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1.
Science ; 376(6594): eabl5197, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35549406

RESUMO

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.


Assuntos
Linfócitos B , Aprendizado de Máquina , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos T , Transcriptoma , Células Cultivadas , Humanos , Especificidade de Órgãos
2.
Br J Surg ; 109(2): 152-154, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34435203

RESUMO

During a kidney transplant, a plastic tube (stent) is placed in the ureter, connecting the new kidney to the bladder, in order to keep the new join open during the initial phase of transplantation. The stent is then removed after a few weeks via a camera procedure (cystoscopy), as it is no longer needed. The present study compared performing this in the operating theatre or in clinic for transplanted patients using a new single-use type of camera with an integrated grasper system. The results have shown that it is safe and cost-effective to do this in clinic, despite patients being susceptible to infection after transplantation.


Assuntos
Procedimentos Cirúrgicos Ambulatórios/métodos , Cistoscopia/métodos , Remoção de Dispositivo/métodos , Transplante de Rim , Stents , Ureter , Adolescente , Adulto , Idoso , Procedimentos Cirúrgicos Ambulatórios/efeitos adversos , Procedimentos Cirúrgicos Ambulatórios/economia , Análise Custo-Benefício , Cistoscopia/efeitos adversos , Cistoscopia/economia , Remoção de Dispositivo/efeitos adversos , Remoção de Dispositivo/economia , Estudos de Viabilidade , Feminino , Custos Hospitalares , Humanos , Masculino , Pessoa de Meia-Idade , Salas Cirúrgicas/economia , Cuidados Pós-Operatórios/efeitos adversos , Cuidados Pós-Operatórios/economia , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias , Estudos Retrospectivos , Adulto Jovem
3.
Nature ; 598(7881): 510-514, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34646013

RESUMO

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.


Assuntos
Competição entre as Células , Proliferação de Células , Células Clonais/citologia , Células Clonais/metabolismo , Células Epiteliais/citologia , Neoplasias Esofágicas/patologia , Mutação , Animais , Carcinogênese/imunologia , Morte Celular , Sobrevivência Celular , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Epitélio/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Masculino , Camundongos , Fatores de Tempo
4.
World J Urol ; 39(11): 4247-4253, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33991214

RESUMO

PURPOSE: PCNL requires a lithotrite to efficiently break stones, and some devices include active suction to remove the fragments. We set out to determine the efficacy and safety of the Swiss LithoClast® Trilogy, in a prospective European multicentre evaluation and compared it to published stone clearance rates for Trilogy based on surface area (68.9 mm2/min) and using the 3D calculated stone volume (526.7 mm3/min). METHODS: Ten European centres participated in this prospective non-randomized study of Trilogy for PCNL. Objective measures of stone clearance rate, device malfunction, complications and stone-free rates were assessed. Each surgeon subjectively evaluated ergonomic and device effectiveness, on a 1-10 scale (10 = extremely ergonomic/effective) and compared to their usual lithotrite on a 1-10 scale (10 = extremely effective). RESULTS: One hundred and fifty seven PCNLs using Trilogy were included (53% male, 47% female; mean age 55 years, range 13-84 years). Mean stone clearance rate was 65.55 mm2/min or 945 mm3/min based on calculated 3D volume. Stone-free rate on fluoroscopy screening at the end of the procedure was 83%. Feedback for suction effectiveness was 9.0 with 9.1 for combination and 9.0 for overall effectiveness compared to lithotrite used previously. Ergonomic score was 8.1, the least satisfactory element. Complications included 13 (8.2%) Clavien-Dindo Grade II and 2 (1.3%) Grade III. Probe breakage was seen in 9 (5.7%), none required using a different lithotrite. CONCLUSIONS: We have demonstrated that Trilogy is highly effective at stone removal. From a user perspective, the device was perceived by surgeons to be highly effective overall and compared to the most commonly used previous lithotrite, with an excellent safety profile.


Assuntos
Cálculos Renais/cirurgia , Nefrolitotomia Percutânea/instrumentação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
5.
Br J Surg ; 108(9): 1072-1081, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-33963377

RESUMO

BACKGROUND: Ischaemia-reperfusion (IR) injury makes a major contribution to graft damage during kidney transplantation. Oxidative damage to mitochondria is an early event in IR injury. Therefore, the uptake, safety, and efficacy of the mitochondria-targeted antioxidant MitoQ were investigated in models of transplant IR injury. METHODS: MitoQ uptake by warm and cooled pairs of pig and declined human kidneys was measured when preserved in cold static storage or by hypothermic machine perfusion. Pairs of pigs' kidneys were exposed to defined periods of warm and cold ischaemia, flushed and stored at 4°C with or without MitoQ (50 nmol/l to 250 µmol/l), followed by reperfusion with oxygenated autologous blood in an ex vivo normothermic perfusion (EVNP). Pairs of declined human kidneys were flushed and stored with or without MitoQ (5-100 µmol/l) at 4°C for 6 h and underwent EVNP with ABO group-matched blood. RESULTS: Stable and concentration-dependent uptake of MitoQ was demonstrated for up to 24 h in pig and human kidneys. Total blood flow and urine output were significantly greater in pig kidneys treated with 50 µmol/l MitoQ compared with controls (P = 0.006 and P = 0.007 respectively). In proof-of-concept experiments, blood flow after 1 h of EVNP was significantly greater in human kidneys treated with 50 µmol/l MitoQ than in controls (P ≤ 0.001). Total urine output was numerically higher in the 50-µmol/l MitoQ group compared with the control, but the difference did not reach statistical significance (P = 0.054). CONCLUSION: Mitochondria-targeted antioxidant MitoQ can be administered to ischaemic kidneys simply and effectively during cold storage, and may improve outcomes after transplantation.


Assuntos
Transplante de Rim/efeitos adversos , Rim/irrigação sanguínea , Preservação de Órgãos/métodos , Compostos Organofosforados/farmacologia , Traumatismo por Reperfusão/terapia , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Humanos , Suínos , Ubiquinona/farmacologia
6.
BJS Open ; 5(2)2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33839750

RESUMO

BACKGROUND: There is an unmet need for suitable ex vivo large animal models in experimental gastroenterology and intestinal transplantation. This study details a reliable and effective technique for ex vivo normothermic perfusion (EVNP) of segmental porcine small intestine. METHODS: Segments of small intestine, 1.5-3.0 m in length, were retrieved from terminally anaesthetized pigs. After a period of cold ischaemia, EVNP was performed for 2 h at 37°C with a mean pressure of 80 mmHg using oxygenated autologous blood diluted with Ringer's solution. The duration of EVNP was extended to 4 h for a second set of experiments in which two segments of proximal to mid-ileum (1.5-3.0 m) were retrieved from each animal and reperfused with whole blood (control) or leucocyte-depleted blood to examine the impact of leucocyte depletion on reperfusion injury. RESULTS: After a mean cold ischaemia time of 5 h and 20 min, EVNP was performed in an initial group of four pigs. In the second set of experiments, five pigs were used in each group. In all experiments bowel segments were well perfused and exhibited peristalsis during EVNP. Venous glucose levels significantly increased following luminal glucose stimulation (mean(s.e.m.) basal level 1.8(0.6) mmol/l versus peak 15.5(5.8) mmol/l; P < 0.001) and glucagon-like peptide 1 (GLP-1) levels increased in all experiments, demonstrating intact absorptive and secretory intestinal functions. There were no significant differences between control and leucocyte-depleted animals regarding blood flow, venous glucose, GLP-1 levels or histopathology at the end of 4 h of EVNP. CONCLUSIONS: This novel model is suitable for the investigation of gastrointestinal physiology, pathology and ischaemia reperfusion injury, along with evaluation of potential therapeutic interventions.


Assuntos
Intestino Delgado/irrigação sanguínea , Intestino Delgado/transplante , Preservação de Órgãos/métodos , Perfusão/métodos , Animais , Intestino Delgado/patologia , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico , Masculino , Suínos
7.
Clin Radiol ; 74(11): 894.e1-894.e9, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31288924

RESUMO

AIM: To evaluate the effect of pre-biopsy magnetic resonance imaging (MRI) on cancer diagnostic times, and to report MRI-directed pathology outcomes. MATERIALS AND METHODS: In total, 1483 patients were referred with prostate cancer suspicion during a 30-month period. Upfront MRI was performed in 745 patients: 332 MRIs in the 15 months prior to dedicated scanning slots (group 1), and 413 in the 15 months post-introduction (group 2). A further 88 patients had initial MRI following clinical assessment. Biopsy via the transrectal (TR) or transperineal (TP) approach was performed, with MRI/ultrasound fusion for MRI targets. Clinically significant cancer (csPCa) was defined as Gleason ≥3+4. Negative MRIs were defined as Likert 1-2. Per-case clinical decisions were taken to biopsy or not. RESULTS: 44.4% of patients avoided biopsy. 484/833 (58.1%) MRIs were negative; 37.4% of these patients had biopsy with a negative predictive value (NPV) of 92.8% for Gleason ≥3+4 and 98.3% for ≥4+3. Overall prostate cancer prevalence was 34.3% (24.6% csPCa). In 323 MRI-positive cases, any cancer was present in 78.9% (csPCa 60.4%). Of the 1483 patients, 1232 (83.1%) completed all diagnostic tests within 28 days. Upfront MRI patients met this standard in 621/833 (74.5%), improving from 66.9% to 81.1% with reserved slots (group 2) with a reduced diagnostic time from median 25.5 to 20.9 days. Biopsy scheduling delayed the pathway in 69.7%, with MRI responsible in 22.3%, reducing to 10.3% in group 2. TP biopsies met the 28-day standard in significantly less cases (29.7%), compared to TR (67.4%, p<0.0001). CONCLUSION: Reserved MRI slots reduces time-to-diagnosis, and upfront MRI safely avoids biopsy in a significant proportion of men, whilst maintaining expected csPCa detection rates.


Assuntos
Imageamento por Ressonância Magnética Multiparamétrica/métodos , Próstata/patologia , Neoplasias da Próstata/patologia , Idoso , Procedimentos Clínicos , Detecção Precoce de Câncer , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
8.
Genome Biol ; 21(1): 1, 2019 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-31892341

RESUMO

BACKGROUND: The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design. RESULTS: This study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types. We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific. CONCLUSIONS: In conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.


Assuntos
Análise de Sequência de RNA , Análise de Célula Única , Preservação de Tecido/métodos , Temperatura Baixa , Esôfago/citologia , Humanos , Pulmão/citologia , Refrigeração , Baço/citologia
9.
Am J Transplant ; 18(1): 163-179, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28719059

RESUMO

Pancreatic allograft thrombosis (PAT) remains the leading cause of nonimmunologic graft failure. Here, we propose a new computed tomography (CT) grading system of PAT to identify risk factors for allograft loss and outline a management algorithm by retrospective review of consecutive pancreatic transplantations between 2009 and 2014. Triple-phase CT scans were graded independently by 2 radiologists as grade 0, no thrombosis; grade 1, peripheral thrombosis; grade 2, intermediate non-occlusive thrombosis; and grade 3, central occlusive thrombosis. Twenty-four (23.3%) of 103 recipients were diagnosed with PAT (including grade 1). Three (2.9%) grafts were lost due to portal vein thrombosis. On multivariate analysis, pancreas after simultaneous pancreas-kidney transplantation/solitary pancreatic transplantation, acute rejection, and CT findings of peripancreatic edema and/or inflammatory change were significant risk factors for PAT. Retrospective review of CT scans revealed more grade 1 and 2 thromboses than were initially reported. There was no significant difference in graft or patient survival, postoperative stay, or morbidity of recipients with grade 1 or 2 thrombosis who were or were not anticoagulated. Our data suggest that therapeutic anticoagulation is not necessary for grade 1 and 2 arterial and grade 1 venous thrombosis. The proposed grading system can assist clinicians in decision-making and provide standardized reporting for future studies.


Assuntos
Algoritmos , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto , Transplante de Pâncreas/efeitos adversos , Complicações Pós-Operatórias , Trombose/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Aloenxertos , Criança , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico por imagem , Rejeição de Enxerto/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Trombose/diagnóstico por imagem , Trombose/etiologia , Adulto Jovem
10.
Am J Transplant ; 16(11): 3282-3285, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27273794

RESUMO

We report the successful transplantation of a pair of human kidneys that were declined for transplantation due to inadequate in situ perfusion but subsequently transplanted after perfusion and assessment using ex vivo normothermic perfusion (EVNP). The kidneys were from a 35-year-old man, a donation after circulatory death donor. Both kidneys were declined by all UK transplant centers. On arrival, the kidneys had significant areas of incomplete clearance of blood from the microcirculation that did not clear after a further attempt to flush them. Kidneys underwent 60 min of EVNP with an oxygenated packed red blood cell-based solution warmed to 35.2°C. During EVNP, the patchy areas cleared in both kidneys. The mean renal blood flow and total urine output were 68.0 mL/min/100 g and 560 mL in the left kidney and 59.9 mL/min/100 g, 430 mL in the right, respectively. Based on the EVNP perfusion parameters, both kidneys were deemed suitable for transplantation. They were transplanted without any complications, and both recipients had initial graft function. The serum creatinine levels at 3 months were 1.2 mg/dl in the recipient of the left kidney and 1.62 mg/dl in the recipient of the right kidney. EVNP technology can be used to assess and rescue kidneys previously deemed unsuitable for transplantation.


Assuntos
Transplante de Rim , Fígado/metabolismo , Preservação de Órgãos , Perfusão/métodos , Doadores de Tecidos/provisão & distribuição , Sobrevivência de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Adulto , Idoso , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Testes de Função Renal , Fígado/irrigação sanguínea , Masculino , Avaliação de Resultados em Cuidados de Saúde
11.
Am J Transplant ; 15(11): 2931-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26108421

RESUMO

Most kidneys from potential elderly circulatory death (DCD) donors are declined. We report single center outcomes for kidneys transplanted from DCD donors over 70 years old, using preimplantation biopsy Remuzzi grading to inform implantation as single or dual transplants. Between 2009 and 2012, 43 single transplants and 12 dual transplants were performed from elderly DCD donors. Remuzzi scores were higher for dual than single implants (4.4 vs. 3.4, p < 0.001), indicating more severe baseline injury. Donor and recipient characteristics for both groups were otherwise similar. Early graft loss from renal vein thrombosis occurred in two singly implanted kidneys, and in one dual-implanted kidney; its pair continued to function satisfactorily. Death-censored graft survival at 3 years was comparable for the two groups (single 94%; dual 100%), as was 1 year eGFR. Delayed graft function occurred less frequently in the dual-implant group (25% vs. 65%, p = 0.010). Using this approach, we performed proportionally more kidney transplants from elderly DCD donors (23.4%) than the rest of the United Kingdom (7.3%, p < 0.001), with graft outcomes comparable to those achieved nationally for all deceased-donor kidney transplants. Preimplantation biopsy analysis is associated with acceptable transplant outcomes for elderly DCD kidneys and may increase transplant numbers from an underutilized donor pool.


Assuntos
Doenças Cardiovasculares/mortalidade , Função Retardada do Enxerto/epidemiologia , Transplante de Rim/métodos , Doadores de Tecidos/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/métodos , Fatores Etários , Idoso , Biópsia por Agulha , Estudos de Coortes , Função Retardada do Enxerto/patologia , Feminino , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica , Cuidados Intraoperatórios/métodos , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Masculino , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Estatísticas não Paramétricas , Taxa de Sobrevida , Transplantados/estatística & dados numéricos , Resultado do Tratamento , Reino Unido
12.
Am J Transplant ; 15(9): 2475-82, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25989187

RESUMO

A significant number of pancreases procured for transplantation are deemed unsuitable due to concerns about graft quality and the associated risk of complications. However, this decision is subjective and some declined grafts may be suitable for transplantation. Ex vivo normothermic perfusion (EVNP) prior to transplantation may allow a more objective assessment of graft quality and reduce discard rates. We report ex vivo normothermic perfusion of human pancreases procured but declined for transplantation, with ABO-compatible warm oxygenated packed red blood cells for 1-2 h. Five declined human pancreases were assessed using this technique after a median cold ischemia time of 13 h 19 min. One pancreas, with cold ischemia over 30 h, did not appear viable and was excluded. In the remaining pancreases, blood flow and pH were maintained throughout perfusion. Insulin secretion was observed in all four pancreases, but was lowest in an older donation after cardiac death pancreas. Amylase levels were highest in a gland with significant fat infiltration. This is the first study to assess the perfusion, injury, as measured by amylase, and exocrine function of human pancreases using EVNP and demonstrates the feasibility of the approach, although further refinements are required.


Assuntos
Tomada de Decisão Clínica , Função Retardada do Enxerto/prevenção & controle , Seleção do Doador , Preservação de Órgãos , Transplante de Pâncreas , Perfusão/métodos , Coleta de Tecidos e Órgãos , Adolescente , Adulto , Amilases/metabolismo , Função Retardada do Enxerto/diagnóstico , Função Retardada do Enxerto/metabolismo , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Temperatura
13.
Am J Transplant ; 15(6): 1632-43, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25707303

RESUMO

Early graft loss (EGL) after kidney transplantation is a catastrophic outcome that is assumed to be more likely after the use of kidneys from suboptimal donors. We therefore examined its incidence, risk factors and consequences in our center in relation to different donor types. Of 801 recipients who received a kidney-only transplant from deceased donors, 50 (6.2%) suffered EGL within 30 days of transplantation. Significant risks factors for EGL were donation after circulatory death (DCD) (odds ratio [OR] 2.88; p = 0.006), expanded criteria donor (ECD) transplantation (OR 4.22; p = 0.010), donor age (OR 1.03; p = 0.044) and recipient past history of thrombosis (OR 4.91; p = 0.001). Recipients with EGL had 12.28 times increased risk of death within the first year, but long-term survival was worse for patients remaining on the waiting list. In comparison with patients on the waiting list but not transplanted, and with all patients on the waiting list, the risk of death after EGL decreased to baseline 4 and 23 months after transplantation, respectively. Our findings suggest that DCD and ECD transplantation are significant risk factors for EGL, which is a major risk factor for recipient death. However, long-term mortality is even greater for those remaining on the waiting list.


Assuntos
Cadáver , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/mortalidade , Falência Renal Crônica/cirurgia , Transplante de Rim , Doadores de Tecidos , Adulto , Idoso , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Listas de Espera/mortalidade
14.
Am J Transplant ; 15(3): 754-63, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25639995

RESUMO

Histological assessment of baseline chronic kidney injury may discriminate kidneys that are suitable for transplantation, but has not been validated for appraisal of donation after circulatory death (DCD) kidneys. 'Time-zero' biopsies for 371 consecutive, solitary, deceased-donor kidneys transplanted at our center between 2006 and 2010 (65.5% DCD, 34.5% donation after brain death [DBD]) were reviewed and baseline chronic degenerative injury scored using Remuzzi's classification. High scores correlated with donor age and extended criteria donors (42% of donors), but the spectrum of scores was similar for DCD and DBD kidneys. Transplant outcomes for kidneys scoring from 0 to 4 were comparable (1 and 3 year graft survival 95% and 92%), but were much poorer for kidneys scoring ≥5, with 1 year graft survival only 73%, and 12.5% suffering primary nonfunction. Critically, high Remuzzi scores conferred the same survival disadvantage for DCD and DBD kidneys. On multi-variable regression analysis, time-zero biopsy score was the only independent predictor for graft survival, whereas one-year graft estimated glomerular filtration rate (eGFR) correlated with donor age and biopsy score. In conclusion, the relationship between severity of chronic kidney injury and transplant outcome is similar for DCD and DBD kidneys. Kidneys with Remuzzi scores of ≤4 can be implanted singly with acceptable results.


Assuntos
Transplante de Rim , Rim/lesões , Doadores de Tecidos , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
15.
Br J Cancer ; 107(8): 1384-91, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-22968648

RESUMO

BACKGROUND: We tested the accuracy of immunocytochemistry (ICC) for minichromosome maintenance protein-2 (MCM-2) in diagnosing bladder cancer, using cells retrieved from urine. METHODS: Adequate samples were obtained from 497 patients, the majority presenting with gross haematuria (GH) or undergoing cystoscopic surveillance (CS) following previous bladder cancer. We performed an initial study of 313 patients, followed by a validation study of 184 patients. In all cases, presence/absence of bladder cancer was established by cystoscopy/biopsy. RESULTS: In the initial study, receiver operator characteristic analysis showed an area under the curve of 0.820 (P<0.0005) for the GH group and 0.821 (P<0.01) for the CS group. Optimal sensitivity/specificity were provided by threshold values of 50+ MCM-2-positive cells in GH samples and 200+ cells in CS samples, based on a minimum total cell number of 5000. Applying these thresholds to the validation data set gave 81.3% sensitivity, 76.0% specificity and 92.7% negative predictive value (NPV) in GH and 63.2% sensitivity, 89.9% specificity and 89.9% NPV in CS. Minichromosome maintenance protein-2 ICC provided clinically relevant improvements over urine cytology, with greater sensitivity in GH and greater specificity in CS (P=0.05). CONCLUSIONS: Minichromosome maintenance protein-2 ICC is a reproducible and accurate test that is suitable for both GH and CS patient groups.


Assuntos
Biomarcadores Tumorais/urina , Proteínas de Ciclo Celular/urina , Proteínas Nucleares/urina , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Hematúria , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Componente 2 do Complexo de Manutenção de Minicromossomo , Curva ROC , Neoplasias da Bexiga Urinária/diagnóstico , Adulto Jovem
16.
Br J Cancer ; 106(3): 436-9, 2012 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-22240787

RESUMO

OBJECTIVE: Prostate cancer in the United Kingdom is mainly diagnosed from primary care referrals based on national guidelines published by the Department of Health. Here we investigated the characteristics of cancers detected through the use of these guidelines. METHODS: A prospective two-centre study was established to assess men referred from the primary care based on the UK national guidelines. RESULTS: The overall cancer detection rate was 43% (169 out of 397) with 15% (26 out of 169) of all cancers metastatic at presentation. Amongst 50-69-year-old men these rates were 34% (68 out of 200) and 15% (10 out of 68). Only 21% (25 out of 123) of men with local cancers had low-risk disease. In comparison to a historical cohort from 2001 (n=137) we found no overall differences in rates of metastatic disease, locally advanced tumours, or risk categories. Amongst 50-69-year-old men with local disease, however, we observed an increase in detection of low-risk cancers in a contemporary cohort (P=0.04). This was primarily because of the increased detection of low-stage organ-confined tumours in this group (P=0.02). CONCLUSION: Use of the UK prostate cancer guidelines detects a high proportion of clinically significant cancers. Use of the guidelines does not seem to have led to an overall change in the clinical characteristics of presenting cancers. There may, however, be a specific benefit in detecting more low-risk disease in younger men.


Assuntos
Benchmarking , Guias de Prática Clínica como Assunto , Neoplasias da Próstata/epidemiologia , Encaminhamento e Consulta , Medicina Estatal/normas , Idoso , Estudos de Coortes , Detecção Precoce de Câncer/estatística & dados numéricos , Inglaterra/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/patologia , Sistema de Registros , Fatores de Risco
17.
Int J Surg ; 8(6): 489-93, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20633707

RESUMO

INTRODUCTION: Patients presenting acutely with symptomatic gallstone-related disease have historically had their laparoscopic cholecystectomy (LC) deferred due to perceived increased operative risks in the acute setting, particularly conversion to open surgery. The aim of this study was to compare morbidity and mortality between unselected cohorts of patients undergoing elective and 'emergency' LC in a District General Hospital. METHODS: All gallstone-related elective and emergency admissions under the care of two specialist laparoscopic surgeons during a two-year period were included. Patients admitted acutely with a diagnosis of biliary colic, acute cholecystitis or gallstone pancreatitis underwent 'emergency' LC during the same admission. Data were collected prospectively on patient demographics, inpatient stay, post-operative course and POSSUM scores. RESULTS: 423 patients underwent LC, of which 301 (71.1%) were elective and 122 (28.9%) were 'emergency' procedures. ASA grades and POSSUM physiologic scores were similar between the two groups. The overall morbidity rates were similar in the emergency and elective groups (13.1% vs. 7.3%, p = 0.088), and there was no significant difference in the rates of major complications including conversion to open surgery (0% vs. 0.3%, NS), bile leak or re-operation between the two groups. 30-day mortality rates were similar in the two groups (0.8% vs. 0%, NS). CONCLUSION: When performed by specialist laparoscopic surgeons, LC in the acute setting is safe with mortality and morbidity rates, including conversion to open surgery, comparable to elective LC.


Assuntos
Colecistectomia Laparoscópica/métodos , Colecistite Aguda/cirurgia , Emergências , Cálculos Biliares/complicações , Hospitais Especializados , Pancreatite/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistite Aguda/epidemiologia , Colecistite Aguda/etiologia , Feminino , Seguimentos , Cálculos Biliares/cirurgia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pancreatite/epidemiologia , Pancreatite/etiologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Reino Unido/epidemiologia , Adulto Jovem
18.
Br J Cancer ; 99(4): 663-9, 2008 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-18665176

RESUMO

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a zinc-binding endopeptidase, which plays a crucial role in tumour growth, invasion and metastasis. We have shown previously that MT1-MMP has higher expression levels in the human urothelial cell carcinoma (UCC) tissue. We show here that siRNA against MT1-MMP blocks invasion in UCC cell lines. Invasion is also blocked by broad-spectrum protease and MMP inhibitors including tissue inhibitor of metalloproteinase-1 and -2. Membrane type-1-MMP can also regulate transcription. We have used expression arrays to identify genes that are differentially transcribed when siRNA is used to suppress MT1-MMP expression. Upon MT1-MMP knockdown, Dickkopf-3 (DKK3) expression was highly upregulated. The stability of DKK3 mRNA was unaffected under these conditions, suggesting transcriptional regulation of DKK3 by MT1-MMP. Dickkopf-3 has been previously shown to inhibit invasion. We confirm that the overexpression of DKK3 leads to decreased invasive potential as well as delayed wound healing. We show for the first time that the effects of MT1-MMP on cell invasion are mediated in part through changes in DKK3 gene transcription.


Assuntos
Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Metaloproteinase 14 da Matriz/metabolismo , Transcrição Gênica , Neoplasias da Bexiga Urinária/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Western Blotting , Células COS , Movimento Celular , Proliferação de Células , Células Cultivadas , Quimiocinas , Chlorocebus aethiops , Perfilação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metaloproteinase 14 da Matriz/genética , Inibidores de Metaloproteinases de Matriz , Invasividade Neoplásica , Fenótipo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
19.
Int J Clin Pract ; 60(11): 1411-3, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16911570

RESUMO

The effects of diltiazem treatment on symptoms of chronic anal fissures and their long-term outcome were investigated. One hundred and twelve patients were supplied with 6-week course of 2% diltiazem cream for twice-daily topical application. The medical notes and extended follow-up by telephone for 112 patients were recorded and statistically analysed. The success rate and satisfaction of topical diltiazem were each over two thirds. Nearly 80% of patients reported no adverse effects, and it seems that those complaints attributed to diltiazem rarely led to reduced compliance. After diltiazem therapy for fissure, 59% of patients required further treatment (medical and/or surgical) over the average 2-year period of follow-up. The reported adverse effects of topical diltiazem treatment in patients with anal fissures were more common than previously thought, although compliance was rarely affected. During consultation regarding the advantages and disadvantages of surgical vs. chemical sphincterotomy, patients should be aware that the majority of patients receiving diltiazem as the primary treatment for anal fissure subsequently require further treatment.


Assuntos
Diltiazem/administração & dosagem , Fissura Anal/tratamento farmacológico , Vasodilatadores/administração & dosagem , Adulto , Diltiazem/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversos
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