at our facility and subsequently treated to near-resolution of symptoms by multiple hyperbaric oxygen treatments. This case highlights the importance of considering this rare complication during or following common invasive procedures. Furthermore, the unique training and experience of physicians with expertise in diving medicine and their ability to recognize these types of injury in the hospital setting highlights the importance of continued training in these fields within Military Medicine in addition to civilian Undersea and Hyperbaric Medicine fellowships.


Assuntos
Mergulho , Embolia Aérea/etiologia , Embolia Aérea/terapia , Endoscopia do Sistema Digestório/efeitos adversos , Médicos Hospitalares , Oxigenoterapia Hiperbárica/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Militares , Distúrbios Somatossensoriais/etiologia
2.
J Clin Immunol ; 36(2): 117-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26801501

RESUMO

PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency. METHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting. RESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding. CONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.


Assuntos
Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Genes Recessivos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Proteínas Serina-Treonina Quinases/deficiência , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/metabolismo , Imunofenotipagem , Molécula 1 de Adesão Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Linfócitos/imunologia , Linfócitos/metabolismo , Linhagem , Fenótipo , Irmãos
4.
J Clin Immunol ; 35(7): 598-603, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26399252

RESUMO

ICOS encodes the Inducible T-cell Co-Stimulator (ICOS). Deficiency of this receptor in humans causes a common variable immunodeficiency (CVID) characterised by an absence of class-switched memory B cells and hypogammaglobulinemia. Three pathogenic mutations in ICOS have been described to date in a total of 13 cases. Here we report a novel homozygous 10 base pair frameshift deletion in exon 2 discovered by whole exome sequencing of two siblings from a family of Pakistani origin. Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6. Activated patient CD3(+)CD4(+) T lymphocytes demonstrated a complete absence of ICOS expression and, consistent with previous reports, we detected a reduction in circulating T follicular helper cells. Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.


Assuntos
Enterite/diagnóstico , Hepatite/diagnóstico , Herpesvirus Humano 6/imunologia , Síndromes de Imunodeficiência/diagnóstico , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Infecções por Roseolovirus/diagnóstico , Linfócitos T Auxiliares-Indutores/imunologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Enterite/etiologia , Éxons/genética , Evolução Fatal , Feminino , Mutação da Fase de Leitura/genética , Hepatite/etiologia , Humanos , Síndromes de Imunodeficiência/complicações , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Masculino , Paquistão , Linhagem , Infecções por Roseolovirus/imunologia , Deleção de Sequência/genética , Irmãos , Linfócitos T Auxiliares-Indutores/virologia
6.
J Clin Med ; 13(20)2024 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-39458007

RESUMO

Background/Objectives: The aetiology of inflammatory bowel disease (IBD), particularly if occurring early in childhood, is a diverse and patient-focused treatment that is required when standard therapy is ineffective. Materials and Methods: A clinical case report is presented of a child with very early-onset IBD (VEOIBD) and evidence of high serum IL-18 responding to anti-IL-18 immunotherapy. Detailed cytokine profiling was performed by ELISA and multiplex assay flow cytometry. Results: A four-year-old girl with recalcitrant VEOIBD from six weeks old due to an IL-18opathy, characterised by high blood IL-18 concentration, responded to therapy with a novel neutralising anti-IL-18 antibody (GSK1070806). After two years of hospitalisation, the child's systemic inflammation and extensive upper and lower gastrointestinal mucosal ulceration remitted with this cytokine inhibitor, allowing the discontinuation of total parenteral nutrition and the resumption of normal oral intake and daily activities. After 18 months on regular GSK1070806, the patient remains in disease remission. Conclusions: VEOIBD can be associated with evidence of an underlying IL18opathy and responds to anti-IL-18 antibody therapy. IL-18 should be measured in patients with IBD unresponsive to conventional treatments, and, if elevated, anti-IL-18 antibody therapy should be considered as a potential therapy.

8.
Med Chem ; 19(5): 478-484, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35993460

RESUMO

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.


Assuntos
Antimaláricos , Malária , Animais , Camundongos , Plasmodium falciparum , Antimaláricos/farmacologia , Malária/tratamento farmacológico , Plasmodium berghei , Fígado
9.
J Allergy Clin Immunol Pract ; 11(8): 2476-2483, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37146882

RESUMO

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.


Assuntos
Angioedemas Hereditários , Humanos , Feminino , Masculino , Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Danazol/uso terapêutico , Reino Unido/epidemiologia , Inquéritos e Questionários
10.
Life (Basel) ; 13(1)2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36676064

RESUMO

Malignant pleural effusions remain a significant clinical problem resulting in greater than 125,000 hospitalizations per year and leading to over 5 billion dollars in healthcare utilization costs. Not only are health care expenditures related to malignant pleural effusion significant, but malignant pleural effusions also often result in significant patient discomfort and distress, largely at the end of life. Advances in management over the past several years have provided patients with greater autonomy as they are able to provide self-aid at home either alone or with family assistance. Additionally, practice changes have allowed for fewer interventions allowing patients to spend more time out of the clinic or inpatient wards.

12.
Am J Med Genet A ; 155A(12): 3087-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22052851

RESUMO

The panniculitides are a group of heterogeneous inflammatory diseases involving the subcutaneous fat, the pathogenesis of which is poorly understood. Here, we report on a female infant with Prader-Willi syndrome who developed a systemic inflammatory disorder in the neonatal period demonstrating recurrent panniculitis as a prominent feature. This is the second report of an association between Prader-Willi syndrome and panniculitis. Such an association might be explained by the unmasking of a recessive allele as a consequence of hemizygosity, in the case of a 15q11 deletion, or homozygosity, in the case of maternal isodisomy.


Assuntos
Paniculite/complicações , Paniculite/genética , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Deleção Cromossômica , Cromossomos Humanos Par 15 , Evolução Fatal , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Paniculite/diagnóstico , Paniculite/tratamento farmacológico , Síndrome de Prader-Willi/diagnóstico , Pele/patologia
13.
Chest ; 160(3): e289-e293, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34488970

RESUMO

CASE PRESENTATION: A 24-year-old man, never smoker, with no medical or surgical history, not currently on medications, presented to the ED with a second episode of gross hemoptysis, 4 months after an initial episode that had not previously been evaluated. He described the current episode of hemoptysis as "enough to fill the sink"; however, he did not further quantify. He has no history of recurrent epistaxis, hematemesis, or other evidence of clotting disorder. He denied any fevers, chills, night sweats, or recent travel. He denied any sick contacts and has no history of TB exposure or risk factors. The patient denied any shortness of breath, wheezing, or chest pain. He had no lower extremity pain or swelling. He routinely exercises and generally lives a healthy lifestyle. He is a health care worker who has not routinely worked with patients infected with SARS-CoV-2, although he received his second (of two) COVID-19 vaccines 4 days before presentation.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/terapia , Hematemese/etiologia , Linfadenopatia/diagnóstico , SARS-CoV-2/imunologia , Humanos , Masculino , Tórax , Adulto Jovem
14.
J Leukoc Biol ; 109(6): 1147-1154, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32930428

RESUMO

The glucose-6-phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss-of-function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra-hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony-stimulating factor (G-CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency-associated IBD. G6PC3 deficiency was associated with early-onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G-CSF treatment. In vitro studies on the patients' blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL-8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G-CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency-associated IBD refractory to immune suppressants.


Assuntos
Suscetibilidade a Doenças , Glucose-6-Fosfatase/genética , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Mutação com Perda de Função , Neutrófilos/imunologia , Neutrófilos/metabolismo , Biomarcadores , Citocinas/metabolismo , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas , Humanos , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Ativação de Neutrófilo/genética , Ativação de Neutrófilo/imunologia
16.
Mil Med ; 185(11-12): e2131-e2136, 2020 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-32627820

RESUMO

INTRODUCTION: Nearly 10% of all combat injuries during the most recent conflicts in Iraq and Afghanistan involve thoracic trauma. The long-term outcomes of these combat-related injuries with respect to lung function have not been fully evaluated. Limited research in civilian polytrauma patients have shown significant obstructive physiology in nearly half of their population without clear etiology. We sought to further characterize the extent to which these active duty service members (ADSM) are chronically affected by their thoracic injuries. MATERIALS AND METHODS: We conducted a retrospective chart review and analysis of ADSM who sustained thoracic injuries while deployed in support combat operations from 2003 to 2013. Using the Department of Defense Trauma Registry, 2,049 patients were found to have sustained thoracic trauma during these conflicts, of which we were able to identify 298 patients with postinjury pulmonary function testing (PFT) available for analysis. Following standardization of these tests using the established reference values, PFT was compared to a representative population of ADSM. Additional analysis was completed to detect incidence of abnormal PFTs when compared to both type of injury (burn, blunt, penetrating, and other) and also Injury Severity Score. RESULTS: In our patient population, there was a significant increase in abnormal PFTs when compared to a representative population. Of these, 31.8% of patients displayed obstructive physiology versus 3.7% in the control (P < 0.001), 24.5% displayed restrictive or restrictive pattern (those without full lung volumes available utilizing forced vital capacity) versus 4.9% (P < 0.0001), and 7.9% displaying mixed pattern. Further, increasing rates of abnormal PFTs were identified in comparison to Injury Severity Score (odds ratio 1.03). There was no significant increase in abnormal PFTs when stratified by type of injury. Finally, there was no significant change identified in pulmonary function before and after injury in our limited population of 19 patients. CONCLUSIONS: There is a significant increase in the percent of abnormal PFTs in ADSM following thoracic injury when compared to patients with similar risk factors and baseline health. It is unclear why the rates of obstruction are high in our population as previous research has not definitively shown increased rates of asthma in previously deployed, uninjured ADSM; however, this finding is consistent with limited previous research in civilian trauma patients. Further research into the long-term outcomes of thoracic trauma and occupational exposures of combat is paramount for improved outcomes going forward.


Assuntos
Militares , Traumatismos Torácicos , Campanha Afegã de 2001- , Afeganistão , Humanos , Iraque , Guerra do Iraque 2003-2011 , Sistema de Registros , Estudos Retrospectivos , Traumatismos Torácicos/epidemiologia
17.
World J Gastroenterol ; 26(15): 1841-1846, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32351297

RESUMO

BACKGROUND: Aminoacyl tRNA synthetases/ligases (ARSs) are highly conserved enzymes involved in attaching amino acids to tRNA promoting protein synthesis. Although deficiencies of ARSs localized to the mitochondria classically present with neuropathology, the clinical features of cytosolic ARS deficiencies are more variable. They have previously been associated with neonatal hepatitis, but never with early-onset inflammatory bowel disease. CASE SUMMARY: A nine-year-old Bangladeshi boy presented with neonatal liver failure and deranged clotting, transaminitis and cholestasis. His parents were first cousins. Two older brothers and a sister were well. The patient suffered from loose stools from early infancy which became more troublesome and persistent from five years old with ten bloody motions a day. Repeated endoscopies showed persistent pancolitis, which was refractory to mesalazine, corticosteroids, azathioprine, sirolimus and anti-TNF (adalimumab) therapy, but has improved recently with subcutaneous methotrexate.Whole Genome Sequencing revealed a novel pathogenic missense variant (c.290A > G) in the cytosolic isoleucyl-tRNA synthetase gene, leading to an amino acid substitution (p.Asp97Gly). Pathogenic variants in other genes associated with inflammatory bowel disease (IBD) (ADAM17, EGFR, FOXP3, IL10RA, IL10RB, IL21R, NCF4, STAT3) were excluded. Cytokine assays demonstrated markedly elevated IL-2, IL-5, IL-13, IL-9 and IL-10 by the patient's CD4+ T-cells, while IL-17A, IL-17F, IFNß were lower, and TNFα not significantly different when compared to healthy controls. CONCLUSION: This case report provides evidence that recessive mutations in cytosolic isoleucyl-tRNA synthetase are a novel monogenic cause of IBD, which should be considered, particularly in infants and children with a history of neonatal hepatitis and very early-onset IBD poorly responsive to treatment.


Assuntos
Doenças Inflamatórias Intestinais/genética , Isoleucina-tRNA Ligase/deficiência , Idade de Início , Biópsia , Criança , Colo/patologia , Resistência a Medicamentos/genética , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Isoleucina-tRNA Ligase/genética , Masculino , Mutação
18.
Clin Transl Allergy ; 10: 10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32337019

RESUMO

BACKGROUND: Pollen and house dust mite (HDM) subcutaneous immunotherapy (SLIT) and pollen subcutaneous immunotherapy (SCIT) are effective therapies for children with allergic rhinoconjunctivitis (AR). There are no previous direct comparative studies investigating quality of life (QoL) of all three immunotherapy regimes. The aim of this study was to compare QoL and safety in children receiving these immunotherapies for AR. METHODS: Demographic characteristics, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Visual Analogue (VAS) scores were assessed in 249 children undergoing HDM and pollen immunotherapy at a UK specialist paediatric centre between 2007 and 2019. RESULTS: All three immunotherapy regimes led to a > 50% improvement in QoL and VAS after 3 years of therapy, with significant improvements by the end of the first year (p < 0.05) and further improvements between 1 and 3 years (p < 0.05). Age, gender, ethnicity and route of administration had no significant bearing on efficacy. Older, polysensitised children and those receiving HDM SLIT were all more likely to discontinue their treatment (all with p < 0.05). The only patient to suffer from anaphylaxis requiring intramuscular adrenaline, and 80% experiencing exacerbations of their asthma had received pollen SCIT. CONCLUSIONS: Pollen SCIT and pollen and HDM SLIT all lead to significant improvements in QoL. The risk of anaphylaxis is low, but SCIT is associates with a 1 in 5 chance of asthma flares in the days after its administration. Discontinuation of therapy is more frequent in older, polysensitised children, and those undergoing HDM immunotherapy.

19.
Vaccine ; 38(35): 5718-5725, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32654902

RESUMO

BACKGROUND: Concomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants. METHODS: In a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM197 protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8). RESULTS: Per protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose. CONCLUSIONS: DTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.


Assuntos
Vacinas Anti-Haemophilus , Haemophilus influenzae tipo b , Vacinas Meningocócicas , Animais , Anticorpos Antibacterianos , Vacina contra Difteria, Tétano e Coqueluche , Humanos , Lactente , Vacina Antipólio de Vírus Inativado , Coelhos , Sorogrupo , Vacinas Combinadas , Vacinas Conjugadas
20.
JCI Insight ; 5(5)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161190

RESUMO

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.


Assuntos
Carbono-Nitrogênio Ligases/genética , Diferenciação Celular , Homozigoto , Linfócitos/imunologia , Mutação , Sistemas CRISPR-Cas , Linhagem Celular , Proliferação de Células , Humanos , Imunofenotipagem , Células Jurkat , Ativação Linfocitária
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