Immunologische Untersuchungen zur biomodulatorischen Therapie der akuten myeloischen Leukämie

Die akute myeloische Leukämie (engl. acute myeloid leukemia; AML) ist eine rasch progrediente, maligne Erkrankung des Knochenmarks. Betroffen sind überwiegend Erwachsene, 80% der Erkrankten sind älter als 65 Jahre. Unter der Therapie bestehend aus Chemotherapie und allogener Stammzelltransplantation (engl. haematopoietic stem cell transplantation; HSCT) beträgt die 5-Jahres-Überlebensrate bei jüngeren Patienten ( 60 Jahre) 5-15%. Eine Sonderstellung nimmt die akute Promyelozytenleukämie (engl. acute promyelocytic leukemia; APL) als Unterform der AML ein. APL Zellen können mit dem Medikament All-trans-Retinsäure (engl. all-trans- retinoic acid; ATRA) zur Differenzierung gebracht werden. Mit der Standardtherapie bestehend aus ATRA und Chemotherapeutika oder Arsentrioxid können APL Patienten in 75- 80% der Fälle langfristig geheilt werden. Bei anderen Formen der AML ist ATRA allerdings wenig wirksam8. Insgesamt haben sich Therapie und Prognose der AML in den letzten 50 Jahren verbessert. Jedoch ist die Prognose bei älteren Patienten, deren Erkrankung chemotherapierefraktär ist, oder die aufgrund von Komorbiditäten nicht mehr für eine intensive Chemotherapie in Betracht kommen, weiterhin schlecht. Dies macht die Erforschung neuer Therapien notwendig. Die vorliegende Arbeit basiert auf der Beobachtung von Thomas et al., dass ATRA in Kombination mit dem Peroxisomen-Proliferator-aktivierten Rezeptor γ Agonisten (engl. peroxisome proliferator-activated receptor γ; PPAR-γ) Pioglitazon (engl. pioglitazone; PGZ) und der hypomethylierenden Substanz 5-Azacytidin (engl. 5-azacytidine; AZA) bei älteren, therapierefraktären Patienten eine komplette Remission der AML induzieren kann. Bei zytomorphologischen Untersuchungen von Blutproben dieser Patienten fielen im peripheren Blut vermehrt reife Granulozyten auf. In diesen Zellen konnten spezifische Mutationen der ursprünglichen AML Blasten nachgewiesen werden. AML Blasten zeigen in der Regel zytomorphologisch Ähnlichkeit mit unreifen hämatopoetischen Stammzellen. Der Nachweis von Tumorzellen mit Ausreifungszeichen legte den Schluss nahe, dass durch die Kombinationstherapie APA (ATRA + PGZ + AZA) eine Differenzierung der Blasten zu reiferen, myeloischen Zellen (Granulozyten) induziert worden war. Immunsuppression und Infektneigung durch Knochenmarksinfiltration11 und zytostatische Therapeutika wie 5- Azacytidin oder Cytarabin tragen wesentlich zur Mortalität von AML Patienten bei. Mit der Ausdifferenzierung von AML Blasten zu funktionsfähigen Immunzellen könnte man dem entgegenwirken. In dieser Arbeit wurden anhand von in vitro Modellen die Auswirkungen der Medikamentenkombination APA auf primäre AML Zellen von Patienten untersucht. Es sollte herausgefunden werden, ob und wie intensiv die Behandlung zur Zytoreduktion oder auch Ausdifferenzierung von Blasten führt. Die behandelten Zellen wurden zytomorphologisch und durchflusszytometrisch auf Merkmale ihrer Differenzierung hin untersucht. Im Hinblick darauf, dass man sich durch APA die Entwicklung funktionsfähiger Immunzellen erhoffte, wurden auch die funktionellen Eigenschaften (Fähigkeit zur Phagozytose, Fähigkeit zur Bildung reaktiver Sauerstoffspezies) der AML Zellen betrachtet. Es konnte gezeigt werden, dass die Behandlung von AML Blasten mit APA sowohl im Vergleich zur unbehandelten Kontrolle (p = 0,01), als auch im Vergleich zur ATRA- Monotherapie (p = 0,04) zu einer signifikanten Reduktion der Zellzahl führt. Entsprechend war der Anteil Annexin V+ Zellen als Maß der Apoptoserate gegenüber der unbehandelten Kontrolle nach APA-Behandlung signifikant erhöht (p = 0,005). Der Anteil zytomorphologisch differenzierter, myeloischer Zellen war nach APA-Behandlung signifikant höher als in der unbehandelten Kontrolle (p = 0,02). Analog hierzu konnte eine signifikant erhöhte Phagozytosefähigkeit im Vergleich zur Kontrolle (p = 0,02), sowie eine vermehrte ROS-Bildung (engl. reactive oxygen species; reaktive Sauerstoffspezies) (p = 0,02) nachgewiesen werden. Somit kann durch die Behandlung von primären AML Blasten mit APA in vitro sowohl eine Zytoreduktion als auch eine Ausreifung zu funktionsfähigen Immunzellen erreicht werden

The workplace as a learning environment: Perceptions and experiences of undergraduate medical students at a contemporary medical training university in Uganda

Background. One of the most effective ways of translating medical theory into clinical practice is through workplace learning, because practice is learnt by practising. Undergraduate medical students at Makerere University College of Health Sciences, Kampala, Uganda, have workplace rotations at Mulago National Referral and Teaching Hospital (MNRTH), Kampala, for the purpose of learning clinical medicine. Objectives. To explore undergraduate medical students’ perceptions and experiences regarding the suitability of MNRTH as a learning environment to produce competent health professionals who are ready to meet the demands of contemporary medical practice, research and training. Methods. This was a cross-sectional study with a mixed-methods approach. Students’ perceptions and experiences were assessed using the Dundee Ready Educational Environment Measure (DREEM), as well as focus group discussions (FGDs). Data from DREEM were analysed as frequencies and means of scores of perceptions of the learning environment. FGD data were analysed using thematic analysis. Results. The majority of students perceived the learning environment as having more positives than negatives. Among the positive aspects were unrestricted access to large numbers of patients and a wide case mix. Negative aspects included overcrowding due to too many students, and inadequate workplace affordances. Conclusions. The large numbers of patients, unrestricted access to patients and the wide case mix created authentic learning opportunities for students – they were exposed to a range of conditions that they are likely to encounter often once they qualify. The areas of concern identified in the study need to be addressed to optimise learning at the workplace for undergraduate medical students

Corneal Intrastromal Implantation Surgery by means of MyoRing Corneal Implant for the Treatment of Keratoconus: A Review

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Safety and Precision of Two Different Flap-morphologies Created During Low Energy Femtosecond Laser-assisted LASIK

Purpose: Currently, two major principles exist to create LASIK flaps: firstly, a strictly horizontal (2D) cut similar to the microkeratome-cut and secondly an angled cut with a “step-like” edge (3D). The strictly horizontal (2D) cut method can be performed using apparatus such as the low-energy FEMTO LDV Z8 laser and its predecessors which are specific to this type. Alternatively, the low-energy FEMTO LDV Z8 laser’s 3D flap design creates an interlocking flap-interface surface which potentially contributes toward flap stability. In addition, the FEMTO LDV Z8 offers flap-position adjustments after docking (before flap-creation). The current study analyzed precision, safety, efficacy, as well as patient self-reported pain and comfort levels after applying two different types of LASIK flap morphologies which were created with a low-energy, high-frequency femtosecond (fs) laser device. Methods: A prospective, interventional, randomized, contralateral eye, single-center comparison study was conducted from November 2019 to March 2020 at the Hamburg vision clinic/ zentrumsehstärke, Hamburg, Germany. Eleven patients and 22 eyes received low-energy fs LASIK treatment for myopia or myopic astigmatism in both eyes. Before the treatment, the eyes were randomized (one eye was treated with the 2D, the other eye with the 3D method). Results: The mean central flap thickness one month after surgery was 110.7 ± 1.6 μm (2D) and 111.2 ± 1.7 μm (3D); P = 0.365 (2D vs 3D). Flap thickness measured at 13 different points resulted in no statistically significant differences between any of the measurement points within/between both groups; demonstrating good planarity of the flap was achieved using both methods. Despite not being statistically significant, the surgeons recognized an increase in the presence of an opaque bubble layer in the 3D flap eyes during surgery and some patients reported higher, yet not statistically significant, pain scores in the 3D flap eyes during the first hours after the treatment. Overall, safety- and efficacy indices were 1.03 and 1.03, respectively. Conclusion: In this prospective, randomized, contralateral eye study, the low-energy fs laser yielded predictable lamellar flap thicknesses and geometry at one-month followup. Based on these results, efficacy and safety of the corresponding laser application, that is, 2D vs 3D, are equivalen

Bilateral Crystalline Corneal Deposits as First Clinical Manifestation of Monoclonal Gammopathy: A Case Report

Aims: To report the clinical and diagnostic findings of a patient with bilateral corneal deposits caused by an underlying monoclonal gammopathy. Methods: Slit-lamp biomicroscopy, confocal microscopy and additional serological tests were performed on a 35-year-old man presenting with bilateral crystalline corneal deposits. Results: The patient was diagnosed as having monoclonal gammopathy based on elevated levels of serum immunoglobulin G. Confocal microscopy showed highly reflective (protein) deposits throughout the entire cornea, with the highest density in the epithelium and anterior stromal keratocytes. Conclusions: Monoclonal gammopathy, a potential sign of a life-threatening disease, can lead to dense, bilateral corneal deposits. As such changes can occur long before ocular or systemic discomforts appear, an early diagnosis is crucial. Ophthalmologists should be aware of corneal deposits as potential warning signs of monoclonal gammopathy

Solving the TTC 2011 Reengineering Case with Henshin

This paper presents the Henshin solution to the Model Transformations for Program Understanding case study as part of the Transformation Tool Contest 2011.Comment: In Proceedings TTC 2011, arXiv:1111.440

Saying Hello World with Henshin - A Solution to the TTC 2011 Instructive Case

This paper gives an overview of the Henshin solution to the Hello World case study of the Transformation Tool Contest 2011, intended to show basic language concepts and constructs.Comment: In Proceedings TTC 2011, arXiv:1111.440

A modified delphi study to determine the contents of a seizure diary for patients living with epilepsy in South Africa

Background: Epilepsy is a debilitating chronic medical condition affecting many patients globally. A seizure diary is used in monitoring and managing patients with epilepsy. In South Africa, no standardized diary is currently being used. Objective: This study intended to develop a consensus among experts managing patients with epilepsy on the content of a seizure diary. Methods: The modified Delphi method consisted of three survey rounds spanning six months. Using a three-point Likert scale questionnaire, in round one, the panelists were required to choose an option (definitely required, optional, and not required) for 50 items and comment on the contents of the diary. In round two, three items were added based on comments from the panelists. In round three, panelists were allowed to deliberate further on unresolved items and change their responses in view of the group responses. The consensus was determined as a priori threshold of >70% on items definitely required, optional, or not required. Results: Eleven local and two international panelists were enrolled in this study. Twelve completed all three rounds. The consensus was achieved in 21 of 50 items in round 1, three of seven items in round 2, and one of two items in round 3, of which 18 were definitely required as contents of a seizure diary. Conclusions: Based on expert opinions, the modified Delphi study determined the essential contents of a seizure diary for use by patients with epilepsy in South Africa

Strategies to enhance the approach to prostate cancer screening of south African Black men in the Free State: a Delphi study

Background. The incidence and mortality rates of prostate cancer (PCa) are disproportionately on the increase among South African Black men. Recent studies show a greater net benefit of prostate-specific antigen (PSA) screening of Black men compared with the general population. There are, however, knowledge, attitude and practice (KAP) gaps among primary healthcare providers (HCPs) and users (Black men) on PCa screening. Likewise, there is scarcity of research on strategies to address these gaps. Objective. This study sought to determine complementing strategies to enhance the approach to PCa screening of African men in the Free State, South Africa, from the perspectives of primary HCPs and users. Methods. This study utilized a three-round modified Delphi survey to achieve its aim. Consensus was determined by an a priori threshold of ≥ 70% of agreement. Results. The survey involved a multidisciplinary panel of 19 experts. The consensus was reached on 34 items (strategies) to enhance the approach to PCa screening in the study setting. Community health education strategies were proffered, relating to relevant topics, methods and venue of delivery, and persons to deliver the education. Continuing education topics and methods of instruction were suggested for primary HCPs. Conclusion. In view of the existing KAP gaps in PCa screening among primary HCPs and users (Black men), an expert consensus was determined, on complementing strategies to enhance the approach to PCa screening of South African Black men in the study setting