Search

Objective: The goal of this study was to investigate the association between neighborhood socioeconomic status (NSES) and BMI and to what extent this association is moderated by availability of fast-food (FF) outlets and pay-for-use physical activity (PA) facilities., Methods: Baseline data of adults in Lifelines (N = 146,629) were linked to Statistics Netherlands and a register using geocoding to compute, respectively, NSES (i.e., low, middle, high) and the number of FF outlets and PA facilities within 1 km of the residential address. Multivariable multilevel linear regression analyses were performed to examine the association between NSES and BMI. Two-way and three-way interaction terms were tested to examine moderation by FF outlets and PA facilities., Results: Participants living in low NSES areas had a higher BMI than participants living in high (B [95% CI]: 0.76 [0.65 to 0.87]) or middle NSES areas (B [95% CI]: 0.40 [0.28 to 0.51]), independent of individual socioeconomic status. Although two- and three-way interactions between NSES, FF outlets, and PA facilities were significant, stratified analyses did not show consistent moderation patterns., Conclusions: People living in lower NSES areas had a higher BMI, independent of their individual socioeconomic status. The study found no clear moderation of FF outlets and PA facilities. Environmental factors that may mitigate NSES differences in BMI should be the subject of future research., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Objectives: Infantile hemangiomas (IHs) are the most common benign tumors in children. Color Doppler ultrasound is a noninvasive imaging modality that can show subclinical anatomic parameters in a wide range of dermatologic conditions. The purpose of this study was to describe the ultrasound characteristics of IHs and look for subclinical features with the potential to influence the involution and therapeutic response., Methods: A review of the ultrasound database of children with clinical and ultrasound IH diagnoses was conducted. The clinically reported duration and the ultrasound assessment of the proliferative phase were compared. Descriptive and statistical analyses of qualitative and quantitative parameters of the series were performed. Significance was set at P < .05., Results: A total of 204 IHs were included. Twenty percent had arteriovenous shunts; 15% had afferent branches from main regional arteries; and almost 30% showed involvement of deep structures. Sixty-one percent of IHs were in the head and neck. Deep hemangiomas showed significantly thicker lesional vessels. A prolonged proliferative stage was significantly associated with a higher presence of arteriovenous shunts and a higher peak systolic velocity of the arterial vessels (≥15 cm/s) within the lesions., Conclusions: Color Doppler ultrasound can support the detection of subclinical anatomic features that may potentially influence the involution and response to treatment of IHs. Some of these characteristics may serve as potential markers to predict and manage IHs in prolonged proliferative stages., (© 2020 American Institute of Ultrasound in Medicine.)

This study dealt with the use of quinoa flour (QF) or teff flour (TF) as partial beef fat replacers in the formulation of emulsion-type sausages. A control (C) group was manufactured with 20% beef fat, while the other three groups were formulated with 10% beef fat plus 5% QF (Q), 5% TF (T), and 2.5% QF+2.5% TF (QT). Water-holding capacity of the emulsions was higher in Q (81.81%), T (82.20%), and QT (84.10%) samples than in C (64.83%) samples. Total expressible fluid and expressible fat were the lowest in Q and T samples, indicating the highest emulsion stability of those groups. Incorporation of QF and TF into formulations increased moisture and carbohydrate contents while decreased fat and energy values. Besides, the use of QF was effective to increase protein and dietary fiber contents. T sausages had lower luminosity (L*) and higher yellowness (b*) than C sausages, whilst Q sausages did not result in significant color changes. Higher cook yield values were recorded in Q (97.96%), T (98.21%), and QT (98.15%) samples compared with C (96.44%) samples. Inclusion of QF and TF to formulation led to lower hardness and gumminess, while utilization of TF was also effective to decrease chewiness. Consequently, healthier emulsified sausages were obtained by the inclusion of QF or TF that could decrease the fat content more than 50% without sacrificing overall quality, bringing advantages by quinoa over teff for increasing nutritional value and leading minimal modifications on color and texture., Competing Interests: The authors declare no potential conflicts of interest., (© Korean Society for Food Science of Animal Resources.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background and Objective: Given the increasing discussions of the impact of genetic medicine within family medicine, it is important to determine the most effective way of teaching this material to family medicine residents (FMRs). The objective of this study was to evaluate and compare the impact of three methods of delivering primary care genetic content to FMRs., Methods: Curriculum materials and assessment tools were created to teach and evaluate knowledge, skills, and attitudes around four core competencies in primary care genetics, with a focus on hereditary colorectal cancer (CRC). Participants were randomly allocated to four learning conditions: (1) no intervention (control), (2) web-based module outlining genetic concepts applied to CRC, (3) live presentation of the web-based material, (4) live presentation and subsequent standardized patient (SP) encounter. Three months later, all participants completed a written knowledge test, attitude survey, and a standardized patient-based performance assessment., Results: Sixty FMRs completed the study. All three educational interventions resulted in significantly improved outcome measures in knowledge and skills but not attitudes, compared to control. There was no significant difference in outcomes between intervention groups., Conclusion: FMRs acquired knowledge and improved skills in genetic medicine with three educational methods. Resources such as faculty expertise in genetic medicine and cost should guide decisions on curricular development for this rapidly expanding field. This may be especially relevant for programs with distributed teaching sites.

Context and Objectives: Chronic myeloid leukemia (CML) requires strict daily compliance with oral medication and regular blood and bone marrow control tests. The objective was to evaluate CML patients' perceptions about the disease, their access to information regarding the diagnosis, monitoring and treatment, adverse effects and associations of these variables with patients' demographics, region and healthcare access., Design and Setting: Prospective cross-sectional study among CML patients registered with the Brazilian Lymphoma and Leukemia Association (ABRALE)., Methods: CML patients receiving treatment through the public healthcare system were interviewed by telephone., Results: Among 1,102 patients interviewed, the symptoms most frequently leading them to seek medical care were weakness or fatigue. One third were diagnosed by means of routine tests. The time that elapsed between first symptoms and seeking medical care was 42.28 ± 154.21 days. Most patients had been tested at least once for Philadelphia chromosome, but 43.2% did not know the results. 64.8% had had polymerase chain reaction testing for the BCR/ABL gene every three months. 47% believed that CML could be controlled, but 33.1% believed that there was no treatment. About 24% reported occasionally stopping their medication. Imatinib was associated with nausea, cramps and muscle pain. Self-reported treatment adherence was significantly associated with normalized blood count, and positively associated with imatinib., Conclusions: There is a lack of information or understanding about disease monitoring tools among Brazilian CML patients; they are diagnosed quickly and have good access to treatment. Correct comprehension of CML control tools is impaired in Brazilian patients.

A series of styrylquinolines and quinolineamides based on the 8-hydroxyquinoline moiety were investigated as potential antimycobacterial agents. The lipophilicity of the compounds was measured using RP-HPLC and the tests of their activity against Mycobacterium kansasii, the M. avium complex, M. smegmatis, M. abscessus, M. tuberculosis and M. avium paratuberculosis was performed. Several of the compounds that were obtained appeared to be more effective than isoniazid and ciprofloxacin. The 5,7-dinitro-8-hydroxyquinoline derivative possessed the highest potency against M. abscessus and M. Smegmatis, which was about twice as effective as ciprofloxacin, while 2-(2-hydroxystyryl)-8-hydroxyquinoline-7-carboxylic acid appeared to be comparable with the standard drugs that are against the M. avium complex. The structure activity relationships are discussed.

Purpose: The purpose of this study was to evaluate the quality of life (QOL) of patients receiving treatment by the public health system in Brazil for chronic myeloid leukemia (CML), a disease requiring daily and strict compliance to oral medication and regular blood and bone marrow controls, which are invasive exams., Methods: Between 2008 and 2010, patients with CML were surveyed by telephone. Quality of life was evaluated by the functional assessment of chronic illness therapy (FACIT) tool., Results: The mean QOL among CML patients was 92.53 (out of 124 total points) in the trial outcome index, 78.50 (out of 108) in the general total score, and 130.43 (out of 176) in the leukemia total score. Patients who had the prescriptions recently changed anyway had better QOL general score (p = 0.012) and leukemia-specific score (p = 0.043) than those who remained with the same treatment. Imatinib was not associated with this change in QOL (p > 0.797). The more the patient felt able to work, the higher the scores in all three FACIT scales (p < 0.001, Spearman's correlation). The use of imatinib (p = 0.012) was associated with a better ability to work, while chemotherapy (p = 0.017) and the use of hydroxyurea (p = 0.001) were inversely associated with work capability., Conclusions: A recent change in medication can improve quality of life. The ability to work is an important component of quality of life of patients with CML. Ability to work should be specifically considered in CML treatment.

Background: Standardised patients (SPs) are often asked to portray complex physical roles in which authenticity is paramount; however, SPs come from a variety of backgrounds, and may lack knowledge of basic anatomy and physiology that can hamper their portrayal. This lack of knowledge can lead to gaps in accuracy and credibility., Context: In our efforts to bridge the gap and create training that would lead to authentic and confident portrayals, we developed the 'gut bucket'. This three-dimensional learning tool is tactile, portable, simple and affordable., Innovation: The 'gut bucket' has life-size abdominal organs made from fabric resting in a standard plastic washbasin. The organs can be easily removed and manipulated to simulate different disease states (for example: appendicitis, kidney stones or cholecystitis). The tool is visually engaging and durable, encouraging SPs to handle the organs and become familiar with their size and placement within the basin and on themselves., Implications: The SPs in our programme found that the 'gut bucket' provided a deeper level of knowledge, made them more confident in their portrayal and enhanced their experience, and they generally preferred the 'gut bucket' over traditional methods of training. This was demonstrated using 'gut bucket' training evaluation forms. The 'gut bucket' can easily be incorporated into training sessions to provide a kinaesthetic approach as well as increased engagement for the SPs. We hope others may benefit by sharing our experience with the 'gut bucket'., (© 2014 John Wiley & Sons Ltd.)

This article reports on the quality of care delivered by private and public providers of primary health care services in rural and urban India. To measure quality, the study used standardized patients recruited from the local community and trained to present consistent cases of illness to providers. We found low overall levels of medical training among health care providers; in rural Madhya Pradesh, for example, 67 percent of health care providers who were sampled reported no medical qualifications at all. What's more, we found only small differences between trained and untrained doctors in such areas as adherence to clinical checklists. Correct diagnoses were rare, incorrect treatments were widely prescribed, and adherence to clinical checklists was higher in private than in public clinics. Our results suggest an urgent need to measure the quality of health care services systematically and to improve the quality of medical education and continuing education programs, among other policy changes.

Background: The literature on simulated or standardized patient (SP) methodology is expanding. However, at the level of the program, there are several gaps in the literature. We seek to fill this gap through documenting experiences from four programs in Australia, Canada, Switzerland and the United Kingdom. We focused on challenges in SP methodology, faculty, organisational structure and quality assurance., Methods: We used a multiple case study method with cross-case synthesis. Over eighteen months during a series of informal and formal interactions (focused meetings and conference presentations) we documented key characteristics of programs and drew on secondary document sources., Results: Although programs shared challenges in SP methodology they also experienced differences. Key challenges common to programs included systematic quality assurance and the opportunity for research. There were differences in the terminology used to describe SPs, in their recruitment and training. Other differences reflected local conditions and demands in organisational structure, funding relationships with the host institution and national trends, especially in assessments., Conclusion: This international case study reveals similarities and differences in SP methodology. Programs were highly contextualised and have emerged in response to local, institutional, profession/discipline and national conditions. Broader trends in healthcare education have also influenced development. Each of the programs experienced challenges in the same themes but the nature of the challenges often varied widely.

In this essay we set out clinical communication challenges in surgical oncology. We draw directly on relevant examples where they are available. Otherwise, we refer to the more generic surgical and medical literature. We offer 'macro' and 'micro' perspectives on clinical communication. That is, exploring communication challenges at the level of the organization and between individuals, doctors and patients and interprofessionally across different settings. Training content and methods are reported that address the complex communication challenges associated with surgical oncology. Innovations in simulation-based education offer exciting new opportunities for formative and summative assessment. We outline limitations of the essay and finally propose the content of a surgical oncology communication program., (Copyright © 2010. Published by Elsevier Ltd.)

Crystal structures of three small molecular scaffolds based on quinoline, 2-methylquinoline-5,8-dione, 5-hydroxy-quinaldine-6-carboxylic acid and 8-hydroxy-quinaldine-7-carboxylic acid, were characterised. 5-Hydroxy-quinaldine-6-carboxylic acid was co-crystallized with cobalt(II) chloride to form a model of divalent metal cation-ligand interactions for potential HIV integrase inhibitors. Molecular docking into active site of HIV IN was also performed on 1WKN PDB file. Selected ligand-protein interactions have been found specific for active compounds. Studied structures can be used as scaffolds in fragment-based design of new potent drugs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Simulated patients (SPs) play a critical role in medical education. The development of SP methodology has resulted in wide ranging responsibilities. For SPs to work effectively, we believed it was important to clearly articulate their responsibilities, and that this would be best achieved by consultation with all stakeholders-SPs, students, tutors, and administrators., Methods: As part of a quality assurance initiative, we designed a questionnaire and focus group study to explore stakeholders' perceptions of the responsibilities of SPs in teaching. Convenience and purposive sampling was used to recruit participants to questionnaires and focus groups, respectively. Data were analyzed thematically., Results: Eighty-six questionnaires were collected, and six focus groups were conducted. Five sets of guidelines on responsibilities were produced. In addition, guidelines were established for feedback that SPs and tutors could use to maximize impact., Discussion: The results highlight the complexity of SP-based teaching. Clarification of all stakeholders' responsibilities demonstrates the importance of a team approach to SP-based teaching. Focusing attention on just one set of stakeholder's responsibilities is unlikely to improve perception of quality. The process for developing the guidelines may be valuable for those who work with SPs. Stakeholder engagement is likely to ensure greater commitment than those developed by faculty.

In the study, a series of twelve ring-substituted 4-hydroxy-1H-quinolin-2-one derivatives were prepared. The procedures for synthesis of the compounds are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity and tested for their photosynthesis-inhibiting activity using spinach (Spinacia oleracea L.) chloroplasts. All the synthesized compounds were also evaluated for antifungal activity using in vitro screening with eight fungal strains. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed, as well as their structure-activity relationships (SAR).

Purpose: The Integrated Procedural Performance Instrument (IPPI) consists of clinical scenarios in which bench-top models are positioned to simulated patients. Trainees are required to perform technical skills while engaging with the patient. The purpose of this study was to determine whether an IPPI format examination could discriminate between different levels of trainees., Methods: Sixteen fourth-year medical students and 16 first-year surgery residents participated in 4 IPPI scenarios. Videotaped performances were scored by 2 blinded independent clinician raters on previously validated instruments: checklist of technical skills, Global Rating Scale of technical skills, and communication scale. We conducted separate mixed design analyses of variance (level x cases) on the 3 scales., Results: Residents performed better than medical students on the checklist (74% vs 60%, P < .05), the Global Rating Scale of technical skills (75% vs 56%, P < .01), and the coherence communication subscale (79% vs 69%, P < .05)., Conclusions: An IPPI examination discriminated between students' and residents' technical skills and coherence in communication skills. It also highlighted a potential gap in the training of residents' communication skills.

Background: The Integrated Procedural Performance Instrument (IPPI) uses various bench-top models positioned to standardized patients (SP) to recreate realistic clinical encounters. This study assessed the effectiveness of using an IPPI format as a teaching tool for communication skills., Method: Thirty-two participants underwent 2 videotaped IPPI scenarios before randomization into 2 groups--experimental (SP-led feedback) or control (no feedback). Participants then completed 2 further IPPI format scenarios. Videotapes were scored by 2 blinded independent raters using validated assessment scales (communication and technical)., Results: The experimental group performed significantly better on the communication scores following feedback compared with the control group (mean 77% vs 66%, P < .05). No difference in scores for technical skills post-intervention were demonstrated (checklist: experimental mean = 64% vs control = 59%, P = .40; global ratings: experimental mean = 66% vs no control = 62%, P = .37)., Conclusions: The IPPI is an effective tool for teaching communication skills in residents and medical students and should be considered for incorporation into undergraduate and surgical curricula.

Two series of amides based on quinoline scaffold were designed and synthesized in search of photosynthesis inhibitors. The compounds were tested for their photosynthesis-inhibiting activity against Spinacia oleracea L. and Chlorella vulgaris Beij. The compounds lipophilicity was determined by the RP-HPLC method. Several compounds showed biological activity similar or even higher than that of the standard (DCMU). The structure-activity relationships are discussed.

Allogeneic stem cell transplantation has been increasingly performed for a variety of hematologic diseases. Clinically significant acute graft-versus-host disease (GVHD) occurs in 9 to 50% of patients who receive allogeneic grafts, resulting in high morbidity and mortality. There is no standard therapy for patients with acute GVHD who do not respond to steroids. Studies have shown a possible benefit of anti-TNF-a (infliximab)for the treatment of acute GVHD. We report here on the outcomes of 10 recipients of related or unrelated stem cell transplants who received 10 mg/kg infliximab, iv, once weekly for a median of 3.5 doses (range: 1-6) for the treatment of severe acute GVHD and who were not responsive to standard therapy. All patients had acute GVHD grades II to IV (II = 2, III = 3, IV = 5). Overall, 9 patients responded and 1 patient had progressive disease. Among the responders, 3 had complete responses and 6 partial responses. All patients with cutaneous or gastrointestinal involvement responded, while only 2 of 6 patients with liver disease showed any response. None of the 10 patients had any kind of immediate toxicity. Four patients died, all of them with sepsis. Six patients are still alive after a median follow-up time of 544 days (92-600) after transplantation. Considering the severity of the cases and the bad prognosis associated with advanced acute GVHD, we find our results encouraging. Anti-TNF-a seems to be a useful agent for the treatment of acute GVHD.

The structure-activity relationships of new quinoline based compounds were investigated. Quinoline-5,8-dione and styrylquinoline scaffolds were used for the design of potentially active compounds. The novel analogues had comparable antiproliferative activity to cisplatin when evaluated in a bioassay against the P388 leukemia cell line. However, these compounds appeared far less efficient against SK-N-MC neuroepithelioma cells. Analogues without the 5,8-dione structure but containing the 8-carboxylic acid group were also found to induce antiproliferative activity. Hydrophobicity as measured by HPLC did not correlate with antiproliferative activity.

Background: Competency-based models of medical education require reliable and valid assessment of multiple physician roles., Aims: To develop and evaluate an objective structured clinical examination (OSCE) designed to assess 7 physician competencies (CanMEDS Roles)., Methods: Twenty four candidates from 4 neonatal-perinatal medicine training programs participated in a 10-station OSCE. Ten 5-point rating scales were developed and used to assess the CanMEDS Roles of Medical Expert, Communicator, Collaborator, Manager, Health Advocate, Scholar and Professional. Three descriptors of performance anchored the ratings. For each station, examiners completed appropriate CanMEDS ratings, a station-specific binary checklist and an overall process-related global rating. Trained standardized patients (SP) and standardized health professionals (SHP) completed rating scales that assessed verbal and non-verbal expression, empathy and coherence as well as the overall global rating., Results: Each station incorporated 3-5 physician Roles. Interstation alpha was 0.80 for checklist scores and 0.88 for examiners' overall global rating. Median interstation alpha for individual CanMEDS ratings was 0.72 (range 0.08-0.91). There were significant correlations between examiner Medical Expert scores and SP/SHP overall global scores and between examiner Communicator scores and 4 SP/SHP assessments of communication skills. Second year trainees' CanMEDS scores for each competency were significantly higher than those of first year trainees (p < 0.05)., Conclusions: The OSCE may be useful as a reliable and valid method of simultaneously assessing multiple physician competencies.

We used comparative molecular surface analysis to design molecules for the synthesis as part of the search for new HIV-1 integrase inhibitors. We analyzed the virtual combinatorial library (VCL) constituted from various moieties of styrylquinoline and styrylquinazoline inhibitors. Since imines can be applied in a strategy of dynamic combinatorial chemistry (DCC), we also tested similar compounds in which the -C=N- or -N=C- linker connected the heteroaromatic and aromatic moieties. We then used principal component analysis (PCA) or self-organizing maps (SOM), namely, the Kohonen neural networks to obtain a clustering plot analyzing the diversity of the VCL formed. Previously synthesized compounds of known activity, used as molecular probes, were projected onto this plot, which provided a set of promising virtual drugs. Moreover, we further modified the above mentioned VCL to include the single bond linker -C-N- or -N-C-. This allowed increasing compound stability but expanded also the diversity between the available molecular probes and virtual targets. The application of the CoMSA with SOM indicated important differences between such compounds and active molecular probes. We synthesized such compounds to verify the computational predictions.

Objectives: To describe the use of patient-actors as educators in a senior-level pharmacy practice course, and to contrast the value and application of "standardized patient" and "simulated patient" educational methodologies., Design: The objective structured clinical examination (OSCE) of the licensing examination were utilized during and at the end of the course along with external assessment to determine the impact of this educational methodology. Interviews with a randomly selected cohort of 14 students were undertaken 3 years after graduation and licensure to evaluate long-term impact of this course., Assessment: Overall, students responded positively to the shift from "standardized" patients to "simulated" patients, recognizing their value in teaching clinical and pharmaceutical care skills. Concerns were expressed regarding objectivity in assessment and individual grading. Over 98% of students successfully passed the OSCE component of the licensing examination. Long-term follow-up suggests students valued this approach to education and that it provided them with a foundation for better understanding of the psychosocial needs of patients in practice., Conclusions: Simulated-patient educators can play an important role in the pharmacy curriculum, and can complement practitioner-educators in providing students with a real-world context for understanding complex patient care needs.

Objective: To develop a Professional Skills Enhancement Workshop (PSEW) to assist practitioners who require skills training to maintain competency and meet new standards of practice. Participants for this workshop were identified as those pharmacists who completed the peer review assessment process and who did not meet standards of practice expectations., Design: The full-day workshop consists of a half-day introduction to use of clinical drug information resources and approaches to addressing practice-based questions. The second part of the workshop introduces participants to the use of structured patient-interviewing techniques to elicit information using standardized patients. Participants in the workshop completed self-assessments as well as course evaluations. Subsequent to completion of the course, participants rechallenged the peer review assessment process, a test of their clinical skills consisting of a written test of clinical knowledge and an objective structured clinical examination (OSCE), to provide objective evidence of skills acquisition., Assessment: Over 90% of participants "agreed" or "strongly agreed" that the PSEW was helpful in reacquainting them with current standards of professional practice. Sixty-nine percent of participants who completed the peer review assessment rechallenge process following completion of the course were able to meet standards of practice expectations., Conclusions: In developing continuous professional development programs, first identifying the needs of all practitioners is essential. The PSEW provides one model for skills training for practitioners who, for a variety of reasons, may not have maintained the expected level of competency.

Background and Objectives: The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score., Design and Methods: The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively., Results: Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52% among the other donor-recipient pairs (p=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (p<0.001 and p<0.003, respectively). In our experience, age and interval between diagnosis and transplant did influence OS, DFS, TRM, and relapse rate., Interpretation and Conclusions: Our results validate the EBMT risk score in the context of a developing country and confirm its usefulness for making point decisions in the imatinib era.

In our work, leading to new styrylquinoline and styrylquinazoline inhibitors of HIV integrase, we analyzed virtual combinatorial library that includes these compounds. Using this method we were able to find interesting synthetic targets. We optimized synthetic procedure yielding such compounds and obtained a couple of new analogues. Their activity will be evaluated in the near future.

Philadelphia positive (Ph+) acute myeloid leukemia (AML) is a rare and heterogeneous condition, mainly reported in adults, associated to poor prognosis and unfavorable response to therapy. Here we report clinical and laboratory findings in an 8-year-old patient diagnosed with Ph+ acute leukemia with myeloid (FAB M4) morphology. The patient consistently expressed variable levels of m-bcr, e1a2 transcripts during a 42-month follow-up after two different stem cell transplantation protocols. An immunophenotypic switch was documented, from a mixed, myeloid-lymphoid lineage to a full lymphoid phenotype following stem cell transplants, in association with an immature B-cell gene rearrangement profile and clonal instability during clinical progression. This report indicates a stem cell origin as previously suggested for Ph+ AML., (Copyright 2004 Taylor and Francis Ltd)

Purpose: Teaching medical students to spontaneously identify biopsychosocial issues (e.g. family violence) remains a challenge. We examined the extent to which using unannounced standardised patients (SPs) presenting in a clerk's clinical setting could assist with this teaching challenge., Methods: All clerks attended a family violence seminar in their family medicine rotation. Intervention students additionally saw an unannounced SP portraying 1 of 2 scenarios in their preceptor's office during the rotation, and received immediate feedback about their performance. An end of rotation objective structured clinical examination (OSCE) included an SP presentation similar to that seen by the intervention students., Results: Clerks who received the intervention demonstrated increased questioning about family violence, from 0% (0 of 29 students) to 19% (5 of 26 students) in 1 OSCE scenario (P = 0.019), and from 40% (12 of 30 students) to 76% (19 of 25 students) in the other (P = 0.007)., Conclusions: Seeing unannounced SPs had a dramatic effect on later student performance. This potentially powerful intervention could be applied to a range of clinical issues.

Striking progress has been observed in the number of volunteer donors for hematopoietic stem cell transplantation in the last years in Brazil. By the end of 1998, the number of donors barely reached 4200 but it has grown progressively. It was close to 48,000 by the end of May 1993. It is possible to notice a steady increase from the first (1993 to 2000) to the last years (2001 to 2003). The regulation of each procedure by the Brazilian Health System, with the collaboration of the Hematology Societies, was essential for the success of Redome and for the stem cell transplantation program in Brazil. However, when analyzing these results some problems were detected: 95% of Redome donors come from the south and southeastern regions of the country, while few donors are from the north, northeast, and central parts of Brazil. The different miscegenation of races in different regions and states of Brazil makes this an important issue: to represent the whole Brazilian population, Redome must improve the donor search in such places. It also became clear that several other centers involved in unrelated hematopoietic transplantation must be accredited to avoid a long line of patients with compatible donors a waiting transplantation.

Retinoid therapy for acute promyelocytic leukemia (APL) is one of the major achievements of leukemia research in the last 15 years. Use of all trans retinoic acid (ATRA) has changed the prognosis of APL from a fatal leukemia to a highly curable disease. This case-based review examines the available clinical and scientific data to form evidence-based decisions in the management of APL. The main aim of this review is to highlight recent progress made in the management of APL and address the role of maintenance therapy, prognostic factors for relapse and treatment of relapsed disease.

Background: PBSC transplant provides 10 times more T cells than BMT However, the incidence and severity of acute GvHD is similar among recipients of both types of transplants. Studies in mouse models suggest that the similar clinical outcome in BMT and PBSCT is due to differences in the lymphokine profiles., Methods: PBMC, PBMC from G-CSF mobilized donors (G-PBMC)and BM mononuclear cells (BM-MC) were analyzed by flow cytometry and ELISA to detect gamma-IFN and IL-4 production. Hematoxylin and eosin staining was used to identify morphology and annexin/propidium-iodide was used for apoptosis assays., Results: We show decreased production of gamma-interferon (85%) and IL-4 (60%) in G-PBMC when compared with either PBMC or BM-MCT cells on ex vivo assays. Surprisingly, 85% of fresh G-PBMC is composed of low-density granulocytes (LDG), which undergo apoptosis after 48 h in culture. At this same time, gamma-IFN production from G-PBMC T cell was reverted. In vitro, G-CSF converts granulocytes into LDGs, able to inhibit T-cell function by H2O2 production, and not through immune-deviation towards a Th2-type phenotype., Discussion: We show that the estimated numbers of Th1 and Th2 cells infused in BMT and PBSCT do not differ significantly. These findings are discussed with reference to the relatively low incidence of acute GvHD in PBSCT shown in the literature. We suggest that these results might depend on the high number of granulocytes and progenitors infused. The potential use of granulocytes as immunosupressive short-term therapy is now being investigated by our group using a mouse experimental model.

In order to assess the effect of delaying G-CSF administration after autologous peripheral blood progenitor cell (PBPC) transplantation on the duration of neutropenia, 87 patients were randomized to receive G-CSF 5 microg/kg/day starting on day +1 (n = 45) or +5 (n = 42) following PBPC transplantation, until recovery of the neutrophils. The duration of neutropenia (<0.5 x 10(9)/l) was shorter in the day +1 group (7 vs 8 days; P = 0.02), especially in patients receiving melphalan 200 mg/m(2) and CD34(+) cell doses >3.0 x 10(6)/kg. These patients had a later onset of neutropenia after transplant. There were no differences in time to neutrophil and platelet engraftment, or in the incidence of fever and documentation of infection. Although the duration of antibiotic therapy (7 vs 10.5 days; P = 0.01) and time to hospital discharge (13 vs 15 days; P = 0.02) were shorter in the day +1 group, these differences could not be predicted by the day of G-CSF initiation in multivariate analysis. Starting G-CSF on day +1 does not result in faster neutrophil engraftment but in later onset and consequently, slightly shorter duration of neutropenia in patients who receive melphalan 200 mg/m(2) and CD34(+) cell doses >3.0 x 10(6)/kg.

We report a case of capillary leak syndrome in a 37-year-old female PBPC donor who received G-CSF 900 microg/day for 4 days and underwent leukapheresis. This lady had remained well and stable despite marked leukocytosis during G-CSF treatment, but developed hypotension during leukapheresis, quickly followed by hypoxemia, ascites, pericardial and pleural effusion, shock, edema, neurologic changes and hepatocellular injury. Upon G-CSF withdrawal, dopamine and crystalloid infusion, methylprednisolone treatment and suspension of apheresis, the clinical situation fully reversed. We hypothesize that leukapheresis, in the presence of marked leukocytosis and high doses of G-CSF, may have triggered neutrophil activation and the release of inflammatory mediators, resulting in tissue damage and systemic manifestations of increased capillary permeability.

We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 x 107 CD3+ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m(2)/4 days and melphalan 70 mg/m(2)/2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n = 4), MDS (n = 1), ALL (n = 3), CML (n = 3) and multiple myeloma (n = 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n = 3), acute GVHD (n = 3), chronic GVHD (n = 1) and disease relapse (n = 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day +30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear.

Several studies have demonstrated the prognostic value of cytogenetic analysis in MDS both for survival and progression to AML. However it is unknown which are the numerical or structural abnormalities required for leukemic transformation. In this report we studied clinically and cytogenetically 127 patients: 125 with primary MDS and two with AML with a previous history of MDS. Thirty-one patients (24%) showed evolution of the disease during the follow-up study. Chromosomal abnormalities found at diagnosis in patients that progressed toward AML included: del(5)(q15), +6, del(6)(q21), t(5;8)(q32;q22),-7, del(7)(q22), der(7)t(1;7)(q10;p10), t(7;11)(p15;p15), +8, del(11)(q23), del(12p), del(3)(q21), del(20)(q12) and complex karyotypes. Eight of these patients were studied cytogenetically during transformation and showed acquisition of chromosomal alterations involving dup(1q), +8, del(11)(q23), and translocations between chromosomes 1 and 8 or 7 and 17. In addition we also observed gain of ploidy and monosomy 21. These results suggest that chromosomal alterations during evolution of the disease include special chromosome gains or abnormalities of chromosomes 1, 7, 8, 11 and 17 with involvement of ETV-1, Hox-A9, Pax 4, MLL genes besides a putative gene mapped at 17q25. We also applied the International Prognostic Scoring System (IPSS) to 114 patients, excluding those submitted to allogeneic bone marrow transplant. Our patients were classified into four distinct risk groups. The analysis of risk groups presented by 27 patients who showed evolution of the disease revealed 18 at the high risk group and four at the intermediate-2 group. From the intermediate-1 risk group only five patients showed evolution of the disease. Three of these patients evolved from RA to RAEB with gain of a del(11)(q23) or an expansion of a del(12)(p12) clone. Our results suggest that some chromosomal alterations are responsible for each step in the evolution of the disease. As the pathway of evolution is not unique it has been very difficult to define what genetic alteration comes first. However from several results in the literature and our own, it seems that some chromosomal alterations may predict the evolution of the disease and are correlated with short survival, as for example the trisomy of chromosome 8, and might be incorporated in the high risk group in the IPSS. This score system has been proved to be useful for predicting survival and evolution from MDS to AML.

Single-step Multiplex RT-PCR was used as a rapid and highly sensitive method for screening patients with myeloproliferative conditions and ALL for the presence of underlying BCR-ABL gene fusions. Positive and negative results obtained with the multiplex assay were subsequently confirmed by nested PCR. We studied 21 patients for detecting the presence of b3a2, b2a2 and e1a2 BCR-ABL transcripts at diagnosis and following treatment with different therapeutical procedures. These studies allowed the molecular characterisation of patients with different haematological disorders and for demonstrating BCR-ABL transcripts in Ph-CML. In a Ph+ CML patient, a switch of isoforms was detected after bone marrow transplantation and infusion with donor lymphocytes, implying substitution of e1a2 for b3a2 coexisting with a myeloid/lymphoid biphenotypic profile. In ALL, one Ph+ patient showed coexpression of e1a2 and b2a2 at diagnosis followed by persistence of e1a2 after bone marrow transplantation. Our results were compared to previous findings in the literature on molecular diagnosis of leukaemias.

The development of acute megakaryoblastic leukemia (ANLL-M7) following myelodysplastic syndrome (MDS) has been described only in a few reports, and the mutations necessary for this transformation are still unknown. In this study, we describe a case of ANLL-M7 with a previous history of MDS presenting a complex karyotype 46,XX, t(4;11)(q21;q23),del(5)(q13q33),t(12;13)(p13;q21) and N-RAS point mutation. During MDS, the patient showed a hypercellular myelogram with dysplasia of the three myeloid lineages and the clinical symptoms characteristic of the 5q- syndrome. During the follow-up, we observed the appearance of two additional subclones, one with an isochromosome 17q and another with polyploidy. The presence of an isochromosome 17q in one subclone and polyploidy in another is probably due to the genetic instability generated by the malignant transformation.

Polymerase chain reaction (PCR) is a powerful and rapid method for specifically detecting BCR-ABL rearrangement by amplification of the complementary DNA (cDNA) produced by reverse transcription of BCR-ABL mRNA. We studied 29 patients for detecting the presence of BCR-ABL transcripts before and after bone marrow transplantation (BMT). Our sample was composed of two different groups of patients: one group (n = 18) was studied by serial follow-ups before and after BMT; a second group (n = 11) was studied several years after BMT. Detection of BCR-ABL was carried out with different primer sets at different periods of the clinical outcome of chronic myeloid leukaemia (CML). A comparison of PCR data and clinical-haematological conditions showed clear differences between patients. In the first group, eight patients showed a positive correlation between a favourable clinical outcome and molecular remission. Conversely, in the second group, six patients were BCR-ABL positive between 20 and 117 months after BMT, while only two of these patients showed signs of clinical relapse. Among all patients whose isoforms were known at some time during the course of CML, the more frequent isoform was b3a2. These results were compared to previous findings in the literature on diagnosis, outcome and prognosis of CML.

A cytogenetic and N-ras point mutation study was done in patients with primary myelodysplastic syndrome (MDS) from Rio de Janeiro, Brazil, in order to evaluate the progression of preleukemic states to overt leukemia. Cytogenetic analysis was performed in 50 patients with MDS and clonal chromosomal abnormalities were detected in 19 (38%) of them. Patients with refractory anemia (RA) or with ringed sideroblasts (RARS) presented normal karyotypes or single abnormalities as del(5q) or -Y, while patients in more advanced states as RA with excess of blasts (RAEB), RAEB in transformation (RAEB-t) and chronic myelomonocytic leukemia (CMML) showed complex karyotypes and single abnormalities involving chromosomes 7 or 8, which were related to poor prognosis and elevated risk of transformation to acute myeloid leukemia (AML). The frequency of ras activation was studied in these 50 patients with MDS. Samples of bone marrow were screened for oncogenic point mutations by DNA amplification followed by oligonucleotide hybridization analysis (PCR-ASO) at codon 12 of N-ras proto-oncogene. We detected N-ras point mutations in 21 patients (42%). Progression from MDS to AML was observed in 9 patients (18%). The correlation analysis between N-ras point mutations and specific chromosomal abnormalities indicated that although mutated N-ras was found in cells with del(5q) and monosomy 7, cells with those abnormalities and normal N-ras were also identified. Otherwise trisomy of chromosome 8 showed a correlation with N-ras point mutations and in all cases, patients showed progression of MDS to AML during the follow-up study. MDS comprises a heterogeneous group of hematopoietic disorders and probably several steps are implicated in the evolution to AML. In this work we suggest that one possible pathway of leukemogenesis in MDS includes N-ras point mutations in association with trisomy of chromosome 8.

Clinical, karyotypic, immunophenotypic, and molecular profiles of three TALL cases carrying a t(11;14) are discussed and compared with data in the literature. As previously reported, t(11;14)(p13;q11) was associated in one patient with a TALL profile of intermediate stage of maturation (CD7+, CD4+, CD8+). However, the same translocation was found to be present in another patient with a more immature, pro-TALL profile (CD7+, CD4-, CD8-). Both patients showed molecular rearrangements of the TCR beta chain gene. A third patient, with a very immature pro-TALL profile (CD34+, CD7+, CD4-, CD8-), carrying a t(11;14)(p15;q11), showed molecular rearrangements of the TCR beta and gamma chain genes, while the IgH chain genes were in germline configuration. Our data indicate that t(11;14) can also be present in TALLs of more immature stages of intrathymic development; the significant factor determining the clinical behavior of TALLs is apparently related more to cell differentiation than to the presence of this chromosome rearrangement.

The immunological reconstitution that follows bone marrow transplantation (BMT) was studied in 40 leukaemia patients: 19 with chronic myeloid leukaemia (CML), 12 with acute myeloid leukaemia (AML) and the remaining 9 with acute lymphoblastic leukaemia (ALL). The recovery of the CML group was slower than that of the ALL and AML groups. This difference was produced by the T cell compartment, as NK cell activity and B cell numbers did not differ significantly. Factors such as conditioning treatment and graft versus host disease (GVHD) prophylaxis were analysed. Our experience suggests that all leukaemia patients should not be considered as one group when analysing their immunological reconstitution, as factors related to the original disease may affect their outcome.

Twenty-nine patients with severe aplastic anaemia (SAA) were submitted to bone marrow transplantation (BMT) and their immunological recovery analysed. Total lymphocyte counts, estimation of B lymphocytes, T lymphocytes and their subsets, natural-killer (NK) activity were performed. Cells with the CD8+ phenotype and NK activity were the first signs of immunological recovery, whereas the CD4+ subset recovered later in patients who suffered from acute graft versus host disease (GvHD) and infections. Acute and chronic GvHD, cirrhosis, rejection and HIV viral infection contributed to the persistence of the profound immunodeficiency status observed after BMT. Our results did not differ greatly from the others and confirmed that BMT may be performed in underdeveloped countries despite the difficulties it might pose.