Autoimmune cytopenias in chronic lymphocytic leukemia: a growing challenge in targeted therapies?

As the world’s population ages, the incidence of chronic lymphocytic leukemia (CLL) will continue to increase. CLL-related autoimmune cytopenias (AICs) are becoming a growing challenge in daily clinical practice. AICs occur in c.10% of CLL patients, and include autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, and autoimmune granulocytopenia. The complication can appear at any disease stage, both in treated and previously untreated patients. In some cases, AICs precede the diagnosis of the underlying disease. The diagnostic process of autoimmune complications is often difficult. First of all, however, it requires differentiation from bone marrow infiltration resulting from underlying disease progression. A properly established diagnosis has prognostic and therapeutic implications. Autoimmune cytopenias are more often associated with high-risk CLL (with 17p deletion, 11q deletion, wild-type variant of gene encoding immunoglobulin heavy chain variable region) and show a complex pathogenesis. CLL cells and the surrounding microenvironment are involved in autoimmune mechanisms. Treatment of AICs depends on CLL stage. In the case of isolated symptoms of AICs, without accompanying features of CLL progression, glucocorticosteroids or rituximab are recommended in the first line treatment. No response or a suboptimal response to treatment implies further therapeutic decisions. According to significant advances in the treatment of chronic lymphocytic leukemia, therapeutic strategies for autoimmune cytopenias also need to be optimized. The widespread introduction of ibrutinib, idelalisib, and venetoclax has highlighted the need for understanding the interplay between targeted therapies and AICs

Paternity leaves as an institutional proof of changes in the perception of the father’s role over the years

Charakterystyczne dla współczesności przemiany społeczne widoczne w obszarze rodziny wywołały także znaczące zmiany w postrzeganiu roli ojca. Tradycyjne ujęcie ojca jako autorytetu i głowy rodziny, zajętej „męskimi” sprawami, takimi jak organizowanie bytu i zarabianie pieniędzy, ustąpiły miejsca modelowi ojca-partnera matki we wszystkim, a więc także w opiece nad dzieckiem, w tym małym. Celem artykułu jest pokazanie transformacji ojcowskiego wizerunku w kontekście tego, w jaki sposób współcześni ojcowie biorą udział w opiece nad dziećmi kilkumiesięcznymi i młodszymi ze szczególnym uwzględnieniem urlopów tacierzyńskich jako instytucjonalnej zmiany w postrzeganiu wizerunku i roli ojca.The social changes characteristic of the present days, visible in the area of the family, have also caused significant changes in the perception of the father’s role. The traditional perception of him as the authority and head of the family, busy with “male” matters, like organizing one’s existence and earning money, gave way to the father-mother’s partner model in everything, including caring for the child as well as the little one. The aim of the article is to show the transformation of the paternal image in the context of how with particular emphasis on paternity leave as an institutional change in the percep contemporary fathers take part in caring for children several months old and younger,tion of the image and role of the father

The Experience of Being a Foster Parent in Non-Kinship Placements: Emotional and Psychological Impacts

Due to previous life experiences, children who enter the foster care system have been significantly impacted in numerous ways; and the individuals who act as their caregivers may encounter behavioral challenges as they seek to address the result of what years of abuse and trauma have created. However, as placements progress over time, the foster child may also become an integrated member of the foster family and thus attachments are formed. As a result, foster parents may experience the significant impacts of managing severe and challenging behaviors as well as breaking strong attachments with the foster child who has largely become family. Therefore, the intent of this research study was to gauge how managing behavioral challenges and forming attachments with foster children may impact the families in non-kinship placements, emotionally as well as psychologically. Furthermore, it was important to determine if these impacts additionally served as deterrents for foster families to continue their placements. The process of data collection consisted of interviews conducted with foster parents individually as well as a couple when applicable, with a previously established interview protocol serving as a guiding framework. The interviews were then transcribed and assessed for emerging themes, commonalities as well as discrepancies. Lastly, the psychological and emotional impacts of managing behavioral challenges and forming attachments were identified and discussed. As the findings indicate, despite their intensity, these impacts did not serve to deter participants from continuing their role as foster parents. Overall, the findings of the present study were largely consistent with previously cited research and provided additional implications as well as recommendations for future policy and practice

Clinical and experimental studies of mechanisms of action, efficacy and tolerability of glucocorticoids in patients with inflammatory rheumatic diseases

Titel Gutachter Gliederung Abkürzungsverzeichnis Einführung Zielsetzung Patienten und Methoden Ergebnisse Diskussion Zusammenfassung Literaturverzeichnis Anhang Danksagung Erkläerung an Eides StattKlinische und experimentelle Untersuchungen zu Wirkmechanismen, Wirksamkeit und Verträglichkeit von Glucocorticoiden bei Patienten mit entzündlich- rheumatischen Erkrankungen Teil I Expression von membranständigen Glucocorticoidrezeptoren auf peripheren mononukleären Blutzellen bei Patienten mit ankylosierender Spondylitis (AS) HINTERGRUND: Kürzlich wurde von unserer Arbeitsgruppe zum ersten Mal eine Expression von membranständigen Glucocorticoidrezeptoren (mGCR) auf Zellen des peripheren Blutes (PBMC) und deren Hochregulation bei Patienten mit aktiver rheumatoider Arthritis (RA) demonstrieret. Auch bei Patienten mit systemischem Lupus erythematodes (SLE) war die Frequenz von mGCR positiven Monozyten (CD14+) signifikant höher als bei gesunden Kontrollen. Weiterhin konnte eine glucocorticoid-abhängige Herunterregulation der mGCR beobachtet werden, welches auf einen negativen Feedbackmechanismus zur Modulation der Glucocorticoidwirkung hindeutet. FRAGESTELLUNG: Wir untersuchten die Expression von mGCR bei Patienten mit ankylosierender Spondylitis (AS) ohne Glucocorticoidtherapie in Abhängigkeit von der Krankheitsaktivität. METHODEN: Für diese Untersuchung wurden 21 Patienten mit einer gesicherten ankylosierenden Spondylitis (M. Bechterew) nach den modifizierten New York Kriterien ausgewählt. Erhobene klinische Parameter : Alter, Erkrankungsdauer, Medikamentenanamnese, klinische/radiologische/Laborparameter, BASDAI, BASDAI 6 (6 Wochen) und NRS. Es wurden Patienten ohne Glucocorticoidtherapie und ohne einen erinnerlichen Infekt in den letzten vier Wochen ausgewählt. Eine hoch-sensitive Liposomenfärbung wurde zur Detektion der mGCR auf PBMC von Patienten und Kontrollpersonen angewandt. Die Verwendung von magnetofluoreszenten antikörperkonjugierten Liposomen ermöglichte es, die Signalintensität um das 100- bis 1000-fache im Vergleich zur konventionellen Färbung zu verstärken und somit eine Detektion von 50-100 Molekülen pro Zelle mit Hilfe der Durchflusszytometrie (FACS) zu erzielen. ERGEBNISSE: Wir konnten eine mGCR Expression auf humanen PBMC der gesunden Kontrollen zeigen. Monozyten (4.8±1.4%), B-Lymphozyten (4.4±3.6%), jedoch keine T-Lymphozyten zeigten eine mGCR Expression. Im Vergleich dazu war die Frequenz mGCR-positiver Monozyten (Mittelwert 12,5 ± 9,2%) und B-Zellen (9,0 ± 6,0%) bei Patienten mit AS (p<0,05) signifikant höher. Es konnte jedoch keine Korrelation zwischen der Frequenz mGCR-positiver Zellen und CRP, BSG, BASDAI, BASDAI 6 sowie NRS festgestellt werden. Wir konnten aber eine Korrelation zwischen dem Anteil der mGCR-positiven Monozyten und B-Zellen finden (p<0,05). Wir untersuchten auch PBMC in der Synovialflüssigkeit bei AS Patienten und fanden, dass die Frequenz mGCR-positiver Monozyten im Gelenkpunktat im Vergleich zum Blut um das Zweifache erhöht war. Die Frequenz mGCR-positiver B-Zellen war in beiden Kompartimenten vergleichbar. FAZIT: Patienten mit AS zeigen eine signifikante Hochregulation der mGCR auf Monozyten und B Lymphozyten, welche keine Korrelation mit humoralen oder anderen Krankheitsaktivitätsparametern aufweist. mGCR sind auf T Lymphozyten nicht vorhanden. Unsere Daten sind möglicherweise Ausdruck des nur begrenzten Ansprechens einer low-dose Therapie im Gegensatz zur Hochdosistherapie bei AS Patienten. Selektive mGCR-bindende Pharmaka könnten demnach eine neue Therapieoption für AS darstellen. Teil II Krankheitskontrolle und Nebenwirkungsprofil der low-dose Methylprednisolontherapie im Vergleich zur medium-dose Therapie bei Patienten mit entzündlichen rheumatoiden Erkrankungen HINTERGRUND: Die Glucocorticoide sind sehr effektive und häufig angewandte Medikamente für viele entzündliche Autoimmunerkrankungen. Leider ist die Anzahl ihrer Nebenwirkungen ebenso umfangreich wie die Zahl ihrer Anwendungsmöglichkeiten. Neue Erkenntnisse über einen krankheitsmodulierenden Effekt der low-dose Therapie (< 7,5 mg Prednisolon pro Tag) bei rheumatoiden Erkrankungen hat zu einer Neubewertung der Glucocorticoid-Therapie geführt. Um das Nebenwirkungsprofil zu minimieren, wird eine low-dose Therapie insbesondere bei Patienten in einem frühen Erkrankungsstadium diskutiert. FRAGESTELLUNG: Das Ziel dieser Studie war der Vergleich des Wirkungs- Nebenwirkungsprofils bei Patienten mit low-dose und medium-dose Glucocorticoidtherapie. METHODEN: Studiendesign: Es wurde eine Stichprobe von 70 Patienten mit entzündlich-rheumatischen Erkrankungen der Medizinischen Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie der Charité untersucht. In zwei aufeinanderfolgenden Jahren wurde eine Querschnittsuntersuchung von 70 Patienten sowie eine Langzeituntersuchung bei 14 Patienten durchgeführt. Jeder Patient wurde seit mindestens einem Jahr mit Methylprednisolon behandelt. Das Studienkollektiv wurde in Abhängigkeit von der im letzten Jahr durchschnittlich verabreichten MP-Dosis in zwei Gruppen aufgeteilt (Gruppe 1 MP < 6 mg/d; Gruppe 2 MP ≥ 6 mg/d). Die Gruppen waren bezüglich des Alters, des Geschlechts und der Einnahme anderer Medikamente (außer MP) vergleichbar. Screening und diagnostische Methoden: Erhobene Parameter: klinische Untersuchung, Laborparameter, Knochendichtemessung an der Lendenwirbelsäule sowie dem linken Schenkelhals mittels dual-energy X-ray absorptiometry (DXA), Fragebögen zum Gesundheitszustand wie der Short Form 36-item Health Survey (SF-36) und Health Assessment Questionnaire (HAQ) wurden erhoben. Prophylaxe und Zusatztherapie: Unsere Patienten erhielten als Begleittherapie in unterschiedlicher Häufigkeit Calcium und Vitamin D, eine Hormonersatztherapie, Bisphosphonate, und andere Medikamente in Abhängigkeit von den Begleiterkrankungen. ERGEBNISSE: Zu den sehr häufigen GC- Nebenwirkungen gehörten Hautveränderungen (89% der Patienten), cushingoider Habitus (64,3% der Patienten), Erhöhung der Calcitriol- sowie der Cholesterolwerte (77,1% bzw. 41,4% der Patienten). In der Querschnittstudie wurden statistisch signifikante Unterschiede zwischen Gruppe 1 und Gruppe 2 für das Vorliegen eines Glaukoms (p = 0,014) sowie für Osteoporoseschmerzen bei Bewegung (p = 0,04) beobachtet. Tendenzielle Unterschiede wurden bezüglich des physischen Wohlbefindens (SF-36: p = 0,06, HAQ: p = 0,096), der Calcidiolwerte (p = 0,098) sowie bezüglich der Hautveränderungen (Unterblutungen, p = 0,086) festgestellt. In der Langzeitstudie zeigten sich Gruppenunterschiede in den Calcidiol-, Calcitriol- sowie in den BSG- und CRP- Werten. FAZIT: Unsere Studie zeigt, dass die low-dose Glucocorticoid-Therapie zu einer Minimierung des Nebenwirkungsprofil führt. Um jedoch das genaue Risiko-Nutzen-Profil einer low-dose Therapie zu beurteilen, müssen weitere Parameter, wie das individuelle Ansprechen auf Glucocorticoide berücksichtigt werden.Clinical and experimental studies of mechanisms of action, efficacy and tolerability of glucocorticoids in patients with inflammatory rheumatic diseases Part I Membrane glucocorticoid receptor expression on peripheral blood mononuclear cells in patients with ankylosing spondylitis BACKGROUND: Recently we have demonstrated for the first time the expression of membrane- bound glucocorticoid receptors (mGCR) on normal peripheral blood mononuclear cells (PBMC) and their up-regulation in patients with active rheumatoid arthritis (RA). Also the frequency of mGCR positive monocytes (CD14+) are significantly higher in patients with systemic lupus erythematosus (SLE) than in healthy controls. In these patients mGCR are down-regulated by glucocorticoids, suggesting a negative feedback loop to control glucocorticoid action. OBJECTIVE: Here we investigated the expression of membrane-bound glucocorticoid receptors (mGCR) on peripheral blood mononuclear cells (PBMC) in patients with ankylosing spondylitis (AS) of various disease activities, but not treated with glucocorticoids. METHODS: 21 consecutive patients were examined fulfilling the modified New York criteria for AS. Clinical assessment included: age, disease duration, treatment, clinical/radiological/laboratory data, and the calculation of the BASDAI, BASDAI 6 (6 week) and NRS. Patients without glucocorticoids and no signs of infection for the last 4 weeks were included in the study. To analyze the expression of mGCR on PBMC obtained from patients and healthy controls, we used a highly sensitive immunofluorescence FACS based procedure. Using magnetofluorescent liposomal conjugated antibodies, our technique allows us to increase the signal-to-noise ratio up to 1000-fold compared to conventional methods. This enables us to detect down to 50-100 target molecules per cell. RESULTS: We found a considerable expression of mGCR on human PBMC of healthy controls. Monocytes (4.8±1.4%), B-lymphocytes (4.4±3.6%), but not T lymphocytes were positive for mGCR. In contrast, the number of mGCR positive cells (monocytes: 9.0±6.0%, B cells: 12.5±9.2%) was significantly higher in patients with AS (p<0.05). There was no significant correlation between the frequency of mGCR positive cells and CRP, BSG, BAS-DAI, BASDAI 6 or NRS. However, we found a significant correlation between mGCR positive monocytes and mGCR positive B cells (p<0.05) in the AS group. The disease activity parameters were positively correlated to each other. We also examined immune cells from the synovial fluid obtained from AS patients and found the frequency of mGCR positive monocytes to be doubled as compared with monocytes from the peripheral blood. In contrast, the number of mGCR positive B cells was comparable in both compartments. CONCLUSION: Patients with AS show a significant up-regulation of mGCR on monocytes and B-lymphocytes that is neither correlated with humoral activity of inflammation nor with overall disease activity. mGCR are not present on T lymphocytes. Our findings may be related to the limited benefit of low-dose and the efficacy of high-dose glucocorticoid treatment in AS. Drugs binding selectively to mGCR may be a new therapeutic option for AS. Part II Does low-dose methylprednisolone therapy evoke fewer side effects in patients with inflammatory autoimmune diseases? BACKGROUND: Glucocorticoids are commonly and widely used effective agents for the control of many inflammatory autoimmune diseases. However, glucocorticoid usage is associated with a high incidence of unpleasant side effects. Recent evidence for a disease-modifying potential of low-dose glucocorticoids in the treatment of rheumatoid arthritis has renewed the debate on the risk benefit ratio with this therapy. To minimize side effects, low-dose glucocorticoid therapy (< 7.5 mg prednisone per day) is being reconsidered in particular for patients with early disease. OBJECTIVES: The aim of this study was to compare the control of disease activity and the prevalence of side effects between patients receiving low-dose or medium-dose glucocorticoid therapy respectively. METHODS: Study design: A sample of 70 patients with rheumatic diseases has been recruited and assessed from the outpatient department of rheumatology and clinical immunology, Charité. We conducted a cross-selectional study on 70 patients and a longitudinal study on 14 patients over two consecutive years. Each patient has been treated for at least one year with metylprednisolone. A total of 70 patients were divided into two groups according to the dose of methylprednisolone (group 1 < 6mg methylprednisolone/d and group 2 ≥ 6 mg methylprednisolone/d). The two investigated groups did not differ for age, gender and other medication than methylprednisolone. Screening and diagnostic methods: clinical evaluation and laboratory parameters, measurement of bone mineral density at the lumbal spine and femor neck by dual-energy X-ray absorptiometry (DXA), generic health outcome questionnaires such as the short form 36-item health survey (SF-36) and the Health Assessment Questionnaire (HAQ). Prophylactic and corrective therapies: calcium and vitamin-D nutritional supplementation, ovarian hormonal therapy, anti-osteoporosis medication (bisphosphonates), other unrelated drugs. RESULTS: Frequent side effects were skinchanges (89% of patients), cushingoid manifestation (64,3% of patients), increase in calcitriol (77,1% of patients) und hyperchloesterolaemia (41,4% of patients). Both investigated groups differed significantly with respect to the prevalence of glaucoma (p=0,014), osteoporotic back pain among force (p=0,04), physical functioning score of SF-36 (p=0,06), HAQ (p=0,096), decrease of plasma 25-hydroxyvitamin D concentration (p=0,098) and subcutaneous haematomas (p=0,086). The longitudinal study revealed significant differences in 25-hydroxyvitamin D and 1.25-hydroxyvitamin D levels, erythrocyte sedimentation and C-reactive protein concentration. Conclusion: We conclude that low-dose glucocorticoid therapy may minimize some side effects of glucocorticoid treatment, however to clarify the risk benefit ratio for patients receiving low-dose therapy further parameters such as the individual glucocorticoid responsiveness need to be considered

Sensitive subject matters: What determines vulnerability in Social Work research?

While research standards routinely discuss the protection of vulnerable populations, social work historically has emphasized populations-at-risk in the training of social work students. These terms do not necessarily refer to the same populations or mutually exclude each other. How do social work instructors assist students in topic selection for research endeavors and negotiate appropriate human subjects protections? What work should/ should not be completed in the social work research classroom? This paper explores the recent work of a student investigator that created new dynamics for one department and yielded further introspection about our own processes and examination into how other schools handle student research at the Masters level

"Excitonic" and Photoionization Absorption Spectra of Iron in III-V Materials

We report optical absorption measurements of Fe-doped GaAs, InP and GaP crystals obtained with the help of different doping techniques. In all these crystals photoionization spectra corresponding to Fe$\text{}^{3+}$ → Fe$\text{}^{2+}$ transitions with sharp "excitonic" lines were observed. The intensities of these lines are not proportional to the intensities of photoionization absorption bands, i.e. to the concentration of the Fe$\text{}^{3+}$ centers. Variation of more than one order of magnitude was observed for different semiconductors and for different crystals of the same material. These results suggest that only some iron centers are responsible for the "excitonic" spectra