Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention: prospective studies in HIV-uninfected men and women

Thesis (Ph.D.)--University of Washington, 2016-06

The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation

Purpose. The aim of this study was to report the influence of hepatitis C virus (HCV) genotype and rejection episodes on the outcome of orthotopic liver transplantation (OLT), hepatitis recurrence, and progression to graft cirrhosis after OLT. Methods. Fifty-three patients who all had undergone OLT for end-stage liver cirrhosis were selected for this study. Hepatitis C genotype was determined. Recurrent hepatitis and rejection were diagnosed based on elevated liver function tests and a liver biopsy. Results. The patients were followed up for a mean of 51.9 +/- 34.3 months. The cumulative survival rate was no different in OLT for hepatitis C and OLT for all other liver diseases. After OLT, serum HCV RNA was detected in 93%. Histological recurrence occurred in 85% of all patients. The 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively. Of the 41 patients with recurrent hepatitis C, 4 (10%) had cirrhosis, 18 (44%) had hepatitis with fibrosis, and 91 (46%) had hepatitis without fibrosis at the end of follow-up. A total of 32% of the patients were infected by HCV genotype 1b and 68% by other HCV genotypes. The recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes (p = 0.04). Twenty of 48 patients (42%) experienced acute rejection. There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis (p < 0.01). Conclusion. Our findings showed the genotype 1b to result in a higher recurrence rate after OLT. On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis.

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment. (C) 2003 Elsevier Ireland Ltd. All fights reserved.

Short-term peaks in glucose promote renal fibrogenesis independently of total glucose exposure

Postprandial hyperglycemia is implicated as a risk factor predisposing to vascular complications. This study was designed to assess recurrent short-term increases in glucose on markers of renal fibrogenesis. Human renal cortical fibroblasts were exposed to fluctuating short-term (2 h) increases to 15 mM D-glucose, three times a day over 72 h, on a background of 5 mM D-glucose. To determine whether observed changes were due to fluctuating osmolality, identical experiments were undertaken with cells exposed to L-glucose. Parallel experiments were performed in cells exposed to 5 mM D-glucose and constant exposure to either 15 or 7.5 mM D-glucose. Fluctuating D-glucose increased extracellular matrix, as measured by proline incorporation ( P < 0.05), collagen IV ( P < 0.005), and fibronectin production ( P < 0.001), in association with increased tissue inhibitor of matrix metalloproteinase (MMP) ( P < 0.05). Sustained exposure to 15 mM D-glucose increased fibronectin ( P < 0.001), in association with increased MMP-2 ( P = 0.01) and MMP-9 activity ( P < 0.05), suggestive of a protective effect on collagen matrix accumulation. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA was increased after short-term (90 min) exposure to 15 mM glucose (P < 0.05) and after 24-h exposure to 7.5 mM ? ( P < 0.05). Normalization of TGF-beta(1) secretion occurred within 48 h of constant exposure to an elevated glucose. Fluctuating L-glucose also induced TGF-beta(1) mRNA and a profibrotic profile, however, to a lesser extent than observed with exposure to fluctuating D-glucose. The results suggest that exposure to fluctuating glucose concentrations increases renal interstitial fibrosis compared with stable elevations in D-glucose. The effects are, in part, due to the inherent osmotic changes.

Generalized, pruritic, ulcerating maculopapular rash necessitating cessation of sirolimus in a liver transplantation patient

The use of sirolimus as an alternative to calcineurin antagonists has enabled the continuation of immunosuppression in patients with renal impairment with preservation of kidney function. Sirolimus is generally well tolerated, with the main causes of cessation of therapy related to its effect on blood lipid profile as well as leukopenia and thrombocytopenia. We report a case of a debilitating ulcerating maculopapular rash necessitating cessation of the drug in a liver transplantation patient. A 56-year-old Caucasian liver transplantation patient presented with a diffuse, debilitating rash attributed to sirolimus use. This ultimately necessitated cessation of the immunosuppressant with subsequent resolution of her symptoms. From a review of the current literature, this is a highly unusual adverse reaction to sirolimus.

Functional and perceived benefits of wearing coloured filters by patients with age-related macular degeneration

Background: The aim was to investigate the visual effect of coloured filters compared to transmission-matched neutral density filters, in patients with dry age-related macular degeneration. Methods: Visual acuity (VA, logMAR), contrast sensitivity (Pelli-Robson) and colour vision (D15) were recorded for 39 patients (average age 79.1 ± 7.2 years) with age-related macular degeneration, both in the presence and absence of glare from a fluorescent source. Patients then chose their preferred coloured and matched neutral density transmission filters (NoIR). Visual function tests were repeated with the chosen filters, both in the presence and absence of glare from the fluorescent source. Patients trialled the two filters for two weeks each, in random order. Following the trial of each filter, a telephone questionnaire was completed. Results: VA and contrast sensitivity were unaffected by the coloured filters but reduced through the neutral density filters (p < 0.01). VA and contrast sensitivity were reduced by similar amounts, following the introduction of the glare source, both in the presence and absence of filters (p < 0.001). Colour vision error scores were increased following the introduction of a neutral density filter (from 177.6 ± 60.2 to 251.9 ± 115.2) and still further through coloured filters (275.1 ± 50.8; p < 0.001). In the absence of any filter, colour vision error scores increased by 29.1 ± 55.60 units in the presence of glare (F2,107 = 3.9, p = 0.02); however, there was little change in colour vision error scores, in the presence of glare, with either the neutral density or coloured filters. Questionnaires indicated that patients tended to gain more benefit from the coloured filters. Conclusions: Coloured filters had minimal impact on VA and contrast sensitivity in patients with age-related macular degeneration; however, they caused a small reduction in objective colour vision, although this was not registered subjectively by patients. Patients indicated that they received more benefit from the coloured filters compared with neutral density filters. © 2013 The Authors © 2013 Optometrists Association Australia.

Hypertension, poor glycemic control, and microalbuminuria in Cuban Americans with type 2 diabetes

Purpose: To investigate to what degree the presence of hypertension (HTN) and poor glycemic control (GC) influences the likelihood of having microalbuminuria (MAU) among Cuban Americans with type 2 diabetes (T2D).Methods: A cross-sectional study conducted in Cuban Americans (n = 179) with T2D. Participants were recruited from a randomly generated mailing list purchased from KnowledgeBase Marketing, Inc. Blood pressure (BP) was measured twice and averaged using an adult size cuff. Glycosylated hemoglobin (A1c) levels were measured from whole blood samples with the Roche Tina-quant method. First morning urine samples were collected from each participant to determine MAU by a semiquantitative assay (ImmunoDip).Results: MAU was present in 26% of Cuban Americans with T2D. A significantly higher percentage of subjects with MA had HTN (P = 0.038) and elevated A1C (P = 0.002) than those with normoalbuminuria. Logistic regression analysis showed that after controlling for covariates, subjects with poor GC were 6.76 times more likely to have MAU if they had hypertension compared with those without hypertension (P = 0.004; 95% confidence interval [CI]: 1.83, 23.05). Conclusion: The clinical significance of these findings emphasizes the early detection of MAU in this Hispanic subgroup combined with BP and good GC, which are fundamentals in preventing and treating diabetes complications and improving individuals’ renal and cardiovascular outcomes.

Estudo da resposta Th17 no transplante renal alogênico: contribuição do eixo quimiotático CCR6/CCL20 e dos polimorfismos gênicos em IL17A e IL17RA

Kidney transplantation is the best treatment for patients who have lost kidney function. Renal transplant patients require accurate immunosuppressive drugs to prevent rejection. In this process T helper cells of the immune system perform key role in the immune response to the graft, and recently the Th17 cells has been investigated by production of IL-17 potent proinflammatory cytokine whose role in the rejection has also been described. Increased of Th17 cell expression has an important association with the development of rejection in renal microenvironment, however the likely mechanism is not well understood. This study aimed to evaluate the Th17 response from the influence of the chemotactic axis CCR6/CCL20 and genetic variants in IL-17 and IL-17RA. We conducted a case-control study involving 148 patients transplanted at the University Hospital Onofre Lopes/UFRN in which assessed by immunohistochemistry protein expression of IL-17 and chemokines CCR6/CCL20 and by PCR-RFLP genetic variants in IL17A and IL17RA. Our results showed no influence of genetic polymorphisms on the outcome of the graft or the protein expression of IL-17. In renal graft microenvironment found several sources producing IL-17: tubular epithelial cells, glomerular cells, neutrophils and cell interstitial infiltration, in turn the expression of chemotactic axis CCR6/CCL20 was restricted to the tubular epithelium cells. There was a slight positive linear correlation between the presence of IL-17 and expression of chemotactic axis CCR6/CCL20 in the microenvironment of renal graft. Therefore, we believe that, combined with our results, further studies with increased "n" sample and greater control over the variables involved in obtaining the renal specimen, can determine more clearly the influence of chemotactic axis CCR6 / CCL20 and polymorphisms in cytokines related to Th17 profile on the control of this cell subtype response in rejection processes to renal allograft.

Sorting Test, Tower Test, and BRIEF-SR do not predict school performance of healthy adolescents in preuniversity education

Executive functions (EF) such as self-monitoring, planning, and organizing are known to develop through childhood and adolescence. They are of potential importance for learning and school performance. Earlier research into the relation between EF and school performance did not provide clear results possibly because confounding factors such as educational track, boy-girl differences, and parental education were not taken into account. The present study therefore investigated the relation between executive function tests and school performance in a highly controlled sample of 173 healthy adolescents aged 12–18. Only students in the pre-university educational track were used and the performance of boys was compared to that of girls. Results showed that there was no relation between the report marks obtained and the performance on executive function tests, notably the Sorting Test and the Tower Test of the Delis-Kaplan Executive Functions System (D-KEFS). Likewise, no relation was found between the report marks and the scores on the Behavior Rating Inventory of Executive Function—Self-Report Version (BRIEF-SR) after these were controlled for grade, sex, and level of parental education. The findings indicate that executive functioning as measured with widely used instruments such as the BRIEF-SR does not predict school performance of adolescents in preuniversity education any better than a student's grade, sex, and level of parental education.

Acute Transient Stress Induced Adrenal Hypertrophy and Adrenal Medullary Hyperactivity

Objectives: Adrenal gland hypertrophy can be related to acute stress with abnormal adrenal function tests. It may not always need treatment. Material and methods: An acute presentation of adrenal gland hypertrophy following an abdominal emergency, with subsequent hypoadrenalism was investigated. Results: Adrenal medullary and cortical function fully recovered without treatment. Conclusions: We postulate that the adrenal glands became enlarged and hypertrophied during an acute stress event, possibly caused by acute adrenal medullary hypersecretion and subsequent cortical hyposecretion. A wait and watch policy should be followed if no other clinical symptoms and signs of adrenal disease are present. CT scan remains an important diagnostic tool.

Children's health and indoor air quality in primary schools and homes in Portugal-Study design

The main aim of the research project "On the Contribution of Schools to Children's Overall Indoor Air Exposure" is to study associations between adverse health effects, namely, allergy, asthma, and respiratory symptoms, and indoor air pollutants to which children are exposed to in primary schools and homes. Specifically, this investigation reports on the design of the study and methods used for data collection within the research project and discusses factors that need to be considered when designing such a study. Further, preliminary findings concerning descriptors of selected characteristics in schools and homes, the study population, and clinical examination are presented. The research project was designed in two phases. In the first phase, 20 public primary schools were selected and a detailed inspection and indoor air quality (IAQ) measurements including volatile organic compounds (VOC), aldehydes, particulate matter (PM2.5, PM10), carbon dioxide (CO2), carbon monoxide (CO), bacteria, fungi, temperature, and relative humidity were conducted. A questionnaire survey of 1600 children of ages 8-9 years was undertaken and a lung function test, exhaled nitric oxide (eNO), and tear film stability testing were performed. The questionnaire focused on children's health and on the environment in their school and homes. One thousand and ninety-nine questionnaires were returned. In the second phase, a subsample of 68 children was enrolled for further studies, including a walk-through inspection and checklist and an extensive set of IAQ measurements in their homes. The acquired data are relevant to assess children's environmental exposures and health status.

Purification and biological effects of a C-type lectin isolated from Bothrops moojeni

Snake venom proteins from the C-type lectin family have very distinct biological activities despite their highly conserved primary structure, which is homologous to the carbohydrate recognition region of true C-type lectins. We purified a lectin-like protein (BmLec) from Bothrops moojeni venom and investigated its effect on platelet aggregation, insulin secretion, antibacterial activity, and isolated kidney cells. The BmLec was purified using two chromatographic steps: affinity chromatography and reverse phase high performance liquid chromatography (HPLC). BmLec showed a dose-dependent platelet aggregation and significantly decreased the bacterial growth rate in approximately 15%. During scanning electron microscopy, the profile of Xanthomonas axonopodis pv. passiflorae treated with lectin disclosed a high vesiculation and membrane rupture. BmLec induced a strong and significant increase in insulin secretion at 2.8 and 16.7 mM glucose concentrations, and this effect was seen in the presence of EGTA in both experiments. BmLec (10 mu g/mL) increased the perfusion pressure, renal vascular resistance and urinary flow. The glomerular filtration rate and percentages of sodium, potassium and chloride tubular transport were reduced at 60 minutes of perfusion. Renal alterations caused by BmLec were completely inhibited by indomethacin in all evaluated parameters. In conclusion, the C-type lectin isolated from Bothrops moojeni affected platelet aggregation, insulin secretion, antibacterial activity and isolated kidney function.

Extracorporeal circuit for Panton-Valentine leukocidin-producing Staphylococcus aureus necrotizing pneumonia [Traitement par ECMO d'une pneumopathie nécrosante à Staphylococcus aureus producteur de la leucocidine de Panton-Valentine]

National audience

Caractérisation du syndrome de chevauchement de l’asthme et de la maladie pulmonaire obstructive chronique

Maladies fréquentes, l’asthme touche 8,4% de la population canadienne âgée de 12 ans et plus et la maladie pulmonaire obstructive chronique (MPOC) touche de 5 à 15% de la population âgée entre 35 et 79 ans. L’asthme et la MPOC peuvent coexister chez un patient. Ce phénomène appelé syndrome de chevauchement de l’asthme et de la MPOC (ACOS) toucherait environ 10% à 55% des patients MPOC. Afin de mieux caractériser l’ACOS et les effets indésirables des médicaments utilisés pour traiter la MPOC, deux études ont été mises en place. Une première étude réalisée auprès de pneumologues a permis de décrire les méthodes de diagnostic, de traitement et d’évaluation de la maitrise de l’ACOS dans la pratique clinique. Les pneumologues rapportent que le diagnostic devrait être basé sur les caractéristiques cliniques, les tests de fonction pulmonaire et l'intuition clinique du médecin. De plus, un corticostéroïde inhalé en combinaison et un bronchodilatateur inhalé à longue durée d’action devraient être introduits rapidement dans le plan de traitement. La deuxième étude a permis d’évaluer la fréquence des effets indésirables chez les patients MPOC/ACOS traités avec un bronchodilatateur inhalé à longue durée d’action. Cette étude démontre que les effets indésirables sont fréquents chez les patients MPOC/ACOS et que la sécheresse buccale et la gorge sèche sont les plus rapportés. Ces résultats démontrent que la mise en place de lignes directrices pour l’ACOS ainsi qu’une meilleure connaissance du profil de tolérance des bronchodilatateurs inhalés à longue durée d’action seraient bénéfiques pour les patients