RESUMO
OBJECTIVE: The risk of aortic dissection (AoD) is increased in Turner syndrome (TS) but predicting those at risk is difficult. Based on scarce evidence, preventive aortic surgery is recommended when aortic diameter increases >5 mm/year. To investigate the aortic growth rate in TS and TS-related conditions associated with aortic growth. We also reported our experience of women who suffered aortic dissection (AoD), and who had preventive aortic replacement. METHODS: 151 adult TS were retrospectively identified. Women who had more than one transthoracic echocardiogram (TTE) after age 16 years were included in the aortic growth study. Aortic diameters at sinuses of Valsalva (SoV) and ascending aorta (AA) were analysed by two experts. RESULTS: 70/151 women had more than one TTE (interscan interval 4.7 years). Mean aortic growth was 0.13 ± 0.59 mm/year at SoV and 0.23 ± 0.82 mm/year at AA. Known risk factors for aortic dilatation and TS-related conditions were not associated with aortic growth. 4/151 women experienced AoD (age 25±8 years): two had paired scans for aortic growth, which was 0.67 mm/year at both SoV and AA in the first woman, and 11 mm/year (SoV) and 4 mm/year (AA) in the second. Only 1/4 of women with AoD survived; she used a TS cardiac-alert card to inform emergency personnel about her risk of AoD. 5/151 had a preventive aortic replacement, but one died post-operatively. CONCLUSIONS: Mean aortic growth in our TS population was increased compared to non-TS women and was not associated with currently known risk factors for AoD, suggesting that aortic growth rate itself could be a useful variable to stratify who is at risk for AoD.
Assuntos
Doenças da Aorta , Dissecção Aórtica , Síndrome de Turner , Adulto , Feminino , Humanos , Adolescente , Adulto Jovem , Síndrome de Turner/complicações , Síndrome de Turner/epidemiologia , Estudos Retrospectivos , Doenças da Aorta/complicações , Doenças da Aorta/epidemiologia , Medição de RiscoRESUMO
Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.
RESUMO
Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias da Próstata , Sialiltransferases , Masculino , Humanos , Glicosilação , Polissacarídeos/química , Polissacarídeos/metabolismo , Reino Unido , beta-D-Galactosídeo alfa 2-6-Sialiltransferase , Antígenos CD/metabolismoRESUMO
BACKGROUND: Non-human primates, such as Rhesus macaques, are a powerful model for studies of the cellular and physiological effects of radiation, development of radiation biodosimetry, and for understanding the impact of radiation on human health. Here, we study the effects of 4 Gy total body irradiation (TBI) at the molecular level out to 28 days and at the cytogenetic level out to 56 days after exposure. We combine the global transcriptomic and proteomic responses in peripheral whole blood to assess the impact of acute TBI exposure at extended times post irradiation. RESULTS: The overall mRNA response in the first week reflects a strong inflammatory reaction, infection response with neutrophil and platelet activation. At 1 week, cell cycle arrest and re-entry processes were enriched among mRNA changes, oncogene-induced senescence and MAPK signaling among the proteome changes. Influenza life cycle and infection pathways initiated earlier in mRNA and are reflected among the proteomic changes during the first week. Transcription factor proteins SRC, TGFß and NFATC2 were immediately induced at 1 day after irradiation with increased transcriptional activity as predicted by mRNA changes persisting up to 1 week. Cell counts revealed a mild / moderate hematopoietic acute radiation syndrome (H-ARS) reaction to irradiation with expected lymphopenia, neutropenia and thrombocytopenia that resolved within 30 days. Measurements of micronuclei per binucleated cell levels in cytokinesis-blocked T-lymphocytes remained high in the range 0.27-0.33 up to 28 days and declined to 0.1 by day 56. CONCLUSIONS: Overall, we show that the TBI 4 Gy dose in NHPs induces many cellular changes that persist up to 1 month after exposure, consistent with damage, death, and repopulation of blood cells.
Assuntos
Transcriptoma , Irradiação Corporal Total , Animais , Macaca mulatta , Proteoma , Proteômica , Multiômica , Células Sanguíneas , Doses de RadiaçãoRESUMO
Male infertility affects â¼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.
Assuntos
Pontos de Checagem do Ciclo Celular/genética , Infertilidade Masculina/genética , Meiose/genética , Mutação/genética , Proteínas/genética , Espermatogênese/genética , Adulto , Alelos , Animais , Azoospermia/genética , Homozigoto , Humanos , Masculino , Camundongos , Fenótipo , Espermatozoides/anormalidades , Testículo/anormalidades , Turquia , Sequenciamento do Exoma/métodosRESUMO
Following a mass-casualty nuclear/radiological event, there will be an important need for rapid and accurate estimation of absorbed dose for biological triage. The cytokinesis-block micronucleus (CBMN) assay is an established and validated cytogenetic biomarker used to assess DNA damage in irradiated peripheral blood lymphocytes. Here, we describe an intercomparison experiment between two biodosimetry laboratories, located at Columbia University (CU) and Health Canada (HC) that performed different variants of the human blood CBMN assay to reconstruct dose in human blood, with CU performing the assay on isolated lymphocytes and using semi-automated scoring whereas HC used the more conventional whole blood assay. Although the micronucleus yields varied significantly between the two assays, the predicted doses closely matched up to 4 Gy - the range from which the HC calibration curve was previously established. These results highlight the importance of a robust calibration curve(s) across a wide age range of donors that match the exposure scenario as closely as possible and that will account for differences in methodology between laboratories. We have seen that at low doses, variability in the results may be attributed to variation in the processing while at higher doses the variation is dominated by inter-individual variation in cell proliferation. This interlaboratory collaboration further highlights the usefulness of the CBMN endpoint to accurately reconstruct absorbed dose in human blood after ionizing radiation exposure.
Assuntos
Citocinese , Radiometria , Humanos , Radiometria/métodos , Triagem/métodos , Linfócitos , Testes para Micronúcleos/métodosRESUMO
The cytokinesis-block micronucleus (CBMN) assay is an established method for assessing chromosome damage in human peripheral blood lymphocytes resulting from exposure to genotoxic agents such as ionizing radiation. The objective of this study was to measure cytogenetic DNA damage and hematology parameters in vivo based on MN frequency in peripheral blood lymphocytes (PBLs) from adult and pediatric leukemia patients undergoing hematopoietic stem cell transplantation preceded by total body irradiation (TBI) as part of the conditioning regimen. CBMN assay cultures were prepared from fresh blood samples collected before and at 4 and 24 h after the start of TBI, corresponding to doses of 1.25 Gy and 3.75 Gy, respectively. For both age groups, there was a significant increase in MN yields with increasing dose (p < 0.05) and dose-dependent decrease in the nuclear division index (NDI; p < 0.0001). In the pre-radiotherapy samples, there was a significantly higher NDI measured in the pediatric cohort compared to the adult due to an increase in the percentage of tri- and quadri-nucleated cells scored. Complete blood counts with differential recorded before and after TBI at the 24-h time point showed a rapid increase in neutrophil (p = 0.0001) and decrease in lymphocyte (p = 0.0006) counts, resulting in a highly elevated neutrophil-to-lymphocyte ratio (NLR) of 14.45 ± 1.85 after 3.75 Gy TBI (pre-exposure = 4.62 ± 0.49), indicating a strong systemic inflammatory response. Correlation of the hematological cell subset counts with cytogenetic damage, indicated that only the lymphocyte subset survival fraction (after TBI compared with before TBI) showed a negative correlation with increasing MN frequency from 0 to 1.25 Gy (r = -0.931; p = 0.007). Further, the data presented here indicate that the combination of CBMN assay endpoints (MN frequency and NDI values) and hematology parameters could be used to assess cytogenetic damage and early hematopoietic injury in the peripheral blood of leukemia patients, 24 h after TBI exposure.
Assuntos
Leucemia , Irradiação Corporal Total , Adulto , Humanos , Criança , Irradiação Corporal Total/efeitos adversos , Testes para Micronúcleos/métodos , Citocinese/genética , Citocinese/efeitos da radiação , LinfócitosRESUMO
The cytokinesis-block micronucleus assay is a well-established method to assess radiation-induced genetic damage in human cells. This assay has been adapted to imaging flow cytometry (IFC), allowing automated analysis of many cells, and eliminating the need to create microscope slides. Furthermore, to improve the efficiency of assay performance, a small-volume method previously developed was employed. Irradiated human blood samples were cultured, stained, and analyzed by IFC to produce images of the cells. Samples were run using both manual and 96-well plate automated acquisition. Multiple parameter-based image features were collected for each sample, and the results were compared to confirm that these acquisition methods are functionally identical. This paper details the multi-parametric analysis developed and the resulting calibration curves up to 10 Gy. The calibration curves were created using a quadratic random coefficient model with Poisson errors, as well as a logistic discriminant function. The curves were then validated with blinded, irradiated samples, using relative bias and relative mean square error. Overall, the accuracy of the dose estimates was adequate for triage dosimetry (within 1 Gy of the true dose) over 90% of the time for lower doses and about half the time for higher doses, with the lowest success rate between 5 and 6 Gy where the calibration curve reached its peak and there was the smallest change in MN/BNC with dose. This work describes the application of a novel multi-parametric analysis that fits the calibration curves and allows dose estimates up to 10 Gy, which were previously limited to 4 Gy. Furthermore, it demonstrates that the results from samples acquired manually and with the autosampler are functionally similar.
Assuntos
Citocinese , Radiometria , Humanos , Citocinese/genética , Testes para Micronúcleos/métodos , Citometria de Fluxo/métodos , Radiometria/métodosRESUMO
Peripheral blood mononuclear cells (PBMCs) are a useful model for biochemical assays, particularly for etiological studies. We describe here a method for measuring DNA repair capacity (DRC) in archival cryogenically preserved PBMCs. To model DRC, we measured γ-H2AX repair kinetics in thawed PBMCs after irradiation with 3 Gy gamma rays. Time-dependent fluorescently labeled γ-H2AX levels were measured at five time points from 1 to 20 h, yielding an estimate of global DRC repair kinetics as well as a measure of unrepaired double strand breaks at 20 h. While γ-H2AX levels are traditionally measured by either microscopy or flow-cytometry, we developed a protocol for imaging flow cytometry (IFC) that combines the detailed information of microscopy with the statistical power of flow methods. The visual imaging component of the IFC allows for monitoring aspects such as cellular health and apoptosis as well as fluorescence localization of the γ-H2AX signal, which ensures the power and significance of this technique. Application of a machine-learning based image classification improved flow cytometry fluorescent measurements by identifying apoptotic cells unable to undergo DNA repair. We present here DRC repair parameters from 18 frozen archival PBMCs and 28 fresh blood samples collected from a demographically diverse cohort of women measured in a high-throughput IFC format. This thaw method and assay can be used alone or in conjunction with other assays to measure etiological phenotypes in cryogenic biobanks of PBMCs.
Assuntos
Histonas , Leucócitos Mononucleares , Feminino , Animais , Leucócitos Mononucleares/metabolismo , Histonas/genética , Histonas/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , CriopreservaçãoRESUMO
BACKGROUND AND OBJECTIVE: The risk of aortic dissection (AoD) is increased in women with Turner syndrome (TS) but predicting those with this heightened risk is difficult. In response to this, we sought to create a pathway to monitor TS patients to improve efficiency and resource utilisation in our dedicated TS clinic, and to monitor more closely those women thought to be at increased risk of AoD. DESIGN AND PATIENTS: Our pathway was designed based on evidence derived from International Guidelines for the management of aortic disease in women with TS. Women were divided according to those with known risk factors for AoD, and those with no known risk factors. These groups were further subdivided into 4 pathways depending on ascending aortic size which in-turn determined the frequency of outpatient appointments and imaging. RESULTS: Out of the 168 patients included in the analysis, 7 have had ascending aorta replacements, all in the highest risk group. Of the remaining 4 patients in the highest risk groups: 1 dissected whilst awaiting planned aortic surgery, 1 is currently awaiting surgery, 1 has low body mass index, therefore, making her aorta proportionally larger but not necessitating surgery and one has declined surgery. No women changed pathways. CONCLUSION: The risk-stratified pathway safely allowed consolidation of resources to women perceived to be at highest risk of AoD (excluding pregnancy), supporting the efficacy of the pathway and allowing the diversion of resources to those most at risk of AoD.
Assuntos
Doenças da Aorta , Dissecção Aórtica , Síndrome de Turner , Gravidez , Humanos , Feminino , Síndrome de Turner/complicações , Aorta Torácica , Aorta , Doenças da Aorta/etiologiaRESUMO
BACKGROUND: Population studies suggest cancer morbidity may be different in Turner syndrome (TS) compared to the background female population. However, significant variability is observed in cancer associations likely due to heterogeneity in patient cohorts. We explored the prevalence and patterns of cancer amongst a cohort of women with TS attending a dedicated TS clinic. METHODS: Retrospective analysis of the patient database was performed to identify TS women who developed cancer. Population data (available before 2015) from the National Cancer Registration and Analysis Service database were used for comparison. RESULTS: Out of 156 TS women, median age of 32 (range 18-73) years, 9 (5.8%) had a recorded cancer diagnosis. Types of cancers were, bilateral gonadoblastoma, type 1 gastric neuroendocrine tumour (NET), appendiceal-NET, gastrointestinal stromal tumour, plasma cell dyscrasia, synovial sarcoma, cervical cancer, medulloblastoma and aplastic anaemia. Median age at cancer diagnosis was 35 (range 7-58) years and two were detected incidentally. Five women had 45,X karyotype, three received growth hormone treatment and all except one received oestrogen replacement therapy. The cancer prevalence of the background age-matched female population was 4.4%. CONCLUSIONS: We confirm the previous observations that women with TS do not appear to be at overall increased risk of common malignancies. Our small cohort showed a spectrum of rare malignancies that are not typically associated with TS, except for a single patient with a gonadoblastoma. The slightly higher prevalence of cancer in our cohort might simply represent increased cancer prevalence in the background population, or might be related to small sample size and regular monitoring of these women due to TS per se.
Assuntos
Neoplasias Ovarianas , Síndrome de Turner , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos RetrospectivosRESUMO
Assessing and managing pain while evaluating risks associated with substance use and substance use disorders continues to be a challenge faced by health care clinicians. The American Society for Pain Management Nursing and the International Nurses Society on Addictions uphold the principle that all persons with co-occurring pain and substance use or substance use disorders have the right to be treated with dignity and respect, and receive evidence-based, high quality assessment, and management for both conditions. The American Society for Pain Management Nursing and International Nurses Society on Addictions have updated their 2012 position statement on this topic supporting an integrated, holistic, multidimensional approach, which includes nonopioid and nonpharmacological modalities. Opioid use disorder is used as an exemplar for substance use disorders and clinical recommendations are included with expanded attention to risk assessment and mitigation with interventions targeted to minimize the risk for relapse or escalation of substance use. Opioids should not be excluded for anyone when indicated for pain management. A team-based approach is critical, promotes the active involvement of the person with pain and their support systems, and includes pain and addiction specialists whenever possible. Health care systems should establish policies and procedures that facilitate and support the principles and recommendations put forth in this article.
Assuntos
Transtornos Relacionados ao Uso de Opioides , Manejo da Dor , Analgésicos Opioides/efeitos adversos , Humanos , Transtornos Relacionados ao Uso de Opioides/complicações , Dor/tratamento farmacológicoRESUMO
The American Society for Pain Management Nursing and the International Nurses Society on Addictions hold the position that persons with co-occurring pain and substance use disorder have the right to be treated with dignity and respect, and receive evidence-based, high-quality assessment and management for both conditions using an integrated, holistic, multidimensional approach. Non-opioid and nonpharmacological approaches to pain management are recommended. Opioids should not be withheld from anyone if necessary to treat pain, and a team-based approach, including pain and addiction specialists, should be utilized when possible. Pain management should include interventions aimed at minimizing the risk for relapse or escalation of problematic substance use, and actively involve the person and their support persons in the plan of care. Institutions should establish policies and procedures that support this position statement.
Assuntos
Transtornos Relacionados ao Uso de Opioides , Transtornos Relacionados ao Uso de Substâncias , Humanos , Manejo da Dor , Analgésicos Opioides/uso terapêutico , Dor , Transtornos Relacionados ao Uso de Substâncias/terapia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológicoRESUMO
Detonation of an improvised nuclear device highlights the need to understand the risk of mixed radiation exposure as prompt radiation exposure could produce significant neutron and gamma exposures. Although the neutron component may be a relatively small percentage of the total absorbed dose, the large relative biological effectiveness (RBE) can induce larger biological DNA damage and cell killing. The objective of this study was to use a hematopoietically humanized mouse model to measure chromosomal DNA damage in human lymphocytes 24 h after in vivo exposure to neutrons (0.3 Gy) and X rays (1 Gy). The human dicentric and cytokinesis-block micronucleus assays were performed to measure chromosomal aberrations in human lymphocytes in vivo from the blood and spleen, respectively. The mBAND assay based on fluorescent in situ hybridization labeling was used to detect neutron-induced chromosome 1 inversions in the blood lymphocytes of the neutron-irradiated mice. Cytogenetics endpoints, dicentrics and micronuclei showed that there was no significant difference in yields between the 2 irradiation types at the doses tested, indicating that neutron-induced chromosomal DNA damage in vivo was more biologically effective (RBE â¼3.3) compared to X rays. The mBAND assay, which is considered a specific biomarker of high-LET neutron exposure, confirmed the presence of clustered DNA damage in the neutron-irradiated mice but not in the X-irradiated mice, 24 h after exposure.
Assuntos
Citogenética/métodos , Linfócitos/efeitos da radiação , Nêutrons , Raios X , Adulto , Animais , Células Cultivadas , Inversão Cromossômica/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Linfócitos/citologia , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Testes para Micronúcleos/métodos , Pessoa de Meia-IdadeRESUMO
It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations.
Assuntos
Transtornos do Desenvolvimento Sexual , Endocrinologia , Adolescente , Criança , Transtornos do Desenvolvimento Sexual/diagnóstico , Humanos , Pais , Desenvolvimento Sexual , Reino UnidoRESUMO
Sickle cell disease (SCD) is a hematologic disorder defined by presence of sickle-shaped red blood cells that can occlude blood vessels and cause tissue ischemia and pain. Treating SCD pain adequately and safely is difficult given today's opioid climate. Buprenorphine-naloxone has been described as an alternative option to treat chronic pain in the adult literature; however, it historically required discontinuation of full-agonist opioids before initiation, resulting in opioid withdrawal. Herein we present two adolescents with SCD who successfully weaned off large doses of full-agonist opioids by using microdose induction of buprenorphine-naloxone in clinic, without experiencing significant opioid withdrawal. Ambulatory microdose induction may remove hurdles that otherwise would discourage patients from trying this regimen while still controlling pain safely.
Assuntos
Analgésicos Opioides/uso terapêutico , Anemia Falciforme/complicações , Combinação Buprenorfina e Naloxona/uso terapêutico , Dor/tratamento farmacológico , Adolescente , Adulto , Relação Dose-Resposta a Droga , Humanos , Masculino , Dor/etiologia , Dor/patologia , Prognóstico , Adulto JovemRESUMO
Environmental contamination and ingestion of the radionuclide Cesium-137 (137Cs) is a large concern in fallout from a nuclear reactor accident or improvised nuclear device, and highlights the need to develop biological assays for low-dose rate, internal emitter radiation. To mimic low-dose rates attributable to fallout, we have developed a VAriable Dose-rate External 137Cs irradiatoR (VADER), which can provide arbitrarily varying and progressive low-dose rate irradiations in the range of 0.1-1.2 Gy/day, while circumventing the complexities of dealing with radioactively contaminated biomaterials. We investigated the kinetics of mouse peripheral leukocytes DNA damage response in vivo after variable, low-dose rate 137Cs exposure. C57BL/6 mice were placed in the VADER over 7 days with total accumulated dose up to 2.7 Gy. Peripheral blood response including the leukocyte depletion, apoptosis as well as its signal protein p53 and DNA repair biomarker γ-H2AX was measured. The results illustrated that blood leukocyte numbers had significantly dropped by day 7. P53 levels peaked at day 2 (total dose = 0.91 Gy) and then declined; whereas, γ-H2AX fluorescence intensity (MFI) and foci number generally increased with accumulated dose and peaked at day 5 (total dose = 2.08 Gy). ROC curve analysis for γ-H2AX provided a good discrimination of accumulated dose < 2 Gy and ≥ 2 Gy, highlighting the potential of γ-H2AX MFI as a biomarker for dosimetry in a protracted, environmental exposure scenario.
Assuntos
Radioisótopos de Césio , Dano ao DNA , Histonas/metabolismo , Leucócitos/efeitos da radiação , Animais , Apoptose/efeitos da radiação , Biomarcadores/metabolismo , Reparo do DNA , Contagem de Leucócitos , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doses de Radiação , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Thyroid eye disease (TED) is an autoimmune inflammatory disease that can be disfiguring and potentially sight threatening. Suppression of inflammation in active disease can reduce the risk of visual loss and limit long-term sequelae. Current management involves inflammation suppression using glucocorticoids. The aim of this study was to evaluate the efficacy of early disease intervention with targeted immunomodulatory therapy to alter disease course. This paper reports the efficacy of low-dose rituximab in reducing clinical activity in TED in a small population. METHODS: A retrospective audit of consecutive patients with active TED managed primarily with a 100 mg rituximab infusion. Further glucocorticoid or steroid-sparing agents were prescribed if clinically indicated. Clinical activity score, VISA overall severity score and Oxford Quality of Life score were recorded at each visit as well as TSH receptor antibody levels (TRAb), B cell subsets and adverse reactions. RESULTS: Twelve patients had mean follow-up of 6.3 months. Clinical activity scores significantly decreased (mean score 5.08 to 1.58; P < 0.001), VISA overall severity scores reduced by 50% from 12 to 6, P < 0.001 and the mean cumulative dose of IV methylprednisolone was 2.3 g. 100 mg rituximab induced significant CD19+ B cell depletion (n = 8, P < 0.001). There was no significant reduction in serum TRAb (n = 8, P = 0.06). A transient infusion-related rash was the only adverse effect, n = 4. QoL scores did not differ markedly before and after treatment. CONCLUSION: Low-dose rituximab is an efficacious, well-tolerated and safe treatment for active TED; reducing disease activity and allowing reduced administration of systemic steroid.
Assuntos
Oftalmopatias/tratamento farmacológico , Receptores da Tireotropina/imunologia , Rituximab/uso terapêutico , Doenças da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Antígenos CD19/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Oftalmopatias/sangue , Feminino , Humanos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Doenças da Glândula Tireoide/sangue , Adulto JovemRESUMO
BACKGROUND: Pain management is essential for the care of hospitalized children. Although multiple barriers have been identified that interfere with nurses' ability to provide optimal pain management, it is not known how pervasive are these barriers across the United States. AIMS: This study is the third in a series of studies examining barriers to pediatric pain management. The aim of this study was to examine barriers in different organizations using the same tool during the same period of time. SETTINGS/PARTICIPANTS: A sample of 808 nurses from three pediatric teaching hospitals responded to a survey addressing barriers to optimal pain management for children. RESULTS: Barriers unanimously identified as being most significant included inadequate or insufficient physician medication orders, insufficient time allowed to premedicate before procedures, insufficient premedication orders before procedures, and low priority given to pain management by medical staff. CONCLUSIONS: Barriers identified as the most and least significant were similar regardless of hospital location. Revealing similar barriers across multiple pediatric hospitals provides direction for nurses trying to provide solutions to these pain management barriers.
Assuntos
Manejo da Dor/tendências , Pediatria/métodos , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Dor/enfermagem , Manejo da Dor/normas , Pediatria/tendências , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. RESULTS: 41 patients were treated; 34 received AZD0424 once-daily at doses ranging from 5 mg to 150 mg, and 7 received 40 mg bi-daily 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3-5 in severity, with patients treated at doses above 60 mg per day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmax and AUC increased linearly with dose and the mean±standard deviation t1/2 was 8.4±2.8 h. Clear evidence of Src target inhibition was seen at doses ⩾20 mg per day. No responses were observed and 7 patients (17.1%) achieved stable disease lasting 6 weeks or more. CONCLUSIONS: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended.