Frail patients who fall and their risk on major bleeding and intracranial haemorrhage. Outcomes from the Fall and Syncope Registry.

BACKGROUND: Major bleeding, and intracranial bleeding specifically, are severe complications related to the use of anticoagulation. To what extent the risk for major bleeding is elevated among frail older people is not well known because they are underrepresented in the randomized clinical trials (RCTs). This study investigates the risk for major bleeding (MB) and intra cranial haemorrhage (ICH) in frail older people who fall. METHODS: All patients 65 years and older visiting the Fall and Syncope Clinic, between November 2011 and January 2020, and underwent a MRI of the brain were eligible. Frailty was assessed with a Frailty Index, based on the accumulation of deficits model. Cerebral small vessel disease was described and evaluated as proposed in the position paper of Wardlaw and colleagues in 2013. RESULTS: 479 patients were included in this analysis. Mean follow-up was 7 years per patient (ranging from 1 month to 8 years and 5 months). 368 patients (77%) were frail. A total of 81 patients used oral anticoagulation (OAC). 17 extracranial MB of which 3 were traumatic and 14 gastrointestinal, and 16 ICH occurred. There was a total of 603.4 treatment years with OAC, and 8 MBs occurred among patients on OAC (bleeding rate 1.32 per 100 treatment years), of which 2 ICHs (bleeding rate 0.33 per 100 treatment years). The risk for extracranial MB was increased by the use of antiplatelet agents (APA) (adjusted OR 6.9, CI 95% 1.2-38.3), and by the use of OAC (adjusted OR 9.8, CI 95% 1.7-56.1). The risk for ICH was only heightened by white matter hyperintensities (WMH) (adjusted OR 3.8, CI 95% 1.0-13.4). The use of APA (adjusted OR 0.9, CI 95% 0.3-3.3) or OAC (adjusted OR 0.6, CI 95% 0.1-3.3) did not elevate the risk for ICH. CONCLUSION: In contrast to common belief, frail patients on OAC with repeated falls show a comparable bleeding rate as in the large RCTs, and the use of OAC did not increase the risk for ICH. However, the number of MBs was low, and of ICHs very low, despite extensive follow-up in this registry.

The contribution of dynamics to macaque body and face patch responses.

Previous functional imaging studies demonstrated body-selective patches in the primate visual temporal cortex, comparing activations to static bodies and static images of other categories. However, the use of static instead of dynamic displays of moving bodies may have underestimated the extent of the body patch network. Indeed, body dynamics provide information about action and emotion and may be processed in patches not activated by static images. Thus, to map with fMRI the full extent of the macaque body patch system in the visual temporal cortex, we employed dynamic displays of natural-acting monkey bodies, dynamic monkey faces, objects, and scrambled versions of these videos, all presented during fixation. We found nine body patches in the visual temporal cortex, starting posteriorly in the superior temporal sulcus (STS) and ending anteriorly in the temporal pole. Unlike for static images, body patches were present consistently in both the lower and upper banks of the STS. Overall, body patches showed a higher activation by dynamic displays than by matched static images, which, for identical stimulus displays, was less the case for the neighboring face patches. These data provide the groundwork for future single-unit recording studies to reveal the spatiotemporal features the neurons of these body patches encode. These fMRI findings suggest that dynamics have a stronger contribution to population responses in body than face patches.

Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

Critical overview of all available animal models for abdominal wall hernia research.

PURPOSE: Since the introduction of the first prosthetic mesh for abdominal hernia repair, there has been a search for the "ideal mesh." The use of preclinical or animal models for assessment of necessary characteristics of new and existing meshes is an indispensable part of hernia research. Unfortunately, in our experience there is a lack of consensus among different research groups on which model to use. Therefore, we hypothesized that there is a lack of comparability within published animal research on hernia surgery due to wide range in experimental setup among different research groups. METHODS: A systematic search of the literature was performed to provide a complete overview of all animal models published between 2000 and 2014. Relevant parameters on model characteristics and outcome measurement were scored on a standardized scoring sheet. RESULTS: Due to the wide range in different animals used, ranging from large animal models like pigs to rodents, we decided to limit the study to 168 articles concerning rat models. Within these rat models, we found wide range of baseline animal characteristics, operation techniques, and outcome measurements. Making reliable comparison of results among these studies is impossible. CONCLUSION: There is a lack of comparability among experimental hernia research, limiting the impact of this experimental research. We therefore propose the establishment of guidelines for experimental hernia research by the EHS.

Long-term evaluation of adhesion formation and foreign body response to three new meshes.

INTRODUCTION: Mesh-related adhesions are a significant clinical problem following intraperitoneal mesh placement. In this study, we evaluated adhesion formation to three relatively new meshes for intraperitoneal use. METHODS: Three new meshes for intraperitoneal use (Omyra(®) mesh, Physiomesh(®), and Hi-Tex Endo-IP(®)) were implanted intraperitoneally in rats and compared with a polypropylene control mesh (Parietene(®)) after 7 or 90 days. Adhesion formation, incorporation (tensile strength), shrinkage, and foreign body reaction were scored. RESULTS: Hi-Tex Endo-IP and Physiomesh(®) showed significantly less adhesion formation when compared to Parietene at both time points (p < 0.05). Shrinkage was highest in Omyra mesh after 90 days, which was significantly more compared to Parietene(®) (p < 0.001). Physiomesh(®) only showed a significant reduction in craniocaudal mesh length, compared to Parietene and Hi-Tex Endo-IP (p < 0.05). After 90 days, Hi-Tex Endo-IP(®) showed significantly higher and Physiomesh(®) significantly lower incorporation strengths compared to all other groups (p < 0.05). Microscopic evaluation revealed massive foreign body reaction to Hi-Tex Endo-IP(®), leading to an extensive and thick collagenous scar adherent to the abdominal wall. Fractioning of the Physiomesh(®) coating over time led to an increase in interfilamentary granuloma formation, leading to scar plate formation, but with only minimal to no abdominal wall adherence. Both Parietene(®) and Omyra(®) showed a mild foreign body response. CONCLUSION: Although clear distinctions can be made between meshes and some meshes excel, none of the meshes are superior in all aspects required for effective and safe incisional hernia repair.

Laparotomy closure using an elastic suture: a promising approach.

BACKGROUND: Midline laparotomy wound failure like burst abdomen remains one of the major complications after abdominal surgery. The use of sutures with a closer resemblance to abdominal wall physiology, like elastic threads, could decrease the risk of these complications occurring. Thus, we evaluated the possibility of using a new elastic thread composed of thermoplastic polyurethane (TPU) as a suture for the closure of midline laparotomies compared to conventionally used polypropylene (PP) in a rabbit model. METHODS: The elastic TPU thread was processed and tensile tests were performed. Twenty female chinchilla rabbits underwent midline laparotomy. They were randomized to a TPU and a PP group depending on the suture used for fascia closure. After 7 or 21 days, the abdominal walls were assessed macroscopically for wound healing complications and were explanted for histopathological investigation. RESULTS: Tensile tests showed a mean elastic elongation of 55.5% and a sufficient material strength of the TPU thread. In animal experiments, there was no difference between the groups at 7 days; however, the TPU suture showed significantly less CD68 positive cells (p < 0.001) and a higher collagen I/III ratio (p = 0.011) than PP did after 21 days. The amount of apoptotic cells was significantly elevated in the TPU group (p = 0.007) after 21 days. No differences were found concerning granuloma size and number of Ki67-positive cells. CONCLUSIONS: The newly developed TPU thread shows promising tensile characteristics. Midline laparotomy closure is feasible and safe in a rabbit model. Immunohistochemistry indicates similar biocompatibility and wound healing after implantation compared to PP after 21 days. To confirm these findings and to proof long-term capability further studies need to be conducted.

Suitability of PER.C6 cells to generate epidemic and pandemic influenza vaccine strains by reverse genetics.

Reverse genetics, the generation of influenza viruses from cDNA, presents a rapid method for creating vaccine strains. The technique necessitates the use of cultured cells. Due to technical and regulatory requirements, the choice of cell lines for production of human influenza vaccines is limited. PER.C6 cells, among the most extensively characterized and documented cells, support growth of all influenza viruses tested to date, and can be grown to high densities in large bioreactors in the absence of serum or micro carriers. Here, the suitability of these cells for the generation of influenza viruses by reverse genetics was investigated. A range of viruses reflective of vaccine strains was rescued exclusively using PER.C6 cells by various transfection methods, including an animal component-free procedure. Furthermore, a whole inactivated vaccine carrying the HA and NA segments of A/HK/156/97 (H5N1) that was both rescued from and propagated on PER.C6 cells, conferred protection in a mouse model. Thus PER.C6 cells provide an attractive platform for generation of influenza vaccine strains via reverse genetics.

Serum-free transient protein production system based on adenoviral vector and PER.C6 technology: high yield and preserved bioactivity.

Stable E1 transformed cells, like PER.C6, are able to grow at scale and to high cell densities. E1-deleted adenoviruses replicate to high titer in PER.C6 cells whereas subsequent deletion of E2A from the vector results in absence of replication in PER.C6 cells and drastically lowers the expression of adenovirus proteins in such cells. We therefore considered the use of an DeltaE1/DeltaE2 type 5 vector (Ad5) to deliver genes to PER.C6 cells growing in suspension with the aim to achieve high protein yield. To evaluate the utility of this system we constructed DeltaE1/DeltaE2 vector carrying different classes of protein, that is, the gene coding for spike protein derived from the Coronavirus causing severe acute respiratory syndrome (SARS-CoV), a gene coding for the SARS-CoV receptor or the genes coding for an antibody shown to bind and neutralize SARS-CoV (SARS-AB). The DeltaE1/DeltaE2A-vector backbones were rescued on a PER.C6 cell line engineered to constitutively over express the Ad5 E2A protein. Exposure of PER.C6 cells to low amounts (30 vp/cell) of DeltaE1/DeltaE2 vectors resulted in highly efficient (>80%) transduction of PER.C6 cells growing in suspension. The efficient cell transduction resulted in high protein yield (up to 60 picogram/cell/day) in a 4 day batch production protocol. FACS and ELISA assays demonstrated the biological activity of the transiently produced proteins. We therefore conclude that DeltaE1/DeltaE2 vectors in combination with the PER.C6 technology may provide a viable answer to the increasing demand for high quality, high yield recombinant protein.

Distortions in rest-activity rhythm in aging relate to white matter hyperintensities.

Distortions in the rest-activity rhythm in aging are commonly observed. Neurodegenerative changes of the suprachiasmatic nucleus have been proposed to underlie this disrupted rhythm. However, based on previous studies, it can be proposed that white matter hyperintensities (WMH) may also play a role in the altered rest-activity rhythm in aging. The present study focused on the rest-activity rhythm, as assessed with actigraphy, and WMH in nondemented aging. With regard to the rest-activity rhythm, the interdaily stability (IS), intradaily variability (IV) and the amplitude (AMP) of the rhythm were of interest. The white matter hyperintensities were examined separately for the periventricular (PVH) and deep white matter (DWMH) regions, while distinguishing between the various locations within these regions (e.g. occipital PVH). The results indicated that frontal DWMH related to both IS and AMP. A reduction in the most active 10-h period mediated the relationship between frontal DWMH and AMP. Possible underlying mechanisms of these associations are discussed.

Effects of perceptual learning in visual backward masking on the responses of macaque inferior temporal neurons.

Learning is critical for fast and efficient object recognition in primates. To understand the neuronal correlates of behavioral improvements due to training, we recorded the responses of single neurons in the inferior temporal (IT) cortex of monkeys that were trained to recognize briefly presented, backward-masked objects. First we investigated training effects that are specific to the objects shown during training and that do not transfer to untrained objects. Only one of two monkeys tested showed object-specific training effects at the behavioral level, and only this monkey showed a transient object-specific increase in object selectivity for trained compared with untrained backward-masked objects. However, in each monkey a substantial part of the training effect transferred to untrained objects. To investigate the neural correlates of these object-independent training effects, we compared the neural responses to masked objects in trained monkeys to the responses in untrained monkeys. Training was associated with a reduction of the responses to the irrelevant masking patterns. These findings suggest that extensive training in recognizing backward-masked objects results in neural changes that reduce IT responses to the interfering irrelevant masking patterns and enhance the processing of the relevant objects.

A replication-competent adenovirus assay for E1-deleted Ad35 vectors produced in PER.C6 cells.

The presence of replication-competent adenovirus (RCA) is a safety concern for biologics based on recombinant adenoviruses and RCA testing is therefore mandatory for release of clinical material. RCA, which arises from homologous recombination between Ad5 vectors and HEK-293 cells, can be eliminated by the use of PER.C6 cells in combination with a matched vector. However, little is known on RCA formation with vectors based on adenovirus serotypes other than Ad5 and reliable RCA assays to test them are generally lacking. Here we report on the development and qualification of a sensitive RCA assay for Ad35, a promising alternative to Ad5 vectors. The assay is able to detect 1 RCA in 3x10(10) vector particles with 95% confidence, thus meeting current FDA requirements, and can discriminate between RCA and other rare CPE-causing entities, including helper dependent E1 positive particles (HDEP). Using this assay, the first batches of Ad35 vectors produced in PER.C6 cells were analysed and found to be free of RCA and HDEP. Based on the statistical model used, we anticipate that our approach to RCA assay development can be broadly applicable to other adenoviral vectors.

Novel replication-incompetent adenoviral B-group vectors: high vector stability and yield in PER.C6 cells.

Adenoviral vectors based on adenovirus type 35 (rAd35) have the advantage of low natural vector immunity and induce strong, insert-specific T- and B-cell responses, making them prime-candidate vaccine carriers. However, severe vector-genome instability of E1-deleted rAd35 vectors was observed, hampering universal use. The instability of E1-deleted rAd35 vector proved to be caused by low pIX expression induced by removal of the pIX promoter, which was located in the E1B region of B-group viruses. Reinsertion of a minimal pIX promoter resulted in stable vectors able to harbour large DNA inserts (> 5 kb). In addition, it is shown that replacement of the E4-Orf6 region of Ad35 by the E4-Orf6 region of Ad5 resulted in successful propagation of an E1-deleted rAd35 vector on existing E1-complementing cell lines, such as PER.C6 cells. The ability to produce these carriers on PER.C6 contributes significantly to the scale of manufacturing of rAd35-based vaccines. Next, a stable rAd35 vaccine was generated carrying Mycobacterium tuberculosis antigens Ag85A, Ag85B and TB10.4. The antigens were fused directly, resulting in expression of a single polyprotein. This vaccine induced dose-dependent CD4+ and CD8+ T-cell responses against multiple antigens in mice. It is concluded that the described improvements to the rAd35 vector contribute significantly to the further development of rAd35 carriers for mass-vaccination programmes for diseases such as tuberculosis, AIDS and malaria.

Cerebellar haemorrhage after non-traumatic evacuation of supratentorial chronic subdural haematoma: report of two cases.

Cerebellar haemorrhage is an unusual complication of supratentorial neurosurgery. Several causative pre-operative factors and medical risk factors may predispose patients to cerebellar haemorrhage, however its etiology remains still unclear. Only two case reports have previously described the occurrence of cerebellar haemorrhage after subdural haematoma evacuation by burr-hole trepanation. We present two patients with this rare postoperative complication of minor supratentorial neurosurgery and possible underlying pathophysiological mechanisms are discussed. Our two cases support the post- rather than per-operative pathogenetic hypothesis. Although the complication is associated with a significant morbidity and mortality, most cases follow a benign course.

Initial subgingival colonization of 'pristine' pockets.

The treatment of periodontitis/peri-implantitis involves the reduction/eradication of periopathogens. After therapy, beneficial and pathogenic species recolonize the subgingival area. The dynamics of recolonization and especially the role of the supragingival environment in this process are still not well-understood. This prospective, split-mouth study followed the early colonization of 'pristine' pockets created during implant surgery (16 partially edentulous patients), to record the time needed before a complex subgingival flora could be established with the supragingival area as the single source. Four subgingival plaque samples were taken from shallow and medium pockets around implants (test), and neighboring teeth (undisturbed microbiota as reference) 1, 2, and 4 wks after abutment connection. Checkerboard DNA-DNA hybridization and culture data revealed a complex microbiota (including several pathogenic species) in the pristine pockets within a wk, with a minimal increase in counts up to 4 wks. Analysis of these data demonstrated that, even with the supragingival environment as the single source for colonizing bacteria, a complex subgingival microbiota can develop within 1 wk.

Homogeneous forced hydrolysis of aluminum through the thermal decomposition of urea.

Homogeneous hydrolysis of aluminum by decomposition of urea in solution was achieved because the urea coordinates to the Al3+ in solution, forming [Al(H2O)5 (urea)]3+ and to a lesser extent [Al(H2O)4 (urea)2]3+. Upon hydrolysis more hydrolyzed monomeric species, [Al(H2O)5 (OH)]2+, [Al(H2O)4 (OH)2]+, [Al(H2O)4 (urea)(OH)]2+, and [Al(H2O)3 (urea)(OH)2]+, were formed, followed by trimeric species and the Al13 Keggin complex [AlO4Al12(OH)24(H2O)12]7+. The 27Al NMR spectra indicated the formation of other complexes in addition to the Al13 at the end of the hydrolysis reaction.

['Stiff-person'-syndrome]. / 'Stiff-person'-syndroom.

In two patients, a man aged 54 years and a woman aged 49 years, stiff-person syndrome was diagnosed. This is a rare disorder of the central nervous system, with signs of an autoimmune pathogenesis. Patients present with pain and stiffness of the lower back, a complaint that is regularly seen in general practice. Moreover, the disease causes hypertonia and very painful cramps of the lower back and legs. Electromyographic examination in the resting condition reveals continuous muscle activity in the long back muscles, which decreases following the administration of diazepam. In 60% of patients, antibodies to glutamic acid decarboxylase may be found in the serum or cerebrospinal fluid; this enzyme is involved in the production of the inhibiting neurotransmitter gamma-aminobutyric acid. Both patients were treated with diazepam, baclofen and corticosteroids. Stiff-person syndrome is a rare but treatable disorder that should be considered when patients present with stiffness and pain in the lower back and upper legs.

Effects of surface cues on macaque inferior temporal cortical responses.

Humans are able to recognize objects when surface details, such as colour, texture and luminance gradients, are not available. By systematically eliminating colour, texture, shading, contrast and inner contours from given objects, we tested whether certain shape-selective inferior temporal cortex (IT) neurons of awake rhesus monkeys remain selective for these objects as the surface information is reduced. In psychophysical experiments, we established that the rhesus monkey can identify the shape of a coloured object largely independently of its surface characteristics and, to a lesser degree, of its inner contours. Shape selectivity of the neurons does not change when texture and shading are concealed. The responsiveness of the neurons is also affected by the removal of these surface attributes. The IT neurons were found to respond highly similarly to objects brighter or darker than their background. Selectivity for shape is preserved when the contrast is reversed. Deletion of the inner contours, outlining the main parts of the objects, did not affect the responses and selectivity of the IT neurons. These findings indicate that the IT can contribute to the invariant perception of objects having different surface details.

[Clinical relevance of surface characteristics on the formation of plaque on teeth and implants]. / Klinische relevantie van oppervlakte-eigenschappen op de ontwikkeling van plaque op tanden en implantaten.

The mouth is, from an ecologic point of view, an 'open growth system' with a continuous transport of micro-organisms. To cause infection (caries or periodontitis) or even to survive in the oral cavity, micro-organisms need to attach to one of the available surfaces, otherwise they will be removed by a continuous flow of saliva. The mouth, with his ideal growth conditions for micro-organisms, has many places, called niches, that can be colonised with micro-organisms. It is not surprising that the mouth is being colonised with more then 400 different species. This article discusses successively colonisation of the oral cavity, bacterial adhesion, plaque growth from a clinical point of view, the influence of surface properties on the initial plaque adhesion and maturation, and finally important factors influencing the plaque formation on oral implants.

Relating priming and repetition suppression.

We present a prototype of a recently proposed two stage model of the entorhinal-hippocampal loop. Our aim is to form a general computational model of the sensory neocortex. The model--grounded on pure information theoretic principles--accounts for the most characteristic features of long-term memory (LTM), performs bottom-up novelty detection, and supports noise filtering. Noise filtering can also serve to correct the temporal ordering of information processing. Surprisingly, as we examine the temporal characteristics of the model, the emergent dynamics can be interpreted as perceptual priming, a fundamental type of implicit memory. In the model's framework, computational results support the hypothesis of a strong correlation between perceptual priming and repetition suppression and this correlation is a direct consequence of the temporal ordering in forming the LTM. We also argue that our prototype offers a relatively simple and coherent explanation of priming and its relation to a general model of information processing by the brain.

Exploiting the natural diversity in adenovirus tropism for therapy and prevention of disease.

Since targeting of recombinant adenovirus vectors to defined cell types in vivo is a major challenge in gene therapy and vaccinology, we explored the natural diversity in human adenovirus tissue tropism. Hereto, we constructed a library of Ad5 vectors carrying fibers from other human serotypes. From this library, we identified vectors that efficiently infect human cells that are important for diverse gene therapy approaches and for induction of immunity. For several medical applications (prenatal diagnosis, artificial bone, vaccination, and cardiovascular disease), we demonstrate the applicability of these novel vectors. In addition, screening cell types derived from different species revealed that cellular receptors for human subgroup B adenoviruses are not conserved between rodents and primates. These results provide a rationale for utilizing elements of human adenovirus serotypes to generate chimeric vectors that improve our knowledge concerning adenovirus biology and widen the therapeutic window for vaccination and many different gene transfer applications.