Exploring JC polyomavirus sequences and human gene expression in brain tissue of patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare neurological condition associated with reactivation of dormant JC polyomavirus (JCPyV). In this study, we characterized gene expression and JCPyV rearrangements in PML brain tissue. Infection of white matter astrocytes and oligodendrocytes as well as occasional brain cortex neurons was shown. PML brain harbored exclusively rearranged JCPyV variants. Viral transcripts covered the whole genome on both strands. Strong differential expression of human genes associated with neuroinflammation, blood-brain-barrier permeability and neurodegenerative diseases was shown. Pathway analysis revealed wide immune activation in PML brain. The study provides novel insights into the pathogenesis of PML.

Impact of therapeutic plasma exchange on intact protein S, apolipoproteins, and thrombin generation.

INTRODUCTION: Therapeutic plasma exchange (TPE), with solvent/detergent (S/D)-treated plasma as replacement fluid, is an extracorporeal blood purification technique with major impact on both coagulation and lipids. Our previous in vitro study showed that S/D-plasma enhances thrombin generation by lowering intact protein S (PS) levels. AIMS: To evaluate the impact of altered lipid balance on coagulation phenotype during heparin-anticoagulated TPE with S/D-plasma, and to investigate whether the lowered intact PS levels with concomitant procoagulant phenotype, are recapitulated in vivo. METHODS: Coagulation biomarkers, thrombin generation with Calibrated Automated Thrombogram (CAT), and lipid levels were measured before and after the consecutive 1st, 3rd and 5th episodes of TPE performed to six patients with Guillain-Barré syndrome or myasthenia gravis. The effects of in vitro dilution of S/D-plasma on thrombin generation were explored with CAT to mimic TPE. RESULTS: Patients did not have coagulation disorders, except elevated FVIII. Intact PS, lipoproteins, especially LDL, Apolipoprotein CIII (ApoC3) and ApoB/ApoA1 ratio declined (p < 0.05). In contrast, VLDL and triglyceride levels stayed intact. CAT lag time shortened (p < 0.05). In vitro dilution of S/D plasma with co-transfused Ringer's lactate and 4% albumin partially reduced its procoagulant phenotype in CAT, which is mainly seen as peak thrombin, and modestly shortened lag time. CONCLUSIONS: After the five settings of TPE using S/D-plasma in vivo, which associated with heparinization and reduced coagulation factor activities, our observations of declining natural anticoagulant intact PS and apolipoproteins refer to rebalance of the hemostatic and lipid profiles.

JC Polyomavirus Modifies the Expression of Human microRNAs in Progressive Multifocal Leukoencephalopathy Brain.

Progressive multifocal leukoencephalopathy (PML) is a severe neurological condition caused by reactivation of JC polyomavirus (JCPyV) in immunosuppression. Asymptomatic JCPyV persists in peripheral tissues. Upon reactivation, neurotropic rearrangements may emerge, and the virus gains access to the brain. To assess the mechanisms of PML pathogenesis, brain tissue material from PML patients was collected for small RNA sequencing. Upregulation of 8 microRNAs (miRNAs) in PML brain was validated using quantitative microRNA polymerase chain reaction (PCR). Bioinformatics tools were utilized to identify major associations of the upregulated miRNAs: neuroinflammation and blood-brain barrier disruption. The results indicate involvement of human miRNA regulation in PML pathogenesis.

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies.

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].

Single-Molecule Sequencing Revealing the Presence of Distinct JC Polyomavirus Populations in Patients With Progressive Multifocal Leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by reactivation of JC polyomavirus (JCPyV) in immunosuppressed individuals and lytic infection by neurotropic JCPyV in glial cells. The exact content of neurotropic mutations within individual JCPyV strains has not been studied to our knowledge. Methods: We exploited the capacity of single-molecule real-time sequencing technology to determine the sequence of complete JCPyV genomes in single reads. The method was used to precisely characterize individual neurotropic JCPyV strains of 3 patients with PML without the bias caused by assembly of short sequence reads. Results: In the cerebrospinal fluid sample of a 73-year-old woman with rapid PML onset, 3 distinct JCPyV populations could be identified. All viral populations were characterized by rearrangements within the noncoding regulatory region (NCCR) and 1 point mutation, S267L in the VP1 gene, suggestive of neurotropic strains. One patient with PML had a single neurotropic strain with rearranged NCCR, and 1 patient had a single strain with small NCCR alterations. Conclusions: We report here, for the first time, full characterization of individual neurotropic JCPyV strains in the cerebrospinal fluid of patients with PML. It remains to be established whether PML pathogenesis is driven by one or several neurotropic strains in an individual.

Diagnostics and current care of myasthenia gravis.

Myasthenia gravis (MG) is the most common neuromuscular transmission disorder, causing weakness of skeletal muscles on exertion. The course of the disease is highly variable, symptoms and signs may change rapidly due to infection or pregnancy. MG is classified using serological, electrophysiological and pharmaceutical tools. A precise diagnosis allows for the choice of right treatment, predicts the course of disease and hence helps with the follow-up. In this review we present Finnish guidelines for diagnostics, treatment and follow-up of MG patients.

Differentiation of highly pathogenic strains of human JC polyomavirus in neurological patients by next generation sequencing.

BACKGROUND: JC polyomavirus (JCPyV) persists asymptomatic in more than half of the human population. Immunocompromising conditions may cause reactivation and acquisition of neurotropic rearrangements in the viral genome, especially in the non-coding control region (NCCR). Such rearranged JCPyV strains are strongly associated with the development of progressive multifocal leukoencephalopathy (PML). METHODS: Using next-generation sequencing (NGS) and bioinformatics tools, the NCCR was characterized in cerebrospinal fluid (CSF; N = 21) and brain tissue (N = 16) samples from PML patients (N = 25), urine specimens from systemic lupus erythematosus patients (N = 2), brain tissue samples from control individuals (N = 2) and waste-water samples (N = 5). Quantitative PCR was run in parallel for diagnostic PML samples. RESULTS: Archetype NCCR (i.e. ABCDEF block structure) and archetype-like NCCR harboring minor mutations were detected in two CSF samples and in one CSF sample and in one tissue sample, respectively. Among samples from PML patients, rearranged NCCRs were found in 8 out of 21 CSF samples and in 14 out of 16 brain tissue samples. Complete or partial deletion of the C and D blocks was characteristic of most rearranged JCPyV strains. From ten CSF samples and one tissue sample NCCR could not be amplified. CONCLUSIONS: Rearranged NCCRs are predominant in brain tissue and common in CSF from PML patients. Extremely sensitive detection and identification of neurotropic viral populations in CSF or brain tissue by NGS may contribute to early and accurate diagnosis, timely intervention and improved patient care.

Efficacy and safety of Privigen(®) in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study).

This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen(®) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with L-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2 g/kg body weight [bw]) and up to seven maintenance doses (1 g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of ≥1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being ≥35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naïve patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP.

[Aseptic meningitis]. / Aseptinen meningiitti.

Aseptic meningitis is a benign condition often triggered by a virus or an immunological process. For example herpes virus, borrelia, tuberculosis, a fungus or an autoimmune disease may underlie meningitides presenting prolonged or recurrent symptoms. It is essential to identify the meningitis patients among the diverse group of headache patients and carry out focused investigations and treatment, and in mild cases to avoid complications caused by the investigations. Analgesic and antiemetic medication are usually sufficient for symptomatic treatment. Etiological treatment is available for some patients.

[Dysphagia--a multidisciplinary challenge]. / Dysfagia--moniammatillinen haaste.

Difficulty in swallowing, i.e. dysphagia should be distinguished from the sensation of a lump in the throat and the pain on swallowing. A careful anamnesis will help in determining the ailment as a problem of oral, pharyngeal or esophageal stage of swallowing. Videofluorography, FEES investigation and transnasal esophagoscopy as well as gastroscopy are helpful for the diagnosis. Cerebral infarction is the most significant cause of oropharyngeal dysphagia. Esophageal causes include reflux disease, tumors and achalasia. Diagnostics, treatment and rehabilitation of dysphagia patients require multidisciplinary collaboration. In addition, surgical therapy may be required.

[Geriatric rehabilitation as an integral part of geriatric medicine in the nordic countries.].

OBJECTIVE: Firstly to outline the theoretical and practical framework for geriatric rehabilitation in Iceland and other Nordic countries and secondly to survey the scientific medical publications for evidence based geriatric rehabilitation. METHODS: Brain storming on geriatric rehabilitation in a working group of Nordic teachers in geriatric medicine. Papers on scientific programs for geriatric rehabilitation from Internet sources were collected and analyzed. All articles describing randomized studies in geriatric rehabilitation were selected for overview. The papers were divided into four groups according to diseases, infirmity and resource settings; 1) stroke, 2) hip-fractures, 3) acute admissions and 4) programs conducted in nursing homes, day hospitals and home services. RESULTS: A spectrum of biological and social events creates the conditions underlying most causes for illness and disability in old people. The process of established geriatric services promotes the efficiency of geriatric rehabilitation. The literature survey included 27 scientific studies (8586 patients) on randomized studies with valid endpoints. Geriatric rehabilitation programs for stroke patients in geriatric settings, six studies (1138 patients), reduced mortality and the need for nursing home placement but the outcome for ADL. Function and length of stay was more variable between the studies. The outcome of geriatric rehabilitation was even more decisive in the randomized hip-fracture studies, six studies (2171 patients). Eight studies were found comparing the outcome between acute admission of frail elderly to either geriatric (GEMU, GRU) or general medical wards. The outcome as regards to mortality rate at one year, placement to a nursing home, physical function, contentment with services, readmission rate and cost was all significantly better in the geriatric settings. Internal comparisons of geriatric programs in nursing homes, day hospitals and in home service, seven studies (1261 patient), revealed some differences in outcomes in function, contentment and costs. CONCLUSIONS: Specialized geriatric rehabilitation is complicated but effective when properly performed. Interdisciplinary teamwork, targeting of patients, comprehensive assessment and intensive and patient-targeted rehabilitation seem to characterize the most effective programs. Rehabilitation of frail elderly people poses a major challenge for the future and has to be developed further for the sake of quality of life of elderly people as well as for economic reasons.

Geriatric rehabilitation as an integral part of geriatric medicine in the Nordic countries.

OBJECTIVES: First, to outline the theoretical and practical framework for geriatric rehabilitation in the Nordic countries and second, to survey the scientific medical publications for evidence-based geriatric rehabilitation. METHODS: Brainstorming on geriatric rehabilitation in a working group of Nordic teachers in geriatric medicine. Papers on scientific programmes for geriatric rehabilitation from Internet sources were collected and analyzed. All articles describing randomized studies in geriatric rehabilitation were selected for meta-analyses. The papers were divided into four groups according to diseases, infirmity and resource settings: stroke, hip-fractures, acute admissions and programmes conducted in nursing homes, day hospitals and home services. RESULTS: The literature survey included 30 scientific studies (9496 patients) in randomized trials with valid endpoints. Geriatric rehabilitation programmes for stroke patients in geriatric settings (six papers, 1138 patients) reduced mortality and the need for nursing home placement, but the outcome for ADL function was not significantly changed. Function and length of stay varied between the studies. The outcome of geriatric rehabilitation was even more decisive in the randomized hip-fracture studies (seven articles, 2414 patients): the readmission rate and cost were significantly better. Ten studies were found, comparing the outcome of acute admissions of frail elderly patients (4683) with either geriatric (GEMU, GRU) or general medical wards. The effect of rehabilitation regarding mortality rate at one year, placement in a nursing home, physical function, contentment with services, readmission rate and cost was significant improvement in the geriatric settings. Internal comparisons of geriatric programmes in nursing homes, day hospitals and in-home services (seven studies, 1261 patient) revealed some differences in outcomes regarding function, contentment and costs. CONCLUSION: Specialized geriatric rehabilitation is complicated but effective when properly performed. Interdisciplinary teamwork, targeting of patients, comprehensive assessment and intensive and patient-targeted rehabilitation seem to characterize the most effective programmes. Rehabilitation of frail elderly people poses a major future challenge and has to be developed further for the sake of elderly people's quality of life as well as economic reasons.