RESUMO
The United States Food and Drug Administration Final Guidance for Industry titled, "Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion" provides nine strategies for platelet bacterial risk mitigation. Even if it is assumed all strategies are comparable in terms of safety and efficacy, the decision of which to implement remains challenging. Some additional factors that warrant evaluation before selecting a strategy include the financial impact, process for implementation, logistics upon implementation, institutional acceptance by blood bank staff, administration and clinicians, and effect on platelet availability. To assist with this difficult choice, a panel of transfusion service physicians who have expertise on the topic and have already selected strategies for their transfusion services were recruited to provide varied perspectives. In addition, the use of a decision-making tool that objectively evaluates defined criteria for assessment of the nine strategies is described.
Assuntos
Plaquetas/microbiologia , Tomada de Decisões , Hospitais , Transfusão de Plaquetas/normas , Algoritmos , Bactérias/crescimento & desenvolvimento , Armazenamento de Sangue/métodos , Hospitais/normas , Humanos , Transfusão de Plaquetas/efeitos adversos , Risco , Estados UnidosRESUMO
Mycosis fungoides in palmoplantar localization (MFPP) is a rare variant of MF that is confined to the hands and feet. Patients commonly receive treatment over many years for suspected palmoplantar dermatitis before the diagnosis is made. Most MFPP patients remain at patch or plaque stage, and often respond to treatment with radiotherapy. Herein, we describe a 77-year-old man who suffered 6 years of hand and foot dermatitis that failed multiple treatments, most notably TNF-α inhibitors and mycophenolate mofetil. He eventually developed a tumor on the hand, which was biopsied to reveal a dense dermal infiltrate of large lymphocytes (CD3+/CD4-/CD8-/TCR-BetaF1+/partial CD30+). A subsequent biopsy of an eczematous patch from his hand revealed an epidermotropic and syringotropic infiltrate comprised of smaller lymphocytes with a concordant immunophenotype and matching clonal peak with TCR gene rearrangement. He was diagnosed with MFPP and started on radiotherapy with a modest response; therefore, a decision was made to start brentuximab vedotin, which resulted in a complete response. MFPP is an exceedingly rare variant of MF that can show large-cell transformation and progress in stage. We highlight a possible association between disease progression and immunosuppressants and the potential role for treatment with brentuximab.
Assuntos
Imunoconjugados/uso terapêutico , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Idoso , Biomarcadores Tumorais/análise , Brentuximab Vedotin , Ligante CD30/análise , Ligante CD30/biossíntese , Transformação Celular Neoplásica/patologia , Pé , Mãos , Humanos , MasculinoRESUMO
Abundant, sustained expression of prosurvival Mcl-1 is an important determinant of viability and drug resistance in cancer cells. The Mcl-1 protein contains PEST sequences (enriched in proline, glutamic acid, serine, and threonine) and is normally subject to rapid turnover via multiple different pathways. One of these pathways involves a phosphodegron in the PEST region, where Thr-163 phosphorylation primes for Ser-159 phosphorylation by glycogen synthase kinase-3. Turnover via this phosphodegron-targeted pathway is reduced in Mcl-1-overexpressing BL41-3 Burkitt lymphoma and other cancer cells; turnover is further slowed in the presence of phorbol ester-induced ERK activation, resulting in Mcl-1 stabilization and an exacerbation of chemoresistance. The present studies focused on Mcl-1 dephosphorylation, which was also found to profoundly influence turnover. Exposure of BL41-3 cells to an inhibitor of protein phosphatase 2A (PP2A), okadaic acid, resulted in a rapid increase in phosphorylation at Thr-163 and Ser-159, along with a precipitous decrease in Mcl-1 expression. The decline in Mcl-1 expression preceded the appearance of cell death markers and was not slowed in the presence of phorbol ester. Upon exposure to calyculin A, which also potently inhibits PP2A, versus tautomycin, which does not, only the former increased Thr-163/Ser-159 phosphorylation and decreased Mcl-1 expression. Mcl-1 co-immunoprecipitated with PP2A upon transfection into CHO cells, and PP2A/Aα knockdown recapitulated the increase in Mcl-1 phosphorylation and decrease in expression. In sum, inhibition of PP2A prevents Mcl-1 dephosphorylation and results in rapid loss of this prosurvival protein in chemoresistant cancer cells.
Assuntos
Linfoma de Burkitt/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína Fosfatase 2/antagonistas & inibidores , Sítios de Ligação , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Toxinas Marinhas , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Ácido Okadáico/farmacologia , Oxazóis/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/genética , Proteólise , Serina/química , Acetato de Tetradecanoilforbol/farmacologia , Treonina/químicaAssuntos
Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Resfriado Comum/diagnóstico , Infecções por Coronavirus/diagnóstico , Reações Cruzadas , Imunoglobulina G/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Resfriado Comum/imunologia , Infecções por Coronavirus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2RESUMO
The National Heart, Lung, and Blood Institute in collaboration with the American Society for Apheresis, convened a State of the Science Symposium in November of 2012 due to the expanding application of therapeutic apheresis despite the lack of well-designed research to address its efficacy. This article reviews the opportunities that were presented at this meeting in the area of cardiovascular disease (CVD), specifically the use of columns to adsorb autoantibodies in dilated cardiomyopathy or damaging lipids in peripheral vascular disease. Understanding how absorption of these pathologic substances alters the inflammatory response in these disorders is important for the application of these technologies to the treatment of CVD.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Doenças Cardiovasculares/terapia , Adsorção , Adulto , Idoso , Apoptose , Autoanticorpos/química , Cardiomiopatia Dilatada/terapia , Humanos , Sistema Imunitário , Técnicas de Imunoadsorção , Inflamação , Pessoa de Meia-Idade , National Heart, Lung, and Blood Institute (U.S.) , Doenças Vasculares Periféricas/terapia , Prevalência , Projetos de Pesquisa , Estados UnidosRESUMO
Increasing the pool of cells at early T-cell developmental stages enhances thymopoiesis and is especially beneficial when T-cell production is compromised by radiation or aging. Within the immature double-negative (DN; CD4(-)CD8(-)) thymocyte subpopulation, the DN1 subset contains the most primitive cells including the rare early T-cell progenitors (ETPs). In the present study, a human MCL1 transgene, under the control of its endogenous promoter, resulted in enlargement of an undistorted thymus in C57/BL6 mice. Enlargement occurred in females but not males, being seen at 1 month of age and maintained during progression into adulthood as the thymus underwent involution. The small DN1 subset was expanded disproportionally (ETPs increasing from â¼0.016 to 0.03% of thymocytes), while more mature thymocytes were increased proportionally (1.5-fold) along with the stroma. DN1 cells from transgenic females exhibited increased viability with maintained proliferation, and their survival in primary culture was extended. Exposure of transgenic females to γ-irradiation also revealed an expanded pool of radioresistant DN1 cells exhibiting increased viability. While the viability of DN1 cells from transgenic males was equivalent to that of their non-transgenic counterparts directly after harvest, it was enhanced in culture-suggesting that the effect of the transgene was suppressed in the in vivo environment of the male. Viability was increased in ETPs from transgenic females, but unchanged in more mature thymocytes, indicating that primitive cells were affected selectively. The MCL1 transgene thus increases the viability and pool size of primitive ETP/DN1 cells, promoting thymopoiesis and radioresistance in peripubescent females and into adulthood.
Assuntos
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Timócitos/citologia , Timo/crescimento & desenvolvimento , Animais , Sobrevivência Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Linfócitos T/citologia , Linfócitos T/imunologia , Timócitos/imunologia , Timo/citologia , Timo/imunologia , Irradiação Corporal TotalRESUMO
The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.
Assuntos
Pesquisa Biomédica , Remoção de Componentes Sanguíneos/tendências , Congressos como Assunto , Fotoferese , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Remoção de Componentes Sanguíneos/métodos , Remoção de Componentes Sanguíneos/estatística & dados numéricos , Congressos como Assunto/organização & administração , Células Dendríticas/citologia , Humanos , Células Matadoras Naturais/citologia , National Institutes of Health (U.S.)/organização & administração , Fotoferese/estatística & dados numéricos , Linfócitos T/citologia , Estados UnidosRESUMO
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. While the primary risk factor for COPD is cigarette smoke exposure, vitamin D deficiency has been epidemiologically implicated as a factor in the progressive development of COPD-associated emphysema. Because of difficulties inherent to studies involving multiple risk factors in the progression of COPD in humans, we developed a murine model in which to study the separate and combined effects of vitamin D deficiency and cigarette smoke exposure. During a 16-week period, mice were exposed to one of four conditions, control diet breathing room air (CD-NS), control diet with cigarette smoke exposure (CD-CSE), vitamin D deficient diet breathing room air (VDD-NS) or vitamin D deficient diet with cigarette smoke exposure (VDD-CSE). At the end of the exposure period, the lungs were examined by a pathologist and separately by morphometric analysis. In parallel experiments, mice were anesthetized for pulmonary function testing followed by sacrifice and analysis. Emphysema (determined by an increase in alveolar mean linear intercept length) was more severe in the VDD-CSE mice compared to control animals and animals exposed to VDD or CSE alone. The VDD-CSE and the CD-CSE mice had increased total lung capacity and increased static lung compliance. There was also a significant increase in the matrix metalloproteinase-9: tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio in VDD-CSE mice compared with all controls. Alpha-1 antitrypsin (A1AT) expression was reduced in VDD-CSE mice as well. In summary, vitamin D deficiency, when combined with cigarette smoke exposure, seemed to accelerate the appearance of emphysemas, perhaps by virtue of an increased protease-antiprotease ratio in the combined VDD-CSE animals. These results support the value of our mouse model in the study of COPD.
RESUMO
Intraosseous epidermoid inclusion cysts are rare benign bone lesions that occur most commonly in the skull and in the distal phalanges of the fingers. Herein we report a case of an intraosseous epidermoid inclusion cyst occurring in the distal phalanx of the left hallux. Only six occurrences of this lesion have been described in the foot. This patient's presentation, with active drainage (initially appearing as purulent discharge from an acutely tender ingrown hallux nail) and a known inoculation event accompanied by severe peripheral vascular disease, make this case unique.
Assuntos
Cistos Ósseos/diagnóstico , Cisto Epidérmico/diagnóstico , Doenças do Pé/diagnóstico , Hallux/cirurgia , Paroniquia/diagnóstico , Idoso , Amputação Cirúrgica/métodos , Antibacterianos/uso terapêutico , Cistos Ósseos/cirurgia , Diagnóstico Diferencial , Progressão da Doença , Cisto Epidérmico/cirurgia , Seguimentos , Doenças do Pé/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Paroniquia/tratamento farmacológico , Medição de Risco , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Lansoprazole is a potent proton pump inhibitor that has been well tolerated with minimal serious adverse events. One of the most commonly reported side effects is diarrhea in 3-8% of study patients. During 1997, approximately 850 veterans at our institution had their proton pump inhibitor converted from omeprazole to lansoprazole because of a formulary change. A number of patients subsequently developed chronic watery diarrhea. While evaluating six of these patients, we discovered microscopic colitis that resolved with discontinuation of lansoprazole. The diarrhea was described as three to 10 loose, nonbloody bowel movements per day with some abdominal cramping. Colonoscopy in five patients and flexible sigmoidoscopy in one patient revealed normal colonic mucosa, but random biopsies all supported microscopic colitis (five cases of lymphocytic colitis and one case of collagenous colitis). Complete symptom resolution occurred in all patients within 4 to 10 days of discontinuing lansoprazole. In all patients, follow-up biopsies demonstrated normalization of the colonic histology. This is the first published case series of patients with microscopic colitis that correlated clinically and histologically with the initiation and discontinuation of lansoprazole.
Assuntos
Colite/induzido quimicamente , Colite/patologia , Omeprazol/análogos & derivados , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis , Idoso , Anti-Infecciosos/efeitos adversos , Antiulcerosos/efeitos adversos , Colite/complicações , Colonoscopia , Diarreia/etiologia , Inibidores Enzimáticos/efeitos adversos , Humanos , Lansoprazol , Masculino , Pessoa de Meia-Idade , Omeprazol/administração & dosagemRESUMO
A lymphotoxin-beta (LTbeta) receptor-Ig fusion protein (LTbetaR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTbetaR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTbetaR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTbetaR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.