Regional distribution of the prostaglandin E2 receptor EP1 in the rat brain: accumulation in Purkinje cells of the cerebellum

Prostaglandin E2 (PGE2), is a major prostanoid produced by the activity of cyclooxygenases (COX) in response to various physiological and pathological stimuli. PGE2 exerts its effects by activating four specific E-type prostanoid receptors (EP1, EP2, EP3 and EP4). In the present study, we analyzed the expression of the PGE2 receptor EP1 (mRNA and protein) in different regions of the adult rat brain (hippocampus, hypothalamus, striatum, prefrontal cerebral cortex, parietal cortex, brain stem and cerebellum) using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemical methods. On a regional basis, levels of EP1 mRNA were the highest in parietal cortex and cerebellum. At the protein level, we found a very strong expression of EP1 in cerebellum as revealed by Western blotting experiments. Furthermore, the present study provides for the first time evidence that the EP1 receptor is highly expressed in the cerebellum, where the Purkinje cells displayed a very high immunolabeling of their perikaryon and dendrites as observed in the immunohistochemical analysis. Results from the present study indicate that the EP1 prostanoid receptor is expressed in specific neuronal populations, which possibly determine the region specific response to PGE2

Cognitive functions over the course of 1 year in multiple sclerosis patients treated with disease modifying therapies

Objectives: Disease-modifying therapies (DMTs) are applied to delay or prevent disease progression in multiple sclerosis (MS). While this has mostly been proven for physical symptoms, available studies regarding long-term effects of DMTs on cognitive functions are rare and sometimes inconsistent due to methodological shortcomings. Particularly in the case of fingolimod, comprehensive data on cognitive functions are not yet available. Therefore, we set out to reliably assess cognitive functions in patients with relapsing-remitting MS (RRMS) treated with DMTs over 1 year. Methods: Cognitive functions were assessed with eight tests at three timepoints: baseline, 6-month follow up and 12-month follow up. First, we investigated whether the stability of cognitive functions (i.e. not falling below the 5% cut-off in more than one test) over 1 year in RRMS patients (n = 41) corresponds to the stability in healthy individuals (n = 40) of a previous study. Second, we compared the percentage of declined and improved patients in the different tests. Third, we compared patients treated with fingolimod (n = 22) with patients treated with natalizumab (n = 11) with regard to cognitive stability. Fourth, based on the patient data, the Reliable Change Index was applied to compute cut-offs for reliable cognitive change. Results: Approximately 75% of RRMS patients treated with DMTs remained stable over the course of 1 year. The Paced Auditory Serial Addition Test (PASAT) and the Spatial Recall Test (SPART), produced improvements in 12.5% and 30.6%, respectively, probably due to practice effects. Patients treated with fingolimod did not differ from patients treated with natalizumab with regard to cognitive stability. Conclusions: Cognitive functions remain relatively stable under DMT treatment over 1 year, irrespective of the type of medication. Furthermore, the tests PASAT and SPART should be interpreted cautiously in studies examining performance changes over time. The provided RCI norms may help clinicians to determine whether a difference in two measurements observed in a RRMS patient is reliable

Effects of natalizumab treatment on Foxp3+ T regulatory cells.

Background: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients. Methodology: A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs. Principal Findings: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25highCD127lowFoxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment. Conclusions: We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function

Immunological and clinical consequences of splenectomy in a multiple sclerosis patient treated with natalizumab

Objective Here we report a case of a splenectomized white woman with natalizumab-associated progressive multifocal leukoencephalopathy (PML), occurring as early as after 11 infusions and provide blood fluorescence-activated cell sorting (FACS) analyses before and after natalizumab treatment. Design This is a report of a single case with immunological studies. Methods Methods comprised neurologic examination, magnetic resonance imaging, and cerebrospinal fluid (CSF) studies as well as immune cell FACS analyses from blood. Results Diagnosis of PML was established after positive John Cunningham virus (JCV) DNA was detected in the CSF. An immune reconstitution inflammatory syndrome was treated with repeated cycles of steroid pulses and intravenous immunoglobulins. Reduced numbers of memory B cells, which might play an important role in antiviral immune response, were detected in the blood. Moreover the percentage of CD19+ B cells was elevated in our post-splenectomy patient as compared to a control cohort of multiple sclerosis (MS) patients under natalizumab therapy. Conclusion Splenectomy may increase the risk for the development of natalizumab-associated PML via effects on the B cell compartment. It may be regarded as a risk factor in MS patients independent from the duration of disease

Pengaruh Facilitated Tucking Dan Musik Terhadap Respon Nyeri Bayi Prematur Ketika Pengambilan Darah

Manajemen nyeri yang tidak terkontrol pada bayi akan mempengaruhi pertumbuhan dan perkembangan selanjutnya. Salah satu tindakan manajemen nyeri non-farmakologi yang aman bagi bayi prematur adalah facilitated tucking dan pemberian musik. Penelitian ini untuk mengidentifikasi pengaruh kombinasi fasilitated tucking dan musik dalam mengurangi respon nyeri dan durasi menangis bayi prematur saat pengambilan darah. Rancangan kuasi eksperimen dengan pos-ttest control group design dipilih. Sampel penelitian ini adalah 60 bayi prematur yang dirawat di rumah sakit dan dilakukan pengambilan darah. Uji hipotesis menggunakan independent t-test. Kelompok intervensi diberikan facilitated tucking dan musik ketika pengambilan darah. Pengukuran nyeri menggunakan Premature Infant Pain Profile (PIPP) dan durasi menangis diukur dalam detik. Hasil penelitian menunjukkan bahwa rata-rata skor nyeri bayi adalah 7,03 pada kelompok intervensi dan 12,4 pada kelompok kontrol. Rata-rata durasi menangis bayi pada kelompok intervensi adalah 68,5 detik dan kelompok kontrol adalah 105 detik. Uji t menunjukkan perbedaan yang bermakna skor nyeri p 0,000 (α=0,05) dan durasi menangis 0,009 (α=0,05) bayi premature antara kelompok intervensi dan kelompok kontrol. DIsimpulkan bahwa facilitated tucking dan musik telah mengurangi respon nyeri dan durasi tangisan bayi prematur ketika pengambilan darah

Demyelinating disease and anti-N-methyl-D-aspartate receptor immunoglobulin G antibodies: a case report

Background: Anti–N-methyl-D-aspartate receptor immunoglobulin G antibodies directed against the GluN1 subunit are considered highly specific for anti-N-methyl-D-aspartate receptor encephalitis, a severe clinical syndrome characterized by seizures, psychiatric symptoms, orofacial dyskinesia and autonomic dysfunction. Case presentation: Here we report a 33 year old Caucasian male patient with clinically definite multiple sclerosis who was found to be positive for anti-N-methyl-D-aspartate receptor antibodies. Rituximab therapy was initiated. On the 18 months follow-up visit the patient was found to be clinically stable, without typical signs of anti-N-methyl-D-aspartate receptor encephalitis. Conclusion: Our findings add to the growing evidence for a possible association between anti-N-methyl-D-aspartate receptor encephalitis and demyelinating diseases

Neuromyelitis optica presenting with relapses under treatment with natalizumab: a case report

Introduction Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system. To date, optimal therapeutic approaches for neuromyelitis optica have yet to be defined. Natalizumab is highly effective in relapsing-remitting multiple sclerosis and might be considered as an option. Case presentation Here, we describe a 67-year-old Caucasian man with definite neuromyelitis optica with detection of anti-aquaporin-4 antibodies over the course of the disease. After initially discussing the diagnosis of multiple sclerosis at an outside hospital, our patient received interferon beta 1a as well as repeated corticosteroid pulses without success. Under subsequent therapy with natalizumab, he continued to present relapses. It was not until discontinuation of natalizumab, repeated cycles of plasma exchanges and initiation of therapy with rituxan that the disease course started to stabilize. Although B cells were completely depleted, our patient experienced another severe myelitis relapse during further follow-up and an additional immunosuppressive therapy with cyclophosphamide was started. Under this regimen, no further relapses occurred over the next 24 months. Conclusions This case adds further evidence to the previously discussed notion that natalizumab, while highly effective in multiple sclerosis, may not work sufficiently in neuromyelitis optica. It further advocates for repetitive testing of anti-aquaporin-4 antibodies before and after treatment initiation

Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease

Background In the recent years, a role of the immune system in Huntington’s disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease. Results As compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection. Conclusions These data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking

Patient preferences for disease-modifying drugs in multiple sclerosis therapy: a choice-based conjoint analysis

Objectives: With an increasing number of disease-modifying treatments (DMTs) for multiple sclerosis (MS), patient preferences will gain importance in the decision-making process. We assessed patients’ implicit preferences for oral versus parenteral DMTs and identified factors influencing patients’ treatment preference. Methods: Patients with relapsing–remitting MS (n = 156) completed a questionnaire assessing treatment preferences, whereby they had to decide between pairs of hypothetical treatment scenarios. Based on this questionnaire a choice-based conjoint analysis was conducted. Results: Treatment frequency and route of administration showed a stronger influence on patient preference compared with frequency of mild side effects. The latter attribute was more important for treatment-naïve patients compared with DMT-experienced patients. The higher the Extended Disability Status Scale score, the more likely pills, and the less likely fewer side effects were preferred. Pills were preferred over injections by 93% of patients, when treatment frequency and frequency of side effects were held constant. However, preference switched to injections when pills had to be taken three times daily and injections only once per week. Injections were also preferred when pills were associated with frequent side effects. Conclusions: Our results suggest that route of administration and treatment frequency play an important role in the patients’ preference for a given DMT