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Atmospheric microplastics (MPs) are a ubiquitous environmental contaminant of emerging concern. Sampling methods provide information relating to surface area concentration and MP characteristics, without direct comparison with routinely measured standard air quality parameters. This study analysed 6 active air samples generated by a local authority as part of their routine air quality monitoring activities. Continuous sampling totalled 10 months, within the city centre of Kingston-upon-Hull. By using μFTIR analysis, levels of total particles detected using the NOx inlet filters ranged from 5139 ± 2843 particles m−2 day−1, comprising 1029 ± 594 MPs m−2 day−1. The controls displayed a mean level of 2.00 ± 3.49 MPs. The polymers nylon (32%) and polypropylene, PP (22%) were the most abundant. Small fragments of 47.42 ± 48.57 μm (length) and 21.75 ± 13.62 μm (width) were most common. An increase in MP levels during April 2020 coincided with an increase in PM10 levels. This study used robust procedures to measure MPs in the air by exploiting existing air quality monitoring equipment. Knowing the levels, types, and characteristics of MPs can inform toxicity studies to provide more environmentally relevant exposures, which is urgent now that MPs have been reported in human lung tissue.

Burkholderia pseudomallei is the causative agent of melioidosis, a multifaceted disease. A proportion of the mortality and morbidity reported as a result of infection with this organism may be due to the premature cessation of antibiotic therapy typically lasting for several months. The progression of re-emergent disease was characterised in Balb/c mice following cessation of a 14 day treatment course of co-trimoxazole or finafloxacin, delivered at a human equivalent dose. Mice were culled weekly and the infection characterised in terms of bacterial load in tissues, weight loss, clinical signs of infection, cytokine levels and immunological cell counts. Following cessation of treatment, the infection re-established in some animals. Finafloxacin prevented the re-establishment of the infection for longer than co-trimoxazole, and it is apparent based on the protection offered, the development of clinical signs of disease, bodyweight loss and bacterial load, that finafloxacin was more effective at controlling infection when compared to co-trimoxazole.

Contains fulltext : 249119.pdf (Publisher’s version ) (Open Access) Sexual harassment and gendered discrimination in the workplace are global issues that can affect anyone regardless of their age, gender, job title, or field of employment. The medical field is also relevantly concerned, yet effective prevention measures are scarce. The purpose of this study was to explore preventive options for sexual harassment in an academic medical context from the employees' perspective and to develop transferable strategies. We conducted semi-structured interviews with 15 female physicians and 15 female nurses working at a tertiary referral center in Berlin, Germany, in the months of April to November 2015. The one-on-one interviews addressed the perception of sexual harassment and available and desirable preventive measures. Data were analyzed by qualitative content analysis. The participants outlined preventive measures at two levels: individual and institutional. Individual options included personal safety measures and individual protection strategies against patients, peers, and superiors. Institutional strategies included guidelines and workplace policies, structured complaint and reporting procedures, formal training options, and organizational development and leadership strategies. The current study highlights how the prevention of sexual harassment hinges on a combination of individualized and system-wide measures to capture the personal as well as the organizational dimension of sexual harassment. Only a concerted effort addressing both aspects will sensitize the workforce, support the victims, and prevent sexual harassment in medical institutions.

Melioidosis is a neglected tropical disease caused by the bacterium Burkholderia pseudomallei. The bacterium is intrinsically resistant to various antibiotics, and melioidosis is therefore difficult to treat successfully without a relapse in infection. B. pseudomallei is an intracellular pathogen and therefore, to eradicate the infection, antimicrobials must be able to access bacteria in an intracellular niche. This study assessed the ability of a panel of monoclonal antibodies (MAbs) to opsonize Burkholderia species and determine the effect that each antibody has on bacterial virulence in vitro. Murine macrophage infection assays demonstrated that monoclonal antibodies against the capsule of B. pseudomallei are opsonizing. Furthermore, one of these monoclonal antibodies reduced bacterial actin tail formation in our in vitro assays, indicating that antibodies could reduce the intracellular spread of Burkholderia thailandensis. The data presented in this paper demonstrate that monoclonal antibodies are opsonizing and can decrease bacterial actin tail formation, thus decreasing their intracellular spread. These data have informed selection of an antibody for development of an antibody-antibiotic conjugate (AAC) for melioidosis. IMPORTANCE Melioidosis is difficult to treat successfully due to the causal bacterium being resistant to many classes of antibiotics, therefore limiting available therapeutic options. New and improved therapies are urgently required to treat this disease. Here, we have investigated the potential of monoclonal antibodies to target this intracellular pathogen. We have demonstrated that monoclonal antibodies can target the bacterium, increase uptake into macrophages, and reduce actin tail formation required by the bacterium for spread between cells. Through targeting the bacterium with antibodies, we hope to disarm the pathogen, reducing the spread of infection. Ultimately, we aim to use an opsonizing antibody to deliver antibiotics intracellularly by developing an antibody-antibiotic conjugate therapeutic for melioidosis.

Airborne microplastics (MPs) have been sampled globally, and their concentration is known to increase in areas of high human population and activity, especially indoors. Respiratory symptoms and disease following exposure to occupational levels of MPs within industry settings have also been reported. It remains to be seen whether MPs from the environment can be inhaled, deposited and accumulated within the human lungs. This study analysed digested human lung tissue samples (n = 13) using μFTIR spectroscopy (size limitation of 3 μm) to detect and characterise any MPs present. In total, 39 MPs were identified within 11 of the 13 lung tissue samples with an average of 1.42 ± 1.50 MP/g of tissue (expressed as 0.69 ± 0.84 MP/g after background subtraction adjustments). The MP levels within tissue samples were significantly higher than those identified within combined procedural/laboratory blanks (n = 9 MPs, with a mean ± SD of 0.53 ± 1.07, p = 0.001). Of the MPs detected, 12 polymer types were identified with polypropylene, PP (23%), polyethylene terephthalate, PET (18%) and resin (15%) the most abundant. MPs (unadjusted) were identified within all regions of the lung categorised as upper (0.80 ± 0.96 MP/g), middle/lingular (0.41 ± 0.37 MP/g), and with significantly higher levels detected in the lower (3.12 ± 1.30 MP/g) region compared with the upper (p = 0.026) and mid (p = 0.038) lung regions. After subtracting blanks, these levels became 0.23 ± 0.28, 0.33 ± 0.37 and 1.65 ± 0.88 MP/g respectively. The study demonstrates the highest level of contamination control and reports unadjusted values alongside different contamination adjustment techniques. These results support inhalation as a route of exposure for environmental MPs, and this characterisation of types and levels can now inform realistic conditions for laboratory exposure experiments, with the aim of determining health impacts.

Background Parachute airdrop offers a rapid transfusion supply option for humanitarian aid and military support. However, its impact on longer-term RBC survival is undocumented. This study aimed to determine post-drop quality of RBCs in concentrates (RCC), and both RBCs and plasma in whole blood (WB) during subsequent storage. Study design and methods Twenty-two units of leucodepleted RCC in saline, adenine, glucose, mannitol (SAGM) and 22 units of nonclinical issue WB were randomly allocated for air transportation, parachute drop, and subsequent storage (parachute), or simply storage under identical conventional conditions (4 ± 2°C) (control). All blood products were 6-8 days post-donation. Parachute units were packed into Credo Cubes, (Series 4, 16 L) inside a PeliCase (Peli 0350) and rigged as parachute delivery packs. Packs underwent a 4-h tactical flight (C130 aircraft), then parachuted from 250 to 400 ft before ground recovery. The units were sampled aseptically before and after airdrop at weekly intervals. A range of assays quantified the RBC storage lesion and coagulation parameters. Results Blood units were maintained at 2-6°C and recovered intact after recorded ground impacts of 341-1038 m s-2 . All units showed a classical RBC storage lesion and increased RBC microparticles during 42 days of storage. Fibrinogen and clotting factors decreased in WB during storage. Nevertheless, no significant difference was observed between Control and Parachute groups. Air transportation and parachute delivery onto land did not adversely affect, or shorten, the shelf life of fresh RBCs or WB. Discussion Appropriately packaged aerial delivery by parachute can be successfully used for blood supply.

Microplastics (MPs) have contaminated all compartments of the marine environment including biota such as seafood; ingestion from such sources is one of the two major uptake routes identified for human exposure.The objectives were to conduct a systematic review and meta-analysis of the levels of MP contamination in seafood and to subsequently estimate the annual human uptake.MEDLINE, EMBASE, and Web of Science were searched from launch (1947, 1974, and 1900, respectively) up to October 2020 for all studies reporting MP content in seafood species. Mean, standard deviations, and ranges of MPs found were collated. Studies were appraised systematically using a bespoke risk of bias (RoB) assessment tool.Fifty studies were included in the systematic review and 19 in the meta-analysis. Evidence was available on four phyla: mollusks, crustaceans, fish, and echinodermata. The majority of studies identified MP contamination in seafood and reported MP contentThis is the first systematic review, to our knowledge, to assess and quantify MP contamination of seafood and human uptake from its consumption, suggesting that action must be considered in order to reduce human exposure via such consumption. Further high-quality research using standardized methods is needed to cement the scientific evidence on MP contamination and human exposures. https://doi.org/10.1289/EHP7171.

Atmospheric microplastics (MPs) have been consistently captured within air samples on a global scale. Locations with high human activity are reported to have high MP levels. An urban sampling site in the Humber region (U.K.) has been sampled over a 13-month period, providing a seasonal variation profile of MP levels, size, shape, and polymer types that humans are exposed to. Mean MP levels, measured using passive fallout into a container, were 3055 ± 5072 MP m−2 day−1 (1164 median). An increase in levels with a decrease in MP size was observed, consisting of mainly film-shaped MPs (67%) that were polyethylene (31%) and nylon (28%) polymer types. No relationship between rainfall and MP fallout levels was observed. In parallel, MPs within five urbanised locations relevant to human exposure were characterised over a 2-week period. An overall MP mean (and standard deviation) of 1500 ± 1279 was observed (1012 median), from which petroleum resin accounted for 32% of MP polymer type, with a higher prevalence within industrial and roadside zones. These comprised mainly fragment (52%) and film (42%) shapes, and the MPs levels increased with decreasing particle size. The results provide novel information on characterising polymer levels and types, and can inform cellular toxicity studies, investigating the consequences of human MP exposure.

The endocytosis and trafficking of ricin in mammalian cells is an important area of research for those producing ricin anti-toxins and other ricin therapeutics. Ricin trafficking is usually observed by fluorescence microscopy techniques. This gives good resolution and leads to a detailed understanding of the internal movement of ricin within cells. However, microscopy techniques are often hampered by complex analysis and quantification techniques, and the inability to look at ricin trafficking in large populations of cells. In these studies we have directly labelled ricin and assessed if its trafficking can be observed using Imaging Flow Cytometry (IFC) both to the cytoplasmic region of cells and specifically to the Golgi apparatus. Using IDEAS® data analysis software the specific fluorescence location of the ricin within the cells was analysed. Then, using cytoplasmic masking techniques to quantify the number of cells with endocytosed cytoplasmic ricin or cells with Golgi-associated ricin, kinetic endocytosis curves were generated. Here we present, to the authors' knowledge, the first example of using imaging flow cytometry for evaluating the subcellular transport of protein cargo, using the trafficking of ricin toxin in lung cells as a model.

Knowledge regarding the presence of suspended microplastics (MPs) within the air is lacking, especially indoors, yet the importance of indoor air quality and human health is rising. This study is the first to report MPs within multiple homes over a 6-month period, with concentrations exceeding previous outdoor studies. Twenty households, within the City of Hull and Humber region, U.K., were passively sampled, each month, collecting atmospheric fallout at head height for subsequent particle quantification, characterisation and μFTIR validation (n = 3061). A household average of 1414 MP m−2 day−1 ± 1022 (mean ± SD) was observed. Smaller (5–250 μm), fibrous, particles were the most abundant (90%), representing types most likely to enter the human body and cause physiological harm. Polyethylene terephthalate (PET) was present in 90% of samples and accounted for 62% of MPs. Additionally, polyamide (PA) and polypropylene (PP) were common. Results indicate that humans are exposed to significantly (1–45 times) higher concentrations, and ranges, of MPs within homes compared with the outdoor environment. In conclusion, the size range and types of MPs observed will inform laboratory experiments, using either human tissue culture or other approaches. This will allow determination of the wider implications on human health using realistic levels and representative types of indoor MPs.

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Severe injury and hemorrhagic shock (HS) result in multiple changes to hematopoietic differentiation, which contribute to the development of immunosuppression and multiple organ failure (MOF). Understanding the changes that take place during the acute injury phase may help predict which patients will develop MOF and provide potential targets for therapy. Obtaining bone marrow from humans during the acute injury phase is difficult so published data are largely derived from peripheral blood samples, which infer bone marrow changes that reflect the sustained inflammatory response. This preliminary and opportunistic study investigated leucopoietic changes in rat bone marrow 6 h following traumatic injury and HS. Terminally anesthetized male Porton Wistar rats were allocated randomly to receive a sham operation (cannulation with no injury) or femoral fracture and HS. Bone marrow cells were flushed from rat femurs and immunophenotypically stained with specific antibody panels for lymphoid (CD45R, CD127, CD90, and IgM) or myeloid (CD11b, CD45, and RP‐1) lineages. Subsequently, cell populations were fluorescence‐activated cell sorted for morphological assessment. Stage‐specific cell populations were identified using a limited number of antibodies, and leucopoietic changes were determined 6 h following trauma and HS. Myeloid subpopulations could be identified by varying levels CD11b expression, CD45, and RP‐1. Trauma and HS resulted in a significant reduction in total CD11b + myeloid cells including both immature (RP‐1(−)) and mature (RP‐1+) granulocytes. Multiple B‐cell lymphoid subsets were identified. The total percentage of CD90+ subsets remained unchanged following trauma and HS, but there was a reduction in the numbers of maturing CD90(−) cells suggesting movement into the periphery. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Sexual harassment is a form of gender discrimination that affects women and men in all areas of work. According to the International Labour Organization (ILO), sexual harassment can occur in 1 or more of 3 forms: verbal, nonverbal, or physical. Sexual harassment can lead to physical and psychological symptoms and diseases as well as work-related consequences. The prevalence of sexual harassment in medicine has been scantily investigated, and reports differ widely in the applied methodology.

There is a requirement for an efficacious vaccine to protect people against infection fromFrancisella tularensis, the etiological agent of tularemia. The lipopolysaccharide (LPS) ofF. tularensisis suboptimally protective against a parenteral lethal challenge in mice. To develop a more efficacious subunit vaccine, we have used a novel biosynthetic technique of protein glycan coupling technology (PGCT) that exploits bacterial N-linked glycosylation to recombinantly conjugateF. tularensisO-antigen glycans to the immunogenic carrier proteinPseudomonas aeruginosaexoprotein A (ExoA). Previously, we demonstrated that an ExoA glycoconjugate with two glycosylation sequons was capable of providing significant protection to mice against a challenge with a low-virulence strain ofF. tularensis. Here, we have generated a more heavily glycosylated conjugate vaccine and evaluated its efficacy in a Fischer 344 rat model of tularemia. We demonstrate that this glycoconjugate vaccine protected rats against disease and the lethality of an inhalational challenge withF. tularensisSchu S4. Our data highlights the potential of this biosynthetic approach for the creation of next-generation tularemia subunit vaccines.

The use of in vitro models to understand the interaction of bacteria with host cells is well established. In vitro bacterial infection models are often used to quantify intracellular bacterial load by lysing cell populations and subsequently enumerating the bacteria. Modern established techniques employ the use of fluorescence technologies such as flow cytometry, fluorescent microscopy, and/or confocal microscopy. However, these techniques often lack either the quantification of large data sets (microscopy) or use of gross fluorescence signal which lacks the visual confirmation that can provide additional confidence in data sets. Multispectral imaging flow cytometry (MIFC) is a novel emerging field of technology. This technology captures a bright field and fluorescence image of cells in a flow using a charged coupled device camera. It allows the analysis of tens of thousands of single cell images, making it an extremely powerful technology. Here MIFC was used as an alternative method of analyzing intracellular bacterial infection using Burkholderia thailandensis E555 as a model organism. It has been demonstrated that the data produced using traditional enumeration is comparable to data analyzed using MIFC. It has also been shown that by using MIFC it is possible to generate other data on the dynamics of the infection model rather than viable counts alone. It has been demonstrated that it is possible to inhibit the uptake of bacteria into mammalian cells and identify differences between treated and untreated cell populations. The authors believe this to be the first use of MIFC to analyze a Burkholderia bacterial species during intracellular infection. © 2016 Crown copyright. Published by Wiley Periodicals Inc. on behalf of ISAC.

Activation of the canonical Wnt signaling pathway is an attractive anabolic therapeutic strategy for bone. Emerging data suggest that activation of the Wnt signaling pathway promotes bone mineral accrual in osteoporotic patients. The effect of Wnt stimulation in fracture healing is less clear as Wnt signaling has both stimulatory and inhibitory effects on osteogenesis. Here, we tested the hypothesis that transient Wnt stimulation promotes the expansion and osteogenesis of a Wnt-responsive stem cell population present in human bone marrow. Bone marrow mononuclear cells (BMMNCs) were isolated from patients undergoing hip arthroplasty and exposed to Wnt3A protein. The effect of Wnt pathway stimulation was determined by measuring the frequency of stem cells within the BMMNC populations by fluorescence-activated cell sorting and colony forming unit fibroblast (CFU-F) assays, before determining their osteogenic capacity in in vitro differentiation experiments. We found that putative skeletal stem cells in BMMNC isolates exhibited elevated Wnt pathway activity compared with the population as whole. Wnt stimulation resulted in an increase in the frequency of skeletal stem cells marked by the STRO-1bright/Glycophorin A− phenotype. Osteogenesis was elevated in stromal cell populations arising from BMMNCs transiently stimulated by Wnt3A protein, but sustained stimulation inhibited osteogenesis in a concentration-dependent manner. These results demonstrate that Wnt stimulation could be used as a therapeutic approach by transient targeting of stem cell populations during early fracture healing, but that inappropriate stimulation may prevent osteogenesis. Video Highlight: https://youtu.be/Wcs-crLvXbQ

Ricin is a type II ribosome-inactivating toxin that catalytically inactivates ribosomes ultimately leading to cell death. The toxicity of ricin along with the prevalence of castor beans (its natural source) has led to its increased notoriety and incidences of nefarious use. Despite these concerns, there are no licensed therapies available for treating ricin intoxication. Here, we describe the development of a F(ab’)2 polyclonal ovine antitoxin against ricin and demonstrate the efficacy of a single, post-exposure, administration in an in vivo murine model of intoxication against aerosolised ricin. We found that a single dose of antitoxin afforded a wide window of opportunity for effective treatment with 100% protection observed in mice challenged with aerosolised ricin when given 24 h after exposure to the toxin and 75% protection when given at 30 h. Treated mice had reduced weight loss and clinical signs of intoxication compared to the untreated control group. Finally, using imaging flow cytometry, it was found that both cellular uptake and intracellular trafficking of ricin toxin to the Golgi apparatus was reduced in the presence of the antitoxin suggesting both actions can contribute to the therapeutic mechanism of a polyclonal antitoxin. Collectively, the research highlights the significant potential of the ovine F(ab’)2 antitoxin as a treatment for ricin intoxication.

Early activation of the innate immune response is important for protection against infection with Francisella tularensis live vaccine strain (LVS) in mice. The human cathelicidin antimicrobial peptide LL-37 is known to have immunomodulatory properties, and therefore exogenously administered LL-37 may be suitable as an early post-exposure therapy to protect against LVS infection. LL-37 has been evaluated for immunostimulatory activity in uninfected mice and for activity against LVS in macrophage assays and protective efficacy when administered post-challenge in a mouse model of respiratory tularemia. Increased levels of pro-inflammatory cytokine IL-6, chemokines monocyte chemoattractant protein 1 (MCP-1) and CXCL1 with increased neutrophil influx into the lungs were observed in uninfected mice after intranasal administration of LL-37. Following LVS challenge, LL-37 administration resulted in increased IL-6, IL-12 p70, IFNγ and MCP-1 production, a slowing of LVS growth in the lung, and a significant extension of mean time to death compared to control mice. However, protection was transient, with the LL-37 treated mice eventually succumbing to infection. As this short course of nasally delivered LL-37 was moderately effective at overcoming the immunosuppressive effects of LVS infection this suggests that a more sustained treatment regimen may be an effective therapy against this pathogen.

Erleben Menschen häusliche Gewalt, sind Pflegefachpersonen und Ärztinnen in Rettungsstellen oft die ersten und einzigen Ansprechpersonen. Ihre Fachkompetenz und Handlungssicherheit entscheidet darüber, ob den Betroffenen die Hilfe zukommt, die sie brauchen. Der Beitrag präsentiert einen Handlungsleitfaden und wichtige Hintergrundinformationen.

Studies have confirmed the key role of Bacillus anthracis protective antigen (PA) in the US and UK human anthrax vaccines. However, given the tripartite nature of the toxin, other components, including lethal factor (LF), are also likely to contribute to protection. We examined the antibody and T cell responses to PA and LF in human volunteers immunized with the UK anthrax vaccine (AVP). Individual LF domains were assessed for immunogenicity in mice when given alone or with PA. Based on the results obtained, a novel fusion protein comprising D1 of LF and the host cell-binding domain of PA (D4) was assessed for protective efficacy. Murine protection studies demonstrated that both full-length LF and D1 of LF conferred complete protection against a lethal intraperitoneal challenge with B. anthracis STI spores. Subsequent studies with the LFD1-PAD4 fusion protein showed a similar level of protection. LF is immunogenic in humans and is likely to contribute to the protection stimulated by AVP. A single vaccine comprising protective regions from LF and PA would simplify production and confer a broader spectrum of protection than that seen with PA alone.

Physicians frequently represent the first contact person for victims of intimate partner violence (IPV) within the health care system, yet adequate training to comply with these expectations is frequently not incorporated into graduate and post-graduate medical curricula. We developed the first mandatory university-wide training in Germany for the management of IPV victims focusing on communication and legally admissible documentation. Concurrently, we acquired information about previous experiences, attitudes, and barriers for active inquiry about IPV among medical staff. Ninety one percent of the 825 participants completed pre- and post- training surveys and a subgroup participated in a 6–18 month follow-up. Experience, training, and subjective comfort in asking were the most significant predictors of active inquiry in multivariable analyses. Structural limitations, such as time constraints, language barriers, and lack of safe locations represented the primary barriers for active inquiry.

Plague is a highly pathogenic disease caused by the bacterium Yersinia pestis. There is currently no vaccine available for prophylaxis and antibiotic resistant strains have been isolated, thus there is a need for the development of new countermeasures to treat this disease. Survival protein A (SurA) is a chaperone that has been linked to virulence in several species of bacteria, including the close relative Yersinia pseudotuberculosis. In this study, we aimed to evaluate the role of SurA in virulence of the highly pathogenic Y. pestis by creating an unmarked surA deletion mutant. The Y. pestis ΔsurA mutant was found to be more susceptible to membrane perturbing agents and was completely avirulent in a mouse infection model when delivered up to 2.1 × 10(5) CFU by the subcutaneous route. This provides strong evidence that SurA would make a promising antimicrobial target.

Frontal variant-Frontotemporal dementia (fvFTD) and Alzheimer's disease (AD) patients matched for severity of dementia at the Clinical Dementia Rating (CDR) received neuropsychological testing in order to explore if the dysexecutive disorder might characterise fvFTD at early stage, when AD is dominated by the episodic memory defect. We also determined if the behavioural syndrome was more severe in fvFTD than AD, and if specific patterns of behavioural symptoms could differentiate the two types of dementia, using the Neuropsychiatry Inventory (NPI). AD patients performed worse than fvFTD not only in memory but also in executive tasks. Apathy and eating disorders proved to be more severe or frequent in fvFTD even if the two groups did not differ in the total NPI score. CDR score significantly correlated with the NPI score in fvFTD and with the MMSE in AD. Our data confirm that the memory disorders may differentiate the two types of dementia; however, the dysexecutive syndrome is as severe, and even more severe in AD. The severity of the behavioural syndrome is comparable in the two groups but the nature of the behavioural disorders may vary to some extent. We conclude that AD dementia at early stage is a behavioural-cognitive syndrome, while in fvFTD the behavioural disorders appear when the cognitive deficit is still relatively mild.

Unter der posterioren kortikalen Atrophie („posterior cortical atrophy“, PCA) wird ein klinisches Syndrom mit typischen neuropsychologischen Ausfallen verstanden. In der vorliegenden Arbeit wird der klinische und neuropsychologische Befund von vier Patienten mit PCA vorgestellt und ein Uberblick uber Charakteristika und Differenzialdiagnosen dieses Syndroms gegeben. Leitsymptome der PCA sind Beeintrachtigungen visueller und raumlicher Funktionen (meist in Form eines Balint-Syndroms), variabel erganzt durch visuelle Perzeptionsstorungen, topographische Desorientiertheit, visuelle Agnosie sowie Defiziten beim Lesen, Kopieren, Zeichnen und Rechnen. Histopathologisch finden sich bei der PCA meist Alzheimer-typische Veranderungen mit Schwerpunkt in hinteren Hirnabschnitten. Im Unterschied zur Normalvariante der Alzheimer-Demenz sind mnestische und sprachliche Leistungen uber lange Zeit relativ gut erhalten. SPECT- oder PET-Untersuchungen zeigen Perfusions- und Metabolismusstorungen in beiden Parietal- und Okzipitallappen. Die Diagnose der PCA stutzt sich auf neuropsychologische Befunde sowie auf bildgebende Verfahren.

SUMMARY We studied mood disorders (MD) and psychotic symptoms (PS) in patients with frontotemporal dementia (FTD) and Alzheimer's disease (AD) by means of different diagnostic instruments. These were: a subjective scale (subsets of survey psychiatric assessment sche-dule: SPAS), an objective scale (subsets of neuropsychiatric inventory: NPI) and a projective task (Wartegg completion task: WCT). A general tendency of NPI to overestimate the presence of symptoms compared to SPAS was observed, but distribution and severity of symptoms were quite homogeneous in the two dementia-groups, independently of the diagnostic scales. At variance with the scales, the WCT showed a more severe impairment in FTD than in AD. The regression analysis selected neuropsychological models able to predict behavioral disorders only in FTD, in particular, a planning deficit predicted PS. These data confirm the hypothesis that a damage in the frontal areas constitutes the neurobiological basis of PS in degenerative brain diseases. Furthermore, they suggest that mostly in FTD, behavioral disorders, as well as cognitive deficits, should be considered a direct expression of neural damage.

Zusammenfassung: Kognitive Störungen sind zentrale Symptome demenzieller Erkrankungen. Mit Hilfe neuropsychologischer Testverfahren ist es möglich kognitive Defizite schon frühzeitig zu erfassen. Ein detailliertes kognitives Leistungsprofil, wie es im Rahmen einer neuropsychologischen Demenzabklärung erstellt wird, liefert außerdem wichtige Hinweise zur Differentialdiagnostik demenzieller Erkrankungen. Die neuropsychologische Diagnostik sollte daher fixer Bestandteil in der Demenzdiagnostik sein. Anzustreben ist dabei eine ausführliche neuropsychologische Untersuchung, in der folgende kognitive Bereiche überprüft werden: Gedächtnis, frontal-exekutive Leistungen, Aufmerksamkeitsfunktionen, Sprache, visuoperzeptive und räumliche Leistungen. Derartige Untersuchungen sind zeit- und personalaufwändig. Nicht immer ist es daher möglich, eine ausführliche neuropsychologische Demenzdiagnostik durchzuführen. Alternativ können zur Erstabklärung so genannte Demenz-Screeningverfahren eingesetzt werden. Screeningverfahren, wie beispielsweise der Mini Mental Status Test oder der Uhrentest, sind zeitökonomisch und relativ einfach durchzuführen, erlauben allerdings nur eine grobe Abschätzung der kognitiven Leistungsfähigkeit.

Though a few case studies reported a dissociation between intact writing of Arabic and impaired writing of alphabetical script, a detailed experimental analysis of such a dissociation is still lacking. We report a follow-up study of a patient with a parieto-occipital lesion who is affected by severe peripheral agraphia for letters, but not for Arabic digits. While letters in writing to dictation are frequently illegible, distorted, or consist in meaningless strokes, Arabic digits are well-formed and fluently produced. In a series of tasks, including copying of letters with tachistoscopic presentation and handwriting on a digitizing tablet, several processing levels are assessed in order to localize JS' functional writing impairment and to determine different processing routes for letters and for numbers. Overall, the results of the experimental investigation suggest a notation specific deficit in the activation of graphomotor patterns for letters, but not for digits. The study thus adds evidence to the so far reported dissociations between Arabic and alphabetical scripts. (C) 2002 Elsevier Science Ltd. All rights reserved.

Aqueous bifunctional semiconductor polymer nanoparticles (SPNs), approximately 30 nm in diameter (as measured from electron microscopy), were synthesised using hydrophobic conjugated polymers, amphiphilic phospholipids and a gadolinium-containing lipid. Their fluorescence quantum yields and extinction coefficients were determined, and their MRI T1-weighted relaxation times in water were measured. The bimodal nanoparticles were readily taken up by HeLa and murine macrophage-like J774 cells as demonstrated by confocal laser scanning microscopy, and were found to be MRI-active, generating a linear relationship between T1-weighted relaxation rates and gadolinium concentrations The synthesis is relatively simple, and can easily result in milligrams of materials, although we fully expect scale-up to the gram level to be easily realised.

The prophylactic potential of ciprofloxacin was assessed in comparison with doxycycline, an established therapeutic antibiotic, to limit or control infection by Brucella melitensis in an experimental mouse model. Ciprofloxacin treatment reduced bacterial loads in the spleens of challenged mice when administered prior to or at the same time as the bacterial challenge. In comparison, doxycycline provided much greater reductions in bacterial counts, even when treatment was initiated after infection. Doxycycline was able to protect against B. melitensis when administered for 5 days from 24 h after infection and for at least 28 days after cessation of the antibiotic. Overall, these results confirm that ciprofloxacin is less effective than doxycycline but suggest that it may have some utility in providing protection against low-level infections. Combination studies are indicated.

We report a full-scale pseudopotential study of the optical properties of InAs/ and InAs/ superlattices, with particular emphasis on the infrared range of wavelengths. For both structures we examine the detailed origin of the absorption response and how cutoff wavelength varies with the period of the superlattice and with the alloy concentration. This entails a discussion of how wavefunction localization, band mixing and energy band dispersion can affect the absorption coefficient. Particular attention is paid to structures with cutoff wavelength in the ranges 2-5 m and 10-13 m. Calculated absorption spectra are compared with examples obtained experimentally. Although agreement between the spectra is good, it is found that neither the sharp features nor the absolute magnitude is reproduced adequately by the electronic structure obtained from idealized systems. Comparison of the bandgap with the gap between the highest two valence states allows structures where certain Auger recombination processes may be inhibited to be indicated. The effects of alloy scattering in the InAs/ system has also been investigated. A second-order perturbation theory calculation of the linewidth associated with the alloy potential suggests that the effects of alloy scattering are too large to be modelled as a perturbation of the virtual crystal case. A full-scale treatment is required to quantify this effect.

The nucleotide and predicted amino acid sequences of the coat protein coding region of four isolates (UK 1, CZE 1, CDN 1 and GK 1) and a putative mutant of one of these isolates (UK 1M) of turnip mosaic virus (TuMV) were determined. Comparisons between these and those of previously sequenced isolates showed homologies of 88.6–99.9% in nucleotides and 93.4–100% in amino acid sequences. Nucleotide substitutions were revealed at 180 different positions that give rise to 30 predicted amino acid changes. The coat protein coding regions consisted of 864 nucleotides, with the exception of GK 1 which had 861, having a deletion in amino acid position 44. This is the first recorded deletion in the coat protein coding region of TuMV. Alignment of the predicted amino acid sequences of UK 1, CZE 1, CDN 1 and GK 1 isolates with the previously sequenced CDN 2, CHN, JPN 1, JPN 2, JPN (31), L12396 and KOR isolates revealed three distinct groups which, with a few exceptions, were correlated with the geographical and/or host plant origin of isolates. The GK 1 isolate showed the lowest nucleotide (88.6–89.9%) and amino acid (93.4–96.2%) homologies with the other isolates, whereas the UK 1 isolate showed the highest nucleotide homology (89.7–99.9%) and CDN 1 showed the highest amino acid homology (95.9–99%). The coat protein coding region of the putative mutant isolate (UK 1M) had a single nucleotide difference (G to A) from UK 1 at position 9 which did not give rise to any change in the predicted amino acid sequence. UK 1M is able to infect Brassica napus plants possessing a mapped resistance gene ( TuRB01 ) that is effective against UK 1. The phenotypes of most of the sequenced isolates on plants containing TuRB01 are known, and these are consistent with the hypothesis that the single nucleotide substitution at position 9 of the coat protein coding region conditions the interaction with this gene. All isolates tested that had the residue G 9 gave no detectable replication in plants possessing TuRB01 , whereas isolates that had the residue A 9 were either partially virulent on plants carrying TuRB01 causing local infection only, or were fully virulent resulting in full systemic infection. This hypothesis is unprecedented in plant virus interactions and further experimentation utilizing full-length infectious clones of TuMV will be necessary to test its validity.

Whilst the potent effects of NGF and laminin on developing neurons are well documented, relatively little is known about the effects of, or altered availability of or altered responsiveness to, these substances on the growth of adult neurons. We have therefore examined this question using explant cultures of sympathetic neurons from the superior cervical ganglion (SCG) of mature and aged rats. Explants were grown on substrata containing different doses of laminin, either with or without added NGF in culture medium containing FCS. Individually, laminin and NGF had relatively small effects on neurite outgrowth and length, which tended to be reduced in old neurons. In contrast, laminin in the presence of exogenous NGF exerted a powerful effect on nerve growth which was substantially greater than the sum of the effects of the individual factors. This synergy was evident in all experimental groups and was greatest in old explants at high doses of laminin, where growth was comparable to that of mature neurons. The dose-response curve of old neurons to laminin in the presence of added NGF indicated reduced responsiveness. These results suggest that variations in the availability of laminin and/or exogenous NGF, together with altered patterns of neuronal responsiveness, may contribute to impaired neuronal plasticity in old age.

Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei . These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.

Summary What is already known about this subject Approximately 80% of people with type 2 diabetes mellitus (T2DM) are overweight or obese. Weight loss produces numerous benefits in T2DM. People with T2DM have difficulty losing and maintaining weight. What this study adds Provision of a very-low-calorie diet (VLCD) with group support and behaviour therapy for patients with T2DM is feasible within a community-based setting with trained facilitators. VLCD approaches for weight management in T2DM can achieve more than 90% of weight loss as compared with obese individuals without T2DM. Identification of the need to investigate the full impact of this approach in patients with T2DM by assessing changes in glycaemia, liver function and medication. Approximately 80% of people with type 2 diabetes mellitus (T2DM) are overweight or obese, and obesity compounds the cardiovascular risk of T2DM. The aim of this retrospective study was twofold: first, to investigate whether a 12-week community-based very-low-calorie diet (VLCD) programme can result in important weight loss; and second, to investigate any potential difference in the weight loss achieved using this community-based approach in individuals with and without T2DM. Three hundred and fifty-five participants with T2DM were matched for age, body mass index (BMI) and gender to participants without T2DM (total cohort comprised 204 males: 506 females (mean ± standard deviation); age (years) 54.0 ± 9.1; BMI (kg m−2) 41.6 ± 8.1; weight (kg) 116.1 ± 25.1). The programme included a daily intake of 550 kcal in addition to group support and behaviour therapy provided by trained facilitators within a community-based setting. After 12 weeks, there was significant weight loss within each group when compared with baseline (T2DM: 115.0 ± 24.4 kg vs. 96.7 ± 21.4 kg, P

Approximately 80% of people with type 2 diabetes mellitus (T2DM) are overweight or obese. Weight loss produces numerous benefits in T2DM. People with T2DM have difficulty losing and maintaining weight.Provision of a very-low-calorie diet (VLCD) with group support and behaviour therapy for patients with T2DM is feasible within a community-based setting with trained facilitators. VLCD approaches for weight management in T2DM can achieve more than 90% of weight loss as compared with obese individuals without T2DM. Identification of the need to investigate the full impact of this approach in patients with T2DM by assessing changes in glycaemia, liver function and medication. Approximately 80% of people with type 2 diabetes mellitus (T2DM) are overweight or obese, and obesity compounds the cardiovascular risk of T2DM. The aim of this retrospective study was twofold: first, to investigate whether a 12-week community-based very-low-calorie diet (VLCD) programme can result in important weight loss; and second, to investigate any potential difference in the weight loss achieved using this community-based approach in individuals with and without T2DM. Three hundred and fifty-five participants with T2DM were matched for age, body mass index (BMI) and gender to participants without T2DM (total cohort comprised 204 males: 506 females (mean ± standard deviation); age (years) 54.0 ± 9.1; BMI (kg m(-2) ) 41.6 ± 8.1; weight (kg) 116.1 ± 25.1). The programme included a daily intake of 550 kcal in addition to group support and behaviour therapy provided by trained facilitators within a community-based setting. After 12 weeks, there was significant weight loss within each group when compared with baseline (T2DM: 115.0 ± 24.4 kg vs. 96.7 ± 21.4 kg, P 0.0001; non-T2DM: 117.2 ± 25.8 kg vs. 97.3 ± 22.2 kg, P 0.0001). At 12 weeks, weight change (-18.3 ± 7.3 kg vs. -19.9 ± 7.0 kg, P = 0.012) and BMI change (-6.7 ± 2.9 kg m(-2) vs. -7.1 ± 2.1 kg m(-2) , P = 0.011) were significantly less in the T2DM group when compared with the non-T2DM group. Our results suggest that the use of VLCD approaches for weight management in T2DM can achieve more than 90% of the weight loss seen in obese individuals without T2DM.

The Toll/interleukin (IL)-1 receptor (TIR) domain is an essential component of eukaryotic innate immune signalling pathways. Interaction between TIR domains present in Toll-like receptors and associated adaptors initiates and propagates an immune signalling cascade. Proteins containing TIR domains have also been discovered in bacteria. Studies have subsequently shown that these proteins are able to modulate mammalian immune signalling pathways dependent on TIR interactions and that this may represent an evasion strategy for bacterial pathogens. Here, we investigate a TIR domain protein from the highly virulent bacterium Yersinia pestis, the causative agent of plague. When overexpressed in vitro this protein is able to downregulate IL-1β- and LPS-dependent signalling to NFκB and to interact with the TIR adaptor protein MyD88. This interaction is dependent on a single proline residue. However, a Y. pestis knockout mutant lacking the TIR domain protein was not attenuated in virulence in a mouse model of bubonic plague. Minor alterations in the host cytokine response to the mutant were indicated, suggesting a potential subtle role in pathogenesis. The Y. pestis mutant also showed increased auto-aggregation and reduced survival in high-salinity conditions, phenotypes which may contribute to pathogenesis or survival.