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1.
Ann Hematol ; 98(3): 625-632, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30680506

RESUMO

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.


Assuntos
Cadeias Leves de Imunoglobulina/sangue , Transtornos Linfoproliferativos/sangue , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Biomarcadores/sangue , Criança , Cistatina C/sangue , Feminino , Seguimentos , Humanos , Testes de Função Renal , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Indução de Remissão
2.
J Investig Allergol Clin Immunol ; 29(5): 357-364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30411700

RESUMO

BACKGROUND: Although anaphylaxis has been considered a priority public health issue in the world allergy community, epidemiological data on morbidity and mortality remain suboptimal. We performed the first multicenter epidemiological study in French emergency departments (EDs). The study covered 7 EDs over a period of 1 year. The objectives were to identify areas that are amenable to change and to support ongoing national and international efforts for better diagnosis, management, and prevention of anaphylaxis. METHODS: Ours was a descriptive study based on data routinely reported to French institutional administrative databases from 7 French public health institutions in the Lorraine region between January and December 2015. Data were collected based on the anaphylaxisrelated codes of the International Classification of Diseases (ICD)-10, and cases were clinically validated as anaphylaxis. RESULTS: Of the 202 079 admissions to the EDs, 4817 had anaphylaxis-related codes; of these, 323 were clinically validated as anaphylaxis. Although 45.8% were severe, adrenaline was prescribed in only 32.4% of cases. Of the 323 cases, 57.9% were subsequently referred for an allergy work-up or evaluation (after or during hospitalization), and 17.3% were prescribed autoinjectable epinephrine. CONCLUSION: Our results highlight an urgent need for improved public health initiatives with respect to recognition and treatment of anaphylaxis. We flag key problems that should be managed in the coming years through implementation of national and international actions.


Assuntos
Anafilaxia/epidemiologia , Serviços Médicos de Emergência/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anafilaxia/diagnóstico , Anafilaxia/etiologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , França/epidemiologia , Hospitalização , Humanos , Lactente , Recém-Nascido , Classificação Internacional de Doenças , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Índice de Gravidade de Doença , Avaliação de Sintomas , Adulto Jovem
3.
Zentralbl Chir ; 142(2): 161-168, 2017 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-23696203

RESUMO

The immunological monitoring in organ transplantation is based mainly on the determination of laboratory parameters as surrogate markers of organ dysfunction. Structural damage, caused by alloreactivity, can only be detected by invasive biopsy of the graft, which is why inevitably rejection episodes are diagnosed at a rather progressive stage. New non-invasive specific markers that enable transplant clinicians to identify rejection episodes at an earlier stage, on the molecular level, are needed. The accurate identification of rejection episodes and the establishment of operational tolerance permit early treatment or, respectively, a controlled cessation of immunosuppression. In addition, new prognostic biological markers are expected to allow a pre-transplant risk stratification thus having an impact on organ allocation and immunosuppressive regimen. New high-throughput screening methods allow simultaneous examination of hundreds of characteristics and the generation of specific biological signatures, which might give concrete information about acute rejection, chronic dysfunction as well as operational tolerance. Even though multiple studies and a variety of publications report about important advances on this subject, almost no new biological marker has been implemented in clinical practice as yet. Nevertheless, new technologies, in particular analysis of the genome, transcriptome, proteome and metabolome will make personalised transplantation medicine possible and will further improve the long-term results and graft survival rates. This article gives a survey of the limitations and possibilities of new immunological markers in organ transplantation.


Assuntos
Biomarcadores/sangue , Rejeição de Enxerto/imunologia , Monitorização Imunológica , Escores de Disfunção Orgânica , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Rejeição de Enxerto/diagnóstico , Humanos , Terapia de Imunossupressão/métodos , Complicações Pós-Operatórias/diagnóstico , Valor Preditivo dos Testes , Disfunção Primária do Enxerto/diagnóstico , Disfunção Primária do Enxerto/imunologia , Tolerância ao Transplante/imunologia
4.
Z Gastroenterol ; 54(7): 665-84, 2016 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-27429106

RESUMO

With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.


Assuntos
Antivirais/administração & dosagem , Antivirais/normas , Hepatite C/etiologia , Hepatite C/terapia , Transplante de Fígado/efeitos adversos , Guias de Prática Clínica como Assunto , Medicina Baseada em Evidências , Gastroenterologia/normas , Alemanha , Hepatite C/diagnóstico , Humanos , Resultado do Tratamento , Virologia/normas
5.
Z Gerontol Geriatr ; 49(6): 469-76, 2016 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-27457360

RESUMO

The incidence and prevalence of chronic renal disease (CKD) in elderly patients are continuously increasing worldwide. Loss of renal function is not only considered to be part of the aging process itself but also reflects the multimorbidity of many geriatric patients. Calculating the glomerular filtration rate using specific algorithms validated for the elderly population and measuring the amount of proteinuria allow an estimation of renal function in elderly patients with high accuracy. Chronic renal failure has many clinical consequences and not only results in a delayed excretion of toxins cleared by the kidneys but also affects hematogenesis, water and electrolyte balance as well as mineral bone metabolism. Furthermore, CKD directly leads to and aggravates geriatric syndromes and in particular the onset of frailty. Therapeutic strategies to halt progression of CKD not only comprise treatment of the underlying disease but also efficient blood pressure and diabetic control and the avoidance of nephrotoxic medications.


Assuntos
Envelhecimento , Avaliação Geriátrica/métodos , Testes de Função Renal/métodos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Medicina Baseada em Evidências , Feminino , Alemanha , Humanos , Masculino , Insuficiência Renal Crônica/fisiopatologia , Resultado do Tratamento
6.
Front Cardiovasc Med ; 11: 1355033, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38374995

RESUMO

Introduction: Fabry's disease is an X-linked lysosomal storage disorder caused by reduced activity of α-galactosidase A (GAL), leading to premature death on account of renal, cardiac, and vascular organ failure. Accumulation of the GAL substrate globotriaosylceramide (Gb3) in endothelial and smooth muscle cells is associated with early vascular cell damage, suggesting endothelial dysfunction as a driver of cardiorenal organ failure. Here, we studied the vascular expression of the key angiogenic factors, VEGFα and its antagonist angiostatin, in Fabry α-GAL-Tg/KO mice and determined circulating VEGFα and angiostatin serum levels in patients with Fabry's disease and healthy controls. Methods: Cryopreserved aortic vessels from six α-GAL-Tg/KO and six wild-type (WT) mice were obtained and VEGFα and angiostatin levels were determined by performing Western blot analysis. VEGFα expression was visualized by an immunohistochemical staining of paraffin aortic rings. In addition, VEGFα and angiostatin serum levels were measured by using an enzyme-linked immunosorbent assay in 48 patients with genetically verified Fabry's disease (50% male) and 22 healthy controls and correlated with disease severity markers such as lyso-Gb3, albuminuria, NTproBNP, high-sensitive troponin T (hsTNT), and myocardial wall thickness. Results: It was found that there was a significant increase in VEGFα protein expression (1.66 ± 0.35 vs. 0.62 ± 0.16, p = 0.0009) and a decrease in angiostatin expression (0.024 ± 0.007 vs. 0.053 ± 0.02, p = 0.038) in aortic lysates from α-GAL-Tg/KO compared with that from WT mice. Immunohistochemical staining revealed an adventitial VEGFα signal in α-GAL-Tg/KO mice, whereas no VEGFα signal could be detected in WT mice aortas. No differences in aortic angiostatin expression between α-GAL-Tg/KO- and WT mice could be visualized. The serum levels of VEGFα were significantly upregulated in patients with Fabry's disease compared with that in healthy controls (708.5 ± 426.3 vs. 458.5 ± 181.5 pg/ml, p = 0.048) and positively associated with albuminuria (r = 0.82, p < 0.0001) and elevated NTproBNP (r = 0.87, p < 0.0001) and hsTNT values (r = 0.41, p = 0.048) in male patients with Fabry's disease. For angiostatin, no significant difference was found between patients with Fabry's disease and healthy controls (747.6 ± 390.3 vs. 858.8 ± 599.3 pg/ml). Discussion: In conclusion, an overexpression of VEGFα and downregulation of its counter player angiostatin in aortic tissue of α-GAL-Tg/KO mice support the hypothesis of an underlying vasculopathy in Fabry's disease. Elevated VEGFα serum levels were also observed in patients with Fabry's disease and were positively associated with elevated markers of organ manifestation in males. These findings suggest that angiogenetic markers, such as VEGFα, may be potentially useful biomarkers for the detection of endothelial dysfunction in classical Fabry's disease.

7.
Hand Surg Rehabil ; 42(2): 121-126, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36716964

RESUMO

The aim of this study was to evaluate the outcome of ulnar superficialis slip resection and to determine predictive factors for poor prognosis in patients with advanced trigger finger. Over a 5-year-period, 55 patients (58 fingers) were included. After surgery, two groups were identified: group 1, with complete extension or <10° extension deficit in the proximal interphalangeal (PIP) joint (n = 27 fingers/27 patients); and group 2, with ≥10° residual PIP extension deficit (n = 31 fingers/28 patients). Factors associated with PIP extension deficit were assessed on logistic regression. There was a median extension gain of 20° (range, 10-30°) after surgery. The difference between pre- and post-operative extension deficits was significant (p < 0.001). There was no significant inter-group difference in DASH score (p > 0.9). Two predictive factors were found: >12 months' preoperative symptom duration (OR = 1.02; p = 0.045), and lack of self-rehabilitation (OR = 20; p < 0.001). Ulnar superficialis slip resection was effective in advanced trigger finger. Hand surgeons should operate early on these patients, and encourage self-rehabilitation. LEVEL OF EVIDENCE: 4.


Assuntos
Dedo em Gatilho , Humanos , Dedo em Gatilho/cirurgia , Articulações dos Dedos/cirurgia , Dedos , Ulna/cirurgia , Prognóstico
8.
Physiol Meas ; 44(4)2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-36975197

RESUMO

Objective.Current wearable respiratory monitoring devices provide a basic assessment of the breathing pattern of the examined subjects. More complex monitoring is needed for healthcare applications in patients with lung diseases. A multi-sensor vest allowing continuous lung imaging by electrical impedance tomography (EIT) and auscultation at six chest locations was developed for such advanced application. The aims of our study were to determine the vest's capacity to record the intended bio-signals, its safety and the comfort of wearing in a first clinical investigation in healthy adult subjects.Approach.Twenty subjects (age range: 23-65 years) were studied while wearing the vests during a 14-step study protocol comprising phases of quiet and deep breathing, slow and forced full expiration manoeuvres, coughing, breath-holding in seated and three horizontal postures. EIT, chest sound and accelerometer signals were streamed to a tablet using a dedicated application and uploaded to a back-end server. The subjects filled in a questionnaire on the vest properties using a Likert scale.Main results.All subjects completed the full protocol. Good to excellent EIT waveforms and functional EIT images were obtained in 89% of the subjects. Breathing pattern and posture dependent changes in ventilation distribution were properly detected by EIT. Chest sounds were recorded in all subjects. Detection of audible heart sounds was feasible in 44%-67% of the subjects, depending on the sensor location. Accelerometry correctly identified the posture in all subjects. The vests were safe and their properties positively rated, thermal and tactile properties achieved the highest scores.Significance.The functionality and safety of the studied wearable multi-sensor vest and the high level of its acceptance by the study participants were confirmed. Availability of personalized vests might further advance its performance by improving the sensor-skin contact.


Assuntos
Gravação de Som , Dispositivos Eletrônicos Vestíveis , Adulto , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Voluntários Saudáveis , Pulmão/diagnóstico por imagem , Monitorização Fisiológica , Impedância Elétrica , Tomografia/métodos
9.
Front Surg ; 9: 986297, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36589626

RESUMO

Introduction: Obesity is frequently associated with its hepatic manifestation, the nonalcoholic fatty liver disease (NAFLD). The most effective treatment for morbid obesity is bariatric surgery (BS) also improving NAFLD and liver function. In patients where NAFLD has already progressed to liver cirrhosis, BS can be considered a high-risk procedure. Hence, consideration of the procedure and the most appropriate timing is crucial. Material and Methods: Obese patients suffering from NAFLD who underwent BS from two German University Medical Centers were retrospectively analyzed. Results: Twenty-seven patients underwent BS. Most common procedures were laparoscopic Roux-en-Y-gastric (RYGB) and laparoscopic sleeve gastrectomy (SG). All patients suffered from liver cirrhosis Child A. A preoperative transjugular portosystemic shunt (TIPS) was established in three patients and failed in another patient. Postoperative complications consisted of wound healing disorders (n = 2), anastomotic bleeding (n = 1), and leak from the staple line (n = 1). This patient suffered from intraoperatively detected macroscopic liver cirrhosis. Excess weight loss was 73% and 85% after 1 and 2 years, respectively. Two patients suffered from postoperative aggravation of their liver function, resulting in a higher Child-Pugh score, while three could be removed from the waiting list for a liver transplantation. Conclusion: BS leads to weight loss, both after SG and RYGB, and potential improvement of liver function in liver cirrhosis. These patients need to be considered with care when evaluated for BS. Preoperative TIPS implantation may reduce the perioperative risk in selected patients.

10.
Pathologe ; 31 Suppl 2: 193-8, 2010 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-20812013

RESUMO

Stimulation of the TNF receptors CD30 and CD95 exerts opposite effects. Crosstalk of both receptors is unknown. We aimed to reveal regulatory mechanisms of CD30-induced effects on CD95 signaling of cALCL cell lines. "CD30/CD95 crosstalk analysis" was performed in cALCL cell lines by comparison of CD30 or CD95 stimulation and CD30/CD95 costimulation. Receptor expression and induction of apoptosis was investigated by flow cytometry. mRNA expression of CD30-inducible genes (cFLIP, TRAF1, cIAP2, and A20) was compared by semiquantitative reverse transcription (RT-RQ-) PCR in stimulated and unstimulated cells. Protein expression of IκBα, p100/p52, caspase-8, caspase-3, and cFLIP was analyzed by immunoblotting. A lentiviral-based shRNA-mediated approach was used to inhibit cFLIP expression. CD30/CD95 crosstalk experiments revealed that CD30 ligation leads to NFκB-mediated cFLIP upregulation in cALCL cells, which in turn enhanced resistance to CD95-mediated apoptosis. This effect is based on the CD30-induced upregulation of cFLIP. Knockdown of cFLIP restores sensitivity to CD95-mediated apoptosis. We conclude that the anti-apoptotic function of CD30 antibodies should be kept in mind if CD30 antibody-based therapeutic concepts for ALCL lymphoma are considered.


Assuntos
Apoptose/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Antígeno Ki-1/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/patologia , Receptor Cross-Talk , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Receptor fas/genética , Linhagem Celular Tumoral , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/patologia , Regulação para Cima/genética
11.
Klin Monbl Augenheilkd ; 227(11): 852-6, 2010 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-21077016

RESUMO

AIM OF THE STUDY: Colour comparison tests are a subjective supplement to the swinging flashlight test. We have investigated the specificity and sensitivity, compared 3 exactly defined different colours (red, green, blue), and looked for age relationships. METHOD: 101 patient with various unilateral optic neuropathies were compared to 103 age-correlated healthy controls in randomised order by letting the patient evaluate red, green and blue colour charts of 5.5 cm diameter. RESULTS: The area under the receiver operator characteristics curve was 0.804 for red, 0.821 for green and 0.789 for blue, and for any of the 3 colours 0.835 (at least one colour was seen differently). Best results were obtained when even small differences in colour perception were considered as pathological. 29 healthy controls perceived colours differently in both eyes, 24 of those being older than 50 years. The specificity decreased with age, was significant for green and red, not for blue. DISCUSSION: There were no significant differences between the 3 colours in all age groups. Evaluation of more than one colour does not increase the sensitivity significantly. Even small differences have to be considered as pathological to obtain the highest possible sensitivity. Test specifity decreases with age.


Assuntos
Testes de Percepção de Cores/estatística & dados numéricos , Defeitos da Visão Cromática/diagnóstico , Doenças do Nervo Óptico/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Criança , Limiar Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distúrbios Pupilares/diagnóstico , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
12.
Chirurg ; 91(11): 905-912, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-32710158

RESUMO

In Germany, the scarcity of donor organs has persisted over decades and reached an historical low point in the year 2017. A thorough analysis of the causes revealed structural deficits in the identification and registration of possible donors as one of the central reasons for the low donation rate. This prompted the political authorities to act and resulted in two new laws, which led to a modification of the German Transplantation Act. On 1 April 2019, the Act on Improvement of the Cooperation and the Structural Framework for Organ Donation came into force. This Act strengthens the role of the transplant coordinators in the harvesting hospitals and establishes adequate reimbursement of the organ donation-related costs in the harvesting hospitals. Furthermore, it fosters the cooperation of the transplant coordinators with the German organ procurement organization. On 16 January 2020, the existing opt-in legislation was modified. While the general principle of the opt-in legislation stayed unchanged, different measures were introduced that aim to repeatedly inform all citizens about organ donation and thereby motivate them to make a decision on organ donation. In order to enable a reliable and transparent documentation an organ donor registry will be established. The practical implementation of the various measures of both Acts is supported by a multi-institutional collaborative initiative plan for organ donation. The legal regulations and their practical implementation are depicted in detail.


Assuntos
Transplante de Órgãos , Obtenção de Tecidos e Órgãos , Alemanha , Humanos , Sistema de Registros , Doadores de Tecidos
13.
Biorheology ; 46(1): 57-61, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19252228

RESUMO

The pathology of the disease cystic fibrosis is known to be associated very generally with ionic imbalance in the mucosal secretion which lines the respiratory tract, so-called airway surface liquid (ASL). The imbalance is caused by mutation of a transmembrane protein (CFTR) implicated in the control of ion traffic across the airway epithelium. It is feasible that CFTR malfunction undermines a putative phase-separated texture of healthy ASL which is apparent in electron microscopy images. A molecular statistical description of ASL is presented here with the aim of illustrating this hypothesis at the phenomenological level. The model predicts that a volume criterion and a salt criterion must be met in order to achieve the phase-separated texture. These predictions help to rationalise the findings of clinical trials. In conjunction with further experimental investigation, molecular statistical approaches in this spirit have the potential to play a useful role in the drive towards treatment strategies.


Assuntos
Muco/fisiologia , Transição de Fase , Mucosa Respiratória/fisiologia , Homeostase , Humanos , Íons , Modelos Biológicos , Modelos Químicos , Osmose , Cloreto de Sódio/metabolismo
14.
Cryo Letters ; 29(3): 261-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18754066

RESUMO

Standard protocol of freezing of human ovarian tissue presupposes the very slow cooling (-0.3 C/min) from auto-seeding to -40 C, then slow cooling (-10 C/min) to -140 C and then direct plunging into liquid nitrogen. The aim of this investigation was to compare the -10 C/min cooling rate of human ovarian tissue from -40 C to -140 C with the -220 C/min cooling rate (direct plunging into liquid nitrogen) from -36 degree C. After post-thawing in vitro culture of tissue, hormonal activity as well as follicle viability was evaluated. After culture of fresh tissue pieces (Group 1), pieces after freezing and thawing with slow cooling (-10 C/min) from -40 C (Group 2) and pieces after freezing and thawing with direct plunging into liquid nitrogen (-220 C/min) from -36 C (Group 3), the supernatants showed estradiol 17-ss concentrations of 481, 441 and 459 pg per ml, respectively, and progesterone concentrations of 9.05, 5.06, 4.87 ng per ml, respectively. It is concluded that 94, 96, and 98 percent follicles for Groups 1, 2 and 3, respectively, were normal. Technique of human ovarian tissue cryopreservation with very slow cooling to -36 C and then direct plunging into liquid nitrogen with -220 C/min cooling rate is tolerated without apparent detriment.


Assuntos
Criopreservação/métodos , Oócitos/citologia , Folículo Ovariano/citologia , Estradiol/metabolismo , Feminino , Congelamento , Humanos , Nitrogênio , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Progesterona/metabolismo , Bancos de Tecidos
15.
Placenta ; 69: 9-19, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30213491

RESUMO

INTRODUCTION: We have previously shown that even a single course of antenatal betamethasone (BET) as an inductor for lung maturity reduces birth weight and head circumference. Moreover, animal studies link BET administration to alterations of the hypothalamic-pituitary-adrenal-gland-axis (HPA). The unhindered development of the fetal HPA axis is dependent on the function and activity of 11ß-hydroxysteroiddehydrogenase type 2 (11ß-HSD2), a transplacental cortisol barrier. Therefore, we investigated the effects of BET on this transplacental barrier and fetal growth. METHODS: Pregnant women treated with a single course of BET between 23 + 5 to 34 + 0 weeks of gestation were compared to gestational-age-matched controls. Placental size and neonatal anthropometrics were taken. Cortisol and ACTH levels were measured in maternal and umbilical cord blood samples. Placental 11ß-hydroxysteroiddehydrogenase type 1 (11ß-HSD1) protein levels and 11ß-HSD2 protein and activity levels were determined. Parameters were analyzed independent of sex, and in subgroups divided by gender and gestational age. RESULTS: In term born females, BET administration was associated with reduced head circumference and decreased 11ß-HSD2 protein levels and enzyme activity. Males treated with BET, especially those born prematurely, showed increased 11ß-HSD2 protein levels. CONCLUSION: A single course of BET alters placental glucocorticoid metabolism in a sex-specific manner. Decreased 11ß-HSD2 levels in term born females may lead to an increased placental transfer of maternal cortisol and therefore result in a reduced head circumference and a higher risk for altered stress response in adulthood. Further research is needed to conclude the significance of increased 11ß-HSD2 levels in males.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Betametasona/farmacologia , Desenvolvimento Fetal/efeitos dos fármacos , Glucocorticoides/farmacologia , Placenta/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Antropometria , Betametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Cabeça/anatomia & histologia , Humanos , Hidrocortisona/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Fatores Sexuais
16.
Leukemia ; 32(3): 663-674, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28690315

RESUMO

Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation. Reconstitution of nucleolin expression in nucleolin-knockdown DLBCL cells prevented TopIIA targeting agent-induced apoptosis. Nucleolin binding to TopIIA was mapped to RNA-binding domain 3 of nucleolin, and this interaction was essential for blocking DNA damage and apoptosis. Nucleolin silencing decreased TopIIA decatenation activity, but enhanced formation of TopIIA-DNA cleavable complexes in the presence of etoposide. Moreover, combining nucleolin inhibitors: aptamer AS1411 or nucant N6L with doxorubicin reduced DLBCL cell survival. These findings are of clinical importance because low nucleolin levels versus high nucleolin levels in DLBCL predicted 90-month estimated survival of 70% versus 12% (P<0.0001) of patients treated with R-CHOP-based therapy.


Assuntos
Antineoplásicos/farmacologia , Linfoma Difuso de Grandes Células B/metabolismo , Fosfoproteínas/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , DNA Topoisomerases Tipo II/metabolismo , Feminino , Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Terapia de Alvo Molecular , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Nucleolina
17.
Clin Pharmacol Ther ; 81(2): 228-34, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17192769

RESUMO

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Transplante de Rim , Sirolimo/farmacocinética , Tacrolimo/farmacocinética , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/uso terapêutico , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Quimioterapia Combinada , Feminino , Variação Genética , Genótipo , Meia-Vida , Humanos , Imunossupressores/metabolismo , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/metabolismo , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Prednisolona/metabolismo , Prednisolona/farmacocinética , Prednisolona/uso terapêutico , Sirolimo/metabolismo , Sirolimo/uso terapêutico , Tacrolimo/metabolismo , Tacrolimo/uso terapêutico
18.
J Phys Chem B ; 111(40): 11626-8, 2007 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-17880201

RESUMO

Short-range attraction between colloidal particles such as proteins can drive a glass-like structural arrest. For monodisperse systems, mode-coupling theory affords a simple asymptotic prediction of the transition. Here, using a depletion mapping framework, we extend this result to incorporate size polydispersity. For comparison, we also give an energy landscape formulation of the transition. We comment on the relevance to subcellular crowding, recombinant protein expression, and osmotic stress in microbial organisms.


Assuntos
Coloides/química , Vidro/química , Modelos Químicos , Tamanho da Partícula
19.
J Hand Surg Eur Vol ; 42(2): 188-193, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27765865

RESUMO

The primary aim of this study was to assess the clinical and radiological results after hemi-hamate resurfacing arthroplasty in patients with acute or chronic unstable fractures of the base of the middle phalanx and to describe technical features that can facilitate the surgical procedure. Hemi-hamate arthroplasties were done in 19 patients (mean age 39 years) with an isolated fracture at the base of the middle phalanx that involved more than 40% of the articular surface. We assessed ten chronic cases (treated >6 weeks after fracture) and nine acute ones (<6 weeks) at a mean of 24 months. Pain scores, QuickDASH scores, grip strengths, range of motion and radiological findings were recorded at follow-up. At follow-up, the mean active flexion at the proximal interphalangeal joint was to 83° with a mean fixed flexion of 17° (active range of motion 66°). The mean active distal interphalangeal motion was 41°. The mean visual analogue scale score was 1.1. The mean QuickDASH score was 11. The mean pinch strength was 82% of the opposite side. Radiographs revealed one partial graft lysis. LEVEL OF EVIDENCE: IV.


Assuntos
Artroplastia/métodos , Articulações dos Dedos , Hamato/transplante , Fraturas Intra-Articulares/cirurgia , Luxações Articulares/cirurgia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
20.
Arch Pediatr ; 24 Suppl 1: S16-S27, 2017 Feb.
Artigo em Francês | MEDLINE | ID: mdl-27793516

RESUMO

The French Society of Research and Sleep Medicine (SFRMS) organized a meeting on obstructive sleep apnea syndrome (OSAS) in children. A multidisciplinary group of specialists (pulmonologists, ENT surgeons, pediatricians, neurophysiologists, sleep specialists) drew up a consensus document on the value of electrophysiological recordings in the diagnosis of OSAS in children. Technical considerations and recommended sensors, respiratory event definitions, and scoring criteria are presented according to the 2012 and 2014 recommendations of the American Academy of Sleep Medicine (AASM). Polysomnographic criteria for sleep-disordered breathing in children and the French National Authority for Health guidelines for indications of polysomnographic studies were reported. Relevance and limits of in-lab PSG, home PSG, and respiratory polygraphy were presented and guidelines were proposed to improve the diagnosis and follow-up of these children.


Assuntos
Apneia Obstrutiva do Sono/diagnóstico , Criança , Humanos , Polissonografia , Testes de Função Respiratória
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