[Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)]. / Analyse zur Häufigkeit einer gerinnungshemmenden Medikation bei Patientinnen mit kognitiven Störungen und zerebraler Amyloidangiopathie (CAA).

OBJECTIVES: To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load. MATERIALS AND METHODS: Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review. RESULTS: Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9 years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. A total of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634). CONCLUSION: CAA is a frequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with a higher number of cortical and subcortical microbleeds.

[Therapeutic effects of complex multimodal rheumatologic treatment in the Rheumatology Center, Rhineland-Palatinate]. / Therapieeffekte der multimodalen rheumatologischen Komplexbehandlung im Rheumazentrum Rheinland-Pfalz.

INTRODUCTION: The concept of complex multimodal rheumatologic treatment (CMRT) has been established for several years in German rheumatologic departments and aims at a multifaceted therapeutic approach to patients with rheumatic diseases. Objective of this study was to examine the therapeutic effect of CMRT in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in an acute rheumatology center. METHODS: The treatment success of CMRT was evaluated by epidemiologic data, patient questionnaires on visual analog scales (VAS) regarding morning stiffness, pain and disease activity (DA), as well as clinical scores (Disease Activity Score 28 [DAS28], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Bath Ankylosing Spondylitis Functional Index [BASFI]), laboratory inflammation markers (CRP, erythrocyte sedimentation rate) and medication in three visits: visit 1 = begin of CMRT; visit 2 = end of CMRT; visit 3 = 3 months after CMRT. RESULTS: In this study 162 patients from the Rheumatology Center, Rhineland-Palatinate, Germany (96 (59.3%) RA, 30 (18.8%) AS, 36 (22.2%) PsA) were recruited. Statistical examinations revealed a significant improvement of VAS(DA) (visit 2 versus visit 1: RA: p = 0.02, AS: p < 0.001, PsA: p < 0.001), morning stiffness (RA: p < 0.001, AS: p = 0.03, PsA: p < 0.001) and patient reported pain (all; p < 0.001) in the context of CMRT. In the RA and AS subgroups improvements of DAS28 and BASDAI could also be observed (visit 2 versus visit 1: both; p < 0.001). Moreover, significant improvement of patient reported outcomes could be observed 3 months after CMRT regarding VAS(DA) (RA: p = 0.02 und AS: p = 0.03, morning stiffness (PsA: p = 0.02) and patient reported pain (RA: p = 0.01)). Interestingly, subgroup analyses showed that the therapeutic benefit was independent of the concomitant pharmacotherapy. CONCLUSION: The results of this study suggest a therapeutic benefit for patients being treated by CMRT and highlight the high value of this therapeutic concept in patients with systemic-inflammatory rheumatic diseases.

Are national suicide prevention programs effective? A comparison of 4 verum and 4 control countries over 30 years.

BACKGROUND: Suicide and non-fatal suicidal behavior are significant public health issues worldwide requiring effective preventive interventions. METHODS: The aim of the present study was to analyze the effectiveness of national suicide prevention programs taking a statistical approach involving the segmented regression analysis of interrupted time series data. RESULTS: This study demonstrates that National Suicide Prevention Programs are effective, but this effect seems to correlate with age and sex. Our data have shown a statistical significant decline in suicide rates in the verum countries in males, with the strongest effects in groups aged 25-to-44 years and 45-to-64 years. CONCLUSION: Our study implies that the implementation of a national strategy is an effective tool to reduce suicide rates.

Sleep spindles in bipolar disorder - a comparison to healthy control subjects.

OBJECTIVE: Bipolar disorder is a severe mental disorder for which currently no reliable biomarkers exist. It has been shown that patients with schizophrenia but not with unipolar depression have a reduced density of fast sleep spindles during N2 sleep. The aim of this study was to assess fast sleep spindle density in euthymic patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all-night polysomnography. Sleep spindles within stage N2 sleep were identified by visual inspection and subdivided into fast (>13 Hz) and slow (≤13 Hz) spindles. All spindles were subsequently characterised by density, frequency, amplitude, duration and coherence. RESULTS: Euthymic patients with bipolar disorder were found to have a reduced density and a lower mean frequency of fast spindles. Slow spindle density and frequency did not differ between groups. There were no differences regarding amplitude, duration or coherence. CONCLUSIONS: A reduction in fast spindle density during N2 sleep points towards thalamic dysfunction as a potential neurobiological mechanism of relevance in bipolar disorder. In addition, a reduced sleep spindle density could be interpreted as a common endophenotype shared with schizophrenia but not unipolar depression and may - if replicated - be of utility in early recognition and risk stratification.

[Merkel cell carcinoma: cutaneous manifestation of a highly malignant pre-/pro-B cell neoplasia? : Novel concept about the cellular origin of Merkel cell carcinoma]. / Merkelzellkarzinom: kutane Manifestation einer hochmalignen Prä-/pro-B-Zell-Neoplasie? : Neues Konzept zum zellulären Ursprung des Merkelzellkarzinoms.

Merkel cell carcinoma (MCC) is a relatively rare but highly malignant non-melanoma skin cancer of the elderly and immunosuppressed patients. The discovery of the Merkel cell polyomavirus (MCPyV) in 2008 significantly impacted the understanding of the etiopathogenesis of MCC. MCPyV is clonally integrated into the MCC genome and approximately 80% of MCC are MCPyV-positive. Recent results of clinical trials using blockade of the PD-1 immune modulatory pathway are promising for the future treatment of MCC. Despite this major progress of the past few years, the cellular origin of MCC still remains obscure. Based on histomorphology, gene expression profiling, and molecular analyses, we have recently hypothesized that MCC originates from pre­/pro-B cells. Here we review putative cells of MCC, including Merkel cells, (epi­)dermal stem cells, and pro­/pre-B cells. In the present work, the focus is on the concept of pre­/pro-B cells as the cellular origin of MCC, which might also impact the understanding of other human small cell malignancies of unknown cellular origin, such as small cell carcinomas of the lung and other anatomical locations. In addition, this concept might pave the way for novel treatment options, especially for advanced MCC.

Core hole-electron correlation in coherently coupled molecules.

We study the core hole-electron correlation in coherently coupled molecules by energy dispersive near edge x-ray absorption fine-structure spectroscopy. In a transient phase, which exists during the transition between two bulk arrangements, 1,4,5,8-naphthalene-tetracarboxylicacid-dianhydride multilayer films exhibit peculiar changes of the line shape and energy position of the x-ray absorption signal at the C K-edge with respect to the bulk and gas phase spectra. By a comparison to a theoretical model based on a coupling of transition dipoles, which is established for optical absorption, we demonstrate that the observed spectroscopic differences can be explained by an intermolecular delocalized core hole-electron pair. By applying this model we can furthermore quantify the coherence length of the delocalized core exciton.

Positional cloning of the gene associated with X-linked juvenile retinoschisis.

X-linked juvenile retinoschisis(RS) is a recessively inherited vitreo-retinal degeneration characterized by macular pathology and intraretinal splitting of the retina. The RS gene has been localized to Xp22.2 to an approximately 1 Mb interval between DXS418 and DXS999/DXS7161. Mapping and expression analysis of expressed sequence tags have identified a novel transcript, designated XLRS1, within the centromeric RS locus that is exclusively expressed in retina. The predicted XLRS1 protein contains a highly conserved motif implicated in cell-cell interaction and thus may be active in cell adhesion processes during retinal development. Mutational analyses of XLRS1 in affected individuals from nine unrelated RS families revealed one nonsense, one frameshift, one splice acceptor and six missense mutations segregating with the disease phenotype in the respective families. These data provide strong evidence that the XLRS1 gene, when mutated, causes RS.

An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.

The locus for the incomplete form of X-linked congenital stationary night blindness (CSNB2) maps to a 1.1-Mb region in Xp11.23 between markers DXS722 and DXS255. We identified a retina-specific calcium channel alpha1-subunit gene (CACNA1F) in this region, consisting of 48 exons encoding 1966 amino acids and showing high homology to L-type calcium channel alpha1-subunits. Mutation analysis in 13 families with CSNB2 revealed nine different mutations in 10 families, including three nonsense and one frameshift mutation. These data indicate that aberrations in a voltage-gated calcium channel, presumably causing a decrease in neurotransmitter release from photoreceptor presynaptic terminals, are a frequent cause of CSNB2.

[Organoids for the advancement of intraoperative diagnostic procedures]. / Organoide zur Weiterentwicklung der intraoperativen Diagnostik.

In the context of cancer surgery, there is always a trade-off between oncological safety and preservation of function. This is especially true in pelvic surgery due to the close relationship to the pelvic floor muscles, blood supply and nerves. Currently, risk models, preoperative imaging, the surgeon's assessment, and the intraoperative frozen section serve as the basis for decision-making. New imaging techniques and standardization in frozen section have significantly improved this in recent years. However, limitations remain due to time delays as well as more difficult correct anatomical assignment in the follow-up. Alternative intraoperative techniques may overcome this limitation in the future. Patient-derived organoids have emerged as an important new research vehicle in recent years. They are based on tumor stem cells that, under special culture conditions, form three-dimensional replicas of the original tissue. This makes them ideally suited for testing individual system therapies but also as a validation technique for new intraoperative diagnostic procedures. The Research Training Group 2543/I, which is funded by the German Research Foundation, is researching the potential of new diagnostic methods in an interdisciplinary team regarding validation in addition to intraoperative frozen sections.

Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience.

BACKGROUND: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. METHODS: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. RESULTS: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-beta and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18+ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40+ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. CONCLUSIONS: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection.

Neuronal correlates of affective theory of mind in schizophrenia out-patients: evidence for a baseline deficit.

BACKGROUND: Schizophrenia out-patients have deficits in affective theory of mind (ToM) but also on more basal levels of social cognition, such as the processing of neutral and emotional expressions. These deficits are associated with changes in brain activation in the amygdala and the superior temporal sulcus (STS). However, until now there have been no studies that examined these different levels of social cognition and their neurobiological underpinnings in patients within one design. METHOD: Sixteen medicated schizophrenia out-patients and 16 matched healthy controls were studied with functional magnetic resonance imaging (fMRI) during a social cognition task that allows the investigation of affective ToM (aToM), emotion recognition and the processing of neutral facial expressions. RESULTS: Patients showed a deficit in emotion recognition and a more prominent deficit in aToM. The performance in aToM and in emotion recognition was correlated in the control group but not in the schizophrenia group. Region-of-interest analysis of functional brain imaging data revealed no difference between groups during aToM, but a hyperactivation in the schizophrenia group in the left amygdala and right STS during emotion recognition and the processing of neutral facial expressions. CONCLUSIONS: The results indicate that schizophrenia out-patients have deficits at several levels of social cognition and provide the first evidence that deficits on higher-order social cognitive processes in schizophrenia may be traced back to an aberrant processing of faces per se.

P2 receptor-mediated stimulation of the PI3-K/Akt-pathway in vivo.

ATP acts as a growth factor as well as a toxic agent by stimulating P2 receptors. The P2 receptor-activated signaling cascades mediating cellular growth and cell survival after injury are only incompletely understood. Therefore, the aim of the present study was to identify the role of the phosphoinositide 3 kinase (PI3-K/Akt) and the mitogen-activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) pathways in P2Y receptor-mediated astrogliosis after traumatic injury and after microinfusion of ADP beta S (P2Y(1,12,13) receptor agonist) into the rat nucleus accumbens (NAc). Mechanical damage and even more the concomitant treatment with ADP beta S, enhanced P2Y(1) receptor-expression in the NAc, which could be reduced by pretreatment with the P2X/Y receptor antagonist PPADS. Quantitative Western blot analysis indicated a significant increase in phosphorylated (p)Akt and pERK1/2 2 h after ADP beta S-microinjection. Pretreatment with PPADS or wortmannin abolished the up-regulation of pAkt by injury alone or ADP beta S-treatment. The ADP beta S-enhanced expression of the early apoptosis marker active caspase 3 was reduced by PPADS and PD98059, but not by wortmannin. Multiple immunofluorescence labeling indicated a time-dependent expression of pAkt and pMAPK on astrocytes and neurons and additionally the colocalization of pAkt, pMAPK, and active caspase 3 with the P2Y(1) receptor especially at astrocytes. In conclusion, the data show for the first time the involvement of PI3-K/Akt-pathway in processes of injury-induced astroglial proliferation and anti-apoptosis via activation of P2Y(1) receptors in vivo, suggesting specific roles of P2 receptors in glial cell pathophysiology in neurodegenerative diseases.

Implementation of a clinical guideline to decrease laboratory tests in newborns evaluated for early onset sepsis.

BACKGROUND: Creation of a clinical guideline to reduce the number of complete blood counts (CBCs) obtained on healthy term infants for early onset sepsis (EOS) evaluation secondary to maternal chorioamnionitis. METHODS: A clinical guideline was introduced at four neonatal intensive care units (NICU) to reduce laboratory tests during EOS evaluation. Measures include frequency and timing of CBCs, culture negative sepsis, length of stay, and readmission rate. RESULTS: Mean number of CBCs per patient significantly decreased (2.31±0.62 versus 1.52±0.65) without increasing trends for patients with culture negative sepsis, length of stay, or re-admission. CONCLUSION: The clinical guideline demonstrated a significant reduction in the number of CBCs obtained in well-appearing infants admitted to the NICU secondary to maternal chorioamnionitis.

Effect of long term aspirin use on the incidence of prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening. METHODS: A systematic review on the association between aspirin use ≥3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria. RESULTS: In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97). CONCLUSION: This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement.

Reviewing the current evidence supporting early B-cells as the cellular origin of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly malignant skin cancer characterized by early metastases and poor survival. Although MCC is a rare malignancy, its incidence is rapidly increasing in the U.S. and Europe. The discovery of the Merkel cell polyomavirus (MCPyV) has enormously impacted our understanding of its etiopathogenesis and biology. MCCs are characterized by trilinear differentiation, comprising the expression of neuroendocrine, epithelial and B-lymphoid lineage markers. To date, it is generally accepted that the initial assumption of MCC originating from Merkel cells (MCs) is unlikely. This is owed to their post-mitotic character, absence of MCPyV in MCs and discrepant protein expression pattern in comparison to MCC. Evidence from mouse models suggests that epidermal/dermal stem cells might be of cellular origin in MCC. The recently formulated hypothesis of MCC originating from early B-cells is based on morphology, the consistent expression of early B-cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells. In this review we elaborate on the cellular ancestry of MCC, the identification of which could pave the way for novel and more effective therapeutic regimens.

Quantitative Macroscopic Anatomy of the Giraffe (Giraffa camelopardalis) Digestive Tract.

Quantitative data on digestive anatomy of the world's largest ruminant, the giraffe, are scarce. Data were collected from a total of 25 wild-caught and 13 zoo-housed giraffes. Anatomical measures were quantified by dimension, area or weight and analysed by allometric regression. The majority of measures scaled positively and isometrically to body mass. Giraffes had lower tissue weight of all stomach compartments and longer large intestinal length than cattle. When compared to other ruminants, the giraffe digestive tract showed many of the convergent morphological adaptations attributed to browsing ruminants, for example lower reticular crests, thinner ruminal pillars and smaller surface area of the omasal laminae. Salivary gland weight of the giraffe, however, resembled that of grazing ruminants. This matches a previous finding of similarly small salivary glands in the other extant giraffid, the okapi (Okapia johnstoni), suggesting that not all convergent characteristics need be expressed in all species and that morphological variation between species is a combination of phylogenetic and adaptational signals.

Impaired perception of self-motion (heading) in abstinent ecstasy and marijuana users.

RATIONALE: Illicit drug use can increase driver crash risk due to loss of control over vehicle trajectory. This study asks, does recreational use of +/-3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) and tetrahydrocannabinol (THC; marijuana) impair cognitive processes that help direct our safe movement through the world? OBJECTIVE: This study assesses the residual effects of combined MDMA/THC use, and of THC use alone, upon perceived trajectory of travel. METHODS: Perception of self-motion, or heading, from optical flow patterns was assessed using stimuli comprising random dot ground planes presented at three different densities and eight heading angles (1, 2, 4 and 8 degrees to the left or right). On each trial, subjects reported if direction of travel was to the left or the right. RESULTS: Results showed impairments in both drug groups, with the MDMA/THC group performing the worst. CONCLUSIONS: The finding that these psychoactive agents adversely affect heading perception, even in recently abstinent users, raises potential concerns about MDMA use and driving ability.

[A malignant tumour in the breast is not always primary breast cancer]. / Een maligne mammatumor: niet altijd een primair mammacarcinoom.

In a 75-year-old woman with a swelling in her left breast, a 39-year-old woman with an anal fissure due to diarrhoea and a 65-year-old woman with chest pain, a mammary tumour was diagnosed that did not originate in mammary tissue. These were a recurrent melanoma, a carcinoma of the thyroid and a B-cell lymphoma, respectively. All patients were treated. The first patient developed new metastases one year later, the second died, partly as a result of the tumour, and the third showed no recurrence of the tumour after two years. Breast cancer is one of the most frequently occurring neoplasms in women. Primary tumours in the breast from other origins and metastatic lesions to the breast from extramammary tumours are rare. Most of these cases concern haematological malignancies and metastases from melanoma and lung cancer. Despite the fact that metastases to the breast are rare, one should always consider the possibility.

Horner's syndrome in childhood.

During a 36-month period, seven cases of Horner's syndrome were encountered in a general pediatric hospital. The most common site of involvement was the ipsilateral sympathetic chain, although multiple sites were involved. Several causes of Horner's syndrome in childhood that have received little previous attention are reported-internal carotid artery thrombosis, subclavian artery aneurysm, and nasopharyngeal tumor. Suggestions for routine evaluation are given. Angiography and x-rays of the temporal and sphenoid bones are valuable in the diagnosis of intracranial lesions causing Horner's syndrome. Horner's syndrome is not rare in childhood and is associated with serious underlying disease.

Isolated vertigo as a manifestation of vertebrobasilar ischemia.

OBJECTIVE: We sought to demonstrate that isolated episodes of vertigo can be the only manifestation of vertebrobasilar ischemia. BACKGROUND: Isolated persistent vertigo is classically ascribed to labyrinthine disorders and is only rarely considered to reflect vertebrobasilar ischemia. METHODS: We retrospectively analyzed all of the records of the Saint Louis University Stroke Registry between January 1, 1992 and September 1, 1993. We set out to identify those patients discharged with a diagnosis of transient ischemic attack (TIA) in the vertebrobasilar system. We reviewed their clinical records and the results of their diagnostic studies. RESULTS: We screened 600 admissions and found 29 patients with vertebrobasilar circulation TIAs. Of these, five men and one woman had episodic vertigo for at least 4 weeks as their only presenting symptom. All six patients had one of two abnormal patterns on magnetic resonance angiography (MRA): focal basilar stenosis or widespread vertebrobasilar slow flow. In three patients, the MRA findings were confirmed by cerebral angiography. Five patients were treated with warfarin and one with aspirin. Two patients developed brainstem infarctions, one of them fatal. CONCLUSIONS: Isolated vertigo can be the only manifestation of vertebrobasilar ischemia. Its frequency may be underestimated in clinical practice. Noninvasive testing is helpful both for diagnosis and follow-up.