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1.
Eur J Med Genet ; : 104347, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619368

RESUMO

We present a case with congenital syndromic asplenia associated with immune deficiency, glandular hypospadias and cryptorchidism. Genetic analysis identified a likely pathogenic de novo variant in NR2F2. Pathogenic NR2F2 variants have been associated with other congenital anomalies affecting the central axis, such as congenital heart disease and diaphragmatic hernia, which were not part of our patient's clinical features. The association between NR2F2 and asplenia (including glandular hypospadias and cryptorchidism) has been described in animal models and our report is the first expanding the NR2F2 clinical spectrum in humans to include asplenia.

2.
J Am Anim Hosp Assoc ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606584

RESUMO

This case report details a previously undescribed malignancy of the tendon sheath in a golden retriever. This dog originally presented with lameness of the left forelimb, at which point radiographs revealed a monostotic, lytic lesion of the distal radius with overlying soft-tissue swelling. A fine-needle aspirate was performed, and cytology was compatible with a sarcoma, with the primary differential being an osteosarcoma. After amputation, the leg was submitted for histopathology, which revealed inconsistencies with a typical osteosarcoma lesion, including lack of osteoid deposition. Second opinion histopathology showed a fibrosarcoma that appeared to have originated in the tendon sheath of an extensor tendon and then secondarily invaded the radius. At the time of publication, ~17 mo after amputation, the dog continues to do well without any evidence of recurrent or metastatic disease.

3.
Am J Emerg Med ; 50: 156-159, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34365065

RESUMO

INTRODUCTION: Alcohol withdrawal syndrome (AWS) is a serious consequence of alcohol use disorder (AUD). Due to the current COVID-19 pandemic there was a closure of Pennsylvania (PA) liquor stores on March 17, 2020. METHODS: This is a retrospective, observational study of AWS patients presenting to a tertiary care hospital. We used descriptive statistics for continuous and categorical variables and compared AWS consults placed to the medical toxicology service for six months preceding liquor store closure to those placed between March 17, 2020 and August 31, 2020. We compared this to consults placed to the medical toxicology service placed from October 1, 2019 through March 16, 2020. Charts were identified based on consults placed to the medical toxicology service, and alcohol withdrawal was determined via chart review by a medical toxicologist. This study did not require IRB approval. We evaluated Emergency Department (ED) length of stay (LOS), weekly and monthly consultation rate, rate of admission and ED recidivism, both pre- and post-liquor store closure. RESULTS: A total of 324 AWS consults were placed during the ten month period. 142 (43.8%) and 182 (56.2%) consults were pre- and post-liquor store closure. The number of consults was not statistically significant comparing these two time frames. There was no significant difference by patient age, gender, or race or by weekly or monthly consultation rate when comparing pre- and post-liquor store periods. The median ED LOS was 7 h (95% Confidence Interval (CI) Larson et al. (2012), Pollard et al. (2020) [5, 11]) and did not significantly differ between pre- and post-liquor store periods (p = 0.78). 92.9% of AWS patients required admission without significant difference between the pre- and post-liquor store closure periods (94.4% vs. 91.8%, p = 0.36). There was a significant increase in the number of AWS patients requiring a return ED visit (Odds Ratio 2.49; 95% CI [1.38, 4.49]) post closure. CONCLUSION: There were nearly 2.5 times greater odds of ED recidivism among post-liquor store closure AWS patients compared with pre-closure AWS patients.

4.
Am J Emerg Med ; 50: 202-206, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390903

RESUMO

AIM OF THE STUDY: Targeted temperature management is a class I indication in comatose patients after a cardiac arrest. While the literature has primarily focused on innovative methods to achieve target temperatures, pharmacologic therapy has received little attention. We sought to examine whether pharmacologic therapy using antipyretics is effective in maintaining normothermia in post cardiac arrest patients. MATERIALS AND METHODS: Patients ≥18 years who were resuscitated after an in-hospital or out-of-hospital cardiac arrest and admitted at our institution from January 2012 to September 2015 were retrospectively included. Patients were divided into groups based on the method of temperature control that was utilized. The primary outcome was temperature control <38 °C during the first 48 h after the cardiac arrest. RESULTS: 671 patients were identified in Group 1 (no hypothermia), 647 in Group 2 (antipyretics), 44 in Group 3 (invasive hypothermia), and 51 in Group 4 (invasive hypothermia and antipyretics). Mean patient age was 59 (SD ±15.7) years with 40.6% being female. Using Group 1 as the control arm, 57.7% of patients maintained target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the combined hypothermia groups 3&4 (p = 0.01). Patients receiving both invasive hypothermia and antipyretics (Group 4), had the greatest mean temperature decrease of 5.2 °C. CONCLUSIONS: Among patients undergoing targeted temperature management, relying solely on as needed use of antipyretics is not sufficient to maintain temperatures <38 °C. However, antipyretics could be used as an initial strategy if given regularly and/or in conjunction with more aggressive cooling techniques.

5.
Lupus ; : 9612033211033979, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34266320

RESUMO

OBJECTIVE: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls. PATIENTS AND METHODS: 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF < 0.005), uncommon (MAF 0.005-0.02), and common (MAF >0.02). This was compared to the results for 65 randomly selected genes. RESULTS: Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, individuals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants. CONCLUSIONS: Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.

6.
Vet Dermatol ; 32(5): 515-e143, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34240483

RESUMO

BACKGROUND: Feline indolent cutaneous T-cell lymphoma (ICL) is an uncommon neoplastic disease. There is currently no consensus on treatment recommendations for ICL. OBJECTIVE: To report the clinical outcome of three cats with ICL treated with hypofractionated electron-beam radiotherapy (RT). ANIMALS: Three privately owned cats with ICL. MATERIALS AND METHODS: Medical records and client surveys were reviewed. A diagnosis of probable ICL was based on history, clinical presentation and histopathological findings, and confirmed using CD3 immunohistochemical analysis and PCR for antigen receptor gene rearrangement (PARR). All cats were treated with hypofractionated RT (four fractions of 8 Gy). RESULTS: All cats presented with skin lesions characterised by erythema and alopecia that were refractory to previous treatment with systemic glucocorticoids. Before hypofractionated RT treatment, lesions were histologically described as having diffuse infiltration of the dermis with CD3+ T cells. Molecular clonality analysis revealed clonal T-cell receptor gamma gene rearrangement. After RT, two cats showed histological improvement defined by decreased infiltration of lymphocytes, with cellular infiltrate present only in the deeper dermis; one cat had near complete histological resolution of lesions with only minimal residual lymphocytes. One cat was determined to have a complete clinical response while the other showed partial responses. No acute adverse effects of radiation were observed; chronic effects included leukotrichia, partial alopecia and mild fibrosis. All clients reported improvement in quality of life for their cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical and histological improvement in these cats suggests that hypofractionated RT can be a useful treatment modality for cats with ICL.


Assuntos
Doenças do Gato , Linfoma Cutâneo de Células T , Animais , Doenças do Gato/radioterapia , Gatos , Linfócitos , Linfoma Cutâneo de Células T/radioterapia , Linfoma Cutâneo de Células T/veterinária , Reação em Cadeia da Polimerase/veterinária , Qualidade de Vida
7.
PLoS Pathog ; 17(6): e1009683, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34166473

RESUMO

COVID-19 is a global crisis of unimagined dimensions. Currently, Remedesivir is only fully licensed FDA therapeutic. A major target of the vaccine effort is the SARS-CoV-2 spike-hACE2 interaction, and assessment of efficacy relies on time consuming neutralization assay. Here, we developed a cell fusion assay based upon spike-hACE2 interaction. The system was tested by transient co-transfection of 293T cells, which demonstrated good correlation with standard spike pseudotyping for inhibition by sera and biologics. Then established stable cell lines were very well behaved and gave even better correlation with pseudotyping results, after a short, overnight co-incubation. Results with the stable cell fusion assay also correlated well with those of a live virus assay. In summary we have established a rapid, reliable, and reproducible cell fusion assay that will serve to complement the other neutralization assays currently in use, is easy to implement in most laboratories, and may serve as the basis for high throughput screens to identify inhibitors of SARS-CoV-2 virus-cell binding and entry.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Bioensaio/métodos , COVID-19/virologia , Receptores de Coronavírus/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/genética , COVID-19/sangue , Fusão Celular , Células HEK293 , Humanos , Receptores de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/genética , Transfecção , Ligação Viral
8.
Nat Methods ; 18(7): 771-774, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34168373

RESUMO

We develop an automatic method for synaptic partner identification in insect brains and use it to predict synaptic partners in a whole-brain electron microscopy dataset of the fruit fly. The predictions can be used to infer a connectivity graph with high accuracy, thus allowing fast identification of neural pathways. To facilitate circuit reconstruction using our results, we develop CIRCUITMAP, a user interface add-on for the circuit annotation tool CATMAID.


Assuntos
Encéfalo/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Sinapses/fisiologia , Animais , Encéfalo/citologia , Bases de Dados Factuais , Drosophila melanogaster , Microscopia Eletrônica , Vias Neurais
9.
PLoS Med ; 18(5): e1003595, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34003832

RESUMO

BACKGROUND: Hospitals, clinics, and health organizations have provided psychosocial support interventions for medical patients to supplement curative care. Prior reviews of interventions augmenting psychosocial support in medical settings have reported mixed outcomes. This meta-analysis addresses the questions of how effective are psychosocial support interventions in improving patient survival and which potential moderating features are associated with greater effectiveness. METHODS AND FINDINGS: We evaluated randomized controlled trials (RCTs) of psychosocial support interventions in inpatient and outpatient healthcare settings reporting survival data, including studies reporting disease-related or all-cause mortality. Literature searches included studies reported January 1980 through October 2020 accessed from Embase, Medline, Cochrane Library, CINAHL, Alt HealthWatch, PsycINFO, Social Work Abstracts, and Google Scholar databases. At least 2 reviewers screened studies, extracted data, and assessed study quality, with at least 2 independent reviewers also extracting data and assessing study quality. Odds ratio (OR) and hazard ratio (HR) data were analyzed separately using random effects weighted models. Of 42,054 studies searched, 106 RCTs including 40,280 patients met inclusion criteria. Patient average age was 57.2 years, with 52% females and 48% males; 42% had cardiovascular disease (CVD), 36% had cancer, and 22% had other conditions. Across 87 RCTs reporting data for discrete time periods, the average was OR = 1.20 (95% CI = 1.09 to 1.31, p < 0.001), indicating a 20% increased likelihood of survival among patients receiving psychosocial support compared to control groups receiving standard medical care. Among those studies, psychosocial interventions explicitly promoting health behaviors yielded improved likelihood of survival, whereas interventions without that primary focus did not. Across 22 RCTs reporting survival time, the average was HR = 1.29 (95% CI = 1.12 to 1.49, p < 0.001), indicating a 29% increased probability of survival over time among intervention recipients compared to controls. Among those studies, meta-regressions identified 3 moderating variables: control group type, patient disease severity, and risk of research bias. Studies in which control groups received health information/classes in addition to treatment as usual (TAU) averaged weaker effects than those in which control groups received only TAU. Studies with patients having relatively greater disease severity tended to yield smaller gains in survival time relative to control groups. In one of 3 analyses, studies with higher risk of research bias tended to report better outcomes. The main limitation of the data is that interventions very rarely blinded personnel and participants to study arm, such that expectations for improvement were not controlled. CONCLUSIONS: In this meta-analysis, OR data indicated that psychosocial behavioral support interventions promoting patient motivation/coping to engage in health behaviors improved patient survival, but interventions focusing primarily on patients' social or emotional outcomes did not prolong life. HR data indicated that psychosocial interventions, predominantly focused on social or emotional outcomes, improved survival but yielded similar effects to health information/classes and were less effective among patients with apparently greater disease severity. Risk of research bias remains a plausible threat to data interpretation.


Assuntos
Pacientes Internados/estatística & dados numéricos , Longevidade , Pacientes Ambulatoriais/estatística & dados numéricos , Sistemas de Apoio Psicossocial , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Pacientes Internados/psicologia , Pacientes Ambulatoriais/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos
10.
Vet Comp Oncol ; 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34033204

RESUMO

While the majority of canine osteosarcomas (OSA) arise from the medullary cavity, a subset arises from the surface of bone. In humans, surface OSA often has a more indolent disease course with better outcomes than medullary OSA. The aim of this retrospective case series was to evaluate the clinical outcome and potential prognostic factors of dogs with surface OSA. Medical records from 11 dogs previously diagnosed with surface OSA were included. Histopathology of cases was evaluated during case review by two veterinary anatomic pathologists. Median progression free interval (PFI) and overall median survival time (OST) were estimated using Kaplan-Meier methods. Intergroup comparisons were performed using log-rank tests. Six dogs were diagnosed with periosteal OSA, 4 dogs with parosteal OSA, and one dog with an unclassified surface OSA. Two dogs were found to have metastatic disease at the time of diagnosis and four developed metastatic lesions after treatment. The median PFI and median OST for all dogs with surface OSA was 425 and 555 days, respectively. The 6 dogs diagnosed with periosteal OSA had a median PFI of 461 days and median OST of 555 days, while the 4 dogs with parosteal OSA had a PFI of 350 days and the OST could not be calculated. Multiple prognostic factors (surgery, systemic adjunctive therapy, elevated alkaline phosphatase at diagnosis, appendicular vs axial location, mitotic count, and tumour grade) were evaluated and none were prognostic for PFI or OST. Dogs with surface OSA appear to have prolonged PFI and OST, consistent with humans with surface OSA.

11.
Psychol Addict Behav ; 35(3): 263-273, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33539106

RESUMO

OBJECTIVE: Research suggests that it is common for emerging adults in the U.S. and other countries to participate in a drinking game (DG). Playing DGs is associated with greater alcohol consumption and increased risk for experiencing alcohol-related harms. Gender differences in emerging adults' DG behavior and negative alcohol-related consequences have also been documented but the results have been mixed. We conducted the present meta-analysis in order to (a) quantify the association between DG participation and alcohol use and related consequences, and examine the moderating effect of gender and methodological factors on these associations, and (b) provide effect size estimates for power analyses for future DGs research. METHOD: 48 manuscripts, representing 31 independent samples, were included in the meta-analysis. RESULTS: We found medium effect sizes between DG participation and frequency of alcohol use (r = .47) and binge drinking (r = .50), quantity of alcohol use (r = .38) and consumption while playing DGs (r = .45), alcohol use (frequency × consumption index; r = .49), and alcohol-related consequences (r = .38). CONCLUSIONS: Playing DGs is associated with greater frequency of alcohol use, higher alcohol consumption, and more alcohol-related consequences. Findings also indicated that as the percentage of women in the sample increased, the association between DG participation and quantity of alcohol use strengthened. No gender moderation effect was found for the associations between DG participation and the other alcohol outcomes variables, which suggests that men and women who play DGs are equally at risk for experiencing alcohol-related consequences and may benefit from clinical attention. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/psicologia , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Etanol/efeitos adversos , Jogos Recreativos/psicologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Feminino , Humanos , Masculino , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Universidades , Adulto Jovem
12.
J Biol Chem ; 296: 100045, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33465707

RESUMO

The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory protein called the virion infectivity factor (Vif), which recruits A3 proteins to cullin-RING E3 ubiquitin ligases such as cullin-5 (Cul5) for ubiquitylation and subsequent proteasomal degradation. Although Vif proteins from primate lentiviruses such as HIV-1 utilize the transcription factor core-binding factor subunit beta as a noncanonical cofactor to stabilize the complex, the maedi-visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Because core-binding factor subunit beta and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for the MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that although some common motifs between the HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in the MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.


Assuntos
Vírus Visna-Maedi/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Aminoácidos , Proteínas Culina/metabolismo , Ciclofilina A/metabolismo , Ligação Proteica , Domínios Proteicos , Proteólise , Zinco/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/química
13.
Org Lett ; 23(2): 559-564, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33410700

RESUMO

An auto-tandem catalytic double allylic rearrangement of N-alloc-N-allyl ynamides was developed. This reaction proceeds through two separate and distinct catalytic cycles with both decarboxylative Pd-π-allyl and Pd(0)-promoted aza-Claisen rearrangements occurring. A detailed mechanistic study supported by computations highlights these two separate mechanisms. Previously unreported reversible C-N ionization and a Pd(0)-catalyzed [3,3]-sigmatropic rearrangement were discovered. This study provides new reaction pathways for both π-allyl and sigmatropic rearrangements.

14.
J Infect Dis ; 223(1): 10-14, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33009908

RESUMO

Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been hampered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay-based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0-1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.


Assuntos
Anticorpos Antivirais/análise , COVID-19/diagnóstico , Ensaio de Imunoadsorção Enzimática , Estudos Soroepidemiológicos , Antígenos Virais/imunologia , Austrália , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Humanos , Imunoglobulina G/análise , Fosfoproteínas/imunologia , Sensibilidade e Especificidade , Glicoproteína da Espícula de Coronavírus/imunologia
15.
J Med Toxicol ; 17(1): 16-26, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32557176

RESUMO

INTRODUCTION: The Toxicology Investigators Consortium (ToxIC) database, created in 2010 by the American College of Medical Toxicology (ACMT), compiles data recorded by medical toxicologists. In January 2017, the data field for transgender (and if transgender, male-to-female or female-to-male) was added to the ToxIC form. Little is known regarding trends in poisonings among transgender patients. We sought to review consultations managed by a bedside toxicologist and provide descriptive data in trends among types of exposures within the transgender demographic. METHODS: A retrospective ToxIC database evaluation of cases in which the patient identified as transgender were reviewed from January 2017-June 2019 and descriptive demographics reported. RESULTS: The registry contained 113 cases that involved transgender patients. Of those with complete data, 41 (36.6%) were male-to-female, 68 (60.7%) were female-to-male, and 3 (2.7%) identified as gender non-conforming. Of those with complete data, the most common reason for encounter was intentional use of a pharmaceutical drug (N = 97, 85.8%), of which 85 (87.6%) were classified as intentional pharmaceutical use intended for self-harm. Analgesics were the most common class of drugs used out of those reported (N = 24, 22%). Forty-six (90.2%) patients aged 13-18 with complete data were identified as encounters due to self-harm. Attempt at self-harm was the most common reason for intentional pharmaceutical encounter among the sample of transgender patients with complete data (N = 85, 87.6%); with female-to-male patients having an N = 53 (77.9%). CONCLUSION: Among transgender patients in the ToxIC registry, the most common primary reason for the encounter was intentional use of a pharmaceutical drug intended for self-harm. In this small cohort, there were some age and transition differences in prevalence. These findings may inform poisoning prevention practices as well as sex- and gender-based management of patients in this vulnerable population.

16.
Intern Med J ; 51(6): 939-947, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32388900

RESUMO

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder with a poor prognosis characterised by substantial immune activation leading to end-organ failure. In childhood, genetic defects that impair cytotoxic function of natural killer cells and T cells. (HLH) are often identified. In adults, clinical manifestations are similar to those observed in children but the aetiology is often unclear. AIMS: To evaluate whether poor prognosis for adult HLH is in part due to lack of awareness of the disorder, which results in incomplete investigation and failure to implement timely treatment. METHODS: We performed a retrospective case series of adult-onset HLH in a tertiary hospital in Australia. We evaluated clinical characteristics, treatment and outcome, and related these to application of standard diagnostic criteria for HLH. RESULTS: In our centre, incomplete assessment of HLH criteria was common. Serum ferritin was the criterion most commonly assessed. Hyperferritinaemia ≥10 000 µg/L was highly sensitive in detecting patients with adult-onset HLH; however, the majority of patients who had hyperferritinaemia ≥10 000 µg/L did not have adult-onset HLH. CONCLUSION: The present study highlights the importance of comprehensive application of diagnostic criteria to improve accuracy and timelines of the diagnosis of adult onset HLH.

17.
Europace ; 23(3): 441-450, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33200177

RESUMO

AIMS: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions. METHODS AND RESULTS: Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. CONCLUSION: A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.

18.
J Exp Med ; 218(2)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33107914

RESUMO

NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.


Assuntos
Autoimunidade/genética , Subunidade p52 de NF-kappa B/genética , Animais , Feminino , Humanos , Proteínas I-kappa B/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , Receptores de Antígenos de Linfócitos T/genética
19.
Subst Use Misuse ; 56(2): 275-285, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33342341

RESUMO

Background: Social anxiety has been associated with higher rates of negative alcohol use consequences, and this relationship appears to be accounted for by coping drinking motives. Dissociation is commonly present in anxiety disorders, including social anxiety disorder, and may serve to unconsciously reduce negative emotions when more effortful coping strategies are not effective. Objectives: The present study examined whether the relationship between social anxiety, coping motives, and alcohol consequences was moderated by dissociative symptoms. It was hypothesized that coping motives would mediate the relationship between social anxiety and alcohol consequences, and that dissociation would moderate the relationship between social anxiety and coping motives. Undergraduate students who endorsed alcohol use within the past 30 days (n = 320) were recruited from a large public university. Participants completed measures of social anxiety, dissociation, alcohol motives, and alcohol consequences as part of a larger online questionnaire. Results: Coping motives were found to mediate the relationship between social anxiety and alcohol consequences. Dissociation did not moderate the relationship between social anxiety and coping motives. Dissociation was significantly associated with alcohol consequences via coping motives. Conclusions: Future research should include longitudinal research designs or ecological momentary assessment designs and should examine these relationships in clinical and community samples.


Assuntos
Adaptação Psicológica , Ansiedade , Consumo de Bebidas Alcoólicas , Medo , Humanos , Motivação
20.
Artigo em Inglês | MEDLINE | ID: mdl-33271867

RESUMO

The following case study aims to provide a broad overview of the initial Australian epidemiological situation of the novel coronavirus disease (COVID-19) pandemic. We provide a case presentation of Australia's current demographic characteristics and an overview of their health care system. The data we present on Australia's COVID-19 situation pertain to the initial wave of the pandemic from January through to 20 April 2020. The results of our study indicate the number of reported COVID-19 cases in Australia reduced, and Australia initially managed to successfully flatten the curve-from an initial doubling time of 3.4 days at the end of March 2020 to a doubling time of 112 days as of 20 April 2020. Using SEIR mathematical modelling, we investigate a scenario assuming infections increase once mitigation measures are lifted. In this case, Australia could experience over 15,000 confirmed cases by the end of April 2020. How Australia's government, health authorities and citizens adjust to preventative measures to reduce the risk of transmission as well as the risk of overburdening Australia's health care system is crucial. Our study presents the initial non-pharmaceutical intervention measures undertaken by the Australian health authorities in efforts to mitigate the rate of infection, and their observed and predicted outcomes. Finally, we conclude our study by presenting the observed and expected economic, social, and political disruptions Australians may endure as a result of the initial phase of the pandemic.


Assuntos
COVID-19/epidemiologia , Pandemias , Austrália/epidemiologia , Humanos , SARS-CoV-2
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