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AIMS: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas-Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. METHODS: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. RESULTS: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. CONCLUSIONS: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.
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Navegação de Pacientes , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Masculino , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Texas/epidemiologia , México/epidemiologia , Detecção Precoce de CâncerRESUMO
Introduction Despite its toxic and carcinogenic nature, formaldehyde is a widely used reactant for specimen preservation. With the need of specimens for both anatomical and surgical training, alternative preservation solutions (PS) have been proposed, however, their use is limited due to high costs and complexity. Hence, a new formaldehyde-free solution (FFS) is evaluated as a potential alternative for anatomical and surgical training. Methods Qualitative and Quantitative data were acquired. Specimens preserved using three different methods were selected. Flexibility was measured by joints goniometry and pneumoperitoneum pressures were evaluated followed by an exploratory laparoscopy. Undergraduate student's perceptions on cadavers preserved with different PS were obtained using surveys and focus groups. Results The main reason why cadaveric specimens were considered as useful tools was the perceived interaction with real tissues and the practical concept of getting in touch with what students would be facing in the future as physicians, what we call hands on activities. FFS treated specimens showed better joint-movement ranges in comparison to other methods and pneumoperitoneum was acquired after 5mmHg CO2 pressure. Students appreciated working with corpses regardless the technique used, however FFS specimens were defined as less uncomfortable, while presenting no sensory discomfort. Conclusions Even though alternative PS are effective, high costs and complexity restrict their usage. Cadavers preserved with FFS had similar range of movements compared with Thiel. Students preferred to work with FFS rather than FF due to flexibility, color, and no sensorial hassles. Thus, we propose FFS as viable alternative to traditional PS (AU)
Introducción A pesar de su naturaleza carcinogénica y tóxica, el formaldehido continúa siendo utilizado para preservar especímenes. Debido a la necesidad de especímenes para entrenamiento anatómico y quirúrgico, se han propuesto soluciones preservadoras (SP) alternativas; sin embargo, su uso es limitado debido a los altos costos y a su complejidad. En consecuencia, se evalúa una nueva solución libre de formol (FFS) como una alternativa para el uso en entrenamiento anatómico y quirúrgico. Métodos Se obtuvieron datos cualitativos y cuantitativos. Se seleccionaron especímenes preservados utilizando diferentes métodos y se analizaron biopsias de cada uno. Se midió la flexibilidad mediante goniometría, y se evaluó la presión del neumoperitoneo. Utilizando encuestas y grupos focales se obtuvo la percepción de estudiantes de pregrado respecto a cadáveres preservados con diferentes soluciones. Resultados Los principales motivos por los que los estudiantes refirieron percibir los cadáveres como herramientas útiles fueron poder interactuar con tejidos reales y el concepto de «practicidad» generado por actividades percibidas como similares a la práctica como médicos profesionales. Los especímenes tratados con FFS demostraron mejor movimiento articular en comparación con otras soluciones, además de lograr neumoperitoneo con 5mmHg de CO2. Los estudiantes refirieron sentir menos molestias sensoriales al utilizar cadáveres preservados con FFS. Conclusiones Aunque otras SP son efectivas, los altos costos y la complejidad restringen su uso. Cadáveres preservados con FFS presentan arcos de movimiento similares a Thiel. Los estudiantes prefirieron trabajar con FFS en vez de FF, debido a la flexibilidad, el color y la ausencia de molestias sensoriales. Proponemos FFS como una alternativa viable a las SP tradicionales (AU)
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Humanos , Cadáver , Educação Médica/métodos , Formaldeído , Preservação Biológica/métodos , Anatomia/educaçãoRESUMO
BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.
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Fibrose Cística/terapia , Aplicativos Móveis , Monitorização Fisiológica/métodos , Monitorização Fisiológica/psicologia , Qualidade de Vida , Adolescente , Ansiedade , COVID-19/epidemiologia , Criança , Pré-Escolar , Depressão , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Pelvic exenteration remains a viable and effective treatment option for the management of locally advanced or recurrent pelvic malignancy. The aim of this study was to present an early experience of robotic multivisceral resection of pelvic malignancy, and to compare this experience with similar series through a systematic review of the literature. METHODS: A retrospective study was performed on patients who had robotic-assisted multi-visceral resection for pelvic malignancy at a single Colorectal Surgical unit based between two tertiary academic hospitals. Primary outcomes observed included operation type, operation time, perioperative complications, and hospital length of stay. Secondary outcomes included R0 resection status, lymph node harvest, and rate of recurrence at clinical follow-up. RESULTS: Eight cases of robotic multivisceral resection were performed for primary locally advanced pelvic malignancy involving a rectal resection as part of their operative management. The median age of patients undergoing resection was 56 years (range 29-83 years). The male:female ratio was 6:2. The mean total operating time was 8.3 h (range 6-10 h). Perioperative blood transfusion requirements were minimal. Mean hospital length of stay was 15 days (range 7-26 days). No patients experienced any serious postoperative morbidity or mortality. All patients had clear margins on histological assessment and no patients have recurrence at 12-month follow-up. CONCLUSIONS: Robotic multivisceral resection for malignant disease of the pelvis is a safe and feasible minimally invasive approach in highly selected cases.
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Exenteração Pélvica , Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Robótica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: The decision to perform an abdominoperineal excision (APR) rather than restorative bowel resection relies on a number of clinical factors. There remains great variability in APR rates internationally. The aim of this study was to demonstrate trends of APR surgery in low rectal cancer (< 6 cm from the anal verge) in Australasia and identify predictors of nonrestoration. METHOD: This study reviewed a prospectively maintained colorectal registry - the Binational Colorectal Cancer Audit (BCCA) - from general/colorectal surgical units across Australia and New Zealand. Data were analysed to determine factors predictive of nonrestorative resection. Patients were analysed based on the presence (control) or absence (comparison) of a primary anastomosis. RESULTS: Of 3628 patients with rectal cancer, 2096 were diagnosed with low rectal cancer between 2007 and 2017. The incidence of APR remained constant over the study period, with 58% of all resections of low rectal cancer being APR. The majority of resections were performed by consultants in urban hospitals (86% vs 14%). Tumours ≤ 3 cm from the anal verge, T4, M1 disease and neoadjuvant therapy were the greatest predictors of APR (P < 0.001). A significantly increased rate of restorative surgery was observed in public hospital settings (59% vs 41%, P < 0.05). The rate of positive circumferential resection margin (CRM) was 7.95%, with significantly increased rates in patients undergoing APR (12.2% vs 6.2%, P < 0.001). CRM positivity was increased in open approaches, T4, N2 and M1 staged disease and in an emergency/urgent setting (P < 0.001 and P < 0.045, respectively). Significantly increased wound and pulmonary complications were observed in the APR cohort (P < 0.01). CONCLUSION: The rates of APR in Australia and New Zealand remain high but are comparable to international figures, with one-third of rectal cancers being treated by APR. The main determinants of APR are tumour height, T stage and neoadjuvant therapy requirement. CRM positivity was higher in APR patients.
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Protectomia , Neoplasias Retais , Humanos , Recidiva Local de Neoplasia , Períneo/cirurgia , Protectomia/efeitos adversos , Neoplasias Retais/epidemiologia , Neoplasias Retais/cirurgia , Reto/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: Robotic transanal minimally invasive surgery (R-TAMIS) is gaining traction around the globe as an alternative to laparoscopic conventional TAMIS for local excision of benign and early malignant rectal lesions. The aim was to analyse patient and oncological outcomes of R-TAMIS for consecutive cases in a single centre. METHODS: A prospective analysis of consecutive R-TAMIS procedures over a 12-month period was performed. Data were collated from hospital databases and theatre registers. RESULTS: Eleven patients (six men, five women), mean age 69.81 years (51-92 years), underwent R-TAMIS over 12 months utilizing a da Vinci Xi platform. The mean lesion size was 36 mm (20-60 mm) with a mean distance from the anal verge of 7.5 cm (3-14 cm). Five lesions were posterior in anatomical location, four anterior, one right lateral and one left lateral. All procedures were performed in the lithotomy position using a GelPOINT Path Platform. Mean operative time was 64 min (40-100 min). Complete resection was achieved in 10/11 patients with two patients being upgraded to a diagnosis of adenocarcinoma. Nine patients were diagnosed with dysplastic lesions. Four patients had a false positive diagnosis of an invasive tumour on MRI. Six patients required suturing for full-thickness resections. One patient had a postoperative bleed requiring repeat endoscopy and clipping. One patient (full-thickness resection of T3 tumour) proceeded to a formal resection without difficulty with no residual disease (T0N0, 0/22). One patient with a fully resected T2 tumour is undergoing a surveillance protocol. The mean length of stay was 1 day with two patients having a length of stay of 2 days and one patient of 4 days. CONCLUSION: R-TAMIS could potentially represent a safe novel approach for local resection of rectal lesions.
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Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Cirurgia Endoscópica Transanal , Idoso , Canal Anal/cirurgia , Feminino , Humanos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos , Neoplasias Retais/cirurgia , Reto , Resultado do TratamentoRESUMO
AIM: Currently, there is no clear consensus on the role of extended pelvic resections for locally advanced or recurrent disease involving major vascular structures. The aims of this study were to report the outcomes of consecutive patients undergoing extended resections for pelvic malignancy involving the aortoiliac axis. METHODS: Prospective data were collected on patients having extended radical resections for locally advanced or recurrent pelvic malignancies, with aortoiliac axis involvement, requiring en bloc vascular resection and reconstruction, at a single institution between 2014 and 2018. RESULTS: Eleven patients were included (median age 60 years; range 31-69 years; seven women). The majority required resection of both arterial and venous systems (n = 8), and the technique for vascular reconstruction was either interposition grafts or femoral-femoral crossover grafts. The median operative time was 510 min (range 330-960 min). Clear resection margins (R0) were achieved in nine patients. The median length of stay was 25 days (range 7-83 days). Seven patients did not suffer an early complication. There was one serious complication (Clavien-Dindo ≥ 3), an arterial graft occlusion secondary to thrombus in the immediate postoperative period, requiring a return to theatre and thrombectomy. The median length of follow-up in this study was 22 months (range 4-58 months). CONCLUSION: This series demonstrates that en bloc major vascular resection and reconstruction can be performed safely and can achieve clear resection margins in selected patients with locally advanced or recurrent pelvic malignancy at specialist surgery centres.
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Exenteração Pélvica , Neoplasias Pélvicas , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Exenteração Pélvica/efeitos adversos , Neoplasias Pélvicas/cirurgia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Metabolic changes accompanying a step-wise malignant transformation was investigated using a syngeneic lineage of human fibroblasts. Cell immortalization was associated with minor alterations in metabolism. Consecutive loss of cell cycle inhibition in immortalized cells resulted in increased levels of oxidative phosphorylation (OXPHOS). Overexpression of the H-Ras oncoprotein produced cells forming sarcomas in athymic mice. These transformed cells exhibited increased glucose consumption, glycolysis and a further increase in OXPHOS. Because of the markedly increased OXPHOS in transformed cells, the impact of a transaminase inhibitor, aminooxyacetic acid (AOA), which decreases glutamine influx to the tricarboxylic acid (TCA) cycle, was tested. Indeed, AOA significantly decreased proliferation of malignantly transformed fibroblasts and fibrosarcoma-derived cells in vitro and in vivo. AOA also decreased proliferation of cells susceptible to malignant transformation. Metabolomic studies in normal and transformed cells indicated that, in addition to the anticipated effect on the TCA cycle, AOA decreased production of nucleotides adenosine triphosphate (ATP) and uridine monophosphate. Exogenous nucleotides partially rescued decreased proliferation of the malignant cells treated with AOA. Our data indicate that AOA blocks several metabolic pathways essential for growth of malignant cells. Therefore, OXPHOS may provide important therapeutic targets for treatment of sarcoma.
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Transformação Celular Neoplásica/patologia , Fibroblastos/patologia , Fibrossarcoma/patologia , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Metaboloma/efeitos dos fármacos , Pele/patologia , Ácido Amino-Oxiacético/farmacologia , Animais , Apoptose , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Glicólise , Humanos , Camundongos , Camundongos Nus , Fosforilação Oxidativa , Pele/efeitos dos fármacos , Pele/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Autophagy is a lysosome degradation pathway through which damaged organelles and macromolecules are degraded within the cell. A decrease in activity of the autophagic process has been linked to several age-associated pathologies, including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction. Here, we examined the differences in the autophagic response using autophagy-inducer rapamycin (Rapa) in peripheral blood mononuclear cells (PBMCs) from young (21.8 ± 1.9 years) and old (64.0 ± 3.7 years) individuals. Furthermore, we tested the interplay between the heat shock response and autophagy systems. Our results showed a significant increase in LC3-II protein expression in response to Rapa treatment in young but not in old individuals. This was associated with a decreased response in MAP1LC3B mRNA levels, but not SQSTM1/p62. Furthermore, HSPA1A mRNA was upregulated only in young individuals, despite no differences in HSP70 protein expression. The combined findings suggest a suppressed autophagic response following Rapa treatment in older individuals.
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Envelhecimento/fisiologia , Autofagia/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Leucócitos Mononucleares/fisiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: No standardized measures specifically assess cancer survivors' and healthcare providers' experience of Survivor Care Plans (scps). We sought to develop two care plan evaluation (cpe) measures, one for survivors (cpe-s) and one for healthcare providers (cpe-p), examine initial psychometric qualities in Alberta, and assess generalizability in Manitoba, Canada. METHODS: We developed the initial measures using convenience samples of breast (n = 35) and head and neck (n = 18) survivors who received scps at the end of active cancer-centre treatment. After assessing Alberta's scp concordance with Institute of Medicine (iom) recommendations using a published coding scheme, we examined psychometric qualities for the cpe-s and cpe-p. We examined generalizability in Manitoba, Canada, with colorectal survivors discharged to primary care providers for follow-up (n = 75). RESULTS: We demonstrated acceptable internal consistency for the cpe-s and cpe-p subscales and total score after eliminating one item per subscale for cpe-s, two for cpe-p, resulting in revised scales with four 7-item and 6-item subscales, respectively. Subscale scores correlated highly indicating that for each measure the total score may be the most reliable and valid. We provide initial cpe-s discriminant, convergent, and predictive validity using the total score. Using the Manitoba sample, initial psychometrics similarly indicated good generalizability across differences in tumour groups, scp, and location. CONCLUSIONS: We recommend the revised cpe-s and cpe-p for further use and development. Studies documenting the creation and standardization of scp evaluations are few, and we recommend further development of patient experience measures to improve both clinical practice and the specificity of research questions.
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Established methods of recruiting population controls for case-control studies to investigate gastrointestinal disease outbreaks can be time consuming, resulting in delays in identifying the source or vehicle of infection. After an initial evaluation of using online market research panel members as controls in a case-control study to investigate a Salmonella outbreak in 2013, this method was applied in four further studies in the UK between 2014 and 2016. We used data from all five studies and interviews with members of each outbreak control team and market research panel provider to review operational issues, evaluate risk of bias in this approach and consider methods to reduce confounding and bias. The investigators of each outbreak reported likely time and cost savings from using market research controls. There were systematic differences between case and control groups in some studies but no evidence that conclusions on the likely source or vehicle of infection were incorrect. Potential selection biases introduced by using this sampling frame and the low response rate are unclear. Methods that might reduce confounding and some bias should be balanced with concerns for overmatching. Further evaluation of this approach using comparisons with traditional methods and population-based exposure survey data is recommended.
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Estudos de Casos e Controles , Surtos de Doenças , Gastroenteropatias/epidemiologia , Marketing , Feminino , Humanos , Internet , Entrevistas como Assunto , Masculino , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Standardized training and clinical protocols using biofeedback for the treatment of fecal incontinence (FI) are important for clinical care. Our primary aims were to develop, implement, and evaluate adherence to a standardized protocol for manometric biofeedback to treat FI. METHODS: In a Pelvic Floor Disorders Network (PFDN) trial, participants were enrolled from eight PFDN clinical centers across the United States. A team of clinical and equipment experts developed biofeedback software on a novel tablet computer platform for conducting standardized anorectal manometry with separate manometric biofeedback protocols for improving anorectal muscle strength, sensation, and urge resistance. The training protocol also included education on bowel function, anal sphincter exercises, and bowel diary monitoring. Study interventionists completed online training prior to attending a centralized, standardized certification course. For the certification, expert trainers assessed the ability of the interventionists to perform the protocol components for a paid volunteer who acted as a standardized patient. Postcertification, the trainers audited interventionists during trial implementation to improve protocol adherence. KEY RESULTS: Twenty-four interventionists attended the in-person training and certification, including 46% advanced practice registered nurses (11/24), 50% (12/24) physical therapists, and 4% physician assistants (1/24). Trainers performed audio audits for 88% (21/24), representing 84 audited visits. All certified interventionists met or exceeded the prespecified 80% pass rate for the audit process, with an average passing rate of 93%. CONCLUSIONS & INFERENCES: A biofeedback protocol can be successfully imparted to experienced pelvic floor health care providers from various disciplines. Our process promoted high adherence to a standard protocol and is applicable to many clinical settings.
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Biorretroalimentação Psicológica/métodos , Terapia Cognitivo-Comportamental/métodos , Incontinência Fecal/psicologia , Incontinência Fecal/terapia , Manometria/métodos , Terapia Cognitivo-Comportamental/normas , Feminino , Humanos , Manometria/normas , Resultado do TratamentoRESUMO
REASONS FOR PERFORMING STUDY: Double plate fixation has been reported in a small number of horses with comminuted fractures of the middle phalanx. There are no published reports using this technique in the management of other injuries that destabilise the proximal interphalangeal joint (PIJ), including biaxial palmar/plantar eminence fractures and disruption of the palmar/plantar soft tissue support structures of the PIJ. Furthermore, there is a paucity of information on the long-term prognosis for horses undergoing double plate fixation to manage destabilising injuries of the PIJ. OBJECTIVES: To document further the clinical use of double plate fixation for management of injuries to the PIJ resulting in palmar/plantar instability and compare these results with other methods of management. STUDY DESIGN: Retrospective case series. METHODS: The case records and radiographs of 30 horses with destabilising injuries to the PIJ treated by double plate fixation at Texas A&M University between 1987 and 2013 were analysed. Long-term follow-up information was obtained by telephone interview with the client or referring veterinarian. RESULTS: Thirty-one disruptive PIJ injuries were double plated in 30 cases. Twenty-nine of 30 horses were discharged from the hospital. The medial time for post operative external coaptation was 41 days. Long-term follow-up (>2 years) was available for 25 horses, of which 15 (60%) returned to useful function. Radiographic evidence of fracture healing and arthrodesis of the PIJ was evident in 28 (90%) repairs at 6 months following repair. CONCLUSIONS: The use of 2 abaxially placed dorsal plates for management of destabilising injuries to the PIJ results in a very good prognosis for survival and a reasonable prognosis for return to functional use.
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Placas Ósseas/veterinária , Doenças dos Cavalos/cirurgia , Instabilidade Articular/veterinária , Animais , Feminino , Membro Anterior/patologia , Membro Anterior/cirurgia , Membro Posterior/patologia , Membro Posterior/cirurgia , Cavalos , Instabilidade Articular/cirurgia , Masculino , Estudos RetrospectivosRESUMO
Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.
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Inibidores de Calcineurina/toxicidade , Ciclosporina/toxicidade , Células Epiteliais/efeitos dos fármacos , Imunossupressores/toxicidade , Túbulos Renais Distais/efeitos dos fármacos , Alça do Néfron/efeitos dos fármacos , Membro 1 da Família 12 de Carreador de Soluto/agonistas , Animais , Arginina Vasopressina/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Células Epiteliais/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/fisiopatologia , Alça do Néfron/metabolismo , Alça do Néfron/fisiopatologia , Masculino , Ratos Brattleboro , Ratos Wistar , Renina/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/genética , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/agonistas , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Fatores de Tempo , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
INTRODUCTION: Anal squamous cell cancers are uncommon, and primary treatment is radical chemoradiotherapy. The role of radical surgery is in salvage of patients with residual and recurrent disease. The primary aim of the study is to determine how often such salvage surgery is required, while the secondary aim is to determine which features indicate salvage surgery may be required and to determine the outcome of salvage surgery. METHODS: A prospective database was analysed of all patients with anal cancer over an 18 year period (Dec 1996-Jan 2015). The records of patients requiring salvage surgery were reviewed. RESULTS: 203 Patients were identified with anal cancers, of which 180 had squamous cell anal carcinoma. 112 Female (median age 59.4, range 33-92) 68 male (median age 63.8 range 36-87). Of these 27 patients (15%) required salvage surgery. 23 Patients had a R0 resection. 18 Patients had an extended resection (16 R0) while 9 had a routine APR (7 R0). The 30-day post-operative mortality rate was 0%. The overall 5 year survival was 78%, not significantly different from those not requiring salvage surgery (p = 0.23). Age, gender, AJCC stage, T stage, radiation therapy alone, were not predicators of the need for salvage surgery. CONCLUSIONS: Salvage surgery is uncommonly required. Extended surgery beyond routine APR is often required to obtain an R0 resection. Excellent patient survival can be achieved in highly selected cases. There were no identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors.
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Neoplasias do Ânus/cirurgia , Carcinoma de Células Escamosas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de SalvaçãoRESUMO
OBJECTIVES: This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation. METHODS: Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). RESULTS: DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20â mmâ Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions. CONCLUSIONS: Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.
Assuntos
Artrite Reumatoide/fisiopatologia , Metabolismo Energético/fisiologia , Fibroblastos/metabolismo , Aminoácidos Dicarboxílicos/metabolismo , Movimento Celular/fisiologia , Células Cultivadas , Citocinas/análise , DNA Mitocondrial/metabolismo , Glucose/análise , Humanos , Hipóxia/metabolismo , Articulações/metabolismo , Ácido Láctico/análise , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Membrana Sinovial/citologiaRESUMO
This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2-3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0-0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05-0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.
Assuntos
Coinfecção/epidemiologia , Diabetes Mellitus/epidemiologia , Hepacivirus/isolamento & purificação , Hepatite C/epidemiologia , Adulto , Coinfecção/etiologia , Estudos Transversais , Diabetes Mellitus/etiologia , Feminino , Hepatite C/virologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Texas/epidemiologiaRESUMO
BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by synovitis and destruction of articular cartilage/bone. Janus-kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathway is implicated in the pathogenesis of PsA. OBJECTIVES: To examine the effect of tofacitinib (JAK inhibitor) on proinflammatory mechanisms in PsA. METHODS: Primary PsA synovial fibroblasts (PsAFLS) and ex vivo PsA synovial explants were cultured with tofacitinib (1 µM). PhosphoSTAT3 (pSTAT3), phosphoSTAT1 (pSTAT1), suppressor of cytokine signaling-3 (SOCS3), protein inhibitor of activated Stat3 (PIAS3) and nuclear factor kappa B cells (NFκBp65) were quantified by western blot. The effect of tofacitinib on PsAFLS migration, invasion, Matrigel network formation and matrix metallopeptidase (MMP)2/9 was quantified by invasion/migration assays and zymography. Interleukin (IL)-6, IL-8, IFN-gamma-inducible protein 10 (IP-10) monocyte chemoattractant protein (MCP)-1, IL-17, IL-10, MMP3 and tissue inhibitor of metalloproteinases 3 (TIMP3) were assessed by ELISA. RESULTS: Tofacitinib significantly decreased pSTAT3, pSTAT1, NFκBp65 and induced SOCS3 and PIAS3 expression in PsAFLS and synovial explant cultures (p<0.05). Functionally, PsAFLS invasion, network formation and migration were inhibited by tofacitinib (all p<0.05). In PsA explant, tofacitinib significantly decreased spontaneous secretion of IL-6, IL-8, MCP-1, MMP9/MMP2, MMP3 (all p<0.05) and decreased the MMP3/TIMP3 ratio (p<0.05), with no effect observed for IP-10 or IL-10. CONCLUSIONS: This study further supports JAK-STAT inhibition as a therapeutic target for the treatment of PsA.