Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response

Neutrophil granulocytes are important mediators of innate immunity, but also participate in the pathogenesis of (auto)inflammatory diseases. Neutrophils express a specific set of proteolytic enzymes, the neutrophil serine proteases (NSPs), which are stored in cytoplasmic granules and can be secreted into the extra- and pericellular space upon cellular activation. These NSPs, namely cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3), have early been implicated in bacterial defense. However, NSPs also regulate the inflammatory response by specifically altering the function of cytokines and chemokines. For instance, PR3 and NE both inactivate the anti-inflammatory mediator progranulin, which may play a role in chronic inflammation. Here, we provide a concise update on NSPs as modulators of inflammation and discuss the biological and pathological significance of this novel function of NSPs. Mounting evidence support an important proinflammatory function for PR3, which may have been underestimated in the past.     

Urothelkarzinom-assoziierte Acanthosis nigricans – symptomatische Therapie mit Calcipotriol

Bei der Acanthosis nigricans handelt es sich um eine Differenzierungsst?rung der Haut- und Schleimh?ute unterschiedlicher ?tiologie, welche klinisch durch Hyperpigmentierung, samtartige Hautverdickung, vergr?bertes Hautrelief und Ausbildung von verruk?sen Exkreszenzen besonders in den intertrigin?sen Arealen charakterisiert ist. Bei der Acnathosis nigricans maligna liegt in der überwiegenden Zahl der F?lle ein Adenokarzinom des Intestinaltraktes vor, welches zum Zeitpunkt der Diagnosestellung oft nur noch palliativ behandelt werden kann. Wir berichten über die seltene Assoziation einer Acanthosis nigricans mit einem Urothelkarzinom der Harnblase. Ein symptomatischer Behandlungsversuch mit Calcipotriol-Salbe führte zu einem deutlichen Rückgang der hyperkeratotischen und papillomat?sen Hautver?nderungen.     

German register for glaucoma patients with dry eye. I. Basic outcome with respect to dry eye

Background  The purpose of this register was to determine the links between glaucoma, age, concomitant disease, medication, and dry eye in a large group of glaucoma patients. Methods  A total of 20,506 patients from 900 centers across Germany were included. The first 30 consecutive glaucoma patients at each center were recruited. Epidemiological data as well as information on glaucoma, medication, concomitant diseases, dry eye, and local symptoms were elicited by means of a questionnaire. We analyzed primary open-angle glaucoma (POAG), pseudoexfoliation glaucoma (PEX), and pigmentary glaucoma (PDG). Results  According to the register data, more women develop dry eye and glaucoma than men (56.9 vs. 45.7%). The most frequent concomitant systemic diseases were hypertension (48.1%), diabetes mellitus (22.5%), and dry mouth, nose, and skin (11.3%). As expected, the highest incidence of dry eye was found in those patients with dry mouth, nose, and skin. Dry eye occurred with dissimilar frequencies in association with the various glaucoma types: PEX>POAG>PDG. The incidence of dry eye increases with age. The gender difference in the occurrence of dry eye becomes apparent from the age of 50. Dry eye occurred more frequently when three or more antiglaucoma drugs were used and increased with the duration of glaucoma disease. Conclusions  We publish the first results from the German Glaucoma and Dry Eye Register. We found that the occurrence of dry eye is linked to several factors. Thus, the type of glaucoma has an impact on the risk of dry eye. The quantity of eye drops applied also plays a role in the development of the dry eye syndrome if more than three medications are used. While POAG is usually treated with one drug, PEX and PDG tend to be treated with multiple drugs. The gender difference in the occurrence of dry eye becomes apparent from the age 50 years. Because of the vicious circle of dry eye, antiglaucoma eye drops containing benzalkonium chloride compromises patient compliance. The results of the register are therefore of key relevance for the care of glaucoma patients. Sponsoring organizations: Chibret Pharmazeutische GmbH     

A test of concordance between patient and psychiatrist valuations of multiple treatment goals for schizophrenia

Background While much discussion has been placed on the problem of poor compliance in the treatment of schizophrenia, there has been little discussion on the concordance between patients and psychiatrists, an important contributing factor to patient‐centred care. Objective To estimate the concordance between patients’ and psychiatrists’ (ordinal and cardinal) valuations of multiple goals for schizophrenia treatment and to illustrate the utility of the self‐explicated method in valuing a large number of treatment goals. Design Twenty treatment goals were identified during focus groups and literature review and were presented to patients and psychiatrists during structured interviews. Respondents were asked to rank the multiple treatment goals and rate them on a 5‐point Likert scale. Three scores were calculated based on the ranking (1–20), rating (Likert scale) (1–5) and a self‐explicated method estimated as the product of rating and ranking score (1–100). Concordance was tested using Spearman’s rho for overall ordinal rankings and via anova and F‐test for the cardinal values assigned to a specific treatment goal. Participants A total of 105 outpatients diagnosed with schizophrenia and 160 psychiatrists in Germany. Results Patient and psychiatrist values were concordant when the ordinal properties of their valuations were assessed by rating (ρ = 0.63; P = 0.002), ranking (ρ = 0.51; P = 0.02) and self‐explicated methods (ρ = 0.54; P = 0.01). Significant discordances were found when comparing the cardinal value placed on any given treatment goal using all three approaches, but the self‐explicated method produced a more discerning statistic. Relative to patients, psychiatrists significantly (P < 0.05) overvalued reduced lack of emotion, improved sexual pleasure and improved communication while undervaluing reuptake of activities of daily living, improved satisfaction and recovered capacity for work. Conclusions While there is an overall concordance between patients’ and psychiatrists’ valuation, significantly different valuations on specific goals can be identified. Here, psychiatrists tend to focus on ‘textbook’ outcomes, while patients are more concerned with functioning and living a normal life. This study also demonstrates the importance of comparing the concordance in treatment goals and the importance of preference‐based methods, such as the self‐explicated method, in the study of concordance.     

Childhood near‐tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases

Objectives: Patients with near‐tetraploid (karyotype: 81 – 103 chromosomes) acute lymphoblastic leukemia (NT‐ALL) constitute about 1% of childhood ALL and data reported on them are limited and controversial. The aim of the study was to enlarge the knowledge on these rarely occurring ALL. Methods: The members of the European Group for Immunophenotyping of Leukemias (EGIL) searched retrospectively their databases for NT‐ALL patients. Results: We collected data of 36 European children from seven European countries with NT‐ALL diagnosed since 1992. All patients reached complete remission (CR) after induction chemotherapy. Their blasts were negative for peroxidase and BCR‐ABL1. Ten children were diagnosed as T‐cell ALL (T‐ALL) EGIL categories (T‐I n = 2, T‐II n = 2, T‐III n = 3, T‐IV n = 3) and four displayed various structural chromosomal abnormalities. Eight of 10 T‐ALL remained in 1st CR; one died in CR from sepsis and one is alive in 2nd CR. Median survival was 88 (7–213) months. B‐cell precursor (BCP) ALL was diagnosed in 26 children. Thirteen were positive for ETV6‐RUNX1 and are alive in 1st CR for 32–147 months. Ten children were ETV6‐RUNX1 negative and remained in 1st CR for 16–163 months. One girl with hypodiploid and NT metaphases and ETV6‐RUNX1‐negative BCP‐ALL and one of two boys with NT‐BCP‐ALL not examined for ETV6‐RUNX1 died of infection after stem cell transplantation in 2nd/3rd CR. Secondary myelodysplastic syndrome developed in two patients with NT‐BCP‐ALL. Conclusions: Our data demonstrate immunophenotypic, cytogenetic, and molecular heterogeneity of NT‐ALL and favorable prognosis of most NT‐ALL across different immunophenotypic and/or genetic ALL subtypes.     

Vision and visual cortical maps in mice with a photoreceptor synaptopathy: Reduced but robust visual capabilities in the absence of synaptic ribbons

How little neurotransmission in the visual system is sufficient to promote decent visual capabilities? This question is of key importance for therapeutic approaches to restore vision in patients who suffer from degenerative retinal diseases. In the retinae of mice, mutant for the presynaptic scaffolding protein Bassoon (Bsn), signal transfer at photoreceptor ribbon synapses is severely disturbed due to impaired ribbon attachment to the active zone. We have used two different behavioural tasks and optical imaging of intrinsic signals to probe vision in young and adult Bsn?/? mice and their wild-type littermates. Here we show that while visual acuity was significantly reduced in mutants compared to controls, vision guided behavioural decisions and optical imaging revealed essentially unperturbed cortical signals and retinotopy in spite of the photoreceptor synaptopathy. In addition, both vision and visual cortical maps were adult-like at 4 weeks of age. These results show that (i) while Bassoon-dependent fast exocytosis is essential for normal vision surprisingly good visual performance can be achieved in the absence of synaptic ribbons, (ii) both the development and maintenance of visual cortical maps is independent of synaptic ribbons and (iii) visual development in the mutants is completed at 4 weeks of age indicating that later developing ectopic synapses do not affect vision. Thus, the central visual system can make use of slow and weak retinal signals to subserve surprisingly robust vision.     

Functional organization of the spinal reflex pathways from forelimb afferents to hindlimb motoneurons in the cat. II. Conditions of the interneuronal connections

The interneuronal conditionsof the descending pathways from forelimb afferents to hindlimb motoneurones were investigated by testing spatial interactions in these pathways and between these pathways and segmental lumbar reflex pathways. In high spinal unanaesthetized cats hindlimb motoneuroneswere intracellularly recorded and spatial interactions were tested between effects evoked by stimulation of pairs of ipsi- and contralateral forelimb nerves or pairs of a forelimb and an ipsilateral hindlimb nerve. The excitatory and late inhibitory pathways from forelimb afferents projecting to most of the hindlimb motoneurone pools, showed an interactive pattern which was distinctly different to the fast inhibitory pathway projecting specifically for ipsilateral forelimb afferents to flexor digitorum and hallucis longus (FDHL) motoneurones. Stimulation of homonymous or heteronymous pairs of two forelimb nerves of both sides evoked generally a distinct spatial facilitation of the excitatory and late inhibitory effects, while the specific early IPSPs to FDHL motoneurones were not facilitated. Paired stimulation of two forelimb nerves of one side only produced spatial facilitation of EPSPs or late IPSPs if low strength stimuli were used, using higher strength which induced larger effects, generally caused occlusion instead. In case of large IPSPs this may be due to the vicinity to the equilibrium potential. Except for an inhibition of cutaneous reflex pathways, the spatial interaction of the excitatory and late inhibitory pathways onto segmental lumbar reflex pathways was weak and variable. The fast inhibitory pathway to FDHL motoneurone showed a partial spatial facilitatory interaction with lumbar reflex pathways from cutaneous and group II muscle afferents. The second IPSP wave evoked by this pathway was inhibited by antidromic stimulation of the ventral root L7S1 and of the α-efferents of the antagonistic peroneal nerve. From the results conclusions are drawn on the interneuronal organization of the descending pathways from forelimb afferents to hindlimb motoneurones.     

Prognosefaktoren für das Auftreten einer Peritonealcarcinose beim Magencarcinom

Einleitung: Zur Verbesserung der Behandlungsm?glichkeiten vor dem Hintergrund eines adjuvanten Therapiekonzepts des Magencarcinoms erscheint es sinnvoll, geeignete Prognosefaktoren für das Auftreten einer Peritonealcarcinose zu bestimmen. Damit wird eine enge Auswahl der m?glicherweise von einer intraperitonealen Chemotherapie profitierenden Patienten m?glich. Methoden: Im Zeitraum von 6/1975–12/1999 wurden 575 Magenresektionen bei Carcinomen in unserer Klinik durchgeführt. Seit dem 1.1.1986 werden die Daten der operierten Patienten prospektiv erfasst. Die zuvor operierten Patienten wurden retrospektiv ausgewertet. S?mtliche Daten zur pr?operativen Diagnostik, Operation, histopathologischen Ergebnissen, klinischem Verlauf und überleben werden in einer Exceldatei prospektiv gesammelt und statistisch ausgewertet. Ergebnisse: Die multivariate Auswertung mittels logistischer Regressionsanalyse erbrachte eine signifikante Korrelation nur für die Variablen pT3, pN2, G3 und für Carcinome des gesamten Magens sowie für Magenstumpfcarcinome. Bezüglich der Variablen Laurenklassifikation, Siegelringzellcarcinom, Auftreten von Lebermetastasen und Tumorlokalisation im distalen oder proximalen Magen konnte keine signifikante Korrelation gefunden werden. Allerdings hatte nur ein Drittel der Patienten mit einer Lebermetastasierung gleichzeitig eine Peritonealcarcinose (n = 29). Schlussfolgerungen: Die Ergebnisse zeigen den klinischen Zusammenhang zwischen der Tumorlokalisation, der Lymphknotenmetastasierung, der Serosainfiltration und dem Grading mit dem Auftreten einer Peritonealcarcinose. Die Daten bilden eine gute Grundlage für weitere immunhistochemische und molekularbiologische Untersuchungen, wie der Adh?sionsmoleküle zur Absch?tzung des Risikos einer peritonealen Metastasierung nach Magencarcinom.