Publications by authors named "Johanna Schneider"

36 Publications

Case Report: Blurred Vision and Eruptive Nevi - Bilateral Diffuse Uveal Melanocytic Proliferation With Mucocutaneous Involvement in a Lung Cancer Patient.

Front Oncol 2021 13;11:658407. Epub 2021 Apr 13.

Eye Center, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

We describe a case of a 65-year old patient presenting with unusual mucocutaneous melanocytic proliferations of a Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) imitating a multifocal melanoma in situ, which improved dramatically after plasmapheresis. The patient first presented at the dermatology department due to rapidly evolving brown and black macules on the glans penis. Further skin involvement of the perineal and perianal region, mamillae and oral mucosa was stated. Histology from a penile biopsy was compatible with a melanoma in situ. Due to the distribution pattern and elevated serum tumor marker S100B, metastatic melanoma was considered. Staging examinations using PET-CT scan however, revealed a lung tumor, later confirmed as a Non-small-cell lung cancer (NSCLC). Primary radio chemotherapy was initiated to treat NSCLC. Shortly after initiation of radio chemotherapy the patient developed massive vision impairment and a NSCLC-associated BDUMP was diagnosed which led to the correct classification of melanocytic skin lesions as mucocutaneous BDUMP manifestation. Plasmapheresis was started resulting in a rapid improvement of vision starting ten days after the first plasmapheresis. In contrast skin manifestations started to disappear with a marked delay 4 months after the last plasmapheresis cycle. This case highlights the importance of memorizing multiple rapidly progressing melanocytic skin and/or mucous membrane spots together with visual impairment as a possible paraneoplastic BDUMP that needs a fundamentally different therapeutic approach compared to multifocal melanoma in situ. What is already known about this topic? Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) is a paraneoplastic syndrome with melanocytic uveal proliferation leading to vision impairment. Extraocular manifestation is rare, mainly affect the subepidermal compartment and is hard to treat. Plasmapheresis has been shown to be an effective treatment mainly for vision improvement in some but not all cases. What does this study add? Our BDUMP case with widespread skin and mucosal involvement initially mimicked a multifocal melanoma and showed an excellent treatment response to plasmapheresis. Improvement of mucocutaneous lesions has not been documented well in the literature so far. We show a more than one year lasting follow up still underlining the beneficial effect of plasmapheresis in this case. In-vitro data supports the hypothesis that plasma exchange eliminates a "Cultured melanocyte elongation and proliferation (CMEP)" factor out of patient blood leading to decreased melanocyte proliferation shown numerically in-vitro and clinically in-vivo. Our case clearly indicates that before establishing a definite diagnosis and therapy in patients with rapidly evolving melanocytic skin and/or mucosal lesions BDUMP mimicking multifocal melanoma should be considered making a thorough diagnostic workup mandatory.
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http://dx.doi.org/10.3389/fonc.2021.658407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076566PMC
April 2021

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19.

Ann Intern Med 2021 Mar 30. Epub 2021 Mar 30.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (A.M.L., D.A.R., L.Y., C.F.W., L.M.N., J.J.B., R.W.E., J.S.S., E.J.E.).

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.
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http://dx.doi.org/10.7326/M21-1043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025940PMC
March 2021

Experiences and Short-Term Outcomes of Kidney Transplantation During the Coronavirus Disease 2019 Pandemic From a Medium-Volume Transplantation and Superregional Coronavirus Disease 2019 Treatment Center.

Transplant Proc 2021 Jan 20. Epub 2021 Jan 20.

Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Introduction: The coronavirus, which first appeared in 2019, developed into a pandemic during 2020. It remains unclear to what extent the pandemic endangers the safety of kidney transplantation programs. In this study, we evaluated the short-term outcomes of our patients receiving a kidney transplant during the first phase and compared them with patients who received a kidney transplant immediately before the coronavirus pandemic.

Materials And Methods: Our retrospective study includes 34 kidney transplant recipients between October 1, 2019, and April 30, 2020. Nineteen patients from the phase immediately prior to the first coronavirus wave (pre-corona group), and 15 patients from the phase of the first coronavirus wave (corona group) were studied. We retrospectively evaluated demographic data, postoperative short-term outcomes and complications, immunosuppression regime, coronavirus infection status, and behavior during the first phase of the pandemic.

Results: There were no differences between the 2 groups regarding short-term outcomes and postoperative complications or in immunosuppressive medication. After the introduction of intensified hygienic conditions and routine swabs prior to transplantation, no nosocomial SARS-CoV-2 infections occurred. In the outpatient setting, none of the patients developed a SARS-CoV-2 infection. The majority of patients performed voluntary quarantine.

Conclusions: The short-term outcomes after kidney transplantation during the first phase of the coronavirus pandemic were comparable to pre-pandemic patients, and no SARS-CoV-2-associated death or transplant failure occurred in our small cohort. We considered patient compliance with hygiene and self-isolation measures very high. Nevertheless, in further phases of the pandemic, the continuation of the living kidney donation program must be critically evaluated.
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http://dx.doi.org/10.1016/j.transproceed.2021.01.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816559PMC
January 2021

[Hypertensive Disorders in Pregnancy].

Dtsch Med Wochenschr 2021 Feb 16;146(4):279-286. Epub 2021 Feb 16.

Hypertensive disorders occur in up to 10 % of pregnancies and increase both maternal and fetal morbidity and mortality. The most important differential diagnoses comprise pre-existing chronic hypertension, pregnancy-associated hypertension, and preeclampsia with simultaneous proteinuria. Antihypertensive therapy during pregnancy should be initiated when blood pressure is 150-160/100-110 mmHg. With regard to an earlier initiation of therapy, the data situation is not clear. Pre-eclampsia is defined as new or pre-existing elevated blood pressure ≥ 140/90 mmHg in pregnancy with at least one new organ manifestation, usually proteinuria ≥ 300 mg/day or ≥ 30 mg/mmol in the protein-creatinine ratio. Thrombotic microangiopathies TTP and aHUS are altogether rare but potentially life-threatening diseases that should be clarified in case of severe or atypical courses.
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http://dx.doi.org/10.1055/a-1233-7685DOI Listing
February 2021

Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.

BMC Nephrol 2021 Jan 18;22(1):32. Epub 2021 Jan 18.

Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 53, D-79106, Freiburg, Germany.

Background: Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.

Case Presentation: The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.

Conclusion: In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
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http://dx.doi.org/10.1186/s12882-020-02226-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814610PMC
January 2021

Refocusing Human Microbiota Research in Infectious and Immune-mediated Diseases: Advancing to the Next Stage.

J Infect Dis 2020 Nov 14. Epub 2020 Nov 14.

Office of Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1093/infdis/jiaa706DOI Listing
November 2020

Long-term Follow-up of ABO-Incompatible Kidney Transplantation in Freiburg, Germany: A Single-Center Outcome Report.

Transplant Proc 2021 Apr 9;53(3):848-855. Epub 2020 Oct 9.

Faculty of Medicine, University of Freiburg, Freiburg, Germany; Renal Division, Department of Internal Medicine, Bürgerspital Solothurn, Solothurn, Switzerland. Electronic address:

Background: ABO-incompatible kidney transplantation (ABOi-KT) is an established way to enlarge the donor pool around the world. Comparability of long-term success and complications to ABO-compatible kidney transplantation (ABOc-KT) are still under debate.

Methods: We evaluated all patients with a living donor kidney transplantation performed between April 1, 2004, and March 31, 2019.

Results: A total of 137 ABOi-KT and 346 ABOc-KT were analyzed. We excluded 4 ABOi-KT recipients and 178 ABOc-KT recipients with cyclosporine A-based immunosuppression or without basiliximab induction. Three patients of the ABOi-KT cohort and 6 patients of the ABOc-KT cohort were lost to follow-up and therefore excluded. The patient characteristics were comparable except for the higher age of transplant recipients in the ABOc-KT cohort and longer follow-up of the ABOi-KT cohort. The mean estimated 15-year recipient survival was 89% in the ABOi-KT cohort and 91% in the ABOc-KT cohort (P = .39). Mean estimated graft survival was 71% in the ABOi-KT cohort and 87% in the ABOc-KT cohort (P = .68). The estimated glomerular filtration rate (Modification of Diet in Renal Disease) measured in the last follow-up was 51 mL/min/1.73 m in the ABOi-KT cohort and 50 mL/min/1.73 m in the ABOc-KT cohort (P = .36). The incidence for antibody-mediated rejection, T cell-mediated rejections, and infectious complications requiring hospitalization was not different between the cohorts. In the ABOi-KT cohort, we found significantly more lymphoceles and consequent surgical revision procedures.

Conclusions: At our center, ABOi-KT has as good long-term results as ABOc-KT in terms of patient survival, graft survival, and complications, with the exception of increased lymphocele formation.
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http://dx.doi.org/10.1016/j.transproceed.2020.09.001DOI Listing
April 2021

Psychosocial emergency care in times of COVID-19: the Essen University Hospital concept for corona-infected patients, their relatives, and medical staff.

Int Arch Occup Environ Health 2021 02 22;94(2):347-350. Epub 2020 Sep 22.

Department of Psychosomatic Medicine and Psychotherapy, LVR University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany.

Due to the SARS CoV-2-virus (COVID-19), anxiety, distress, and insecurity occur more frequently. In particular, infected individuals, their relatives, and medical staff face an increased risk of high psychological distress as a result of the ongoing pandemic. Thus, structured psychosocial emergency concepts are needed. The University hospital of Essen has taken up this challenge by creating the PEC concept to reduce psychosocial long-term consequences for infected patients, relatives, and medical staff at the university hospital. The concept includes professional medical as well as psychological support to convey constructive coping strategies and the provision of adequate tools such as the low-threshold online training program (CoPE It), which is accessible via the webpage www.cope-corona.de .
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http://dx.doi.org/10.1007/s00420-020-01580-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508238PMC
February 2021

Dapsone-Induced Hemolytic Anemia in Multiple Myeloma: Case Report of Various Differential Diagnoses.

Clin Lymphoma Myeloma Leuk 2020 Nov 2;20(11):e821-e825. Epub 2020 Jul 2.

Department of Medicine I (Hematology, Oncology, and Stem Cell Transplantation), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2020.06.021DOI Listing
November 2020

Simultaneous ipsilateral nephrectomy during kidney transplantation in autosomal dominant polycystic kidney disease: a matched pair analysis of 193 consecutive cases.

Langenbecks Arch Surg 2020 Sep 23;405(6):833-842. Epub 2020 Jul 23.

Faculty of Medicine, Department of General and Digestive Surgery, Section of Transplant Surgery, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany.

Background: In end-stage renal transplant recipients with autosomal-dominant polycystic kidney disease (ADPKD), the imperative, optimal timing, and technique of native nephrectomy remains under discussion. The Freiburg Transplant Center routinely performs a simultaneous ipsilateral nephrectomy.

Methods: From April 1998 to May 2017, we retrospectively analyzed 193 consecutive ADPKD recipients, receiving per protocol simultaneous ipsilateral nephrectomy and compared morbidity, mortality, and outcome with 193 non-ADPKD recipients of a matched pair control.

Results: The incidence of surgical complications was similar with respect to severe medical, surgical, urological, vascular, and wound-related complications as well as reoperation rates and 30-day mortality. Intraoperative blood transfusions were required more often in the ADPKD (22.8%) compared with the control group (6.7%; p < 0.0001). Early postoperative urinary tract infections occurred more frequent (ADPKD 40.4%/control 29.0%; p = 0.0246). Time of surgery was prolonged by 30 min (ADPKD 169 min; 95%CI 159.8-175.6 min/control 139 min; 95%CI 131.4-145.0 min; p < 0.0001). One-year patient (ADPKD 96.4%/control 95.8%; p = 0.6537) and death-censored graft survival (ADPKD 94.8%/control 93.7%; p = 0.5479) were comparable between both groups.

Conclusions: With respect to morbidity and mortality, per protocol, simultaneous native nephrectomy is a safe procedure. Especially in asymptomatic ADPKD KTx recipients, the number of total operations can be reduced and residual diuresis preserved up until transplantation. In living donation, even preemptive transplantation is possible.
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http://dx.doi.org/10.1007/s00423-020-01939-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471159PMC
September 2020

Techniques, Methods, and Dissemination of Community-Based Psychological Support Strategies in Times of the COVID-19 Pandemic.

J Prim Care Community Health 2020 Jan-Dec;11:2150132720943328

University of Duisburg-Essen, Clinic for Psychosomatic Medicine and Psychotherapy, LVR University-Hospital Essen, Essen, Germany.

In times of the coronavirus pandemic caused by SARS-CoV-2 psychological support needs to meet certain requirements. Due to the lockdown in many countries of the world, the every-day activities of millions of people are reduced to a minimum. This may cause increased psychosomatic symptoms in persons with pre-existing mental illnesses, and additionally raises new challenges for the general population. As a result of the current contact restrictions, access to psychotherapy is further complicated. To guarantee the best possible care under the given conditions, we developed the CoPE (Coping with Corona: Extended Psychosomatic care in Essen) concept. CoPE is delivered by telephone or video calls as well as online contents. The materials presented at our webpage www.cope-corona.de aim to easily reach citizens affected by symptoms such as worries, depression or anger and let them receive readily understandable expert knowledge and training in basic self-help methods.
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http://dx.doi.org/10.1177/2150132720943328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372604PMC
July 2020

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP.

Blood Adv 2020 07;4(13):3093-3101

Klinikum der Universität München-Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Munich, Germany.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.
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http://dx.doi.org/10.1182/bloodadvances.2020001987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362349PMC
July 2020

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Blood Adv 2020 07;4(13):3085-3092

Klinikum der Universität München-Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Munich, Germany.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362370PMC
July 2020

Psychiatric Manifestation of Anti-LGI1 Encephalitis.

Brain Sci 2020 Jun 16;10(6). Epub 2020 Jun 16.

Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.

Background: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is typically characterized by limbic encephalitis, faciobrachial dystonic seizures and hyponatremia. The frequency with which milder forms of anti-LGI1 encephalitis mimic isolated psychiatric syndromes, such as psychoses, or may lead to dementia if untreated, is largely unknown.

Case Presentation: Here, the authors present a 50-year-old patient who had suffered from neurocognitive deficits and predominant delusions for over one and a half years. He reported a pronounced feeling of thirst, although he was drinking 10-20 liters of water each day, and he was absolutely convinced that he would die of thirst. Due to insomnia in the last five years, the patient took Z-drugs; later, he also abused alcohol. Two years prior to admission, he developed a status epilepticus which had been interpreted as a withdrawal seizure. In his serum, anti-LGI1 antibodies were repeatedly detected by different independent laboratories. Cerebrospinal fluid analyses revealed slightly increased white blood cell counts and evidence for blood-brain-barrier dysfunction. Magnetic resonance imaging showed hyperintensities mesio-temporally and in the right amygdala. In addition, there was a slight grey-white matter blurring. A cerebral [F] fluorodeoxyglucose positron emission tomography (FDG-PET) examination of his brain showed moderate hypometabolism of the bilateral rostral mesial to medial frontal cortices. Treatment attempts with various psychotropic drugs remained unsuccessful in terms of symptom relief. After the diagnosis of probable chronified anti-LGI1 encephalitis was made, two glucocorticoid pulse treatments were performed, which led to a slight improvement of mood and neurocognitive deficits. Further therapy was not desired by the patient and his legally authorized parents.

Conclusion: This case study describes a patient with anti-LGI1 encephalitis in the chronified stage and a predominant long-lasting psychiatric course with atypical symptoms of psychosis and typical neurocognitive deficits. The patient's poor response to anti-inflammatory drugs was probably due to the delayed start of treatment. This delay in diagnosis and treatment may also have led to the FDG-PET findings, which were compatible with frontotemporal dementia ("state of damage"). In similar future cases, newly occurring epileptic seizures associated with psychiatric symptoms should trigger investigations for possible autoimmune encephalitis, even in patients with addiction or other pre-existing psychiatric conditions. This should in turn result in rapid organic clarification and-in positive cases-to anti-inflammatory treatment. Early treatment of anti-LGI1 encephalitis during the "inflammatory activity state" is crucial for overall prognosis and may avoid the development of dementia in some cases. Based on this case, the authors advocate the concept-long established in many chronic inflammatory diseases in rheumatology-of distinguishing between an "acute inflammatory state" and a "state of organ damage" in autoimmune psychosis resembling neurodegenerative mechanisms.
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http://dx.doi.org/10.3390/brainsci10060375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348933PMC
June 2020

Lipid Apheresis to Manage Severe Hypertriglyceridemia during Induction Therapy in a Child with Acute Lymphoblastic Leukemia.

Pediatr Hematol Oncol 2020 Sep 6;37(6):530-538. Epub 2020 May 6.

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

PEG asparaginase is an important and established drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). Severe hypertriglyceridemia is a rare complication of PEG asparaginase in combination with glucocorticoids. We report a case of excessive hypertriglyceridemia in a child during ALL induction therapy successfully treated by lipid apheresis and give a literature review on the management of hypertriglyceridemia in children treated for ALL.
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http://dx.doi.org/10.1080/08880018.2020.1756999DOI Listing
September 2020

Antibody-mediated rejection with detection of donor-specific anti-human leucocyte antigen Class II antibodies 3 years after heart transplantation: a case report.

Eur Heart J Case Rep 2020 Feb 25;4(1):1-4. Epub 2020 Jan 25.

Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Germany.

Background: Antibody-mediated rejection (AMR) in cardiac transplantation may manifest early within the first weeks after transplantation but also late after months to years following transplantation resulting in mild heart failure to cardiogenic shock. While patients with early cardiac AMR are less affected and seem to have survival rates comparable to transplant recipients without AMR, late cardiac AMR is frequently associated with graft dysfunction, fulminant forms of cardiac allograft vasculopathy, and a high mortality rate. Nevertheless, AMR of cardiac allografts remains difficult to diagnose and to treat.

Case Summary: We report the case of a 47-year-old male patient with late AMR of the cardiac allograft 3 years after heart transplantation. Antibody-mediated rejection was confirmed by endomyocardial biopsy and the presence of donor-specific antibodies (DSA). The patient was treated with high dose of prednisolone, plasmapheresis, intravenous Gamma Globulin, rituximab, immunoadsorption, and bortezomib. Under this treatment regimen left ventricular ejection fraction and pro B-type natriuretic peptide recovered, and the patient improved to New York Heart Association Class I. Currently, 3 years after the diagnosis of cardiac AMR, graft function continues to be nearly normal, and there is no evidence for transplant vasculopathy.

Discussion: This case illustrates that AMR can occur at any time after transplantation. Although graft function fully recovered after treatment in our patient, the level of DSA remained high, suggesting that DSA may not be a reliable parameter to determine the intensity and duration of the therapy.
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http://dx.doi.org/10.1093/ehjcr/ytz246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047055PMC
February 2020

Evidence of Interleukin-2-Receptor-Antibody Induction in Low-Risk Living Donor Kidney Transplantation: A Single-Center Pilot Study.

Transplant Proc 2020 Apr 26;52(3):780-784. Epub 2020 Feb 26.

Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: The recommended standard immunosuppressive therapy for renal transplant recipients comprises an initial induction therapy mainly with an interleukin-2-receptor antibody (IL2-RA) and a triple maintenance therapy. With tacrolimus and mycophenolate acid it is unknown whether IL2-RA application affects the short- and long-term results. This question is addressed in the present analysis.

Methods: From July 2007 to June 2019 a total of 127 living donor kidney transplant recipients meeting the center-specific definition of immunologic low risk situation (first transplantation, HLA-mismatch ≤3, panel reactive antibody ≤10%) were identified. In 83 recipients with a first-degree relationship to the donor we omitted the IL2-RA induction (IL2-RA-). The remaining 44 recipients, mostly not first-degree relatives, served as controls (IL2-RA+). Biopsy-proven acute rejection and long-term patient and graft survival rates were compared.

Results: Biopsy-proven acute rejection rates after 3 months were similar in both groups with 4.8% (IL2-RA-) vs 13.7% (IL2-RA+; P = .0937), including borderline rejection rates of 18.0% (IL2-RA-) vs 18.3% (IL2-RA+; P = 1.000), respectively. Ten-year long-term survival rates were comparable between the IL2-RA- and the IL2-RA+ group with 95.6% vs 93.5% (patient survival; P = .5465) and 92.1% vs 90.6% (death-censored graft survival; P = .8893).

Conclusion: For low-risk living donor kidney transplant recipients with first-degree relationship to the donor, it is safe to omit induction therapy with IL2-RA.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.036DOI Listing
April 2020

Recuperation of severe tumoral calcinosis in a dialysis patient: A case report.

World J Clin Cases 2019 Dec;7(23):4004-4010

Department of Medicine IV, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

Background: One of the common late sequela in patients with end-stage renal disease (ESRD) is the calcium phosphate disorder leading to chronic hypercalcemia and hyperphosphatemia causing the precipitation of calcium salt in soft tissues. Tumoral calcinosis is an extremely rare clinical manifestation of cyst-like soft tissue deposits in different periarticular regions in patients with ESRD and is characterized by extensive calcium salt containing space-consuming painful lesions. The treatment of ESRD patients with tumoral calcinosis manifestation involves an increase in or switching of renal replacement therapy regimes and the adjustment of oral medication with the goal of improved hypercalcemia and hyperphosphatemia.

Case Summary: We describe a 40-year-old woman with ESRD secondary to IgA-nephritis and severe bilateral manifestation of tumoral calcinosis associated with hypercalcemia, hyperphosphatemia and tertiary hyperparathyroidism. The patient was on continuous ambulatory peritoneal dialysis and treatment with vitamin D analogues. After switching her to a daily hemodialysis schedule and adjusting the medical treatment, the patient experienced a significant dissolution of her soft tissue calcifications within a couple of weeks. Complete remission was achieved 11 mo after the initial diagnosis.

Conclusion: Reduced patient compliance and subsequent insufficiency of dialysis regime quality contribute to the aggravation of calcium phosphate disorder in a patient with ESRD leading to the manifestation of tumoral calcinosis. However, the improvement of the treatment strategy and reinforcement of patient compliance enabled complete remission of this rare disease entity.
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http://dx.doi.org/10.12998/wjcc.v7.i23.4004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906553PMC
December 2019

Comparing modalities of conducting the six-minute walk test in healthy children and adolescents.

Minerva Pediatr 2019 Jun;71(3):229-234

Division of Cardiology, Pulmology, Allergology, and Cystic Fibrosis, Department of Pediatrics, Medical University Innsbruck, Innsbruck, Austria.

Background: The 6-minute walk test (6MWT) in children can be performed in the conventional way, or by using a measuring wheel. This study aimed to compare these test modalities and to determine influencing factors.

Methods: The study included 317 healthy children (172 boys) between 6 and 15 years from elementary schools and high schools, who were randomly assigned to perform a 6MWT either with or without a measuring wheel according to the guidelines of the American Thoracic Society. The 6-minute walk distance (6MWD) was compared between the two measuring modalities as well as different school types.

Results: The use of a measuring wheel during the 6MWT led to a significantly greater 6MWD compared to conventional walking. Students of sports schools walked substantially farther than those attending general high schools, irrespective of test modality. In multivariate regression analysis height, post-test heart rate, male sex and the measuring wheel itself were all independently associated with greater 6MWD.

Conclusions: The use of a measuring wheel during a 6MWT reflects physical performance in children and adolescents more accurately as it includes the stretch of way around the cones during lap turns. Test modalities and sports background should be taken into account, especially when performing longitudinal monitoring and multicenter studies.
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http://dx.doi.org/10.23736/S0026-4946.18.05185-XDOI Listing
June 2019

Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling.

Circ Res 2017 Jun 12;121(1):56-70. Epub 2017 Apr 12.

From the Cardiology, Heart Center (M.M., K.F., M.L., J.G., L.R., C.K., J.S., T.R., M.M., M.H., G.P., D.M., M.A., K.M., T.K.R., S.B., A.K., V.R.), Center for Molecular Medicine Cologne (M.M., K.F., M.L., J.G., L.R., C.K., J.S., T.R., M.M., M.H., G.P., D.M., M.A., K.M., T.K.R., S.B., A.K., V.R.), and Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty (T.S.), University of Cologne, Germany; University Heart Center Hamburg, Germany (J.K., D.L.); General and Interventional Cardiology (F.G.D.) and Experimental Pharmacology and Toxicology (B.G., T.E.), University Heart Center Hamburg, University Hospital Hamburg-Eppendorf (UKE), Germany; Institute of Biophysics, Czech Academy of Sciences, Brno (L.K.); International Clinical Research Center, St. Anne's University Hospital Brno, Czech Republic (L.K., A.K.); Mathematics, Cleveland State University, OH (Y.W.); and Cellular and Molecular Medicine and Cardiovascular Medicine, Cleveland Clinic, OH (W.H.W.T., S.L.H.).

Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling.

Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias.

Methods And Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/HO incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation.

Conclusions: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.310870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482785PMC
June 2017

Multikinase inhibitors sorafenib and sunitinib as radiosensitizers in head and neck cancer cell lines.

Head Neck 2017 04 21;39(4):623-632. Epub 2017 Feb 21.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Background: Radioresistance is a common feature of head and neck squamous cell carcinoma (HNSCC). We previously showed that the irradiation- activated vascular endothelial growth factor (VEGF)-extracellular signal-regulated kinase (ERK)-axis is fundamental for the survival of resistant tumors. In this study, we examined if treatment with potent multikinase (MK) inhibitors, sorafenib and sunitinib, could radiosensitize tumor cells.

Methods: Cultured HNSCC cell lines were treated with inhibitors and subsequently irradiated. Radiosensitizing effects were functionally assessed by annexin-V apoptosis and clonogenic assays and confirmed by Western blot. Additionally, we surveyed human HNSCC tissue microarrays (TMAs) for activated ERK expression.

Results: Based on combination indexes, we found that combining irradiation with both inhibitors exerted strong and supra-additive antitumor effects on clonogenic survival. Kinase inhibition enhanced irradiation-induced apoptotic rates and inhibited postradiogenic phospho-ERK-expression. Patients with recurrent HNSCC displayed significantly lower extracellular signal-regulated kinase phosphorylation (pERK) levels than relapse-free patients.

Conclusion: We propose further evaluation of sorafenib and sunitinib as potential radiosensitizing agents in HNSCC treatment. © 2017 Wiley Periodicals, Inc. Head Neck 39: 623-632, 2017.
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http://dx.doi.org/10.1002/hed.24557DOI Listing
April 2017

Predictors of Intraoperative Blood Transfusion in Free Tissue Transfer.

J Reconstr Microsurg 2016 Nov 19;32(9):706-711. Epub 2016 Aug 19.

Department of Plastic and Hand Surgery, Burn Center, Ruhr University, BG University Hospital Bergmannsheil, Bochum, Germany.

 Free tissue transfer has become a safe and reliable procedure and is routinely used in a variety of settings. However, it is associated with lengthy operating times and a high potential for blood loss and consecutive red blood cell transfusions (RBCTs).  To assess the risk for RBCTs, we retrospectively identified 398 patients undergoing free tissue transfer between 2005 and 2014. Based on a multivariate model of risk factors and their respective odds ratio, a risk score was developed to predict the likelihood of the need for intraoperative RBCT.  The median age at the time of operation was 51.3 ± 15 years, and 278 (70%) patients were male. The average body mass index was 25.9 ± 4 and the median ASA score was 2 (range: 1-4). Mean duration of surgery was 319.8 ± 108 minutes and mean duration of hospital stay was 45.8 ± 40 days. A total of 231 patients (58%) required perioperative RBCTs, all of which were allogenic. RBCTs were performed 0 to 48 hours preoperatively in 36 patients (11.3%), intraoperatively in 166 patients (41.7%), and 0 to 48 hours postoperatively in 125 patients (31.4%). The mean amount of overall RBCTs given was 2.5 ± 3.7 units and 1.1 ± 1.9 units for intraoperative transfusions. The following risk factors were statistically significant in the multivariate regression analysis and included in the risk score: age >60 years; a preoperative hemoglobin concentration of <11 g/dL; a preoperative platelet count of >400/nL; history of renal (RI) and cardial insufficiency (CI); defect localization on the proximal extremities, head and neck, or trunk; and the use of myocutaneous flaps. This score assessed the risk for RBCTs with a sensitivity of 77%, a specificity of 81%, and an AUC of the ROC curve of 0.86.  We were able to develop a risk score that allows for the assessment of RBCT likelihood. While most of the identified risk factors cannot be prevented or corrected, it still allows for improved patient counseling and can potentially reduce the number of ordered but not transfused RBCTs.
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http://dx.doi.org/10.1055/s-0036-1586255DOI Listing
November 2016

Functional Recovery of a Human Neonatal Heart After Severe Myocardial Infarction.

Circ Res 2016 Jan 9;118(2):216-21. Epub 2015 Dec 9.

From the IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (B.J.H., J.M.P.); and Department of Pediatrics III-Cardiology, Pulmonology, Allergology, Cystic Fibrosis (J.S., U.S., J.-I.S.), Department of Internal Medicine III (Cardiology and Angiology) (B.J.H., T.S., W.D.), and Department of Anesthesia and Intensive Care (C.V.-S.), Medical University of Innsbruck, Innsbruck, Austria.

Rationale: Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translate findings in model organisms to future therapies in humans: what is the mechanism and can cardiac regeneration indeed occur in newborn humans?

Objective: To assess whether human neonatal hearts can functionally recover after myocardial infarction.

Methods And Results: Here, we report the case of a newborn child having a severe myocardial infarction due to coronary artery occlusion. The child developed massive cardiac damage as defined by serum markers for cardiomyocyte cell death, electrocardiograms, echocardiography, and cardiac angiography. Remarkably, within weeks after the initial ischemic insult, we observed functional cardiac recovery, which translated into long-term normal heart function.

Conclusions: These data indicate that, similar to neonatal rodents, newborn humans might have the intrinsic capacity to repair myocardial damage and completely recover cardiac function.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.307017DOI Listing
January 2016

Sex-, age-, and height-specific reference curves for the 6-min walk test in healthy children and adolescents.

Eur J Pediatr 2015 Jun 10;174(6):837-40. Epub 2014 Dec 10.

Department of Endocrinology & Diabetes, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, UK,

Unlabelled: The 6-min walk test is a simple and accurate method to measure functional exercise capacity in children. We provide smooth reference curves for the modified 6-min walk test in 696 healthy children and adolescents aged 4-19 years, enabling calculation of sex-, age-, and height-specific Z-scores.

Conclusion: These reference curves will allow more accurate grading of mobility and exercise capacity in sick or disabled children and monitoring the effects of intervention or treatment.
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http://dx.doi.org/10.1007/s00431-014-2454-8DOI Listing
June 2015

Action blind: disturbed self-other integration in schizophrenia.

Neuropsychologia 2012 Dec 7;50(14):3775-80. Epub 2012 Nov 7.

Institute for Psychology, Junior Group Neurocognition of Joint Action, University of Muenster, Fliednerstrasse 21, Muenster 48149, Germany.

Recent research using individual task settings suggests that a major problem in schizophrenia is a dysfunctional theory of mind system leading to false mental state attributions. However, if a more low-level deficit to integrate own and other's actions (action blindness) is present in schizophrenia is still unknown. Using a social Simon task, we tested if schizophrenia patients have a deficit in self-other integration. Further, we tested for a possible genetic bias of this dysfunction by studying clinically unaffected first-degree relatives of schizophrenia patients. While schizophrenia patients showed no Social Simon effect, we found a reliable social Simon effect in healthy participants and first-degree relatives of schizophrenia patients. Joint task performance differed statistically between patients and healthy controls. We did not find any differences in the size of the social Simon effects of relatives and healthy controls. The present findings suggest that schizophrenia patients have severe problems with self-other integration, which may lead to problems in social interactions. Since first-degree relatives of schizophrenia patients showed a reliable social Simon effect, the evidence for a genetic bias of this social dysfunction in schizophrenia however is weak.
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http://dx.doi.org/10.1016/j.neuropsychologia.2012.10.027DOI Listing
December 2012

Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis.

Basic Res Cardiol 2011 Jun 10;106(4):591-602. Epub 2011 Mar 10.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, Freiburg, Germany.

Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.
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http://dx.doi.org/10.1007/s00395-011-0166-zDOI Listing
June 2011

Sympathetic alpha(2)-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload.

Cardiovasc Res 2010 Jun 18;86(3):432-42. Epub 2010 Jan 18.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, Freiburg 79104, Germany.

Aims: alpha(2)-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of alpha(2)-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of alpha(2A)-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress.

Methods And Results: Transgenic mice expressing alpha(2A)-adrenoceptors under control of the dopamine beta-hydroxylase (Dbh) promoter were generated and crossed with mice carrying a constitutive deletion in the alpha(2A)- and alpha(2C)-adrenoceptor genes. alpha(2AC)-deficient mice showed increased norepinephrine plasma levels, cardiac hypertrophy, and fibrosis at baseline. Expression of the Dbh-alpha(2A) transgene in sympathetic neurons prevented these effects. In contrast, Dbh-alpha(2A) receptors mediated only a minor part of the bradycardic and hypotensive effects of the alpha(2)-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, the Dbh-alpha(2A) transgene did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy, or fibrosis. In isolated wild-type atria, alpha(2)-agonist-induced inhibition of [3H]norepinephrine release was significantly desensitized after pressure overload. In primary sympathetic neurons from Dbh-alpha(2A) transgenic mice, norepinephrine and medetomidine induced endocytosis of alpha(2A)-adrenoceptors into neurite processes.

Conclusion: alpha(2A)-Adrenoceptors expressed in adrenergic cells are essential feedback inhibitors of sympathetic norepinephrine release to prevent cardiac hypertrophy and fibrosis at baseline. However, these receptors are desensitized by chronic pressure overload which in turn may contribute to the pathogenesis of this condition.
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http://dx.doi.org/10.1093/cvr/cvq014DOI Listing
June 2010

Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster.

J Clin Invest 2009 Sep 17;119(9):2634-47. Epub 2009 Aug 17.

Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim, Germany.

VSMCs respond to changes in the local environment by adjusting their phenotype from contractile to synthetic, a phenomenon known as phenotypic modulation or switching. Failure of VSMCs to acquire and maintain the contractile phenotype plays a key role in a number of major human diseases, including arteriosclerosis. Although several regulatory circuits that control differentiation of SMCs have been identified, the decisive mechanisms that govern phenotypic modulation remain unknown. Here, we demonstrate that the mouse miR-143/145 cluster, expression of which is confined to SMCs during development, is required for VSMC acquisition of the contractile phenotype. VSMCs from miR-143/145-deficient mice were locked in the synthetic state, which incapacitated their contractile abilities and favored neointimal lesion development. Unbiased high-throughput, quantitative, mass spectrometry-based proteomics using reference mice labeled with stable isotopes allowed identification of miR-143/145 targets; these included angiotensin-converting enzyme (ACE), which might affect both the synthetic phenotype and contractile functions of VSMCs. Pharmacological inhibition of either ACE or the AT1 receptor partially reversed vascular dysfunction and normalized gene expression in miR-143/145-deficient mice. We conclude that manipulation of miR-143/145 expression may offer a new approach for influencing vascular repair and attenuating arteriosclerotic pathogenesis.
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http://dx.doi.org/10.1172/JCI38864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735940PMC
September 2009

Soluble TNF-alpha but not transmembrane TNF-alpha sensitizes T cells for enhanced activation-induced cell death.

Eur J Immunol 2009 Nov;39(11):3171-80

Institute of Pathology, Division of Experimental Pathology, University of Bern, Bern, Switzerland.

In addition to its proinflammatory effects, TNF-alpha exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-alpha (tmTNF) and soluble TNF-alpha (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4(+) T cells from wtTNF, TNF-alpha-deficient (TNF(-/-)) and TNF(-/-) mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activation-induced cell death (AICD), however, was significantly attenuated in tmTNF and TNF(-/-), compared with wtTNF CD4(+) T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF(-/-) CD4(+) T cells to levels seen in wtTNF CD4(+) T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4(+) T cells for AICD was also evident in an in vivo model of adoptively transferred CD4(+) T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.
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http://dx.doi.org/10.1002/eji.200939554DOI Listing
November 2009

Modulation of alpha2-adrenoceptor functions by heterotrimeric Galphai protein isoforms.

J Pharmacol Exp Ther 2009 Oct 9;331(1):35-44. Epub 2009 Jul 9.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Germany.

Subtype diversity of heterotrimeric G proteins and G protein-coupled receptors enables a wide spectrum of signal transduction. However, the significance of isoforms within receptor or G protein subfamilies has not been fully elucidated. In the present study, we have tested whether alpha(2)-adrenoceptors require specific Galpha isoforms for their function in vivo. In particular, we analyzed the role of the highly homologous Galpha(i) isoforms, Galpha(i1), Galpha(i2), and Galpha(i3), in typical alpha(2)-adrenoceptor-controlled functions. Mice with targeted deletions in the genes encoding Galpha(i1), Galpha(i2), or Galpha(i3) were used to test the effects of alpha(2)-adrenoceptor stimulation by the agonist medetomidine. The alpha(2)-adrenoceptor agonist medetomidine inhibited [(3)H]norepinephrine release from isolated prefrontal brain cortex or cardiac atria tissue specimens with similar potency and efficacy in tissues from wild-type or Galpha(i)-deficient mice. In vivo, bradycardia, hypotension, induction of sleep, antinociception, and hypothermia induced by alpha(2)-adrenoceptor activation did not differ between wild-type and Galpha(i)-knockout mice. However, the effects of the alpha(2)-agonists medetomidine or 5-bromo-6-(2-imidazolin-2-ylamino)quin-oxaline tartrate (UK14,304) on spontaneous locomotor activity or anesthetic sparing were reduced or absent, respectively, in mice lacking Galpha(i2). In microdissected locus coeruleus neurons or postganglionic sympathetic neurons from stellate ganglia, all three Galpha(i) subunits were expressed as determined by quantitative reverse transcription-polymerase chain reaction, with Galpha(i1) and Galpha(i2) dominating over Galpha(i3). Functional redundancy of the highly homologous Galpha(i) isoforms may predominate over specificity to regulate distinct intracellular pathways downstream of alpha(2)-adrenoceptors in vivo. In contrast, inhibition of locomotor activity and anesthetic sparing may be elicited by a specific coupling of alpha(2A)-adrenoceptors via the Galpha(i2) isoform to intracellular pathways.
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http://dx.doi.org/10.1124/jpet.109.157230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847768PMC
October 2009