Predictors and outcomes in primary depression care (POKAL) - a research training group develops an innovative approach to collaborative care.

BACKGROUND: The interdisciplinary research training group (POKAL) aims to improve care for patients with depression and multimorbidity in primary care. POKAL includes nine projects within the framework of the Chronic Care Model (CCM). In addition, POKAL will train young (mental) health professionals in research competences within primary care settings. POKAL will address specific challenges in diagnosis (reliability of diagnosis, ignoring suicidal risks), in treatment (insufficient patient involvement, highly fragmented care and inappropriate long-time anti-depressive medication) and in implementation of innovations (insufficient guideline adherence, use of irrelevant patient outcomes, ignoring relevant context factors) in primary depression care. METHODS: In 2021 POKAL started with a first group of 16 trainees in general practice (GPs), pharmacy, psychology, public health, informatics, etc. The program is scheduled for at least 6 years, so a second group of trainees starting in 2024 will also have three years of research-time. Experienced principal investigators (PIs) supervise all trainees in their specific projects. All projects refer to the CCM and focus on the diagnostic, therapeutic, and implementation challenges. RESULTS: The first cohort of the POKAL research training group will develop and test new depression-specific diagnostics (hermeneutical strategies, predicting models, screening for suicidal ideation), treatment (primary-care based psycho-education, modulating factors in depression monitoring, strategies of de-prescribing) and implementation in primary care (guideline implementation, use of patient-assessed data, identification of relevant context factors). Based on those results the second cohort of trainees and their PIs will run two major trials to proof innovations in primary care-based a) diagnostics and b) treatment for depression. CONCLUSION: The research and training programme POKAL aims to provide appropriate approaches for depression diagnosis and treatment in primary care.

Impact of G-CSF Therapy on Leukopenia and Acute Rejection Following Kidney Transplantation.

BACKGROUND: Leukopenia is a common problem after kidney transplantation. The therapeutic approach typically includes a reduction of the immunosuppressive therapy, which is associated with an increased risk of rejection and allograft loss. Granulocyte colony-stimulating factor (G-CSF) is used as a therapeutic option to raise the leukocyte blood count; however, the effect on acute rejections is controversial. OBJECTIVE: The goal of this study is to examine the incidence of acute rejections following G-CSF therapy. METHODS: We retrospectively evaluated patients with leukopenia following kidney transplantation and GCSF therapy between January 2007 and December 2017 at our center compared to controls with matched minimal leucocyte blood count in a matched pair analysis. RESULTS: We identified 12 patients, who received G-CSF therapy with a cumulative dose of 10.74 µg/kg body weight over a time frame of 4.3 days. G-CSF therapy resulted in a significantly shorter time period with leucocytes <3,000/µL (9.5 vs. 16.6 days), but also trended towards an increased risk of rejection within the next 30 days with three patients in the G-CSF group and no patient in the control group (p=0.06) developing an acute biopsy-proven rejection. Infection and mortality rate in the subsequent year were not different between groups. CONCLUSION: G-CSF therapy decreases the duration of leukopenia post-kidney transplantation, but may also increase the risk of an acute rejection.

[Neuropsychology of psychoeducation in schizophrenia: results of the Munich COGPIP study]. / Neuropsychologie der Psychoedukation bei Schizophrenie: Ergebnisse der Münchner COGPIP-Studie.

BACKGROUND: The aim of the study was to examine whether the efficacy of psychoeducation in patients with schizophrenia is dependent on their cognitive performance and if a preceding cognitive training can enhance the therapeutic effects of psychoeducation. PATIENTS AND METHODS: A total of 116 inpatients were randomly assigned to either a standardized cognitive training (COGPACK) or to routine occupational therapy, followed by a psychoeducational group program of 8 sessions within 4 weeks for all study patients. The effects of cognitive training and psychoeducation were assessed directly afterwards and in a follow-up after 9 months. RESULTS: The patient knowledge and compliance improved. Neurocognition and especially memory acquisition significantly predicted illness knowledge after psychoeducation, whereas psychopathology did not. No differential effects of the COGPACK training were found. After 9 months 75% of the patients showed a very good compliance and the readmission rate was 18%. The results were comparable under both study conditions. CONCLUSION: Besides baseline illness knowledge neurocognition was the only significant predictor for illness knowledge after psychoeducation. Patients with cognitive deficits can profit from psychoeducation in the long run as well. In future it should be examined whether a modified cognitive training program could achieve a faster improvement of the illness knowledge.

[Organizational forms of emergency medicine from the viewpoint of hospital management. Discipline-specific or interdisciplinary?]. / Organisationsformen der Notfallmedizin aus Sicht des Krankenhausmanagement. Fachspezifisch oder interdisziplinär?

Almost 16 million Germans are treated annually in an emergency room (ER). Most patients are seen in a specialty ER and only 10-20% of all hospitals have a centralized ER facility. Clinical emergency medicine is currently not adequately reimbursed, but represents a major patient entry point for most hospitals. It remains unclear whether the implementation of specialized ER physicians is more cost-effective than centralized specialization. However, it appears reasonable to centralize all ER resources, to optimize the workflow using electronic patient charts and order entry sets and to incorporate the general practitioner into the treatment of simple medical problems.

Rapidly progressive hepatic alveolar echinococcosis in an ABO-incompatible renal transplant recipient.

We report on the case of an ABO-incompatible renal re-transplant recipient maintained on an intensified immunosuppressive regimen for recurrent cellular rejection episodes and transplant glomerulopathy who presented with rapidly growing hepatic tumors, radiologically suggestive of hemangiosarcoma. Upon resection and pathological work-up, the lesions revealed alveolar echinococcosis, a rare but potentially life-threatening parasitosis. Usually infection with Echinococcus multilocularis remains asymptomatic for extended periods of time and can go unrecognized for years. In the case presented, we observed an atypically rapid growth pattern of E. multilocularis that might have been due to the extent of the immunosuppressive regimen, which included repetitive anti-CD20 treatments. Retrospectively performed serological studies with enzyme-linked immunosorbent assays known to provide high sensitivity and specificity for the detection of echinococcosis in the general population, yielded ambiguous results in our immunocompromised host, which could be, in part, explained by B-cell depletion and its effects on antibody production and indirect actions on cellular immunity. In conclusion, this is the first report to our knowledge of hepatic alveolar echinococcosis in a renal transplant recipient. This case documents an altered clinical course of the parasitosis and the challenge of serological diagnostic tools under an intensified regimen of immunosuppressive agents, including rituximab.

Neurocognitive prediction of illness knowledge after psychoeducation in schizophrenia: results from the Munich COGPIP study.

BACKGROUND: Many patients with schizophrenia exhibit neurocognitive impairments, namely, in attentional, mnestic and executive functions. While these deficits limit psychosocial rehabilitation, their effect on psychoeducation is unknown. Within the framework of the longitudinal Munich Cognitive Determinants of Psychoeducation and Information in Schizophrenic Psychoses (COGPIP) study, we examined: (a) whether illness knowledge after psychoeducation could be predicted more precisely from the neurocognitive than from the psychopathological status of the patients; (b) which neurocognitive domains are best predictors. METHOD: A total of 116 in-patients with schizophrenic or schizoaffective disorders were randomized to a neurocognitive training or control condition (2 weeks) followed by a manualized psychoeducational group programme (4 weeks) and then observed over a 9-month follow-up. Repeated measurements included - among others - the Positive and Negative Syndrome Scale and a comprehensive neuropsychological test battery from which normative T scores were used to calculate one global and five domain-specific neurocognitive composite scores. Illness knowledge was measured by a questionnaire (WFB-52) tailored to the psychoeducational programme. RESULTS: Multiple linear regression analyses showed that, apart from baseline illness knowledge, neurocognition significantly predicted knowledge outcome as well as knowledge gain (measured by reliable change indices) after psychoeducation. This was not true for psychopathology. Among the domain-specific neurocognitive composite scores, only memory acquisition was a significant predictor of knowledge outcome and gain. CONCLUSIONS: Neurocognition, not psychopathology, is a significant predictor of illness knowledge after psychoeducation in schizophrenia. This finding should guide efforts to tailor psychoeducational interventions more closely to the patient's needs and resources.

Gender differences in patient and caregiver psychoeducation for schizophrenia.

OBJECTIVE: The aim of this research is to detect gender-related differences in patients and caregivers regarding knowledge about schizophrenia and attitudes towards drugs as well as gender as predictor for changes in these variables during psychoeducation. METHODS: Data sets of one randomised-controlled (study 1) and one naturalistic psychoeducation study (study 2) were reanalysed. Main outcome measures (knowledge about schizophrenia, drug attitude, confidence in medication) were assessed at baseline, post-intervention and 12 months after index discharge. RESULTS: The reanalysed samples consisted in total of 1002 patients and 176 caregivers. In study 2, baseline knowledge was significantly better in male patients and female caregivers. All participants improved significantly their knowledge. The amount of knowledge gain did not differ between genders in either study or either group. Gender was not a major predictor of baseline knowledge or knowledge gain. Only in study 1 did gender significantly impact the knowledge gain from baseline to follow-up. Regarding improvement of drug attitude, females seemed to benefit significantly better from psychoeducation. In both studies, however, changes in drug attitudes respectively confidence in medication were best explained by lower corresponding baseline scores, not gender. Patients' gender did not influence outcomes of their caregivers. CONCLUSION: Our findings suggest that psychoeducational programs might be better adapted to males in order to improve their drug attitude. Concerning knowledge, gender-related changes do not seem to be necessary.

Leflunomide therapy for polyomavirus-induced allograft nephropathy: efficient BK virus elimination without increased risk of rejection.

BACKGROUND: Optimal treatment of polyomavirus-induced allograft nephropathy (PVAN) with immunosuppressive and antiviral therapy is uncertain at present. Reduced immunosuppression is accompanied by increased risk of rejection, and antiviral agents are nephrotoxic. Leflunomide has immunosuppressive and antiviral properties and may be an alternative treatment agent. We report a two-center experience with use of leflunomide for treatment of PVAN. PATIENTS AND METHODS: Thirteen renal allograft recipients were diagnosed with biopsy-proven PVAN. Treatment consisted of lowering the calcineurin-inhibitor trough level, discontinuing mycophenolate mofetil therapy, and initiating leflunomide therapy. In 8 of the 13 patients, the serum concentration of the leflunomide active metabolite A771726 was monitored. RESULTS: Exchange of mycophenolate mofetil with leflunomide in patients with PVAN was well tolerated and safe, with no serious adverse effects or episodes of graft rejection. Mean follow-up after transplantation was 717 days, and after initiation of leflunomide therapy was 465 days. With the modified therapy, 12 patients cleared the virus at a mean of 109 days. One graft was lost due to refractory rejection accompanied by a decreasing viral load. In the other 12 patients, graft function stabilized or improved (mean [median] creatinine concentration at diagnosis, 2.39 [2.5] mg/mL, vs 2.27 [2.0] mg/dL at follow-up). Leflunomide concentration did not correlate with treatment efficiency. CONCLUSIONS: Treatment of PVAN with leflunomide, a low-dose calcineurin inhibitor, and prednisone seems to reduce viral load and stabilize renal graft function without increasing the risk of rejection. Even low serum concentrations of leflunomide support viral elimination and prevention of graft rejection.

[Disseminated histoplasmosis with involvement of mediastinum and skin in an immunocompetent patient]. / Disseminierte Histoplasmose mit Befall des Mediastinums und der Haut bei immunkompetenter Patientin.

HISTORY AND ADMISSION FINDINGS: A 29-years-old Brazilian woman was admitted to hospital because of progressive dyspnoea, shivering and fever. She reported a noticeable swelling at the right mandible and an ulcerative tumor at the side of the nose. INVESTIGATIONS: Laboratory tests showed normocytic, normochromic anemia with an elevation of the inflammatory parameters. Radiology showed an enlargement of the upper mediastinum. Computed tomography revealed extensive, confluent lymphoma. There were groups of cervical lymph nodes, especially in the area of the right jaw. Bronchoscopy showed extensive space-occupying lesions with severe inflammation of the trachea. DIAGNOSIS: Bronchial biopsy revealed necrotizing, granulomatous inflammation with dense infiltration of lymphatic cells. Small and spheroidal pathogens were seen within giant cells. Grocott-silver stain was positive, indicating histoplasmosis. Histological work-up of the ulcerating tumor at the side of the nose also showed Histoplasma capsulatum. TREATMENT AND COURSE: 8 weeks after starting specific treatment with oral itraconazole the inflammatory parameters had fallen to normal and computed tomography showed regression of the mediastinal bulge. CONCLUSION: Large mediastinal and cervical lymphatic masses with space-occupying bronchial lesions suggest should, in the differential diagnosis, consider not only malignant tumor but also infections. If the patient had been abroad (in this case in Brazil), pathogens like Histoplasma capsulatum, which is not present in Europe, have to be considered. In this immunocompetent patient the severe progression and dissemination of the disease, involving mediastinum, throat and skin, is most unusual.

ABO-incompatible kidney transplantation with antigen-specific immunoadsorption and rituximab - insights and uncertainties.

Several protocols have been developed to effectively overcome the blood group barrier in renal transplantation. In the evolution of these protocols, one of the latest steps was the combination of anti-CD20 treatment with antigen-specific immunoadsorptions. Over the last years we have learned that these relatively new protocols carry very promising short-term and intermediate-term results which compare favorably to the outcome of ABO-compatible living donor transplantations. Latest reports suggest that combining immunoadsorptions with rituximab does not result in an increased risk of infectious complications or tumors in the first years after transplantation compared to ABO-compatible living donor transplantations. We recently demonstrated that a majority of patients with isoagglutinin titers >1:128 can be safely transplanted using rituximab and immunoadsorptions without an added risk of early antibody-mediated rejections. We have also shown that a cost saving 'on-demand strategy' of postoperative immunoadsorptions based on careful titer monitoring can be used as an alternative to preemptively scheduled immunoadsorptions. Although rituximab and antigen-specific immunoadsorptions are significantly less invasive than splenectomy and plasma-pheresis, long-term follow-up of patients treated with a combination of anti-CD20 antibody and antigen-specific immunoadsorption will be needed to benchmark this therapeutic option in relation to more established protocols.

Nephrogenic systemic fibrosis following exposure to gadolinium-containing contrast agent.

Nephrogenic systemic fibrosis (NSF) is a disease recently described in patients with kidney failure. It is characterized by scleroderma-like thickening of the skin, subcutaneous edema and ensuing joint contractures leading to profound disability. Furthermore, involvement of internal organs has been described. Whereas the pathogenesis is not known to date, recent reports have linked NSF to high doses of gadolinium-containing contrast agents given at magnetic resonance angiography (MRA). We describe a patient with severe NSF. The patient had received erythropoietin and had undergone vascular interventions which are suspected risk factors for this disease. Notably, the disease developed shortly after the application of gadolinium at an MRA, giving support to the recently published hypothesis that gadolinium-containing contrast agents are among the causative factors. We provide a short overview and hope to raise overall awareness towards this entity and the use of MRA contrast agents in renal patients.

Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways.

Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.

Polycystic kidney disease: cell division without a c(l)ue?

Polycystic kidneys are caused by an amazingly broad array of genetic mutations and manipulations. The ciliary hypothesis has evolved as the unifying concept of cystogenesis: cilia, bend by fluid flow, initiate a calcium influx that prevents cyst formation. The integrity of ciliary functions has been linked to the polycystic kidney disease gene products localizing to the cilium or the basal body/centrosome. Until recently, the signals and cellular programs located downstream of the ciliary-mediated calcium flux have remained elusive. Now, several reports point towards a role of the cilium or the basal body/centrosome complex in planar cell polarity, a pathway that orients cell in the plane of a tissue layer. First, Inversin, a protein mutated in nephronophthisis type II was found to act as a switch between the canonical and the noncanonical Wnt cascade, suggesting that beta-catenin/TCF-dependent gene transcription has to be curtailed to allow normal tubular differentiation. Second, heterozygote deletions of Bardet-Biedl syndrome proteins affect neural tube closure and disrupt the cochlear sterociliary bundles, two typical planar cell polarity defects. Third, tubular epithelial cells undergo oriented cell division during tubular elongation, along the axis of the anterior-posterior axis of the nephron. Thus, the cilium or the basal body/centrosome complex may provide the spatial cues to position the centrosome and the mitotic spindle before the next cell division. Failure to communicate this spatial information may condemn the tubular epithelial cells to proliferate and to form cysts.

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals.

CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, beta-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.

[Effects of esmolol- and sodium nitroprusside-induced controlled hypotension on hepatocellular integrity in patients undergoing endonasal sinus surgery]. / Einfluss der Esmolol- und der Natrium-Nitroprussid-induzierten kontrollierten Hypotension auf die hepatozelluläre Integrität bei endonasalen Nebenhöhleneingriffen.

BACKGROUND: Controlled hypotension (CH) is an established method to reduce intraoperative bleeding. The aim of the study was to investigate the influence of CH induced by sodium nitroprusside (SN) or esmolol on hepatocellular integrity. METHODS: Prospective, randomized, controlled study. 45 patients scheduled for elective endonasal sinus surgery were allocated to one of the following three groups: 1. SN-group (n = 15): CH induced by SN. 2. Esmolol-group: CH induced by esmolol. In both groups mean arterial pressure was kept between 50-55 mmHg. 3. Control group (n = 15): no hypotension was performed (MAP > 70 mmHg). The cytosolic liver enzyme alpha-glutathione S-transferase (alpha-GST) and standard liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) were measured at the following timepoints: preoperative (T0), at the end of surgery (T1), 2 h (T2), 24 h (T3) and 48 h (T4) postoperatively. RESULTS: alpha-GST concentrations were significantly higher in patients receiving CH (SN: 5.9 +/- 3.4; Esmolol: 6.5 +/- 2.8 microg/L) in comparison with controls (2.5 +/- 1.4 microg/L) at T1. Already at T2 there were no significant differences between the three groups. Standard liver enzymes showed a similar course in all groups. CONCLUSION: The small but significant increase of alpha-GST in both hypotension groups suggests that hypotension induces a mild damage of hepatocellular integrity.

[Pathogenetic aspectics of nephrotic syndrome]. / Pathogenetische Aspekte des nephrotischen Syndroms.

Nephrotic syndrome is characterized by protein loss in the urine, hypoalbuminemia, hyperlipidemia and edema. Several diseases cause a nephrotic syndrome, as they damage the glomerular podocytes. These specialized epithelial cells, together with endothelial cells of the glomerular capillaries and the basal membrane, form a filter that retains plasma proteins in the circulation. A disturbance of this filter causes proteinuria. The three most common primary glomerular diseases are minimal change, membranous glomerulonephritis, and the primary focal segmental glomerulosclerosis. The familiar forms are rare; however, the identification of the relevant gene defects has greatly advanced our understanding of podocyte function as well as the pathogenesis of nephrotic syndrome.

[Pathogenesis of cystic kidney diseases]. / Pathogenese von zystischen Nierenerkrankungen.

Several gene mutations cause renal cysts in humans, including PKD1 and PKD2 (autosomal dominant polycystic kidney disease, ADPKD), PKHD1 (autosomal recessive polycystic kidney disease, ARPKD), TSC1 and TSC2 (Tuberous Sclerosis), NPHP1 (Nephronophthisis type I), and VHL (von-Hippel-Lindau syndrome). This raises the question, whether there are common denominators of cyst development. Both polycystin-1 and fibrocystin, the gene products of PKD1 and PKHD1, appear to act as adhesion molecules. Polycystin-2, encoded by PKD2, is a ion channel that requires polycystin-1 to translocate to the plasma membrane. Polycystin-1 mandates TSC2 for the transport to the plasma membrane; thus, mutations of TSC2 could cause cyst formation by compromising the function of polycystin-1. Disturbances of fibrillary adhesion complexes may represent the final common pathway of NPHP1 as well as VHL mutations. Delineating common pathways of cystogenesis may help to design therapeutic strategies that combat the development and/or progression of renal cysts.

Interaction with podocin facilitates nephrin signaling.

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking CD2-associated protein (CD2AP) develop a nephrotic syndrome that resembles NPHS mutations suggesting that all three proteins are essential for the integrity of glomerular podocytes. Although the precise glomerular function of either protein remains unknown, it has been suggested that nephrin forms zipper-like interactions to maintain the structure of podocyte foot processes. We demonstrate now that nephrin is a signaling molecule, which stimulates mitogen-activated protein kinases. Nephrin-induced signaling is greatly enhanced by podocin, which binds to the cytoplasmic tail of nephrin. Mutational analysis suggests that abnormal or inefficient signaling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria.