The immunology underlying CNS autoantibody diseases.

The past two decades have seen a considerable paradigm shift in the way autoimmune CNS disorders are considered, diagnosed, and treated; largely due to the discovery of novel autoantibodies directed at neuroglial surface or intracellular targets. This approach has enabled multiple bona fide CNS autoantibody-associated diseases to thoroughly infiltrate the sphere of clinical neurology, facilitating advances in patient outcomes. This review focusses on the fundamental immunological concepts behind CNS autoantibody-associated diseases. First, we briefly review the broad phenotypic profiles of these conditions. Next, we explore concepts around immune checkpoints and the related B cell lineage. Thirdly, the sources of autoantibody production are discussed alongside triggers of tolerance failure, including neoplasms, infections and iatrogenic therapies. Penultimately, the role of T cells and leucocyte trafficking into the CNS are reviewed. Finally, biological insights from responses to targeted immunotherapies in different CNS autoantibody-associated diseases are summarised. The continued and rapid expansion of the CNS autoantibody-associated field holds promise for further improved diagnostic and therapeutic paradigms, ultimately leading to further improvements in patient outcomes.

[Disease-related knowledge acquisition through structured patient information in rheumatoid arthritis (StruPI-RA) : First results of the StruPI-RA study in Germany]. / Krankheitsbezogener Wissenserwerb durch strukturierte Patienteninformation bei Rheumatoider Arthritis (StruPI-RA) : Erste Ergebnisse der StruPI-RA-Studie in Deutschland.

BACKGROUND/OBJECTIVE: The structured patient information for rheumatoid arthritis (StruPi-RA) program was the first standardized outpatient education program in rheumatoid arthritis (RA) in Germany. The main objective of the study was to determine the efficacy of the StruPi-RA program concerning disease-specific knowledge acquisition in patients with early stage RA or after changing the treatment regimen. METHODS: A total of 61 patients were included in a control group design, 32 in the intervention group (IG) and 29 in the control group (CG). Patients of the IG attended 3 modules of 90 min in a structured patient information program (StruPI-RA) including the topics of diagnostics, treatment and living with RA. Patients in the CG only received information material from the German Rheumatism League. The primary target criterion was the disease-related acquisition of knowledge, measured with the patient knowledge questionnaire (PKQ). Data were collected before and after participation in StruPI-RA. RESULTS: The improvement in knowledge in the IG attending the StruPI-RA compared to the CG was significant in time and group comparisons. No influence of disease duration or educational level was observed. The subscale treatment alone showed a significant difference in the group and time comparison. CONCLUSION: Participation in the StruPI-RA program in early RA was associated with a significant increase in disease-specific knowledge compared to the control group of patients. This leads to better decision-making in terms of treatment, a more beneficial doctor-patient communication and better self-management. In the long term an improvement in treatment adherence and quality of life is expected.

Association of host, agent and environment characteristics and the duration of incubation and symptomatic periods of norovirus gastroenteritis.

We analysed the reported duration of incubation and symptomatic periods of norovirus for a dataset of 1022 outbreaks, 64 of which reported data on the average incubation period and 87 on the average symptomatic period. We found the mean and median incubation periods for norovirus to be 32·8 [95% confidence interval (CI) 30·9-34·6] hours and 33·5 (95% CI 32·0-34·0) hours, respectively. For the symptomatic period we found the mean and median to be 44·2 (95% CI 38·9-50·7) hours and 43·0 (95% CI 36·0-48·0) hours, respectively. We further investigated how these average periods were associated with several reported host, agent and environmental characteristics. We did not find any strong, biologically meaningful associations between the duration of incubation or symptomatic periods and the reported host, pathogen and environmental characteristics. Overall, we found that the distributions of incubation and symptomatic periods for norovirus infections are fairly constant and showed little differences with regard to the host, pathogen and environmental characteristics we analysed.

Changes in nuclear morphology and chromatin texture of basal keratinocytes in melasma.

BACKGROUND: The pathogenesis of melasma and the role of keratinocytes in disease development and maintenance are not completely understood. Dermal abnormalities, the expression of inflammatory mediators, growth factors, epithelial expression of melanocortin and sexual hormones receptors suggest that not only melanocytes, but entire epidermal melanin unit is involved in melasma physiopathology. OBJECTIVES: To compare nuclear morphological features and chromatin texture between basal keratinocytes in facial melasma and adjacent normal skin. METHODS: We took facial skin biopsies (2 mm melasma and adjacent normal skin) from women processed for haematoxylin and eosin. Thirty non-overlapping basal keratinocyte nuclei were segmented and descriptors of area, highest diameter, perimeter, circularity, pixel intensity, profilometric index (Ra) and fractal dimension were extracted using ImageJ software. RESULTS: Basal keratinocyte nuclei from facial melasma epidermis displayed larger size, irregular shape, hyperpigmentation and chromatin heterogeneity by fractal dimension than perilesional skin. CONCLUSION: Basal keratinocytes from facial melasma display changes in nuclear form and chromatin texture, suggesting that the phenotype differences between melasma and adjacent facial skin can result from complete epidermal melanin unit alterations, not just hypertrophic melanocytes.

Risk factors for facial melasma in women: a case-control study.

BACKGROUND: Melasma is a localized chronic acquired hypermelanosis, common in adult women and which has an important impact on their life quality. Its pathology is unknown, despite some recognized triggering factors. OBJECTIVE: To evaluate risk factors for developing facial melasma in women. METHODS: This was a case-control study involving adult women with or without facial melasma, paired by age. Variables were grouped into hierarchical levels: personal characteristic data, exposure variables, links to hormonal stimuli and the State-Trait Anxiety Inventory questionnaire, Brazilian version. The data were analysed using conditional multiple logistic regression. RESULTS: We evaluated 207 patients and 207 controls. The mean age was 38 years. Cases differed from controls for phototype, Amerindian ancestry [odds ratio (OR) 2·59], years of beach or rural residence (OR 1·06), time exposed to sun at work (OR 1·65), time exposed to sun in leisure activities (OR 1·04), antidepressant/anxiolytic use (OR 4·96), menstrual irregularity (OR 3·83), pregnancy history (OR 3·59), years of oral contraceptive use (OR 1·23) and anxiety scores (OR 1·08). A family history of melasma was reported in 61% of cases and 13% of controls (OR 10·40). CONCLUSIONS: Facial melasma is independently associated with elements linked to pigmentation capacity, family ancestry, chronic sun exposure, sexual hormone stimuli, psychotropics and anxiety traits.

The role of booster vaccination and ongoing viral evolution in seasonal circulation of SARS-CoV-2.

Periodic resurgences of COVID-19 in the coming years can be expected, while public health interventions may be able to reduce their intensity. We used a transmission model to assess how the use of booster doses and non-pharmaceutical interventions (NPIs) amid ongoing pathogen evolution might influence future transmission waves. We find that incidence is likely to increase as NPIs relax, with a second seasonally driven surge expected in autumn 2022. However, booster doses can greatly reduce the intensity of both waves and reduce cumulative deaths by 20% between 7 January 2022 and 7 January 2023. Reintroducing NPIs during the autumn as incidence begins to increase again could also be impactful. Combining boosters and NPIs results in a 30% decrease in cumulative deaths, with potential for greater impacts if variant-adapted boosters are used. Reintroducing these NPIs in autumn 2022 as transmission rates increase provides similar benefits to sustaining NPIs indefinitely (307 000 deaths with indefinite NPIs and boosters compared with 304 000 deaths with transient NPIs and boosters). If novel variants with increased transmissibility or immune escape emerge, deaths will be higher, but vaccination and NPIs are expected to remain effective tools to decrease both cumulative and peak health system burden, providing proportionally similar relative impacts.

Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis.

A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence.

Eye changes in space : New insights into clinical aspects, pathogenesis, and prevention.

BACKGROUND: More than ever research into changes in the eye caused by long-term space flight is becoming the focus of the international and national space agencies National Aeronautics and Space Administration (NASA), European Space Agency (ESA) and German Aerospace Center (DLR). In addition to space radiation-induced cataract formation considerable eye changes, summarized under space flight-associated neuro-ocular syndrome (SANS), can occur. OBJECTIVE: This article gives an overview of the current state of research and future directions in the field of research concerned with ocular alterations in SANS and presents the relevance for terrestrial ophthalmological research. MATERIAL AND METHODS: An analysis of existing publications on SANS in PubMed and reports on the risk of SANS published by the NASA of the USA was carried out. RESULTS: The reasons for the development of the eye changes in space have not been clarified. Factors such as the increase in intracranial pressure, fluid shifts, hypercapnia and genetic factors are the subject of intensive research efforts. A terrestrial model for the induction of papilledema could be established (bed rest studies with -6° head-down tilt as a space analogue). Countermeasures for the development of eye changes, such as intermittent artificial gravity, are the subject of current research studies. CONCLUSION: Research into SANS as part of bed rest studies will provide further important insights in the future for space research and also for terrestrial research. Clinical research projects can be derived from space research.

Genetic and environmental factors and the distribution of multiple sclerosis in Europe.

BACKGROUND: The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease-associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. METHODS: We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. RESULTS: We observed that HLA alleles unequivocally interact with a population-wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. CONCLUSIONS: Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.

[Eye changes in space : New insights into clinical aspects, pathogenesis and prevention]. / Augenveränderungen im All : Aktuelles zu Klinik, Pathogenese und Prävention.

BACKGROUND: More than ever research into changes in the eye caused by long-term space flight is becoming the focus of the international and national space agencies National Aeronautics and Space Administration (NASA), European Space Agency (ESA) and German Aerospace Center (DLR). In addition to space radiation-induced cataract formation considerable eye changes, summarized under space flight-associated neuro-ocular syndrome (SANS), can occur. OBJECTIVE: This article gives an overview of the current state of research and future directions in the field of research concerned with ocular alterations in SANS and presents the relevance for terrestrial ophthalmological research. MATERIAL AND METHODS: An analysis of existing publications on SANS in PubMed and reports on the risk of SANS published by the NASA of the USA was carried out. RESULTS: The reasons for the development of the eye changes in space have not been clarified. Factors such as the increase in intracranial pressure, fluid shifts, hypercapnia and genetic factors are the subject of intensive research efforts. A terrestrial model for the induction of papilledema could be established (bed rest studies with -6° head-down tilt as a space analogue). Countermeasures for the development of eye changes, such as intermittent artificial gravity, are the subject of current research studies. CONCLUSION: Research into SANS as part of bed rest studies will provide further important insights in the future for space research and also for terrestrial research. Clinical research projects can be derived from space research.

[Dependency of intraocular pressure on body posture in glaucoma patients : New approaches to pathogenesis and treatment]. / Lageabhängigkeit des Augeninnendruckes bei Glaukompatienten : Neue Ansätze zur Pathogenese und Therapie.

BACKROUND: Human intraocular pressure (IOP) depends on the position of the head in relation to the body in space. Physiologically, the IOP increases in a lying position compared to an upright posture. Microgravity in space also appears to cause an increase in intraocular pressure, accompanied by other ophthalmological changes, which are summarized under the term spaceflight associated neuro-ocular syndrome (SANS). Bed rest studies are being carried out to investigate the effects of weightlessness on the human body. So here there is an intersection between research into SANS and glaucoma. Increased intraocular pressure remains the most important risk factor for glaucoma development and progression that can be influenced by treatment. The influence of position-dependent IOP fluctuations on glaucoma is still not sufficiently understood. MATERIALS AND METHODS: A literature search was carried in PubMed on the subject of IOP fluctuations related to posture. Analysis and evaluation of the published study results and a summary of available clinical data. RESULTS: The increase in IOP when changing from a seated to a lying body position is greater in glaucoma patients with an increase of up to 8.6 mm Hg compared to healthy subjects with an increase up to 5 mm Hg. In small pilot studies the increase in lying IOP in some glaucoma patients and healthy volunteers could be attenuated by elevation of the head by 30%. A lower compartmental pressure in the subarachnoid space has been associated with glaucoma and may represent a risk factor for glaucoma development. Not only the level of IOP but also IOP fluctuations were associated with an increased risk of disease progression. CONCLUSION: The clinical significance of IOP peaks during sleep on glaucoma is still not sufficiently understood. New methods for continuous IOP measurement offer promising opportunities for further research into the importance of IOP fluctuations related to changes of body and head posture.

[Web-based electronic patient record as an instrument for quality assurance within an integrated care concept]. / Webbasierte elektronische Krankenakte im Rahmen eines integrierten Versorgungskonzepts als Instrument der Qualitätssicherung.

OBJECTIVE: A prerequisite for integrated care programmes is the implementation of a communication network meeting quality assurance standards. Against this background the main objective of the integrated care project between the University Eye Hospital Erlangen and the health insurance company AOK Bayern was to evaluate the potential and the acceptance of a web-based electronic patient record in the context of cataract and retinal surgery. METHODS: Standardised modules for capturing pre-, intra- and post-operative data on the basis of clinical pathway guidelines for cataract- and retinal surgery have been developed. There are 6 data sets recorded per patient (1 pre-operative, 1 operative, 4-6 post-operative). For data collection, a web-based communication system (Soarian Integrated Care) has been chosen which meets the high requirements in data security, as well as being easy to handle. This teleconsultation system and the embedded electronic patient record are independent of the software used by respective offices and hospitals. Data transmission and storage were carried out in real-time. RESULTS: At present, 101 private ophthalmologists are taking part in the IGV contract with the University Eye Hospital Erlangen. This corresponds to 52% of all private ophthalmologists in the region. During the period from January 1st 2006 to December 31st 2006, 1844 patients were entered. Complete documentation was achieved in 1390 (75%) of all surgical procedures. For evaluation of this data, a multidimensional report and analysis tool (Cognos) was used. The deviation from target refraction as one quality indicator was in the mean 0.09 diopter. CONCLUSIONS: The web-based patient record used in this project was highly accepted by the private ophthalmologists. However there are still general concerns against the exchange of medical data via the internet. Nevertheless, the web-based patient record is an essential tool for a functional integration between the ambulatory and stationary health-care units. In addition to the telemedicine functions of the system, we achieved the export of the data to a data warehouse system in order to provide a flexible and powerful tool for quality assurance analysis and reporting.

Evidence for supercoughers in an analysis of six tuberculosis cohorts from China, Peru, The Gambia and Uganda.

BACKGROUND: It is very difficult to observe tuberculosis (TB) transmission chains and thus, identify superspreaders. We investigate cough duration as a proxy measure of transmission to assess the presence of potential TB superspreaders.DESIGN: We analyzed six studies from China, Peru, The Gambia and Uganda, and determined the distribution of cough duration and compared it with several theoretical distributions. To determine factors associated with cough duration, we used linear regression and boosted regression trees to examine the predictive power of patient, clinical and environmental characteristics.RESULTS: We found within-study heterogeneity in cough duration and strong similarities across studies. Approximately 20% of patients contributed 50% of total cough days, and around 50% of patients contributed 80% of total cough days. The cough duration distribution suggested an initially increasing, and subsequently, decreasing hazard of diagnosis. While some of the exposure variables showed statistically significant associations with cough duration, none of them had a strong effect. Multivariate analyses of different model types did not produce a model that had good predictive power.CONCLUSION: We found consistent evidence for the presence of supercoughers, but no characteristics predictive of such individuals.

Performance of the QuantiFERON®-TB Gold In-Tube assay in tuberculin skin test converters: a prospective cohort study.

OBJECTIVE: To investigate diagnostic agreement of the QuantiFERON®-TB Gold In-Tube (QFT-GIT) test in adult tuberculin skin test (TST) converters in a high tuberculosis (TB) burden setting. SETTING AND DESIGN: We performed a case-cohort study from 2014 to 2016 in Uganda among residents who were not infected with Mycobacterium tuberculosis. Participants were followed up for 1 year, when they were retested to determine TST conversion. All TST converters and a random sample of participants from baseline were offered QFT-GIT testing. RESULTS: Of 368 enrolled participants, 61 (17%) converted their TST by 1 year. Among 61 converters, 42 were tested using QFT-GIT, 64% of whom were QFT-GIT-positive. Of 307 participants with a persistent negative TST, 48 were tested using QFT-GIT, 83% of whom were QFT-negative. Overall concordance of TST and QFT-GIT was moderate (κ = 0.48, 95%CI 0.30-0.66). Converters with a conversion of 15 mm had a higher proportion of concordant QFT-GIT results (79%) than converters with increments of 10-14.9 mm (52%). CONCLUSION: Concordance between TST and QFT-GIT was moderate among TST converters in this urban African population. These findings call for improved tests that more accurately measure conversion to tuberculous infection.

Is IPT more effective in high-burden settings? Modelling the effect of tuberculosis incidence on IPT impact.

SETTING: Isoniazid preventive therapy (IPT) is effective for preventing active tuberculosis (TB), although its mechanism of action is poorly understood and the optimal disease burden for IPT use has not been defined. OBJECTIVE: To describe the relationship between TB incidence and IPT effectiveness. METHODS: We constructed a model of TB transmission dynamics to investigate IPT effectiveness under various epidemiological settings. The model structure was intended to be highly adaptable to uncertainty in both input parameters and the mechanism of action of IPT. To determine the optimal setting for IPT use, we identified the lowest number needed to treat (NNT) with IPT to prevent one case of active TB. RESULTS: We found that the NNT as a function of TB incidence shows a 'U-shape', whereby IPT impact is greatest at an intermediate incidence and attenuated at both lower and higher incidence levels. This U-shape was observed over a broad range of parameter values; the optimal TB incidence was between 500 and 900 cases per 100 000 per year. CONCLUSIONS: TB burden is a critical factor to consider when making decisions about communitywide implementation of IPT. We believe that the total disease burden should not preclude programmatic application of IPT.

Application of neurosonography to experimental physiology.

When Horsley and Clark invented the stereotaxic technique they revolutionized experimental neurobiology. For the first time it became possible to repeatably place experimental or surgical probes at precise locations within the skull. Unfortunately, variations in the position and size of neuroanatomical structures within the cranium have always limited the efficiency of this technology. Recent advances in diagnostic medical ultrasonography, however, allow for the real-time visualization of anatomical structures, in some cases with resolutions of up to 150 microm. We report here that commercially available ultrasonographs can be used in the laboratory to generate real-time in vivo images of brain structures in both anesthetized and awake-behaving animals. We found that ultrasonic imaging is compatible with many types of experimental probes including single neuron recording electrodes, microinjection pipettes, and electrodes for producing electrolytic lesions. Ultrasonic imaging can be used to place, monitor and visualize these probes in vivo. In our hands, commercially available ultrasonic probes designed for pediatric use allowed us to visualize anatomical structures with sub-millimeter resolution in primate brains. Finally, ultrasonic imaging allowed us to reduce the risk of accidentally damaging major blood vessels, greatly reducing the incidence of stroke as an unintended complication of an experimental neurosurgical procedure. Diagnostic ultrasound holds the promise of reducing the uncertainty associated with stereotaxic surgery, an improvement which would significantly improve the efficiency of many neurobiological investigations, reducing the number of animal subjects employed in this research. While this demonstration focuses on sonographic imaging in non-human primates, similar advances should also be possible for studies in other species, including rodents.

Anterior chamber depth and complications during cataract surgery in eyes with pseudoexfoliation syndrome.

PURPOSE: To look for associations of preoperative A-scan ultrasound ocular dimensions with complications during phacoemulsification in eyes with pseudoexfoliation. METHODS: A total of 174 eyes with pseudoexfoliation of 135 patients undergoing planned cataract surgery were included in a prognostic study based on the review of a clinical database. Preoperatively, A-scan ultrasound examination with measurement of anterior chamber depth, lens thickness, and total axial length was performed. Phacoemulsification with implantation of a posterior chamber intraocular lens was performed by a total of five surgeons. Intraoperative complications (zonular dialysis and/or vitreous loss) were correlated with preoperative findings including ultrasound dimensions. Multivariate logistic regression analysis with a generalized estimating equations method was used for statistical analysis. RESULTS: Intraoperative complications occurred in 12 eyes (6.9%) of 11 patients. The anterior chamber was significantly shallower in eyes with than in eyes without complications (mean, 2.36 +/- 0.44 mm vs 2.74 +/- 0.52 mm; P =.013). The differences in lens thickness (4.93 +/- 0.55 mm vs 4.72 +/- 0.54 mm; P =.30) and the differences in axial length (22.92 +/- 1.09 mm vs 23.66 +/- 1.36 mm; P =.07) between the two groups did not reach statistical significance. In eyes with pseudoexfoliation, an anterior chamber depth of less than 2.5 mm was associated with a risk of 13.4% for intraoperative complications compared with an overall incidence of intraoperative complications of 6.9% and an incidence of 2.8% for an anterior chamber depth of 2.5 mm or more. CONCLUSIONS: A small anterior chamber depth may indicate zonular instability in eyes with pseudoexfoliation syndrome and should alert the cataract surgeon to the possibility of intraoperative complications.

Effect of citric acid on the radiation resistance of Listeria monocytogenes and frankfurter quality factors.

Listeria monocytogenes is a common contaminant of ready-to-eat meat products, including frankfurters. Ionizing (gamma) radiation can eliminate L. monocytogenes from frankfurters. Citric acid (CA) is an antioxidant synergist and anti-microbial agent that can be applied to the surfaces of cured meat products prior to packaging. The effect of CA on the radiation resistance of L. monocytogenes that was surface-inoculated onto frankfurters was determined. The D(10) values, the radiation doses required to inactivate 90% of viable L. monocytogenes, were 0.61, 0.60, 0.54, and 0.53 kGy, on frankfurters dipped in 0, 1, 5 or 10% CA solution, respectively. CA, although an antioxidant synergist, did not increase antioxidant activity (AA) on frankfurter surfaces as determined by the ferric reducing antioxidant power (FRAP) assay. Lipid oxidation, as determined by the Thiobarbituric acid reactive substances (TBARS) assay, was not affected by CA or ionizing radiation. Color of frankfurters, determined by Hunter L, a, b, indicated that ionizing radiation induced a small, but visually imperceptible, loss of redness (a-value). Frankfurter firmness, as measured by maximum shear force, was not affected by ionizing radiation or CA. CA enhanced the lethality of ionizing radiation without negatively impacting frankfurter color, lipid oxidation, firmness, or antioxidant activity.