Evaluation of chromosomal abnormalities by cIg-FISH and association with proliferative and apoptotic indexes in multiple myeloma

Eighty-six newly diagnosed multiple myeloma (MM) patients from a public hospital of São Paulo (Brazil) were evaluated by cIg-FISH for the presence of del(13)(q14), t(4;14)(p16.3;q32) and del(17)(p13). These abnormalities were observed in 46.5, 9.3, and 7.0% of the patients, respectively. In order to identify the possible role of del(13)(q14) in the physiopathology of MM, we investigated the association between this abnormality and the proliferative and apoptotic indexes of plasma cells. When cases demonstrating t(4;14)(p16.3;q32) and del(17)(p13) were excluded from the analysis, we observed a trend towards a positive correlation between the proportion of cells carrying del(13)(q14) and plasma cell proliferation, determined by Ki-67 expression (r = 0.23, P = 0.06). On the other hand, no correlation between the proportion of cells carrying del(13)(q14) and apoptosis, determined by annexin-V staining, was detected (r = 0.05, P = 0.69). In general, patients carrying del(13)(q14) did not have lower survival than patients without del(13)(q14) (P = 0.15), but patients with more than 80% of cells carrying del(13)(q14) showed a lower overall survival (P = 0.033). These results suggest that, when del(13)(q14) is observed in a high proportion of malignant cells, it may have a role in determining MM prognosis. Another finding was a statistically significant lower overall survival of patients with t(4;14)(p16.3;q32) (P = 0.026). In the present study, almost half the patients with t(4;14)(p16.3;q32) died just after diagnosis, before starting treatment. This fact suggests that, in São Paulo, there may be even more patients with this chromosomal abnormality, but they probably die before being diagnosed due to unfavorable socioeconomic conditions. This could explain the low prevalence of this chromosomal abnormality observed in the present study.

Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms

Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON.

Changes in circulating endothelial progenitor cells predict responses of multiple myeloma patients to treatment with bortezomib and dexamethasone

Four cycles of chemotherapy are required to assess responses of multiple myeloma (MM) patients. We investigated whether circulating endothelial progenitor cells (cEPCs) could be a biomarker for predicting patient response in the first cycle of chemotherapy with bortezomib and dexamethasone, so patients might avoid ineffective and costly treatments and reduce exposure to unwanted side effects. We measured cEPCs and stromal cell-derived factor-1α (SDF-1α) in 46 MM patients in the first cycle of treatment with bortezomib and dexamethasone, and investigated clinical relevance based on patient response after four 21-day cycles. The mononuclear cell fraction was analyzed for cEPC by FACS analysis, and SDF-1α was analyzed by ELISA. The study population was divided into 3 groups according to the response to chemotherapy: good responders (n=16), common responders (n=12), and non-responders (n=18). There were no significant differences among these groups at baseline day 1 (P>0.05). cEPC levels decreased slightly at day 21 (8.2±3.3 cEPCs/μL) vs day 1 (8.4±2.9 cEPCs/μL) in good responders (P>0.05). In contrast, cEPC levels increased significantly in the other two groups (P<0.05). SDF-1α changes were closely related to changes in cEPCs. These findings indicate that change in cEPCs at day 21 in the first cycle might be considered a noninvasive biomarker for predicting a later response, and extent of change could help decide whether to continue this costly chemotherapy. cEPCs and the SDF-1α/CXCR4 axis are potential therapeutic targets for improved response and outcomes in MM patients.

Multiple facets of HIV-associated renal disease

HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥200 cells/mm3 was associated with better renal function after 2 years of follow-up.

Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context

Genetic abnormalities are critical prognostic factors for patients diagnosed with multiple myeloma (MM). This retrospective, multicenter study aimed to contribute with the genetic and clinical characterization of MM patients in a country with continental dimensions such as Brazil. Genetic abnormalities were assessed by cIg-fluorescent in situ hybridization (cIg-FISH) in a series of 152 MM patients (median age 55 years, 58.5% men). Overall, genetic abnormalities were detected in 52.7% (80/152) of patients. A 14q32 rearrangement was detected in 33.5% (n=51), including t(11;14), t(4;14) and t(14;16) in 18.4, 14.1, and 1% of cases, respectively. del(13q) was identified in 42.7% (n=65) of patients, of whom 49.2% (32/65) presented a concomitant 14q32 rearrangement. del(17p) had a frequency of 5.2% (n=8). del(13q) was associated with high plasma cell burden (≥50%, P=0.02), and del(17p) with advanced ISS stages (P=0.05) and extramedullary disease (P=0.03). t(4;14) was associated with advanced Durie-Salmon stages (P=0.008), renal insufficiency (P=0.01) and was more common in patients over 60 years old. This study reports similar frequencies of genetic abnormalities to most series worldwide, whereas the t(14;16) and del(17p), two high risk factors for newly diagnosed patients, exhibited lower frequencies. Our results expand the knowledge on the molecular features of MM in Brazil, a country where innovative therapies that could overcome a poor prognosis for some genetic abnormalities are not always available.

Conflicting Memory in Estonia: How Do Estonian Russian-speakers Understand the Events of 1939-40?

This thesis studies the collective memory of the Russian-speaking minority living in Estonia. The minority is exposed to two national narratives regarding the incorporation of Estonia into the Soviet Union in 1940. According to the Estonian narrative, Estonia was occupied and annexed by the Soviet Union while the Soviet-Russian narrative sees the actions to have been legal and voluntary. This thesis firstly examines thoughts the existence of these two opposing narratives evoke among the Russian-speaking minority and secondly it explores whether the views of the minority compare with the two official yet divergent narratives. The study focuses on the second and third generation minority members. The topic belongs to the field of memory studies. The objective is to understand the views the Russian minority have towards the controversial events of the years 1939-40. To accomplish the objectives set, a web-based survey using open-ended and multiple-choice questions was conducted. The open-ended questions addressed the main research questions while the multiple-choice questions contributed to forming a more comprehensive understanding of the subject in question. In order to interpret the data, qualitative content analysis has been applied. Based on the findings, the Russian-speaking minority respondents’ understanding of the events of 1939-40 could be described as fragmented, inconsistent and including viewpoints that resulted from the merger of different storylines. There is no single cohesive or coherent narrative of the past amongst the minority. In addition to that, their views do not generally comply with the narrative of the Russian Federation as often referred to in literature, even though the minority respondents do not want to see the Soviet involvement as critically as the Estonian narrative does. Many respondents conceive the events of 1939-40 as ambiguous revealing the ability to be tolerant and receptive in their views regarding the past.

University students’ regulation of learning and text processing – examples from medical and teacher education

The general aim of the thesis was to study university students’ learning from the perspective of regulation of learning and text processing. The data were collected from the two academic disciplines of medical and teacher education, which share the features of highly scheduled study, a multidisciplinary character, a complex relationship between theory and practice and a professional nature. Contemporary information society poses new challenges for learning, as it is not possible to learn all the information needed in a profession during a study programme. Therefore, it is increasingly important to learn how to think and learn independently, how to recognise gaps in and update one’s knowledge and how to deal with the huge amount of constantly changing information. In other words, it is critical to regulate one’s learning and to process text effectively. The thesis comprises five sub-studies that employed cross-sectional, longitudinal and experimental designs and multiple methods, from surveys to eye tracking. Study I examined the connections between students’ study orientations and the ways they regulate their learning. In total, 410 second-, fourth- and sixth-year medical students from two Finnish medical schools participated in the study by completing a questionnaire measuring both general study orientations and regulation strategies. The students were generally deeply oriented towards their studies. However, they regulated their studying externally. Several interesting and theoretically reasonable connections between the variables were found. For instance, self-regulation was positively correlated with deep orientation and achievement orientation and was negatively correlated with non-commitment. However, external regulation was likewise positively correlated with deep orientation and achievement orientation but also with surface orientation and systematic orientation. It is argued that external regulation might function as an effective coping strategy in the cognitively loaded medical curriculum. Study II focused on medical students’ regulation of learning and their conceptions of the learning environment in an innovative medical course where traditional lectures were combined wth problem-based learning (PBL) group work. First-year medical and dental students (N = 153) completed a questionnaire assessing their regulation strategies of learning and views about the PBL group work. The results indicated that external regulation and self-regulation of the learning content were the most typical regulation strategies among the participants. In line with previous studies, self-regulation wasconnected with study success. Strictly organised PBL sessions were not considered as useful as lectures, although the students’ views of the teacher/tutor and the group were mainly positive. Therefore, developers of teaching methods are challenged to think of new solutions that facilitate reflection of one’s learning and that improve the development of self-regulation. In Study III, a person-centred approach to studying regulation strategies was employed, in contrast to the traditional variable-centred approach used in Study I and Study II. The aim of Study III was to identify different regulation strategy profiles among medical students (N = 162) across time and to examine to what extent these profiles predict study success in preclinical studies. Four regulation strategy profiles were identified, and connections with study success were found. Students with the lowest self-regulation and with an increasing lack of regulation performed worse than the other groups. As the person-centred approach enables us to individualise students with diverse regulation patterns, it could be used in supporting student learning and in facilitating the early diagnosis of learning difficulties. In Study IV, 91 student teachers participated in a pre-test/post-test design where they answered open-ended questions about a complex science concept both before and after reading either a traditional, expository science text or a refutational text that prompted the reader to change his/her beliefs according to scientific beliefs about the phenomenon. The student teachers completed a questionnaire concerning their regulation and processing strategies. The results showed that the students’ understanding improved after text reading intervention and that refutational text promoted understanding better than the traditional text. Additionally, regulation and processing strategies were found to be connected with understanding the science phenomenon. A weak trend showed that weaker learners would benefit more from the refutational text. It seems that learners with effective learning strategies are able to pick out the relevant content regardless of the text type, whereas weaker learners might benefit from refutational parts that contrast the most typical misconceptions with scientific views. The purpose of Study V was to use eye tracking to determine how third-year medical studets (n = 39) and internal medicine residents (n = 13) read and solve patient case texts. The results revealed differences between medical students and residents in processing patient case texts; compared to the students, the residents were more accurate in their diagnoses and processed the texts significantly faster and with a lower number of fixations. Different reading patterns were also found. The observed differences between medical students and residents in processing patient case texts could be used in medical education to model expert reasoning and to teach how a good medical text should be constructed. The main findings of the thesis indicate that even among very selected student populations, such as high-achieving medical students or student teachers, there seems to be a lot of variation in regulation strategies of learning and text processing. As these learning strategies are related to successful studying, students enter educational programmes with rather different chances of managing and achieving success. Further, the ways of engaging in learning seldom centre on a single strategy or approach; rather, students seem to combine several strategies to a certain degree. Sometimes, it can be a matter of perspective of which way of learning can be considered best; therefore, the reality of studying in higher education is often more complicated than the simplistic view of self-regulation as a good quality and external regulation as a harmful quality. The beginning of university studies may be stressful for many, as the gap between high school and university studies is huge and those strategies that were adequate during high school might not work as well in higher education. Therefore, it is important to map students’ learning strategies and to encourage them to engage in using high-quality learning strategies from the beginning. Instead of separate courses on learning skills, the integration of these skills into course contents should be considered. Furthermore, learning complex scientific phenomena could be facilitated by paying attention to high-quality learning materials and texts and other support from the learning environment also in the university. Eye tracking seems to have great potential in evaluating performance and growing diagnostic expertise in text processing, although more research using texts as stimulus is needed. Both medical and teacher education programmes and the professions themselves are challenging in terms of their multidisciplinary nature and increasing amounts of information and therefore require good lifelong learning skills during the study period and later in work life.

A year after Crimea: continuity and change of Finnish-Russian relations reflected in the views of the government officials of Finland and Russia

This thesis discusses the dynamism of bilateral relations between Finland and Russia and their interconnection with wider EU-Russia relations in the sight of the recent conflict in Ukraine. In particular, incorporation of Crimea in the territory of Russia in March 2014 is believed to have triggered a series of disputes between the European Union and Russia and thus, have impacted the course of the bilateral Finnish-Russian relations. The study leans on a premise that there are some historical traditions and regularities in the Finnish foreign policy course towards Russia which make the bilateral Finnish-Russian relations special. These traditions are distinguished and described in the book “Russia Forever? Towards Pragmatism in Finnish/Russian relations” (2008) edited by H. Rytövuori-Apunen. Assuming that the featured traditions take place in modern relations between Finland and Russia, the aim of the thesis is to find out how these traditions reappear during the year shaped by the events in Ukraine. In order to do that, author follows the timeline of happenings around the Ukraine crisis starting with Crimea’s referendum on independence, and exams the way these events were commented on and evaluated by the key government officials and political institutions of Finland and Russia. The main focus is given to the Finnish official discourse on Russia during the study period. The data collection, consisting of mostly primary sources (ministerial press releases and comments, statements, speeches and blog posts of individual policy makers) is processed using the thematic analysis supported by the content analysis. The study reveals that the consequences of the Ukraine crisis have brought, among others, complications to the economic cooperation between Finland and Russia, and have stimulated the increased attention of the Finnish decision makers to the country’s security questions. As a result, the character and importance of some historical regularities of the Finnish foreign policies on Russia, like the Continental Dilemma, have taken new shape.

Vulnerability to adverse consequences of drinking and problem drinker status as predicted by risky drinking behaviours, drug use, sex differences and affect : a test of multiple models /

Although alcohol problems and alcohol consumption are related, consumption does not fully account for differences in vulnerability to alcohol problems. Therefore, other factors should account for these differences. Based on previous research, it was hypothesized that risky drinking behaviours, illicit and prescription drug use, affect and sex differences would account for differences in vulnerability to alcohol problems while statistically controlling for overall alcohol consumption. Four models were developed that were intended to test the predictive ability of these factors, three of which tested the predictor sets separately and a fourth which tested them in a combined model. In addition, two distinct criterion variables were regressed on the predictors. One was a measure of the frequency that participants experienced negative consequences that they attributed to their drinking and the other was a measure of the extent to which participants perceived themselves to be problem drinkers. Each of the models was tested on four samples from different populations, including fIrst year university students, university students in their graduating year, a clinical sample of people in treatment for addiction, and a community sample of young adults randomly selected from the general population. Overall, support was found for each of the models and each of the predictors in accounting for differences in vulnerability to alcohol problems. In particular, the frequency with which people become intoxicated, frequency of illicit drug use and high levels of negative affect were strong and consistent predictors of vulnerability to alcohol problems across samples and criterion variables. With the exception of the clinical sample, the combined models predicted vulnerability to negative consequences better than vulnerability to problem drinker status. Among the clinical and community samples the combined model predicted problem drinker status better than in the student samples.

Cognitive coaching : a multiple case study /

The purpose of this qualitative study was to investigate the application of Cognitive Coaching as a school-based professional development program to improve instructional thought and decision making as well as to enhance staff perceptions, coUegiality and school culture. This topic emerged from personal and professional issues related to the role ofthe reflective practitioner in improving the quality of education, yet cognizant of the fact that little professional development was available to train teachers to become reflective. This case study, positioned within the interpretive sciences, focused on three teachers and how their experiences with cognitive coaching affected their teaching practices. Their knowledge, understanding and use of the four stages of instructional thought (preactive, interactive, reflective and projective) were tested before and at the end of eight coaching cycles, and again after two months to determine whether they had continued to use the reflective process. They were also assessed on whether their attitude towards peer coaching had changed, whether their feelings about teaching had become more positive and whether their professional dialogue had increased. Three methods of data collection were selected to assess growth: interviews, observations and joumaling. Analysis primarily consisted of coding and organizing data according to emerging themes. Although the professed aim of cognitive coaching was to teach the process in order that the teachers would become self-analytical and self-modifying, this study found that the value of the coaching, after trust had been established in both the coach and the process, was in the dialoguing and the time set aside to do it. Once the coaching stopped providing the time to dialogue, to examine one's meanings and beliefs, so did the critical self-reflection. As a result ofthe cognitive coaching experience though, all participants grew in their feelings of efficacy, craftsmanship, flexibility, consciousness and interdependence. The actual and potential significance ofthis study was discussed according to implications for teacher supervision, professional development, school culture, further areas of research and to my personal growth and development.