Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.
It is shown for the first time that FOXO3/FKHRL1 induces caspase-8 expression via the ATM-CREB pathway independent of caspase-8 gene methylation status. Induction of caspase-8 by the DNA-methylation inhibitor 5-azadC also depends on FOXO3, suggesting that 5-azadC triggers gene expression via the FOXO3-ATM-CREB pathway.
Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene. Instead, FOXO3 induced phosphorylation of its binding partner ATM and of the ATM downstream target cAMP-responsive element binding protein (CREB), which was critical for FOXO3-mediated caspase-8 expression. Caspase-8 levels above a critical threshold sensitized neuroblastoma cells to tumor necrosis factor–related apoptosis-inducing ligand–induced cell death. The DNA-demethylating drug 5-Aza-2-deoxycytidine (5-azadC) induced rapid nuclear accumulation of FOXO3, ATM-dependent CREB phosphorylation, and caspase-8 expression in a FOXO3-dependent manner. This indicates that 5-azadC activates the FOXO3-ATM-CREB signaling pathway, which contributes to caspase-8 expression. The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8–negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy.
Parkinson`s disease (PD) is a progressive, disabling neurodegenerative disorder with onset of motor and non-motor features. Both reduce quality of life of PD patients and cause caregiver burden. This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other. MAO-B-Inhibitors, NMDA antagonists, dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD. This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms. These PD features predominantly result from non dopaminergic neurodegeneration. Autonomic features, such as seborrhea, hyperhidrosis, orthostatic syndrome, salivation, bladder dysfunction, gastrointestinal disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis, cognitive dysfunction with impaired execution and impulse control may appear. Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions, - side effects, and altered pharmacokinetic behaviour of applied compounds. Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms. This complicates the differentiation from the disease process itself and influences therapeutic options, which are often limited because of additional morbidity with necessary concomitant drug therapy.
Motor symptoms; Parkinson’s disease; non motor features; drug therapy
Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.
Bats receive increasing attention in infectious disease studies, because of their well recognized status as reservoir species for various infectious agents. This is even more important, as bats with their capability of long distance dispersal and complex social structures are unique in the way microbes could be spread by these mammalian species. Nevertheless, infection studies in bats are predominantly limited to the identification of specific pathogens presenting a potential health threat to humans. But the impact of infectious agents on the individual host and their importance on bat mortality is largely unknown and has been neglected in most studies published to date.
Between 2002 and 2009, 486 deceased bats of 19 European species (family Vespertilionidae) were collected in different geographic regions in Germany. Most animals represented individual cases that have been incidentally found close to roosting sites or near human habitation in urban and urban-like environments. The bat carcasses were subjected to a post-mortem examination and investigated histo-pathologically, bacteriologically and virologically. Trauma and disease represented the most important causes of death in these bats. Comparative analysis of pathological findings and microbiological results show that microbial agents indeed have an impact on bats succumbing to infectious diseases, with fatal bacterial, viral and parasitic infections found in at least 12% of the bats investigated.
Our data demonstrate the importance of diseases and infectious agents as cause of death in European bat species. The clear seasonal and individual variations in disease prevalence and infection rates indicate that maternity colonies are more susceptible to infectious agents, underlining the possible important role of host physiology, immunity and roosting behavior as risk factors for infection of bats.
Different approaches have been applied to develop highly attenuated rabies virus vaccines for oral vaccination of mesocarnivores. One prototype vaccine construct is SAD dIND1, which contains a deletion in the P-gene severely limiting the inhibition of type-1 interferon induction. Immunogenicity studies in foxes and skunks were undertaken to investigate whether this highly attenuated vaccine would be more immunogenic than the parental SAD B19 vaccine strain. In foxes, it was demonstrated that SAD dIND1 protected the animals against a rabies infection after a single oral dose, although virus neutralizing antibody titres were lower than in foxes orally vaccinated with the SAD B19 virus as observed in previous experiments. In contrast, skunks receiving 107.5 FFU SAD dIND1 did not develop virus neutralizing antibodies and were not protected against a subsequent rabies infection.
GPs are often the first point of contact for patients with prodromal schizophrenia. Early intervention, and therefore early detection, of schizophrenia is pivotal for the further disease course. However, recent studies have revealed that, due to its low prevalence in general practice and its insidious features, prodromal schizophrenia often remains unnoticed.
To test whether a repeated sensitisation method using clinical vignettes can improve diagnostic knowledge of GPs.
Design of study
Postal survey using anonymous questionnaires.
Repeated sensitisation model using clinical vignettes.
GPs in three distinct regions in Switzerland covering a general population of 1.43 million.
The study was conducted between September 2008 and October 2009. Questionnaires were sent to 1138 GPs at baseline, and at 6 and 12?months. After randomisation, 591 GPs were sensitised at 1, 3, and 5?months, while no sensitisation was carried out in the remaining 547 GPs.
The overall response rate was 66% (750 GPs).
Sensitised GPs demonstrated a highly significant increase in diagnostic knowledge at 6 and at 12?months when compared to their own baseline knowledge scores and also to non-sensitised GPs (P<0.001). In particular, awareness of insidious features, such as functional decline and social withdrawal as signs of prodromal schizophrenia, accounted for this effect.
Theoretical knowledge of prodromal schizophrenia among GPs can successfully be increased by repeated sensitisation models using clinical vignettes.
family practice; mental health; psychosis, early; schizophrenia, prodromal
A virus isolated from a Natterer’s bat (Myotis nattererii) in Germany was differentiated from other lyssaviruses on the basis of the reaction pattern of a panel of monoclonal antibodies. Phylogenetic analysis supported the assumption that the isolated virus, Bokeloh bat lyssavirus, may represent a new member of the genus Lyssavirus.
rabies; bats; lyssavirus; Natterer’s bat; Myotis nattereri; sequence analysis; zoonosis; Germany; viruses; dispatch
Bacterial contamination remains a leading factor for transfusion-associated serious morbidity and mortality. Pathogen reduction procedures offer a pro-active approach to prevent bacterial contamination of cellular blood components and especially of platelet concentrates. In the past, the laboratory evaluation of the effectiveness of the pathogen reduction procedures to minimise the bacterial load of blood components has been primarily based on log reduction assays similar to the assessment of antiviral activities. Bacteria strains with the ability to multiply in the blood components are seeded in highest possible cell numbers, the pathogen reduction procedure is applied, and the post-treatment number of bacteria is measured. The effectiveness of the procedure is characterised by calculating the log reduction of the post- to pre-treatment bacteria titres. More recently, protocols have been developed for experiments starting with a low bacteria load and monitoring the sterility of the blood component during the entire storage period of the blood component. Results for 3 different pathogen reduction technologies in these experimental models are compared and critical determinants for the results are addressed. The heterogeneity of results observed for different strains suggests that the introduction of international transfusion-relevant bacterial reference strains may facilitate the validity of findings in pathogen reduction experiments.
Bacteria, pathogen reduction; Platelet concentrate; Cellular blood component; Sterility
In fulminant blastomycosis with multiorgan failure, the earliest diagnosis possible is crucial for successful treatment. If severe acute respiratory distress syndrome (ARDS) develops, miniaturised veno-venous extracorporeal membrane oxygenation (ECMO) might provide a unique and efficacious possibility to prolong the time frame for diagnosis and the beginning of treatment. This is the first report on a case of fatal blastomycosis in Germany. It reminds us to add exotic infections to the differential diagnosis in patients with refractory pneumonia in the era of worldwide tourism.
A Mobil Composition of Matter (MCM)-41 type mesoporous silica material containing N-propylacridone groups has been successfully prepared by co-condensation of an appropriate organic precursor with tetraethyl orthosilicate (TEOS) under alkaline sol–gel conditions. The resulting material was fully characterized by means of X-ray diffraction (XRD), N2-adsorption–desorption, transmission electron microscopy (TEM), IR and UV–vis spectroscopy, as well as 29Si and 13C CP-MAS NMR techniques. The material features a high inner surface area and a highly ordered two-dimensional hexagonal pore structure. The fluorescence properties of the organic chromophore can be tuned via complexation of its carbonyl group with scandium triflate, which makes the material a good candidate for solid state sensors and optics. The successful synthesis of highly ordered MCM materials through co-condensation was found to be dependent on the chemical interaction of the different precursors.
acridone; co-condensation; fluorescence; scandium; MCM-41
Canine rabies, responsible for most human rabies deaths, is a serious global public health concern. This zoonosis is entirely preventable, but by focusing solely upon rabies prevention in humans, this “incurable wound” persists at high costs. Although preventing human deaths through canine rabies elimination is feasible, dog rabies control is often neglected, because dogs are not considered typical economic commodities by the animal health sector. Here, we demonstrate that the responsibility of managing rabies falls upon multiple sectors, that a truly integrated approach is the key to rabies elimination, and that considerable progress has been made to this effect. Achievements include the construction of global rabies networks and organizational partnerships; development of road maps, operational toolkits, and a blueprint for rabies prevention and control; and opportunities for scaling up and replication of successful programs. Progress must continue towards overcoming the remaining challenges preventing the ultimate goal of rabies elimination.
Viruses; rabies; zoonoses; European Union; Switzerland; letter
Besides the current efforts devoted to microbial risk reduction, pathogen inactivation technologies promise reduction of the residual risk of known and emerging infectious agents. A novel pathogen reduction process for platelets, the THERAFLEX UV-Platelets system, has been developed and is under clinical evaluation for its efficacy and safety. In addition, proof of principle has been shown for UVC treatment of plasma units. The pathogen reduction process is based on application of UVC light of a specific wavelength (254 nm) combined with intense agitation of the blood units to ensure a uniform treatment of all blood compartments. Due to the different absorption characteristics of nucleic acids and proteins, UVC irradiation mainly affects the nucleic acid of pathogens and leukocytes while proteins are largely preserved. UVC treatment significantly reduces the infectivity of platelet units contaminated by disease-causing viruses and bacteria. In addition, it inactivates residual white blood cells in the blood components while preserving platelet function and coagulation factors. Since no photoactive compound needs to be added to the blood units, photoreagent-related adverse events are excluded. Because of its simple and rapid procedure without the need to change the established blood component preparation procedures, UVC-based pathogen inactivation could easily be implemented in existing blood banking procedures.
Pathogen inactivation; UVC; Platelet concentrates; Plasma; Blood units
Twenty years ago, the molecular basis for the seasonal disappearance of chlorophyll was still enigmatic. In the meantime, our knowledge on chlorophyll breakdown has grown considerably. As outlined here, it has been possible to decipher the basic transformations involved in natural chlorophyll breakdown by identification of chlorophyll catabolites in higher plants, and with the help of the synthesis of (putative) catabolic intermediates. In vascular plants, chlorophyll breakdown typically converts the green plant pigments efficiently into colorless and non-fluorescent tetrapyrroles. It involves colored intermediates only fleetingly and in an (elusive) enzyme-bound form. The non-fluorescent chlorophyll catabolites accumulate in the vacuoles of degreened leaves and are considered the products, primarily, of a detoxification process. However, they are effective antioxidants, and may thus also have physiologically beneficial chemical properties.
Natural products; Chlorophyll; Catabolism; Biomimetic synthesis; Structure elucidation; Tetrapyrroles
apoptosis; bananas; glycerides; glycosides; tetrapyrroles
Cheetah populations are diminishing rapidly in their natural habitat. One reason for their decline is thought to be a high susceptibility to (infectious) diseases because cheetahs in zoos suffer from high disease-induced mortality. Data on the health status of free-ranging cheetahs are scarce, and little is known about their exposure and susceptibility to infectious diseases. We determined seroprevalences to nine key viruses (feline herpesvirus 1, feline calicivirus, feline parvovirus, feline coronavirus, canine distemper virus, feline immunodeficiency virus [FIV], puma lentivirus, feline leukemia virus, and rabies virus) in 68 free-ranging cheetahs on east-central Namibian farmland, 24 nonvaccinated Namibian captive cheetahs, and several other wild carnivore species and conducted necropsies of cheetahs and other wild carnivores. Eight of 11 other wild carnivores were seropositive for at least one of the viruses, including the first record of an FIV-like infection in a wild felid west of the Kalahari, the caracal (Felis caracal). Seroprevalences of the free-ranging cheetahs were below 5% for all nine viruses, which is significantly lower than seroprevalences in nonvaccinated captive cheetahs and those for five of seven viruses in previously studied free-ranging cheetahs from north-central Namibia (L. Munson, L. Marker, E. Dubovi, J. A. Spencer, J. F. Evermann, and S. J. O'Brien, J. Wildl. Dis. 40:23-31, 2004). There was no clinical or pathological evidence of infectious diseases in living or dead cheetahs. The results suggest that while free-ranging wild carnivores may be a source of pathogens, the distribution of seroprevalences across studies mirrored local human population density and factors associated with human habitation, probably reflecting contact opportunities with (nonvaccinated) domestic and feral cats and dogs. They also suggest that Namibian cheetahs respond effectively to viral challenges, encouraging consistent and sustainable conservation efforts.
chlorophyll; fruit; luminescence; pigments; porphyrinoids; tetrapyrrole
antioxidants; chlorophyll; natural products; porphyrinoids; structure elucidation
Here we describe the detection and identification of a yellow chlorophyll catabolite (Cj-YCC) in fresh extracts of senescent leaves of Cercidiphyllum japonicum. In addition, we report its partial synthesis by oxidation of Cj-NCC-1, the major (colourless) “nonfluorescent” chlorophyll catabolite (NCC) found in degreened leaves of C. japonicum. The spectroscopic analysis and structural characterization indicated Cj-YCC to be a simple dehydrogenation product of Cj-NCC-1 (by formal removal of a hydrogen atom at the C(20)- and C(1)-positions). Indeed, NCCs are easily oxidized and were first called “rusty pigments”, as they had a tendency to turn brown upon storage on a dry silica gel plate. The yellow tetrapyrrole Cj-YCC may thus come about by oxidation of Cj-NCC-1 in the leaves. Its presence in the yellow leaves of a deciduous tree provides the first evidence for the contribution of a coloured chlorophyll catabolite to the fall colours.
Instrumental measurement of simple motion sequences reflects impairment in patients with Huntington's disease (HD). The objectives were to study the progress of symptoms of HD and tapping results in 42 patients with HD, without symptomatic drug treatment over 3 years. Assessment moments were at baseline, and at years 1, 2 and 3. Unified Huntington's Disease Rating Scale (UHDRS) total score and UHDRS arm score significantly increased. Motor test outcomes considerably worsened. Instrumental test results significantly correlated with both UHDRS scores at each assessment. Assessment of simple movement sequences is an additional simple method to follow impairment in patients with HD in addition to clinical rating.
Mortality of severe acute respiratory distress syndrome in adults is still unacceptably high. Extracorporeal membrane oxygenation (ECMO) could represent an important treatment option, if complications were reduced by new technical developments.
Efficiency, side effects and outcome of treatment with a new miniaturized device for veno-venous extracorporeal gas transfer were analysed in 60 consecutive patients with life-threatening respiratory failure.
A rapid increase of partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) from 64 (48 to 86) mmHg to 120 (84 to 171) mmHg and a decrease of PaCO2 from 63 (50 to 80) mmHg to 33 (29 to 39) mmHg were observed after start of the extracorporeal support (P < 0.001). Gas exchange capacity of the device averaged 155 (116 to 182) mL/min for oxygen and 210 (164 to 251) mL/min for carbon dioxide. Ventilatory parameters were reduced to a highly protective mode, allowing a fast reduction of tidal volume from 495 (401 to 570) mL to 336 (292 to 404) mL (P < 0.001) and of peak inspiratory pressure from 36 (32 to 40) cmH2O to 31 (28 to 35) cmH2O (P < 0.001). Transfusion requirements averaged 0.8 (0.4 to 1.8) units of red blood cells per day. Sixty-two percent of patients were weaned from the extracorporeal system, and 45% survived to discharge.
Veno-venous extracorporeal membrane oxygenation with a new miniaturized device supports gas transfer effectively, allows for highly protective ventilation and is very reliable. Modern ECMO technology extends treatment opportunities in severe lung failure.
As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used in developing countries as a replacement for RIG in PEP. Five MoMAbs, E559.9.14, 1112-1, 62-71-3, M727-5-1, and M777-16-3, were selected from available panels based on stringent criteria, such as biological activity, neutralizing potency, binding specificity, spectrum of neutralization of lyssaviruses, and history of each hybridoma. Four of these MoMAbs recognize epitopes in antigenic site II and one recognizes an epitope in antigenic site III on the rabies virus (RABV) glycoprotein, as determined by nucleotide sequence analysis of the glycoprotein gene of unique MoMAb neutralization-escape mutants. The MoMAbs were produced under Good Laboratory Practice (GLP) conditions. Unique combinations (cocktails) were prepared, using different concentrations of the MoMAbs that were capable of targeting non-overlapping epitopes of antigenic sites II and III. Blind in vitro efficacy studies showed the MoMab cocktails neutralized a broad spectrum of lyssaviruses except for lyssaviruses belonging to phylogroups II and III. In vivo, MoMAb cocktails resulted in protection as a component of PEP that was comparable to HRIG. In conclusion, all three novel combinations of MoMAbs were shown to have equal efficacy to HRIG and therefore could be considered a potentially less expensive alternative biological agent for use in PEP and prevention of rabies in humans.
Human mortality from endemic canine rabies is estimated to be 55,000 deaths per year in Africa and Asia, yet rabies remains a neglected disease throughout most of these countries. More than 99% of human rabies cases are caused by infections resulting from a dog-bite injury. In the vast majority of human exposures to rabies, patients require post-exposure prophylaxis (PEP), which includes both passive (rabies immunoglobulin, RIG) and active immunization (rabies vaccine). The number of victims requiring PEP has increased exponentially in recent years, and human and equine RIG (HRIG and ERIG) were not sufficiently available in countries where canine rabies is endemic. Rabies virus-neutralizing monoclonal antibodies (MAbs) of mouse (Mo) origin have been identified as promising alternatives to HRIG and ERIG. We have developed and assessed both in vitro and in vivo unique mouse monoclonal antibody (MoMAb) cocktails, which are highly efficacious. Three novel combinations were shown to have an equal or superior efficacy to HRIG and therefore could be considered a potentially less expensive alternative for passive prophylactic use to prevent the development of rabies in humans, particularly where needed most in developing countries.