Evaluation and 1-year follow-up of patients presenting at a Lyme borreliosis expertise centre: a prospective cohort study with validated questionnaires.

OBJECTIVES: To describe the course of symptoms reported by patients with symptoms attributed to Lyme borreliosis (LB) without being subsequently diagnosed with LB. METHODS: We performed a prospective cohort study with patients presenting at the outpatient clinic of two clinical LB centres. The primary outcome was the prevalence of persistent symptoms, which were defined as clinically relevant fatigue (CIS, subscale fatigue), pain (SF-36, subscale bodily pain), and cognitive impairment (CFQ) for ≥ 6 months and onset < 6 months over the first year of follow-up. Outcomes were compared with a longitudinal cohort of confirmed LB patients and a general population cohort. Prevalences were standardised to the distribution of pre-defined confounders in the confirmed LB cohort. RESULTS: Participants (n = 123) reported mostly fatigue, arthralgia, myalgia, and paraesthesia as symptoms. The primary outcome could be determined for 74.8% (92/123) of participants. The standardised prevalence of persistent symptoms in our participants was 58.6%, which was higher than in patients with confirmed LB at baseline (27.2%, p < 0.0001) and the population cohort (21.2%, p < 0.0001). Participants reported overall improvement of fatigue (p < 0.0001) and pain (p < 0.0001) but not for cognitive impairment (p = 0.062) during the follow-up, though symptom severity at the end of follow-up remained greater compared to confirmed LB patients (various comparisons p < 0.05). CONCLUSION: Patients with symptoms attributed to LB who present at clinical LB centres without physician-confirmed LB more often report persistent symptoms and report more severe symptoms compared to confirmed LB patients and a population cohort.

Diagnostic and societal impact of implementing the syncope guidelines of the European Society of Cardiology (SYNERGY study).

BACKGROUND: Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) Syncope Guidelines regarding diagnostic yield, accuracy and costs. METHODS: A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis. RESULTS: We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving €908 per patient; 95% CI €34 to €1782). CONCLUSIONS: ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs. TRIAL REGISTRATION: Netherlands Trial Register, NTR6268.

Ticking on Pandora's box: a prospective case-control study into 'other' tick-borne diseases.

BACKGROUND: Tick-borne pathogens other than Borrelia burgdorferi sensu lato - the causative agent of Lyme borreliosis - are common in Ixodes ricinus ticks. How often these pathogens cause human disease is unknown. In addition, diagnostic tools to identify such diseases are lacking or reserved to research laboratories. To elucidate their prevalence and disease burden, the study 'Ticking on Pandora's Box' has been initiated, a collaborative effort between Amsterdam University Medical Center and the National Institute for Public Health and the Environment. METHODS: The study investigates how often the tick-borne pathogens Anaplasma phagocytophilum, Babesia species, Borrelia miyamotoi, Neoehrlichia mikurensis, spotted fever group Rickettsia species and/or tick-borne encephalitis virus cause an acute febrile illness after tick-bite. We aim to determine the impact and severity of these tick-borne diseases in the Netherlands by measuring their prevalence and describing their clinical picture and course of disease. The study is designed as a prospective case-control study. We aim to include 150 cases - individuals clinically suspected of a tick-borne disease - and 3 matched healthy control groups of 200 persons each. The controls consist respectively of a group of individuals with either a tick-bite without complaints, the general population and of healthy blood donors. During a one-year follow-up we will acquire blood, urine and skin biopsy samples and ticks at baseline, 4 and 12 weeks. Additionally, participants answer modified versions of validated questionnaires to assess self-reported symptoms, among which the SF-36, on a 3 monthly basis. DISCUSSION: This article describes the background and design of the study protocol of 'Ticking on Pandora's Box'. With our study we hope to provide insight into the prevalence, clinical presentation and disease burden of the tick-borne diseases anaplasmosis, babesiosis, B. miyamotoi disease, neoehrlichiosis, rickettsiosis and tick-borne encephalitis and to assist in test development as well as provide recommendations for national guidelines. TRIAL REGISTRATION: NL9258 (retrospectively registered at Netherlands Trial Register, trialregister.nl in in February 2021).

A single dose of doxycycline after an ixodes ricinus tick bite to prevent Lyme borreliosis: An open-label randomized controlled trial.

OBJECTIVES: A single dose of doxycycline after a tick bite can prevent the development of Lyme borreliosis in North America, but extrapolation to Europe is hampered by differences in Borrelia burgdorferi sensu lato genospecies and tick species. We assessed the efficacy of prophylaxis after a tick bite in Europe. METHODS: We conducted an open-label randomized controlled trial, administering a single dose of 200 mg doxycycline within 72 h after removing an attached tick from the skin, compared to no treatment. Potential participants ≥ 8 years of age who reported a recent tick bite online were invited for the study. After informed consent, they were randomly assigned to either the prophylaxis or the no-treatment group. Participants in the prophylaxis group were asked to visit their general practitioner to administer the antibiotics. All participants were followed up by online questionnaires. Our primary outcome was the development of physician-confirmed Lyme borreliosis in a modified-intention-to-treat analysis. This study is registered in the Netherlands Trial Register (NTR3953) and is closed. RESULTS: Between April 11, 2013, and June 10, 2015, 3538 potential participants were randomized, of whom 1689 were included in the modified-intention-to-treat analysis. 10 cases of Lyme borreliosis were reported out of 1041 participants (0.96%) in the prophylaxis group, and 19 cases out of 648 no-treatment participants (2.9%), resulting in a relative risk reduction of 67% (95% CI 31 - 84%), and a number-needed-to-treat of 51 (95% CI 29 - 180). No serious adverse events were reported. CONCLUSIONS: This primary care-based trial provides evidence that a single dose of doxycycline can prevent the development of Lyme borreliosis after an Ixodes ricinus tick bite.

An agenda for research and action toward diverse and just futures for life on Earth.

Decades of research and policy interventions on biodiversity have insufficiently addressed the dual issues of biodiversity degradation and social justice. New approaches are therefore needed. We devised a research and action agenda that calls for a collective task of revisiting biodiversity toward the goal of sustaining diverse and just futures for life on Earth. Revisiting biodiversity involves critically reflecting on past and present research, policy, and practice concerning biodiversity to inspire creative thinking about the future. The agenda was developed through a 2-year dialogue process that involved close to 300 experts from diverse disciplines and locations. This process was informed by social science insights that show biodiversity research and action is underpinned by choices about how problems are conceptualized. Recognizing knowledge, action, and ethics as inseparable, we synthesized a set of principles that help navigate the task of revisiting biodiversity. The agenda articulates 4 thematic areas for future research. First, researchers need to revisit biodiversity narratives by challenging conceptualizations that exclude diversity and entrench the separation of humans, cultures, economies, and societies from nature. Second, researchers should focus on the relationships between the Anthropocene, biodiversity, and culture by considering humanity and biodiversity as tied together in specific contexts. Third, researchers should focus on nature and economies by better accounting for the interacting structures of economic and financial systems as core drivers of biodiversity loss. Finally, researchers should enable transformative biodiversity research and action by reconfiguring relationships between human and nonhuman communities in and through science, policy, and practice. Revisiting biodiversity necessitates a renewed focus on dialogue among biodiversity communities and beyond that critically reflects on the past to channel research and action toward fostering just and diverse futures for human and nonhuman life on Earth.

Una Agenda para la Investigación y la Acción hacia un Futuro Diverso y Justo para la Vida sobre la Tierra Resumen Las décadas de investigación e intervenciones políticas sobre la biodiversidad han tratado significativamente los temas de la degradación de la biodiversidad y la justicia social. Debido a esto, se requieren nuevas estrategias. Diseñamos una agenda de investigación y acción que llama a la labor colectiva de revisar la biodiversidad hacia el objetivo de sustentar un futuro diverso y justo para la vida sobre la Tierra. Cuando se revisa la biodiversidad, se requiere de una reflexión crítica sobre las investigaciones, políticas y prácticas presentes y pasadas sobre la biodiversidad para inspirar un pensamiento creativo acerca del futuro. Desarrollamos la agenda por medio de un proceso de diálogo de dos años que involucró a casi 300 expertos de diversas disciplinas y localidades. Este proceso estuvo orientado por el conocimiento de las ciencias sociales que muestra cómo la investigación y la acción para la biodiversidad están sostenidas por las opciones de cómo están conceptualizados los problemas. Reconocimos al conocimiento, la acción y la ética como inseparables y sintetizamos un conjunto de principios que ayuda a navegar la labor de revisar la biodiversidad. La agenda articula cuatro áreas temáticas para la investigación en el futuro. Primero, los investigadores necesitan revisar las narrativas de la biodiversidad mediante el cuestionamiento de las conceptualizaciones que excluyen a la diversidad y consolidan la separación entre humanos, culturas, economías y sociedades y la naturaleza. Segundo, los investigadores deberían enfocarse en las relaciones entre el antropoceno, la biodiversidad y la cultura al considerar a la humanidad y la biodiversidad como interconectadas en contextos específicos. Tercero, los investigadores deberían enfocarse en la naturaleza y las economías al tener en mejor cuenta la interacción de las estructuras de los sistemas económico y financiero como conductores nucleares de la pérdida de la biodiversidad. Finalmente, los investigadores deberían permitir la investigación y acción transformadoras de la biodiversidad al reconfigurar las relaciones entre las comunidades humanas y no humanas dentro y a través de la ciencia, la política y la práctica. La revisión de la biodiversidad necesita de un enfoque renovado sobre el diálogo entre las comunidades de la biodiversidad y más allá, que reflexione críticamente sobre el pasado para canalizar a la investigación y acción hacia el fomento del futuro justo y diverso para la vida humana y no humana sobre la Tierra.

A practical guide to active stand testing and analysis using continuous beat-to-beat non-invasive blood pressure monitoring.

PURPOSE: The average adult stands approximately 50-60 times per day. Cardiovascular responses evoked during the first 3 min of active standing provide a simple means to clinically assess short-term neural and cardiovascular function across the lifespan. Clinically, this response is used to identify the haemodynamic correlates of patient symptoms and attributable causes of (pre-)syncope, and to detect autonomic dysfunction, variants of orthostatic hypotension, postural orthostatic tachycardia syndrome and orthostatic hypertension. METHODS: This paper provides a set of experience/expertise-based recommendations detailing current state-of-the-art measurement and analysis approaches for the active stand test, focusing on beat-to-beat BP technologies. This information is targeted at those interested in performing and interpreting the active stand test to current international standards. RESULTS: This paper presents a practical step-by-step guide on (1) how to perform active stand measurements using beat-to-beat continuous blood pressure measurement technologies, (2) how to conduct an analysis of the active stand response and (3) how to identify the spectrum of abnormal blood pressure and heart rate responses which are of clinical interest. CONCLUSION: Impairments in neurocardiovascular control are an attributable cause of falls and syncope across the lifespan. The simple active stand test provides the clinician with a powerful tool for assessing individuals at risk of such common disorders. However, its simplicity belies the complexity of its interpretation. Care must therefore be taken in administering and interpreting the test in order to maximise its clinical benefit and minimise its misinterpretation.

Tau positron emission tomography imaging in C9orf72 repeat expansion carriers.

BACKGROUND AND PURPOSE: AV-1451 (18 F-AV-1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. METHODS: Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. RESULTS: C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. CONCLUSION: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort.

Perceived stress is associated with increased rostral middle frontal gyrus cortical thickness: a family-based and discordant-sibling investigation.

Elevated stress perception and depression commonly co-occur, suggesting that they share a common neurobiology. Cortical thickness of the rostral middle frontal gyrus (RMFG), a region critical for executive function, has been associated with depression- and stress-related phenotypes. Here, we examined whether RMFG cortical thickness is associated with these phenotypes in a large family-based community sample. RMFG cortical thickness was estimated using FreeSurfer among participants (n = 879) who completed the ongoing Human Connectome Project. Depression-related phenotypes (i.e. sadness, positive affect) and perceived stress were assessed via self-report. After accounting for sex, age, ethnicity, average whole-brain cortical thickness, twin status and familial structure, RMFG thickness was positively associated with perceived stress and sadness and negatively associated with positive affect at small effect sizes (accounting for 0.2-2.4% of variance; p-fdr: 0.0051-0.1900). Perceived stress was uniquely associated with RMFG thickness after accounting for depression-related phenotypes. Further, among siblings discordant for perceived stress, those reporting higher perceived stress had increased RMFG thickness (P = 4 × 10-7 ). Lastly, RMFG thickness, perceived stress, depressive symptoms, and positive affect were all significantly heritable, with evidence of shared genetic and environmental contributions between self-report measures. Stress perception and depression share common genetic, environmental, and neural correlates. Variability in RMFG cortical thickness may play a role in stress-related depression, although effects may be small in magnitude. Prospective studies are required to examine whether variability in RMFG thickness may function as a risk factor for stress exposure and/or perception, and/or arises as a consequence of these phenotypes.

Noninvasive beat-to-beat finger arterial pressure monitoring during orthostasis: a comprehensive review of normal and abnormal responses at different ages.

Over the past 30 years, noninvasive beat-to-beat blood pressure (BP) monitoring has provided great insight into cardiovascular autonomic regulation during standing. Although traditional sphygmomanometric measurement of BP may be sufficient for detection of sustained orthostatic hypotension, it fails to capture the complexity of the underlying dynamic BP and heart rate responses. With the emerging use of noninvasive beat-to-beat BP monitoring for the assessment of orthostatic BP control in clinical and population studies, various definitions for abnormal orthostatic BP patterns have been used. Here, age-related changes in cardiovascular control in healthy subjects will be reviewed to define the spectrum of the most important abnormal orthostatic BP patterns within the first 180 s of standing. Abnormal orthostatic BP responses can be defined as initial orthostatic hypotension (a transient systolic BP fall of >40 mmHg within 15 s of standing), delayed BP recovery (an inability of systolic BP to recover to a value of >20 mmHg below baseline at 30 s after standing) and sustained orthostatic hypotension (a sustained decline in systolic BP of ≥20 mmHg occurring 60-180 s after standing). In the evaluation of patients with light-headedness, pre(syncope), (unexplained) falls or suspected autonomic dysfunction, it is essential to distinguish between normal cardiovascular autonomic regulation and these abnormal orthostatic BP responses. The prevalence, clinical relevance and underlying pathophysiological mechanisms of these patterns differ significantly across the lifespan. Initial orthostatic hypotension is important for identifying causes of syncope in younger adults, whereas delayed BP recovery and sustained orthostatic hypotension are essential for evaluating the risk of falls in older adults.

Long-term efficacy of combined phacoemulsification plus trabeculectomy versus phacoemulsification plus excimer laser trabeculotomy.

Background Combined cataract and glaucoma procedures, and minimally-invasive glaucoma surgery in particular, have gained increasing interest over the past few years. The aim of this study was to compare the long-term efficacy of combined phaco-trabeculectomy (Phaco-Trab) and combined phacoemulsification plus excimer laser trabeculotomy (Phaco-ELT). Patients and Methods Retrospective, non-randomised, comparative, interventional case series of consecutive patients after Phaco-Trab and Phaco-ELT at the University Hospital of Zurich and the Talacker Eye Center Zurich in Switzerland. Inclusion criteria were diagnosis of glaucoma plus vision-impairing coexisting cataract. Primary outcome measures were change in intraocular pressure (IOP), number of anti-glaucoma drugs (AGDs), and best-corrected visual acuity (BCVA) 1 year and 4 years after the procedure. Secondary outcome measures were surgical complications and requirement of postoperative interventions. Success was defined based on the criteria of the Tube-versus-Trabeculectomy study. Results Mean age was 76.1 ± 8.6 years (29.2 % males; 47.8 % right eyes). Phaco-Trab (n = 62) decreased median IOP from 22.8 to 13.0 at 1 year and to 14.0 mmHg at 4 years. AGDs were reduced from 2 drugs to 0 AGDs at 1 year and 4 years. Median BCVA improved from 0.2 logMAR to 0.0 logMAR at 1 year and 4 years. Phaco-ELT (n = 51) lowered median IOP from 19.0 to 15.0 at 1 year and to 14.0 mmHg (p = 0.002) at 4 years. AGDs were reduced from 2 drugs to 1 AGD at 1 year and 4 years (p = 0.002). BCVA improved from 0.4 logMAR to 0.1 logMAR after 1 year and 4 years. If not stated otherwise, all changes compared to baseline were highly significant (p < 0.001). No perioperative complications occurred; postoperative interventions were performed in 74 % of Phaco-Trab patients. Conclusion Both surgical procedures reduced IOP and AGDs and improved BCVA significantly and persistently during the entire follow-up period of 4 years with a good safety profile. This study validates Phaco-ELT as an option when post-operative target pressure in the mid-teens would be adequate, whereas Phaco-Trab would be the treatment of choice when IOP in the low teens is desired.

A New Glaucoma Severity Score Combining Structural and Functional Defects.

Background In order to assess glaucoma severity and to compare the success of surgical and medical therapy and study outcomes, an objective and independent staging tool is necessary. A combination of information from both structural and functional testing is probably the best approach to stage glaucomatous damage. There has been no universally accepted standard for glaucoma staging. The aim of this study was to develop a Glaucoma Severity Score (GSS) for objective assessment of a patient's glaucoma severity, combining both functional and structural information. Materials and methods The Glaucoma Severity Score includes the following 3 criteria: superior and inferior Retinal Nerve Fibre Layer (RNFL) thickness, perimetric mean defect (MD), and agreement of anatomical and perimetric defects, as assessed by two glaucoma specialists. The specialists defined a staging tool for each of the 3 criteria in a consensus process, assigning specific characteristics to a scale value between 0 and 2 or 0 and 3, respectively. The GSS ranges between 0 and 10 points. In a prospective observational study, the data of 112 glaucoma patients were assessed independently by the two specialists according to this staging tool. Results The GSS was applied to 112 eyes and patients (59.8 % female) with a mean age of 66.3 ± 13.1 years. Mean GSS was 4.73 points. Cohen's kappa coefficient was determined to measure inter-rater agreement between glaucoma specialists for the third criterion. With κ = 0.83, the agreement was very good. Thus, all 3 criteria of the GSS may be regarded as objective. Conclusions The Glaucoma Severity Score is an objective tool, combining both structural and functional characteristics, and permitting comparison of different patients, populations and studies. The Glaucoma Severity Score has proven effective in the objective assessment of 112 glaucoma patients and is relatively user-friendly in clinical practice. A comparative study of the GSS with the results of the FORUM® Glaucoma Workplace (Carl Zeiss Meditec AG, Jena, Germany) will be the next step. If outcomes match, the Glaucoma Severity Score can be accepted as a promising tool to stage glaucoma and monitor changes objectively in patients when comparing glaucoma progression in study analyses.

[Evaluation of correction formulas for tonometry : The Goldmann applanation tonometry in approximation to dynamic contour tonometry]. / Evaluation von Korrekturformeln für die Tonometrie : Die Goldmann-Applanationstonometrie in Annäherung zur dynamischen Contour-Tonometrie.

BACKGROUND: Accurate determination of intraocular pressure (IOP) is essential for correct management of glaucoma. Goldmann applanation tonometry (GAT) is the gold standard for measuring IOP despite its limitations due to its dependence on corneal properties. With the aim of improving the accuracy of GAT readings, several correction formulas have been developed. OBJECTIVE: The aim of this study was to investigate the accuracy and clinical relevance of five correction equations for GAT. MATERIAL AND METHODS: Prospective study of 112 glaucoma patients at the University Hospital and Talacker Eye Center, Zurich, Switzerland. The IOP was measured with GAT and dynamic contour tonometry (DCT) in randomized order. The GAT readings were adjusted with five correction equations. The primary study endpoint was the degree of concordance between corrected GAT and DCT readings. A discordance of ≥2 mm Hg was defined as significant. The association between discordant IOP measurements and central corneal thickness (CCT) was the secondary study endpoint. RESULTS: The mean patient age was 66 ± 13 years (60% females and 56% left eyes). The mean IOP was 17.0 mm Hg for GAT and 20.3 mm Hg for DCT, with a discordance of 3.3 mm Hg between GAT und DCT. The discordances between DCT and the corrected values ranged from 2.7 to 5.4 mm Hg. Spearman's rank testing showed a positive correlation between CCT and the discordances of all correction equations and a negative correlation between CCT and the discordance of DCT and GAT. CONCLUSION: The use of GAT correction formulas involves the risk of creating significant error. The correction equations examined showed extensive scatter and resulted in mean IOP values that were lower than the IOP initially measured by GAT. Thus the use of any correction equation may delay diagnosis of glaucoma and should be avoided.

Clinical Pearls - how my patients taught me: The fainting lark symptom.

BACKGROUND: Compulsive movements, complex tics and stereotypies are frequent, especially among patients with autism or psychomotor retardation. These movements can be difficult to characterize and can mimic other conditions like epileptic seizures or paroxysmal dystonia, particularly when abnormal breathing and cerebral hypoxia are induced. CASE PRESENTATION: We describe an 18-year-old patient with Asperger syndrome who presented with attacks of tonic posturing of the trunk and neck. The attacks consisted of self-induced stereotypic stretching of the neck combined with a compulsive Valsalva-like maneuver. This induced cerebral hypoperfusion and subsequently dysautonomia and some involuntary movements of the arms. CONCLUSION: This patient suffered from a complex tic with compulsive respiratory stereotypies. His symptoms contain aspects of a phenomenon described in early literature as 'the fainting lark'.

Initial orthostatic hypotension in teenagers and young adults.

OBJECTIVE: To assess: (1) the frequency of an abnormally large fall in blood pressure (BP) upon standing from supine in patients with initial orthostatic hypotension (IOH); (2) the underlying hemodynamic mechanisms of this fall in BP upon standing from supine and from squatting. METHODS: In a retrospective study of 371 patients (≤30 years) visiting the syncope unit, the hemodynamic response to standing and squatting were studied in 26 patients who were diagnosed clinically with IOH, based on history taking only. In six patients changes in cardiac output (CO) and systemic vascular resistance (SVR) were determined, and the underlying hemodynamics were analyzed. RESULTS: 15/26 (58 %) patients with IOH had an abnormally large initial fall in systolic BP (≥40 mmHg). There was a large scatter in CO and SVR response after arising from supine [ΔCO at BP nadir median -8 % (range -37, +27 %); ΔSVR at BP nadir median -31 % (range -46, +10 %)]. The hemodynamic response after squatting showed a more consistent pattern, with a fall in SVR in all six patients [ΔCO at BP nadir median +23 % (range -12, +31 %); ΔSVR at BP nadir median -42 %, (range -52, -35 %)]. INTERPRETATION: The clinical diagnosis of IOH is based on history taking, as an abnormally large fall in systolic BP can only be documented in 58 %. For IOH upon standing after supine rest, the hemodynamic mechanism can be either a large fall in CO or in SVR. For IOH upon arising from squatting a large fall in SVR is a consistent finding.

C9orf72 is required for proper macrophage and microglial function in mice.

Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.

The effect of polymer size and charge of molecules on permeation through synovial membrane and accumulation in hyaline articular cartilage.

The treatment of joint related diseases often involves direct intra-articular injections. For rational development of novel delivery systems with extended residence time in the joint, detailed understanding of transport and retention phenomena within the joint is mandatory. This work presents a systematic study on the in vitro permeation, penetration and accumulation of model polymers with differing charges and molecular weights in bovine joint tissue. Permeation experiments with bovine synovial membrane were performed with PEG polymers (6-200 kDa) and methylene blue in customized diffusion chambers. For polyethylene glycol, 2-fold (PEG 6 kDa), 3-fold (PEG 10 kDa) and 13-fold (PEG 35 kDa) retention by the synovial membrane in reference to the small molecule methylene blue was demonstrated. No PEG 200 kDa was found in the acceptor in detectable amounts after 48 h. This showed the potential for a distinct extension of joint residence times by increasing molecular weights. In addition, experiments with bovine cartilage tissue were conducted. The ability for positively charged, high molecular weight chitosans and HEMA-Co-TMAP (HCT) polymers (up to 233 kDa) to distribute throughout the entire cartilage matrix was demonstrated. In contrast, a distribution into cartilage was not observed for neutral PEG polymers (6-200 kDa). Furthermore, the positive charge density of different compounds (chitosan, HEMA-Co-TMAP, methylene blue, MSC C1 (neutral NCE) and MSC D1 (positively charged NCE) was found to correlate with their accumulation in bovine cartilage tissue. In summary, the results offer pre-clinical in vitro data, indicating that the modification of molecular size and charge of a substance has the potential to decelerate its clearance through the synovial membrane and to promote accumulation inside the cartilage matrix.

[Current aspects on the management of normal tension glaucoma]. / Aktuelle Aspekte zum Management des Normaldruckglaukoms.

In a considerable proportion of glaucoma patients (25-50 %) the intraocular pressure (IOP) is not elevated higher than 22 mmHg at first diagnosis and during subsequent follow-up controls. Although the IOP level remains in the low range < 22 mmHg, progression of glaucoma can still occur. A multitude of different factors are assumed to be involved in glaucoma progression, such as very low nocturnal diastolic blood pressure values, a low mean ocular perfusion pressure, extensive fluctuations in perfusion (e.g. in cases of vascular dysregulation), an increased vulnerability of the optic nerve support structures, an increased translaminar pressure gradient and various underlying systemic diseases. The most important evidence-based aspect of treatment in normal tension glaucoma is pharmaceutical or surgical reduction of the IOP by 30 % or more in comparison to the initial pressure level. Vascular and neuroprotective concepts of treatment for normal tension glaucoma have been strongly advocated and the object of experimental and clinical studies. As yet a clear clinical benefit has not been proven by large prospective randomized studies.

[Visual outcome after trabeculectomy - a retrospective study]. / Visusentwicklung nach Trabekulektomie - eine retrospektive Studie.

BACKGROUND: Trabeculectomy (TE) is the standard operation for glaucoma. An alternative interventional treatment of glaucoma is the cyclophotocoagulation (CPC). In a data analysis in 2012, a visual loss was found after transscleral CPC. The aim of this study was to investigate the outcome after TE. PATIENTS AND METHODS: 91 patients with pseudoexfoliation (n=38), open angle (n=22), normal tension (n=8), congenital (n=1) and secondary glaucoma (n=22) were included. The follow-up time was 24 months. Intraocular pressure (IOP), best corrected visual acuity (BCVA) and the total number of antiglaucoma drugs (AGD) were recorded. RESULTS: The mean age was 68.18±12.12 years. Mean IOP reduction after 24 months was 14.76±10.62 mmHg (-49%, p<0.001). On average, 2.34±1.17 (-85%, p<0.001) AGDs could be reduced. A mean BCVA decrease of 0.15 logMAR (±0.26, p<0.001) was found. CONCLUSION: TE is a successful method for lowering the IOD. However, postoperative visual loss is possible.