Emerging Complexity and the Need for Advanced Drug Delivery in Targeting Candida Species.
Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence system utilizes a wide array of the cells, proteins and chemical signals that are distributed in blood and tissues which further constitute the innate and adaptive immune system. The lack of antifungal agents and their limited therapeutic effects have led to high mortality and morbidity related to such infections. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. This article sheds light on novel drug delivery approaches to target the immunological axis for several Candida species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. rugose, C. hemulonii, etc.). It is clear that the novel drug delivery approaches include vaccines, adoptive transfer of primed immune cells, recombinant cytokines, therapeutic antibodies, and nanoparticles, which have immunomodulatory effects. Such advancements in targeting various underpinning mechanisms using the concept of novel drug delivery will provide a new dimension to the fungal infection clinic particularly due to Candida species with improved patient compliance and lesser side effects. This advancement in knowledge can also be extended to target various other similar microbial species and infections.


The cerebellar cognitive affective syndrome.
Anatomical, physiological and functional neuroimaging studies suggest that the cerebellum participates in the organization of higher order function, but there are very few descriptions of clinically relevant cases that address this possibility. We performed neurological examinations, bedside mental state tests, neuropsychological studies and anatomical neuroimaging on 20 patients with diseases confined to the cerebellum, and evaluated the nature and severity of the changes in neurological and mental function. Behavioural changes were clinically prominent in patients with lesions involving the posterior lobe of the cerebellum and the vermis, and in some cases they were the most noticeable aspects of the presentation. These changes were characterized by: impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning and working memory; difficulties with spatial cognition including visual-spatial organization and memory; personality change with blunting of affect or disinhibited and inappropriate behaviour; and language deficits including agrammatism and dysprosodia. Lesions of the anterior lobe of the cerebellum produced only minor changes in executive and visual-spatial functions. We have called this newly defined clinical entity the 'cerebellar cognitive affective syndrome'. The constellation of deficits is suggestive of disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal, superior temporal and limbic cortices with the cerebellum.


Viscoelastic characterization of mesenchymal gap tissue and consequences for tension accumulation during distraction.
Nonlinear viscoelastic analysis was used to characterize the time-dependent behavior of mesenchymal gap tissue generated during distraction osteogenesis. Six (n = 6) lengthened tibiae were harvested from New Zealand white rabbits at 18 days. This gap tissue was subjected to a series of step displacement tests of increasing magnitude, and force relaxation behavior was monitored. Isochrones in stress-strain space were fit to odd cubic functions of strain. An analytic expression, linear in both e and e3, was developed to predict stress accumulation within the gap tissue as a function of time during distraction. Stress relaxation functions were described well by two-term Prony series. The two time constants determined from mechanical testing results were consistent, suggesting the presence of two fundamental physiologic relaxation processes. Gap tissue stresses were predicted to rise considerably during early stages of lengthening when distraction magnitudes exceeded the clinical norm of 0.25 mm. These differences in tension accumulation were less pronounced by the time lengthening was completed. Specifically, these results may in part explain clinical observations of decreased bone regeneration and altered tissue proliferation and differentiation at higher distraction rates. More generally, this work provides a framework for the rigorous characterization of the viscoelastic properties of biologic tissues ordinarily exposed to step strains.


Gene expression profiling in peanut using high density oligonucleotide microarrays.
Transcriptome expression analysis in peanut to date has been limited to a relatively small set of genes and only recently has a significant number of ESTs been released into the public domain. Utilization of these ESTs for oligonucleotide microarrays provides a means to investigate large-scale transcript responses to a variety of developmental and environmental signals, ultimately improving our understanding of plant biology. We have developed a high-density oligonucleotide microarray for peanut using 49,205 publicly available ESTs and tested the utility of this array for expression profiling in a variety of peanut tissues. To identify putatively tissue-specific genes and demonstrate the utility of this array for expression profiling in a variety of peanut tissues, we compared transcript levels in pod, peg, leaf, stem, and root tissues. Results from this experiment showed 108 putatively pod-specific/abundant genes, as well as transcripts whose expression was low or undetected in pod compared to peg, leaf, stem, or root. The transcripts significantly over-represented in pod include genes responsible for seed storage proteins and desiccation (e.g., late-embryogenesis abundant proteins, aquaporins, legumin B), oil production, and cellular defense. Additionally, almost half of the pod-abundant genes represent unknown genes allowing for the possibility of associating putative function to these previously uncharacterized genes. The peanut oligonucleotide array represents the majority of publicly available peanut ESTs and can be used as a tool for expression profiling studies in diverse tissues.


Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.
The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Suppression of insulin levels with metformin might reduce the hyperinsulinaemia and hyperandrogenism suppression of the ovarian response. As a consequence, metformin could improve both pregnancy and live birth rates. To determine the effectiveness of metformin as a co-treatment during IVF or intra-cytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS. The Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, LILACS, the meta Register of Controlled Trials, and reference lists of articles were searched (to week 4, September 2008). Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment. women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors.Types of interventions: metformin administered before and during IVF or ICSI treatment.Types of outcome measures: live birth rate, clinical pregnancy rate, miscarriage rate, incidence of ovarian hyperstimulation syndrome (OHSS), incidence of patient-reported side effects, serum estradiol level on the day of trigger, serum androgen level, and fasting insulin and glucose levels. Two review authors independently extracted the data according to the protocol. The methods of randomisation and allocation concealment, and characteristics of the studied groups were evaluated. This review found no evidence that metformin treatment before or during assisted reproductive technique (ART) cycles improved live birth or clinical pregnancy rates. The pooled odds ratio (OR) for live birth rate (3 RCTs) was 0.77 ( 95% CI 0.27 to 2.18) and for clinical pregnancy rate (5 RCTS) was 0.71 (95% CI 0.39 to 1.28). The risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin (pooled OR 0.27, 95% CI 0.16 to 0.47). This review found no evidence that metformin treatment before or during ART cycles improves live birth or pregnancy rates. The risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin. Further large RCTs are necessary to definitively answer if the use of metformin in PCOS women undergoing ART improves live birth and pregnancy rates.


Psychological and cognitive functioning in children and adolescents with congenital heart disease: a meta-analysis.
Findings in the literature are inconsistent on the impact of congenital heart disease (CHD) on the psychological and cognitive functioning of children and adolescents. The aim of the present study was to systematically review this empirical body of literature. We conducted a meta-analysis to review studies on behavior problems and cognitive functioning in CHD. Only older children and adolescents with CHD displayed an increased risk of overall, internalizing, and to a lesser extent externalizing behavior problems. In addition, patients with severe CHD exhibited lower cognitive functioning than patients with less severe CHD, specifically with respect to performance intelligence. Moreover, decreased cognitive functioning remained relatively stable across different age groups. Children with severe heart disease may benefit from interventions specifically targeting perceptual organizational abilities, such as visual-spatial abilities. Moreover, older children and adolescents with CHD may benefit from psychological interventions reducing anxiety symptoms and depression.


Reverse current pulse method to restore uniform concentration profiles in ion-selective membranes. 2. Comparison of the efficiency of the different protocols.
The membrane potential of ion-selective electrodes is measured at zero current in traditional potentiometric analysis. Recently, pulsed potentiometric methods have gained importance. In pulsed potentiometric methods, the voltage measured at the end of a current pulse is usually the analytical signal. The applied current alters the concentration profiles inside the sensing membrane. For reproducible voltage measurements the original concentration profiles must be restored in the membrane between current pulses. The simplest restoration method is the zero-current relaxation. Unfortunately, the zero-current method is very slow, which limits the frequency of measurements. In analytical practice the controlled voltage restoration method is most commonly used, but the controlled voltage method has no adequate theoretical description. This paper presents a finite element model of the controlled voltage method to predict its efficiency. The model demonstrates for the first time that increasing membrane resistance decreases the efficiency of this restoration method. The model allows estimating the necessary restoration time for voltage errors below an acceptable threshold value and provides guidance for minimizing the voltage error. The efficiency of the controlled voltage method is compared to the reverse current pulse restoration method discussed in part 1 of this set of papers. It is found that the reverse current restoration method is simpler, requires shorter restoration times (i.e., it allows higher measurement frequency), and it has 4 and 10 times smaller voltage errors compared to the controlled voltage method. These theoretical results are confirmed experimentally. The only limitation of the reverse current pulse restoration method is that it cannot be used with membranes containing a background electrolyte (R(+)R(-)) but no excess lipophilic cation exchanger (R(-)). However, lipophilic cation exchanger can often be added to the membrane to reduce restoration times by allowing the reverse current pulse method to be used.


Rab-mediated trafficking in the secondary cells of Drosophila male accessory glands and its role in fecundity.
The male seminal fluid contains factors that affect female post-mating behavior and physiology. In Drosophila, most of these factors are secreted by the two epithelial cell types that make up the male accessory gland: the main and secondary cells. Although secondary cells represent only ~4% of the cells of the accessory gland, their contribution to the male seminal fluid is essential for sustaining the female post-mating response. To better understand the function of the secondary cells, we investigated their molecular organization, particularly with respect to the intracellular membrane transport machinery. We determined that large vacuole-like structures found in the secondary cells are trafficking hubs labeled by Rab6, 7, 11 and 19. Furthermore, these organelles require Rab6 for their formation and many are essential in the process of creating the long-term postmating behavior of females. In order to better serve the intracellular membrane and protein trafficking communities, we have created a searchable, online, open-access imaging resource to display our complete findings regarding Rab localization in the accessory gland.


Managing Chronic Cough Due to Asthma and NAEB in Adults and Adolescents: CHEST Guideline and Expert Panel Report.
Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB. We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents > 12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology. Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism. This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research.


Improving Diabetes care through Examining, Advising, and prescribing (IDEA): protocol for a theory-based cluster randomised controlled trial of a multiple behaviour change intervention aimed at primary healthcare professionals.
New clinical research findings may require clinicians to change their behaviour to provide high-quality care to people with type 2 diabetes, likely requiring them to change multiple different clinical behaviours. The present study builds on findings from a UK-wide study of theory-based behavioural and organisational factors associated with prescribing, advising, and examining consistent with high-quality diabetes care. To develop and evaluate the effectiveness and cost of an intervention to improve multiple behaviours in clinicians involved in delivering high-quality care for type 2 diabetes. We will conduct a two-armed cluster randomised controlled trial in 44 general practices in the North East of England to evaluate a theory-based behaviour change intervention. We will target improvement in six underperformed clinical behaviours highlighted in quality standards for type 2 diabetes: prescribing for hypertension; prescribing for glycaemic control; providing physical activity advice; providing nutrition advice; providing on-going education; and ensuring that feet have been examined. The primary outcome will be the proportion of patients appropriately prescribed and examined (using anonymised computer records), and advised (using anonymous patient surveys) at 12 months. We will use behaviour change techniques targeting motivational, volitional, and impulsive factors that we have previously demonstrated to be predictive of multiple health professional behaviours involved in high-quality type 2 diabetes care. We will also investigate whether the intervention was delivered as designed (fidelity) by coding audiotaped workshops and interventionist delivery reports, and operated as hypothesised (process evaluation) by analysing responses to theory-based postal questionnaires. In addition, we will conduct post-trial qualitative interviews with practice teams to further inform the process evaluation, and a post-trial economic analysis to estimate the costs of the intervention and cost of service use. Consistent with UK Medical Research Council guidance and building on previous development research, this pragmatic cluster randomised trial will evaluate the effectiveness of a theory-based complex intervention focusing on changing multiple clinical behaviours to improve quality of diabetes care. ISRCTN66498413.


Constructing and deconstructing the gate theory of pain.
The gate theory of pain, published by Ronald Melzack and Patrick Wall in Science in 1965, was formulated to provide a mechanism for coding the nociceptive component of cutaneous sensory input. The theory dealt explicitly with the apparent conflict in the 1960s between the paucity of sensory neurons that responded selectively to intense stimuli and the well-established finding that stimulation of the small fibers in peripheral nerves is required for the stimulus to be described as painful. It incorporated recently discovered mechanisms of presynaptic control of synaptic transmission from large and small sensory afferents, which was suggested to "gate" incoming information depending on the balance between these inputs. Other important features included the convergence of small and large sensory inputs on spinal neurons that transmitted the sensory information to the forebrain as well as the ability of descending control pathways to affect the biasing established by the gate. The clarity of the model and its description gave this article immediate visibility, with numerous attempts made to test its various predictions. Although subsequent experiments and clinical findings have made clear that the model is not correct in detail, the general ideas put forth in the article and the experiments they prompted in both animals and patients have transformed our understanding of pain mechanisms.


Dangerous reactions to treatment of onchocerciasis with diethylcarbamazine.
Nine Nigerians with severe onchocerciasis who were treated with diethylcarbamazine developed clinical changes, ranging in severity from mild itching to distress, cough, and syncope. Physiological changes (fever, tachypnoea, tachycardia, or hypotension) were seen in eight. In five patients the systolic blood pressure fell by more than 25 mm Hg, and one patient collapsed on attempting to sit up. Circulating eosinophils decreased profoundly in all cases, reaching their lowest levels just before or during the clinical and physiological changes. A fall in serum complement (c3) accompanied the reaction but there was no fall in antibody titre. Diethylcarbamazine probably acts on the parasite's cuticle, thus exposing it to the body's defence mechansims. The reaction coincides with the death of microfilariae, and the accompanying physiological changes may be so severe, even in generally healthy patients, the treatment should perferably be started in hospital.


Exploring genetic associations with ceRNA regulation in the human genome.
Competing endogenous RNAs (ceRNAs) are RNA molecules that sequester shared microRNAs (miRNAs) thereby affecting the expression of other targets of the miRNAs. Whether genetic variants in ceRNA can affect its biological function and disease development is still an open question. Here we identified a large number of genetic variants that are associated with ceRNA's function using Geuvaids RNA-seq data for 462 individuals from the 1000 Genomes Project. We call these loci competing endogenous RNA expression quantitative trait loci or 'cerQTL', and found that a large number of them were unexplored in conventional eQTL mapping. We identified many cerQTLs that have undergone recent positive selection in different human populations, and showed that single nucleotide polymorphisms in gene 3΄UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in both cis and trans by the ceRNA mechanism. We also discovered that cerQTLs are significantly enriched in traits/diseases associated variants reported from genome-wide association studies in the miRNA binding sites, suggesting that disease susceptibilities could be attributed to ceRNA regulation. Further in vitro functional experiments demonstrated that a cerQTL rs11540855 can regulate ceRNA function. These results provide a comprehensive catalog of functional non-coding regulatory variants that may be responsible for ceRNA crosstalk at the post-transcriptional level.


Companion robots for older people: importance of user-centred design demonstrated through observations and focus groups comparing preferences of older people and roboticists in South West England.
Companion robots, such as Paro, may reduce agitation and depression for older people with dementia. However, contradictory research outcomes suggest robot design is not always optimal. While many researchers suggest user-centred design is important, there is little evidence on the difference this might make. Here, we aimed to assess its importance by comparing companion robot design perceptions between older people (end users) and roboticists (developers). Older people and roboticists interacted with eight companion robots or alternatives at two separate events in groups of two to four people. Interactions were recorded, participants' comments and observations were transcribed, and content was analysed. Subsequently, each group participated in focus groups on perceptions of companion robot design. Discussions were recorded and transcribed, and content was analysed. Seventeen older people (5 male, 12 female, ages 60-99) at a supported living retirement complex, and 18 roboticists (10 male, 8 female, ages 24-37) at a research centre away-day. We found significant differences in design preferences between older people and roboticists. Older people desired soft, furry, interactive animals that were familiar and realistic, while unfamiliar forms were perceived as infantilising. By contrast, most roboticists eschewed familiar and realistic designs, thinking unfamiliar forms better suited older people. Older people also expressed desire for features not seen as important by developers. A large difference was seen in attitude towards ability to talk: 12/17 (71%) older people but only 2/18 (11%) roboticists requested speech. Older people responded positively towards life-simulation features, eye contact, robot personalisation and obeying commands, features undervalued by roboticists. These differences were reflected in preferred device, with 'Joy for All' cat chosen most often by older people, while roboticists most often chose Paro. The observed misalignment of opinion between end users and developers on desirable design features of companion robots demonstrates the need for user-centred design during development.


Associations between polycyclic aromatic hydrocarbon-related exposures and p53 mutations in breast tumors.
Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. We examined this possibility in a population-based case-control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH-DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation-negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11-2.15] but not p53 mutation-positive (OR = 0.77; 95% CI, 0.43-1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C-->A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation.


Eliciting Stuttering in Laboratory Contexts.
Purpose The contextual variability of stuttering events makes it difficult to reliably elicit stuttered speech in laboratory settings. As a result, studies that compare stuttered versus fluent speech are difficult to conduct and, thus, are limited in the literature. The purpose of the current study is to describe a novel approach to elicit stuttering during laboratory testing. Method A semistructured clinical interview leveraging the phenomenon of stuttering anticipation was administered to 22 adults who stutter (1st visit). The interview was used to generate participant-specific anticipated and unanticipated word lists, which were used as stimuli during a 2nd visit so that the validity of the method could be tested. Results The method yielded a near-equal distribution of unambiguously stuttered and fluent utterances (43.6% and 43.5%, respectively). Moreover, 12.9% of the utterances were judged to be ambiguous, that is, not unambiguously stuttered or fluent. Conclusion This approach outperformed previous attempts to elicit stuttering during laboratory testing. It could be implemented in future studies that compare neural, physiological, or behavioral correlates of fluent versus stuttered speech.


Susceptibility of gonococci isolated in London to therapeutic antibiotics: establishment of a London surveillance programme. London Gonococcal Working Group.
To establish the in vitro susceptibility of gonococci isolated in the London area to antibiotics in current therapeutic use and to establish a sentinel surveillance system for monitoring trends in antibiotic resistant gonorrhoea in London. Isolates of Neisseria gonorrhoeae from consecutive patients attending genitourinary medicine clinics at 10 hospitals in the London area were collected over a 3 month period, May to July 1997. The susceptibility to penicillin, ciprofloxacin, tetracycline, and spectinomycin was determined for each isolate. Isolates exhibiting either plasmid or chromosomally mediated resistance were additionally tested for susceptibility to agents used as alternative treatments including azithromycin, ceftriazone, and ofloxacin. The resistant isolates were also tested for plasmid profiles (penicillinase producing N gonorrhoeae, PPNG), type of tetM determinant (tetracycline resistant N gonorrhoeae, TRNG), and presence of gyrA and parC mutations (quinolone resistant N gonorrhoeae, QRNG). A total of 1133 isolates were collected which represents > 95% of the total gonococci isolated in the 3 months. Plasmid mediated resistance was exhibited by 48 (4.2%) isolates; six (0.5%) were PPNG, 15 (1.3%) were PP/TRNG, and 27 (2.4%) were TRNG. The majority of PPNG (18 of 20 tested) carried the 3.2 MDa penicillinase plasmid whereas the two types of tetM determinant were more evenly distributed. High level resistance to ciprofloxacin was detected in four (0.4%) isolates and double mutations were found in the quinolone resistance determining region (QRDR) of the gyrA gene in three QRNG with MICs of 16 mg/l and a single mutation in one isolate with a MIC of 1 mg/l to ciprofloxacin. No parC mutations were found. Of the remaining 1081 isolates, 86 (8.0%) were chromosomally mediated resistant N gonorrhoeae (CMRNG). A unique collection of gonococcal isolates has been established which can be used as a baseline for surveillance of susceptibility to antibiotics and for epidemiological purposes.


Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
To investigate risk factors associated with Barrett's oesophagus and oesophageal adenocarcinoma. This all-Ireland population-based case-control study recruited 224 Barrett's oesophagus patients, 227 oesophageal adenocarcinoma patients and 260 controls. All participants underwent a structured interview with information obtained about potential lifestyle and environmental risk factors. Gastro-oesophageal reflux was associated with Barrett's [OR 12.0 (95% CI 7.64-18.7)] and oesophageal adenocarcinoma [OR 3.48 (95% CI 2.25-5.41)]. Oesophageal adenocarcinoma patients were more likely than controls to be ex- or current smokers [OR 1.72 (95% CI 1.06-2.81) and OR 4.84 (95% CI 2.72-8.61) respectively] and to have a high body mass index [OR 2.69 (95% CI 1.62-4.46)]. No significant associations were observed between these risk factors and Barrett's oesophagus. Fruit but not vegetables were negatively associated with oesophageal adenocarcinoma [OR 0.50 (95% CI 0.30-0.86)]. A high body mass index, a diet low in fruit and cigarette smoking may be involved in the progression from Barrett's oesophagus to oesophageal adenocarcinoma.


The gains in life expectancy by ambient PM2.5 pollution reductions in localities in Nigeria.
Global burden of disease estimates reveal that people in Nigeria are living shorter lifespan than the regional or global average life expectancy. Ambient air pollution is a top risk factor responsible for the reduced longevity. But, the magnitude of the loss or the gains in longevity accruing from the pollution reductions, which are capable of driving mitigation interventions in Nigeria, remain unknown. Thus, we estimate the loss, and the gains in longevity resulting from ambient PM2.5 pollution reductions at the local sub-national level using life table approach. Surface average PM2.5 concentration datasets covering Nigeria with spatial resolution of ∼1 km were obtained from the global gridded concentration fields, and combined with ∼1 km gridded population of the world (GPWv4), and global administrative unit layers (GAUL) for territorial boundaries classification. We estimate the loss or gains in longevity using population-weighted average pollution level and baseline mortality data for cardiopulmonary disease and lung cancer in adults ≥25 years and for respiratory infection in children under 5. As at 2015, there are six "highly polluted", thirty "polluted" and one "moderately polluted" States in Nigeria. People residing in these States lose ∼3.8-4.0, 3.0-3.6 and 2.7 years of life expectancy, respectively, due to the pollution exposure. But, assuming interventions achieve global air quality guideline of 10 μg/m3, longevity would increase by 2.6-2.9, 1.9-2.5 and 1.6 years for people in the State-categories, respectively. The longevity gains are indeed high, but to achieve them, mitigation interventions should target emission sources having the highest population exposures.


QM/MM simulation of liquid water with an adaptive quantum region.
The simulation of complex chemical systems often requires a multi-level description, in which a region of special interest is treated using a computationally expensive quantum mechanical (QM) model while its environment is described by a faster, simpler molecular mechanical (MM) model. Furthermore, studying dynamic effects in solvated systems or bio-molecules requires a variable definition of the two regions, so that atoms or molecules can be dynamically re-assigned between the QM and MM descriptions during the course of the simulation. Such reassignments pose a problem for traditional QM/MM schemes by exacerbating the errors that stem from switching the model at the boundary. Here we show that stable, long adaptive simulations can be carried out using density functional theory with the BLYP exchange-correlation functional for the QM model and a flexible TIP3P force field for the MM model without requiring adjustments of either. Using a primary benchmark system of pure water, we investigate the convergence of the liquid structure with the size of the QM region, and demonstrate that by using a sufficiently large QM region (with radius 6 Å) it is possible to obtain radial and angular distributions that, in the QM region, match the results of fully quantum mechanical calculations with periodic boundary conditions, and, after a smooth transition, also agree with fully MM calculations in the MM region. The key ingredient is the accurate evaluation of forces in the QM subsystem which we achieve by including an extended buffer region in the QM calculations. We also show that our buffered-force QM/MM scheme is transferable by simulating the solvated Cl(-) ion.


Blocking of injected holes at the charge extracting interface.
For an organic crystal with four metal electrodes, we have investigated the charge transfer between the injecting electrode 1 and the extracting electrodes 2-4. Each of the measured I-V curves was decomposed into three components, characterizing the injecting and extracting interfaces, and the squaraine (SQ) crystal. We considered a case, where the resistance of the organic crystal was significantly smaller than that of the interfaces. The different values of the contact resistances measured at different electrodes are related to differing values of the barrier height [Formula: see text] and its width d, which were determined using the Simmons approximation. When the extracting interface has a larger contact resistance compared to that of the SQ crystal and that of the injecting interface, part of the injected holes remains located within the SQ crystal. The voltage V 0, at which the injected hole density begins to exceed the extracted hole density within the SQ crystal, depends on the ratio [Formula: see text] (indices ex and in describe the extracting and injecting electrodes, respectively). The smaller δ is, the larger is voltage V 0.


Symmetry sensitivities of derivative-of-Gaussian filters.
We consider the measurement of image structure using linear filters, in particular derivative-of-Gaussian (DtG) filters, which are an important model of V1 simple cells and widely used in computer vision, and whether such measurements can determine local image symmetry. We show that even a single linear filter can be sensitive to a symmetry, in the sense that specific responses of the filter can rule it out. We state and prove a necessary and sufficient, readily computable, criterion for filter symmetry-sensitivity. We use it to show that the six filters in a second order DtG family have patterns of joint sensitivity which are distinct for 12 different classes of symmetry. This rich symmetry-sensitivity adds to the properties that make DtG filters well-suited for probing local image structure, and provides a set of landmark responses suitable to be the foundation of a nonarbitrary system of feature categories.


Sildenafil increases muscle protein synthesis and reduces muscle fatigue.
Reductions in skeletal muscle function occur during the course of healthy aging as well as with bed rest or diverse diseases such as cancer, muscular dystrophy, and heart failure. However, there are no accepted pharmacologic therapies to improve impaired skeletal muscle function. Nitric oxide may influence skeletal muscle function through effects on excitation-contraction coupling, myofibrillar function, perfusion, and metabolism. Here we show that augmentation of nitric oxide-cyclic guanosine monophosphate signaling by short-term daily administration of the phosphodiesterase 5 inhibitor sildenafil increases protein synthesis, alters protein expression and nitrosylation, and reduces fatigue in human skeletal muscle. These findings suggest that phosphodiesterase 5 inhibitors represent viable pharmacologic interventions to improve muscle function.


The COMT Val158Met polymorphism is associated with novelty seeking in Czech methamphetamine abusers: preliminary results.
Measurable traits of human personality may mark the predisposition to psychopathology. Increased novelty seeking plays an important role in the pathogenesis of substance abuse. Novelty seeking, one of the fundamental traits of the human temperament, is related to dopamine. Catechol-O-methyltransferase (COMT) is essential for dopamine inactivation. The aim of our study was to assess whether the COMT gene Val158Met functional polymorphism in patients dependent on methamphetamine is related to their novelty seeking score. Patients dependent on methamphetamine who had been treated at the Addiction Treatment Unit in Nechanice in 2004 and 2005 agreed to participate in the investigation. We administered the Temperament and Character Inventory (TCI) questionnaire, assessed their novelty seeking score and analysed their DNA samples for COMT Val158Met genotype. The subjects were thirty-seven Czech Caucasians (women N=10) dependent on methamphetamine with an average age of 23.6+/-3.8 years. We found a significantly higher mean novelty seeking score among the patients with the Met allele (Met/Met homozygotes+Val/Met heterozygotes; N=28) than in nine Val/Val homozygotes (27.4 vs 24.1; p=0.042, Two-Sample T-Test). The Met allele of the COMT gene Val158Met polymorphism is associated with low COMT enzyme activity and high endogenous dopamine synaptic levels in the prefrontal cortex. This leads to a decrease in dopaminergic neurotransmission in nucleus accumbens and a need for an increased activity to stimulate it. Novelty seeking behavior corresponds with this need.


Clinical grading and the effects of scaling.
In clinical practice, there has been a need to grade the magnitude or the severity of the functions and qualities that are assessed in the examination. It is popular to use a four-step grading scale to categorize the severity of clinical findings. The authors discuss clinical grading scales and their influence on the clinician's ability to detect change. These principles have been applied to grades or measures derived from either objective measuring instruments, subjective tests, or techniques in which the clinician makes subjective judgments. A hypothetical data set was used to show the problems associated with using grading scales that are too coarse. The authors presented a mathematic model that helps to estimate the benefits of using use of a finer scale. Data were presented from two separate studies, one on visual acuity measurement and the other on grading nuclear opacity, to show the advantages of using finer scales to enhance the sensitivity of clinical measurement. High levels of concordance between independent observations indicated that the grading scale was too coarse and that these scales needlessly reduced the clinician's ability to detect change in the parameter being assessed. For moderate sensitivity, the size of the scale increments should not exceed one standard deviation of the discrepancy so that the concordance of paired comparisons would not exceed 37%. For fine clinical sensitivity, the size of the scale increments should not exceed one third of the standard deviation of the discrepancy, in which case the concordance of paired comparisons would not exceed 13%. The theory and evidence presented here could prompt re-evaluations of common methods of clinical grading.


Frequency domain analysis reveals external periodic fluctuations can generate sustained p53 oscillation.
p53 is a well-known tumor suppressor protein that regulates many pathways, such as ones involved in cell cycle and apoptosis. The p53 levels are known to oscillate without damping after DNA damage, which has been a focus of many recent studies. A negative feedback loop involving p53 and MDM2 has been reported to be responsible for this oscillatory behavior, but questions remain as how the dynamics of this loop alter in order to initiate and maintain the sustained or undamped p53 oscillation. Our frequency domain analysis suggests that the sustained p53 oscillation is not completely dictated by the negative feedback loop; instead, it is likely to be also modulated by periodic DNA repair-related fluctuations that are triggered by DNA damage. According to our analysis, the p53-MDM2 feedback mechanism exhibits adaptability in different cellular contexts. It normally filters noise and fluctuations exerted on p53, but upon DNA damage, it stops performing the filtering function so that DNA repair-related oscillatory signals can modulate the p53 oscillation. Furthermore, it is shown that the p53-MDM2 feedback loop increases its damping ratio allowing p53 to oscillate at a frequency more synchronized with the other cellular efforts to repair the damaged DNA, while suppressing its inherent oscillation-generating capability. Our analysis suggests that the overexpression of MDM2, observed in many types of cancer, can disrupt the operation of this adaptive mechanism by making it less responsive to the modulating signals after DNA damage occurs.


Urinary cadmium concentration and risk of breast cancer: a systematic review and dose-response meta-analysis.
Cadmium is a toxic and persistent heavy metal with estrogenic activities. We conducted a systematic review and meta-analysis of cohort, case-control, and cross-sectional studies of the association between urinary cadmium concentration, a biomarker of cadmium exposure, and breast cancer risk. Studies were identified by searching PubMed and Embase (to March 15, 2015) and by reviewing the reference lists of pertinent articles. Study-specific risk estimates were combined by using a random-effects model. We identified 2 cohort studies (with 67 breast cancer deaths) and 5 case-control studies and 1 cross-sectional study (with 1,416 cases and 5,083 controls) on urinary cadmium concentration in relation to breast cancer risk. The studies were published during the past 10 years (2006-2015). There was no consistent association between urinary cadmium and breast cancer mortality in the cohort studies. In case-control and cross-sectional studies, the pooled odds ratios were 2.24 (95% confidence interval: 1.50, 3.34; I(2) = 63.4%) for the highest versus lowest category of cadmium concentration and 1.66 (95% confidence interval: 1.23, 2.25) for each 0.5-µg/g creatinine increase of cadmium concentration. This meta-analysis suggests that a high cadmium exposure may be a risk factor for breast cancer, but large prospective studies are needed to confirm this finding.


Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002).
COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44-45 weeks) between the first and second dose, and response to a third dose as a booster given 28-38 weeks after the second dose. In this substudy, volunteers aged 18-55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44-45 weeks after first dose) or a third dose of the vaccine (28-38 weeks after second dose). Data from volunteers aged 18-55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8-12 weeks: 267 [83%] of 321; 15-25 weeks: 24 [7%]; or 44-45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8-12 weeks: 115 [44%] of 261; 15-25 weeks: 116 [44%]; and 44-45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44-45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83-91·08] vs 1·75 EUs [1·60-1·93]). 32 participants received a late second dose of vaccine 44-45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525-1764] with an 8-12 week interval; 1860 EUs [917-4934] with a 15-25 week interval; and 3738 EUs [1824-6625] with a 44-45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047-6420]) than 28 days after a second dose (median 1792 EUs [IQR 899-4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127-389] immediately before the third dose to 399 SFUs per milion PBMCs [314-662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.


Dissipative defect modes in periodic structures.
We show that periodic optical lattices imprinted in cubic nonlinear media with strong two-photon absorption and localized linear gain landscapes support stable dissipative defect modes in both focusing and defocusing media. Their shapes and transverse extent are determined by the propagation constant that belongs to a gap of the lattice spectrum, which, in turn, is determined by the relation between gain and losses. One-hump and two-hump dissipative defect modes are obtained.


Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study.
Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy. We conducted a randomized, double-blind, placebo-controlled trial including 5442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition. After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]). These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.


Local-field enhancement in an optical force metallic nanotrap: application to single-molecule spectroscopy.
We study the local-field enhancement in a nanocavity created by optical nanomanipulation. Recently we showed that a metallic probe can modify the optical force experienced by a metallic particle and generate a material selective trapping potential. We show that the same configuration used for optical forces can be used to control both in magnitude and tune the local-field enhancement around the particle at resonance. The spatial resolution and material selectivity of this technique, allied to its capability to manipulate particles at the nanometric level, may offer a new and versatile way to achieve surface-enhanced Raman scattering spectroscopy at the single-molecule level.


An integrated map of structural variation in 2,504 human genomes.
Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.


Laparoscopic approach to cornual ectopic: a step-by-step demonstration.
To concisely review what is known about cornual ectopic pregnancies and to provide a step-by-step demonstration of the resection of a large cornual ectopic pregnancy, highlighting various laparoscopic techniques. A video review of cornual ectopic pregnancy and a laparoscopic approach for treatment featuring a patient case at 9 weeks gestation. Tertiary care facility. A 31-year-old G2P1001 at 9 weeks 0 days by transvaginal ultrasound and with a beta human chorionic gonadotropin of 13,099 presented to the emergency department for vaginal bleeding and cramping left lower quadrant pain. She was hemodynamically stable. Her ultrasound was suspicious for a cornual ectopic pregnancy, which was confirmed by magnetic resonance imaging. The patient was taken to the operating room for resection, given the size of the pregnancy, concern for intraoperative blood loss, concern for persistent pregnancy, and concern that patient would not be able to reliably follow up for multiple appointments. Patient underwent laparoscopic resection of a large cornual ectopic pregnancy. Included is a short review of laparoscopic suturing techniques. Pathology, decline in beta hCG, and post-operative course. The patient's pathology was confirmatory for cornual ectopic pregnancy. Her beta human chorionic gonadotropin decreased as expected, and she had a normal post-operative course. Laparoscopic cornual resection is a safe and effective method for management of large cornual ectopic pregnancy, and fertility outcomes are similar to patients after salpingectomy for non-interstitial ectopic pregnancy.


A molecular phylogeny of the flagellated fungi (Chytridiomycota) and description of a new phylum (Blastocladiomycota).
Chytridiomycota (chytrids) is the only phylum of true Fungi that reproduces with motile spores (zoospores). Chytrids currently are classified into five orders based on habitat, zoospore characters and life cycles. In this paper we estimate the phylogeny of the chytrids with DNA sequences from the ribosomal RNA operon (18S+5.8S+28S subunits). To our surprise the morphologically reduced parasites Olpidium and Rozella comprise two entirely new, and separate, lineages on the fungal tree. Olpidium brassicae groups among the Zygomycota, and Rozella spp. are the earliest branch to diverge in the fungal kingdom. The phylogeny also suggests that Chytridiomycota is not monophyletic and there are four major lineages of chytrids: Rozella spp., Olpidium brassicae, the Blastocladiales and a "core chytrid clade" containing the remaining orders and families and the majority of flagellated fungi. Within the core chytrid group 11 subclades can be identified, each of which correlates well with zoospore ultrastructure or morphology. We provide a synopsis of each clade and its morphological circumscription. The Blastocladiales appears to be the sister taxon of most nonflagellated fungi. Based on molecular phylogenetic and ultrastructural characters this order is elevated to a phylum, the Blastocladiomycota.


STAT3 Single Nucleotide Polymorphism rs4796793 SNP Does Not Correlate with Response to Adjuvant IFNα Therapy in Stage III Melanoma Patients.
Interferon alpha (IFNα) is approved for adjuvant treatment of stage III melanoma in Europe and the US. Its clinical efficacy, however, is restricted to a subpopulation of patients while side effects occur in most of treated patients. Thus, the identification of predictive biomarkers would be highly beneficial to improve the benefit to risk ratio. In this regard, STAT3 is important for signaling of the IFNα receptor. Moreover, the STAT3 single-nucleotide polymorphism (SNP) rs4796793 has recently been reported to be associated with IFNα sensitivity in metastatic renal cell carcinoma. To translate this notion to melanoma, we scrutinized the impact of rs4796793 functionally and clinically in this cancer. Interestingly, melanoma cells carrying the minor allele of rs4796793 were the most sensitive to IFNα in vitro. However, we did not detect a correlation between SNP genotype and STAT3 mRNA expression for either melanoma cells or for peripheral blood lymphocytes. Next, we analyzed the impact of rs4796793 on the clinical outcome of 259 stage III melanoma patients of which one-third had received adjuvant IFNα treatment. These analyses did not reveal a significant association between the STAT3 rs4796793 SNP and patients' progression free or overall survival when IFNα treated and untreated patients were compared. In conclusion, STAT3 rs4796793 SNP is no predictive marker for the efficacy of adjuvant IFNα treatment in melanoma patients.


How may the basal ganglia contribute to auditory categorization and speech perception?
Listeners must accomplish two complementary perceptual feats in extracting a message from speech. They must discriminate linguistically-relevant acoustic variability and generalize across irrelevant variability. Said another way, they must categorize speech. Since the mapping of acoustic variability is language-specific, these categories must be learned from experience. Thus, understanding how, in general, the auditory system acquires and represents categories can inform us about the toolbox of mechanisms available to speech perception. This perspective invites consideration of findings from cognitive neuroscience literatures outside of the speech domain as a means of constraining models of speech perception. Although neurobiological models of speech perception have mainly focused on cerebral cortex, research outside the speech domain is consistent with the possibility of significant subcortical contributions in category learning. Here, we review the functional role of one such structure, the basal ganglia. We examine research from animal electrophysiology, human neuroimaging, and behavior to consider characteristics of basal ganglia processing that may be advantageous for speech category learning. We also present emerging evidence for a direct role for basal ganglia in learning auditory categories in a complex, naturalistic task intended to model the incidental manner in which speech categories are acquired. To conclude, we highlight new research questions that arise in incorporating the broader neuroscience research literature in modeling speech perception, and suggest how understanding contributions of the basal ganglia can inform attempts to optimize training protocols for learning non-native speech categories in adulthood.


Treatment of clavicle fractures.
Clavicle fractures are very common injuries in adults (2-5%) and children (10-15%) (1) and represent the 44-66% of all shoulder fractures (2). Despite the high frequency the choice of proper treatment is still a challenge for the orthopedic surgeon. With this review we wants to focus the attention on the basic epidemiology, anatomy, classification, evaluation and management of surgical treatments in relationship with the gravity of injuries. Both conservative and surgical management are possible, and surgeons must choose the most appropriate management modality according to the biologic age, functional demands, and type of lesion. We performed a review of the English literature thought PubMed to produce an evidence-based review of current concept and management of clavicle fracture. We finished taking a comparison with our survey in order to underline our direct experience.


Fc receptors in immune thrombocytopenias: a target for immunomodulation?
In autoimmune disease, Fc receptors (FcRs) form the interface between immune effector cells and their antibody-coated targets, and as such are attractive targets for immunomodulatory therapy. In this issue of the JCI, two highly novel studies of Fc-FcR interactions provide new insights into the role of FcRs in immune thrombocytopenia. Asahi et al. utilized a comprehensive platform of immunological assays to examine the mechanism underlying Helicobacter pylori-associated immune thrombocytopenic purpura, and Ghevaert et al. describe a specially designed antibody that saturates binding sites on fetal platelets without initiating FcgammaR-mediated platelet phagocytosis, preventing the binding of pathological maternal anti-HLA antibodies that cause fetomaternal alloimmune thrombocytopenia (see the related articles beginning on pages 2939 and 2929, respectively). These reports illustrate how a remarkably detailed molecular understanding of the FcR network may translate into new therapeutic strategies with high clinical impact.


Family caregiver mistreatment of the elderly: prevalence of risk and associated factors.
The detection of elder mistreatment is emerging as a public health priority; however, abusive behaviors exercised by caregivers are little known and rarely detected among primary health care professionals. This study aims to estimate the prevalence of risk of abuse against community-residing elderly with moderate to severe dependency whose caregivers are relatives. In addition, we aim to describe the association between such a risk and socio-demographic variables, cognitive and dependency state of the victim, and the scale of the caregiver's anxiety, depression, and burden. Cross-sectional study developed in 72 Primary Health Care teams from Barcelona, Spain. Participants were caregivers and their dependent care recipients (N = 829). Home interviews included the Caregiver Abuse Screen (CASE); self-reported abuse from care recipient; activities of daily living and cognitive state of the care recipient; anxiety and depression in caregivers and Caregiver Burden Scale. The relationship prior to the dependency, positive aspects of caregiving, and social support for the caregiver were also assessed. Multivariate analysis was performed using logistic regression with risk of abuse as dependent variable. Caregivers were mainly women (82.8%) with a mean age of 63.3 years. Caregivers and care recipients lived in the same household in 87.4% of cases, and 86.6% had enjoyed a good previous relationship. Care recipients were women (65.6%), with a mean age of 84.2 years, and 64.2% had moderate to severe cognitive impairment. CASE demonstrated a prevalence of 33.4% (95% CI: 30.3-36.7) of abuse risk by the caregiver. Logistic regression showed as statistically significant: caregiver burden (OR = 2.75; 95% CI: 1.74-4.33), caregiver anxiety (OR = 2.06; 95% CI: 1.40-3.02), caregiver perception of aggressive behavior in the care recipient (OR = 7.24; 95% CI: 4.99-10.51), and a bad previous relationship (OR = 4.66; 95% CI: 1.25-17.4). Prevalence of risk of abuse is high among family caregivers. Our study has found risk factors in family caregivers that are preventable to an extent, namely: anxiety and feelings of burden. It is essential to become aware of these risk factors and their causes to intervene and help primary as well secondary prevention.


Knowledge of tuberculosis management using directly observed treatment short course therapy among final year medical students in South Western Nigeria.
Equipping medical graduates with the competence to manage tuberculosis is not just imperative but also urgent as the diseases have been consistently listed as one of the major causes of morbidity and mortality in Nigeria. However, there were no baseline studies done on knowledge of final year medical students on various aspects of TB diagnosis and management under directly observed treatment short course therapy (DOTS) which forms the basis of this study. A total of 241 final year medical students from three medical colleges in Nigeria were interviewed. The questions assessed their knowledge about various modes of transmission, symptoms and management of tuberculosis under DOTS. More than half of the respondents (i.e. 69%) had poor knowledge on TB disease. Only 33.6% mentioned sputum smear as the best tool of diagnosing TB according to guideline. Poor knowledge was also exhibited when asked of various categories under DOTS treatment regimen, as 46.1% correctly mentioned cat 1 and 2. Minority 18.7% and 6.7% had complete knowledge of 6 months duration for new TB cases and 8 months for re-treatment cases respectively. Less than one tenth, i.e. 4.6% and 2.9% could correctly defined what is called a new TB case and re-treatment cases according to standard guideline. The study reveals gross inadequacies in TB knowledge and management practices among Nigerian final year medical students. There is urgent need for incorporation of National TB guideline into existing undergraduate medical education curriculum as well as students rotation through activities in DOTS clinic.


[Inhibitory effect of refined Amorphophallus konjac on MNNG-induced lung cancers in mice].
550 seven-wk-old LACA mice were used in 3 batches for studying the inhibitory effect of refined Amorphophallus konjac (Konjaku powder) on MNNG-induced lung cancers. The mice (within each batch) were randomly allocated into four groups, namely, positive control (MNNG), Amorphophallus konjac (A. K.), complex (MNNG+A. K.), and blank control (C) groups. In MNNG group, MNNG (250 micrograms) was injected intravenously once every five days for seven times in each mouse, the total dosage of MNNG being 1.75 mg. In A. K. group, according to w/w, 8% A. K. was well mixed into 92% common diet for long-term breeding. In the complex group, MNNG was given as that in MNNG group and the mice were kept as those in A. K. group. The mice in MNNG group and in C group were all maintained on common diet. The results showed different degrees of inhibitory and preventive effect of refined A. K. on MNNG-induced lung cancers. Refined A. K. not only exerted effect on the number of induced cancer and precancerous lesions, causing a drop in cancer rate from 70.87% to 19.38% and the mean number of cancer and precancerous lesions in each animal, but also altered the constituent ratio of the kinds of tumors, showing a decrease in malignancy (adenoma with malignant change), absence of adenocarcinoma, and relative increase in benign adenoma. The results of experiments in 3 batches also exhibited good reproducibility as well as absence of adverse reaction to Konjaku powder.


[Respiratory and circulatory parameters as indicators of the postoperative analgesic demand in newborns and infants].
Due to immature cognitive functions, infants are unable to communicate their pain perception verbally. To assess postoperative analgesic demand, the anaesthetist has to rely on observational techniques. Generally, pain expression is considered to be a multidimensional phenomenon consisting of physiological, motor-reflex and behavioural patterns. The majority of observational approaches to pain assessment in infants use the behavioural dimension only, regardless of the fact that pain perception might contribute substantially to the stress response. The aim of this study is to evaluate, whether sensitivity and specificity of a behavioural pain scale (CHIPPS [1]) can be improved by adding physiological measures, especially those representing the stress response. 30 infants aged 0-12 months and scheduled for unilateral herniorrhaphy were studied prospectively. In addition to 9 behavioural items (crying, facial expression, wrinkling of the forehead, motoric restlessness; posture of fingers, arms, legs, toes and torso) the ratio of actual physiological measurements (heart rate, respiratory rate, blood pressure) and their respective preoperative baseline values were recorded by a single observer in 5 minutes intervals during the first hour after recovery from anaesthesia. Maximal efforts were made to achieve valid measures. Factor analysis was performed to determine the dimensionality of the complete item pool. For additional validity testing, receiver operating characteristic curves (ROC) were calculated using the independent opinion of an experienced clinician as an external criterion. Discriminant analysis was performed to assess the accuracy of a combined behavioural and physiological scale. The factor analysis resulted in two independent dimensions: behaviour and cardiocirculatory measurements. The strong intercorrelations of all behavioural items and the fact, that the affective pain experience is expressed by a specific mimic behaviour, suggest the behavioural dimension to be regarded as pain expression. Because of the strictly orthogonal structure of the factor system, the circulatory and the respiratory dimension lack any relationship to pain experience. In addition to these statistical reasons, considerations on practicability disprove blood pressure and respiratory rate as useful pain indicators: Whereas the observer never failed to obtain a behavioural score, only 60% of the blood pressure measures and 80% of the respiratory rates were valid. In contrast, heart rate counts were obtained in over 99% and thus have to be considered as the only practicable physiological measurement in the early postoperative period. Corresponding to the results of the factor analysis, ROC curves suggest that the ability of the heart rate alone to assess pain is not substantially better than a random process, whereas the behavioural scale performs well. In addition the heart rate failed to improve the accuracy of the behavioural scale as shown by the results of a discriminant analysis. Despite the multidimensional approach and the corresponding multivariate analyses, a unidimensional scale consisting of behavioural items was found to be a valid indicator of an postoperative analgesic demand. Due to the lack of diagnostic properties and difficulties to obtain sound values even under research conditions, physiological measurements like blood pressure, respiratory rate and heart rate are not suitable for the assessment of a postoperative analgesic demand in infants, neither for clinical nor for research purposes.


Does Elite Sport Degrade Sleep Quality? A Systematic Review.
Information on sleep quality and insomnia symptomatology among elite athletes remains poorly systematised in the sports science and medicine literature. The extent to which performance in elite sport represents a risk for chronic insomnia is unknown. The purpose of this systematic review was to profile the objective and experienced characteristics of sleep among elite athletes, and to consider relationships between elite sport and insomnia symptomatology. Studies relating to sleep involving participants described on a pre-defined continuum of 'eliteness' were located through a systematic search of four research databases: SPORTDiscus, PubMed, Science Direct and Google Scholar, up to April 2016. Once extracted, studies were categorised as (1) those mainly describing sleep structure/patterns, (2) those mainly describing sleep quality and insomnia symptomatology and (3) those exploring associations between aspects of elite sport and sleep outcomes. The search returned 1676 records. Following screening against set criteria, a total of 37 studies were identified. The quality of evidence reviewed was generally low. Pooled sleep quality data revealed high levels of sleep complaints in elite athletes. Three risk factors for sleep disturbance were broadly identified: (1) training, (2) travel and (3) competition. While acknowledging the limited number of high-quality evidence reviewed, athletes show a high overall prevalence of insomnia symptoms characterised by longer sleep latencies, greater sleep fragmentation, non-restorative sleep, and excessive daytime fatigue. These symptoms show marked inter-sport differences. Two underlying mechanisms are implicated in the mediation of sport-related insomnia symptoms: pre-sleep cognitive arousal and sleep restriction.


Harms and responsibilities associated with battery-operated implants (BOI): who controls postmortem explantation?
The postmortem issues raised by battery-operated implants (BOI) are complex and issues of consent, setting (clinical vs research), and environmental risks have received little attention in bioethics literature. Analyzing the issues, the following are argued: (1) Patients receiving BOIs should sign a consent form that includes a requirement for postmortem explant of the device; (2) BOI consent forms should require the explanted devices be returned to their manufacturers for Returned Product Analysis; (3) Failure to explant and analyze devices from the research setting fails the research goal of generation of knowledge for the benefit of future patients; (4) Failure to explant and analyze devices from the clinical setting allows product defects to be potentially hidden from patients, families, clinicians, manufacturers, and regulatory agencies; (5) Bodies buried with BOIs potentially harm the environment; (6) Religious or philosophical objections to autopsy should not supersede the duty to explant and analyze BOIs; (7) The concepts herein for BOIs could potentially extend to non-BOI if the device has failure modes that can lead to a potentially life-threatening event or can cause permanent debilitating health issues, and the burial or cremation of the device poses environmental harm. In these situations, neither the patient (premortem) nor family (postmortem) should have the right to refuse explant.


Monoamines in the pedal plexus of the land snail Megalobulimus oblongus (Gastropoda, Pulmonata).
In molluscs, the number of peripheral neurons far exceeds those found in the central nervous system. Although previous studies on the morphology of the peripheral nervous system exist, details of its organization remain unknown. Moreover, the foot of the terrestrial species has been studied less than that of the aquatic species. As this knowledge is essential for our experimental model, the pulmonate gastropod Megalobulimus oblongus, the aim of the present study was to investigate monoamines in the pedal plexus of this snail using two procedures: glyoxylic acid histofluorescence to identify monoaminergic structures, and the unlabeled antibody peroxidase anti-peroxidase method using antiserum to detect the serotonergic component of the plexus. Adult land snails weighing 48-80 g, obtained from the counties of Barra do Ribeiro and Charqueadas (RS, Brazil), were utilized. Monoaminergic fibers were detected throughout the pedal musculature. Blue fluorescence (catecholamines, probably dopamine) was observed in nerve branches, pedal and subepithelial plexuses, and in the pedal muscle cells. Yellow fluorescence (serotonin) was only observed in thick nerves and in muscle cells. However, when immunohistochemical methods were used, serotonergic fibers were detected in the pedal nerve branches, the pedal and subepithelial plexuses, the basal and lateral zones of the ventral integument epithelial cells, in the pedal ganglion neurons and beneath the ventral epithelium. These findings suggest catecholaminergic and serotonergic involvement in locomotion and modulation of both the pedal ganglion interneurons and sensory information. Knowledge of monoaminergic distribution in this snail s foot is important for understanding the pharmacological control of reflexive responses and locomotive behavior.


The association of physical activity to neural adaptability during visuo-spatial processing in healthy elderly adults: A multiscale entropy analysis.
Physical activity has been shown to benefit brain and cognition in late adulthood. However, this effect is still unexplored in terms of brain signal complexity, which reflects the level of neural adaptability and efficiency during cognitive processing that cannot be acquired via averaged neuroelectric signals. Here we employed multiscale entropy analysis (MSE) of electroencephalography (EEG), a new approach that conveys important information related to the temporal dynamics of brain signal complexity across multiple time scales, to reveal the association of physical activity with neural adaptability and efficiency in elderly adults. A between-subjects design that included 24 participants (aged 66.63±1.31years; female=12) with high physical activity and 24 age- and gender-matched low physical activity participants (aged 67.29±1.20years) was conducted to examine differences related to physical activity in performance and MSE of EEG signals during a visuo-spatial cognition task. We observed that physically active elderly adults had better accuracy on both visuo-spatial attention and working memory conditions relative to their sedentary counterparts. Additionally, these physically active elderly adults displayed greater MSE values at larger time scales at the Fz electrode in both attention and memory conditions. The results suggest that physical activity may be beneficial for adaptability of brain systems in tasks involving visuo-spatial information. MSE thus might be a promising approach to test the effects of the benefits of exercise on cognition.


Compact on-chip temperature sensors based on dielectric-loaded plasmonic waveguide-ring resonators.
The application of a waveguide-ring resonator based on dielectric-loaded surface plasmon-polariton waveguides as a temperature sensor is demonstrated in this paper and the influence of temperature change to the transmission through the waveguide-ring resonator system is comprehensively analyzed. The results show that the roundtrip phase change in the ring resonator due to the temperature change is the major reason for the transmission variation. The performance of the temperature sensor is also discussed and it is shown that for a waveguide-ring resonator with the resonator radius around 5 μm and waveguide-ring gap of 500 nm which gives a footprint around 140 μm(2), the temperature sensitivity at the order of 10(-2) K can be achieved with the input power of 100 μW within the measurement sensitivity limit of a practical optical detector.


A multifactorial approach for the prognosis of patients with carcinoma of the stomach after curative resection.
This study was done to define the prognostic role of some clinical and pathologic variables in patients with carcinoma of the stomach who underwent a curative subtotal gastrectomy for cancer located at the lower two-thirds of the stomach. An univariate and multivariate analysis, according to Cox's regression model, was retrospectively performed upon 361 patients operated upon at the Istituto Nazionale Tumori of Milan from 1965 to 1979 by a curative subtotal gastrectomy. Data were stored by an IBM 4331 computer. Several factors were taken into consideration: age, sex, site and size of tumor, gross appearance, histologic type, invasion of the gastric wall, nodal status and symptoms. Of six variables selected by the univariate analysis, only four (sex, age, lymph node status and degree of invasion in the gastric wall) were validated by the multivariate evaluation, whereas tumor size and symptoms lost their prognostic relevance. The most important variables were nodal status and the degree of invasion in the gastric wall. The influence of age had a different impact on survival time, depending upon nodal status. In fact, patients with positive nodes who were less than 60 years old had the worst prognosis; the same age group with negative nodes had the best prognosis. Multifactorial analysis, according to the automatic interaction detection procedure, showed that prognosis worsened progressively beginning with female patients with negative nodes at pT1 or pT2 (91.6 per cent five year survival rate), male patients with negative nodes at pT1 or pT2 (76.3 per cent five year survival rate), female patients with negative nodes at pT3 or pT4 (62.4 per cent), male patients with negative nodes at pT3 or pT4 (40.0 per cent), patients more than 60 years old with negative nodes (36.8 per cent) and patients less than 60 years old with positive nodes (20.8 per cent). In our opinion, these parameters should be taken into consideration when stratification of patients as candidates to undergo adjuvant treatment after surgical treatment is planned.


Problem gambling and family violence: prevalence and patterns in treatment-seekers.
The primary aim of this study was to explore the prevalence and patterns of family violence in treatment-seeking problem gamblers. Secondary aims were to identify the prevalence of problem gambling in a family violence victimisation treatment sample and to explore the relationship between problem gambling and family violence in other treatment-seeking samples. Clients from 15 Australian treatment services were systematically screened for problem gambling using the Brief Bio-Social Gambling Screen and for family violence using single victimisation and perpetration items adapted from the Hurt-Insulted-Threatened-Screamed (HITS): gambling services (n=463), family violence services (n=95), alcohol and drug services (n=47), mental health services (n=51), and financial counselling services (n=48). The prevalence of family violence in the gambling sample was 33.9% (11.0% victimisation only, 6.9% perpetration only, and 16.0% both victimisation and perpetration). Female gamblers were significantly more likely to report victimisation only (16.5% cf. 7.8%) and both victimisation and perpetration (21.2% cf. 13.0%) than male gamblers. There were no other demographic differences in family violence prevalence estimates. Gamblers most commonly endorsed their parents as both the perpetrators and victims of family violence, followed by current and former partners. The prevalence of problem gambling in the family violence sample was 2.2%. The alcohol and drug (84.0%) and mental health (61.6%) samples reported significantly higher rates of any family violence than the gambling sample, while the financial counselling sample (10.6%) reported significantly higher rates of problem gambling than the family violence sample. The findings of this study support substantial comorbidity between problem gambling and family violence, although this may be accounted for by a high comorbidity with alcohol and drug use problems and other psychiatric disorders. They highlight the need for routine screening, assessment and management of problem gambling and family violence in a range of services.


Reutericyclin producing Lactobacillus reuteri modulates development of fecal microbiota in weanling pigs.
Lactobacillus reuteri is used as probiotic culture in food and feed applications; however, strain specific properties of L. reuteri that mediate probiotic activity remain unknown. This study aimed to determine effects of feed fermentation with exopolysaccharide and reutericyclin producing L. reuteri on the transition of the gut microbiome of piglets after weaning. The reutericyclin and reuteran producing L. reuteri TMW1.656 was compared to the reutericyclin negative and levan producing L. reuteri LTH5794 and unfermented controls. Both strains were fermented at conditions supporting exopolysaccharide formation, or at conditions not supporting exopolysaccharide formation. Fecal microbiota were characterized by partial sequencing of 16S rRNA genes, and by quantitative PCR targeting clostridial toxins. The transition to solid food resulted in a transient increase of Proteobacteria to 12% of total bacteria, and increased bacterial diversity by increasing the abundance of anaerobic fiber fermenting Firmicutes. Three weeks after weaning, Prevotella and Lactobacillus were among the dominant bacterial genera. Feed fermentation with L. reuteri affected the abundance of few bacterial taxa and particularly reduced the abundance of Enterobacteriaceae (P < 0.05) when compared to unfermented controls. Reutericyclin producing L. reuteri increased the abundance of Dialister spp. and Mitsuokella spp. (P < 0.05) but did not influence the abundance of clostridial toxins in the feces. In conclusion, data on the contribution of specific metabolic activities of L. reuteri to probiotic activity will facilitate the strain selection for probiotic applications in food and feed.


Microwave radiometry in living tissue: what does it measure?
The sensitivity of microwave radiometry for detecting subcutaneous targets was studied both experimentally and theoretically. The radiometer used a dielectric loaded rectangular waveguide antenna in contact with a lossy dielectric medium. A cylindrical target with dielectric properties and/or temperature different from that of the surrounding medium was located beneath this surface. For most of the studies, the target and the surrounding medium were maintained at constant, but unequal, temperatures (i.e., heat conduction effects were insignificant). The received radiometric signal was calculated as the location and dielectric properties of the target were varied. Finally, the radiometer signal was calculated for the situation with the target maintained at constant temperature but with the surrounding medium modeled by the bioheat equation. Experimental studies were performed using a radiometer operating at 4.7 GHz. The target was a thin walled tube through which a temperature controlled liquid was circulated, located in a temperature controlled fluid tank. The results indicate that microwave radiometry (as used in this study) responds to the temperature averaged over the field pattern of the antenna with very strong weighting of regions near the surface. A simple quasi-static analysis provides a good indication of the sensitivity of the technique for detecting cylindrical targets whose dielectric properties are different from those of the surrounding medium. A simple estimate of thermal conduction around the target suggest that thermal effects greatly increase the apparent size of the target.


Treatment of Klebsiella pneumoniae carbapenemase (KPC) infections: a review of published case series and case reports.
The emergence of Klebsiella pneumoniae carbapenemases (KPCs) producing bacteria has become a significant global public health challenge while the optimal treatment remains undefined. We performed a systematic review of published studies and reports of treatment outcomes of KPC infections using MEDLINE (2001-2011). Articles or cases were excluded if one of the following was fulfilled: no individual patient data provided, no treatment regimen specified, no treatment outcome specified, report of colonization, or greater than three antibiotics were used to treat the KPC infection. Data extracted included patient demographics, site of infection, organism, KPC subtype, antimicrobial therapy directed at KPC-infection, and treatment outcome. Statistical analysis was performed in an exploratory manner. A total of 38 articles comprising 105 cases were included in the analysis. The majority of infections were due to K. pneumoniae (89%). The most common site of infection was blood (52%), followed by respiratory (30%), and urine (10%). Forty-nine (47%) cases received monotherapy and 56 (53%) cases received combination therapy directed at the KPC-infection. Significantly more treatment failures were seen in cases that received monotherapy compared to cases who received combination therapy (49% vs 25%; p= 0.01). Respiratory infections were associated with higher rates of treatment failure with monotherapy compared to combination therapy (67% vs 29% p= 0.03). Polymyxin monotherapy was associated with higher treatment failure rates compared to polymyxin-based combination therapy (73% vs 29%; p= 0.02); similarly, higher treatment failure rates were seen with carbapenem monotherapy compared to carbapenem-based combination therapy (60% vs 26%; p= 0.03). Overall treatment failure rates were not significantly different in the three most common antibiotic-class combinations: polymyxin plus carbapenem, polymyxin plus tigecycline, polymyxin plus aminoglycoside (30%, 29%, and 25% respectively; p=0.6). In conclusion, combination therapy is recommended for the treatment of KPC infections; however, which combination of antimicrobial agents needs to be established in future prospective clinical trials.


Extreme queen-mating frequency and colony fission in African army ants.
Army ants have long been suspected to represent an independent origin of multiple queen-mating in the social Hymenoptera. Using microsatellite markers, we show that queens of the African army ant Dorylus (Anomma) molestus have the highest absolute (17.3) and effective (17.5) queen-mating frequencies reported so far for ants. This confirms that obligate multiple queen-mating in social insects is associated with large colony size and advanced social organization, but also raises several novel questions. First, these high estimates place army ants in the range of mating frequencies of honeybees, which have so far been regarded as odd exceptions within the social Hymenoptera. Army ants and honeybees are fundamentally different in morphology and life history, but are the only social insects known that combine obligate multiple mating with reproduction by colony fission and extremely male-biased sex ratios. This implies that the very high numbers of matings in both groups may be due partly to the relatively low costs of additional matings. Second, we were able to trace recent events of colony fission in four of the investigated colonies, where the genotypes of the two queens were only compatible with a mother-daughter relationship. A direct comparison of male production between colonies with offspring from one and two queens, respectively, suggested strongly that new queens do not produce a sexual brood until all workers of the old queen have died, which is consistent with kin selection theory.


New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis.
We previously reported that the compound O-2093 is a selective inhibitor of the reuptake of the endocannabinoid anandamide (AEA). We have now re-examined the activity of O-2093 in vivo and synthesized four structural analogs (O-2247, O-2248, O-3246, and O-3262), whose activity was assessed in: (a) binding assays carried out with membranes from cells overexpressing the human CB(1) and CB(2) receptors; (b) assays of transient receptor potential of the vanilloid type-1 (TRPV1) channel functional activity (measurement of [Ca(2+)](i)); (c) [(14)C]AEA cellular uptake and hydrolysis assays in rat basophilic leukaemia (RBL-2H3) cells; (d) the mouse 'tetrad' tests (analgesia on a hot plate, immobility on a 'ring', rectal hypothermia and hypolocomotion in an open field); and (e) the limb spasticity test in chronic relapsing experimental allergic encephalomyelitis (CREAE) mice, a model of multiple sclerosis (MS). O-2093, either synthesized by us or commercially available, was inactive in the 'tetrad' up to a 20 mg kg(-1) dose (i.v.). Like O-2093, the other four compounds exhibited low affinity in CB(1) (K(i) from 1.3 to >10 microM) and CB(2) binding assays (1.3<K(i)< 8 microM), low potency and efficacy in a TRPV1 functional assay (EC(50)>10 microM), very low potency as fatty acid amide hydrolase (FAAH) inhibitors (IC(50)>25 microM) and were inactive in the 'tetrad' up to a 30 mg kg(-1) dose (i.v.). While O-2247 and O-2248 were poor inhibitors of [(14)C]AEA cellular uptake (IC(50)>40 microM), O-3246 and O-3262 were quite potent in this assay. O-3246, which exhibits only a very subtle structural difference with O-2093, is the most potent inhibitor of AEA uptake reported in vitro under our experimental conditions (IC(50)=1.4 microM) and is 12-fold more potent than O-2093. When injected intravenously O-3246 and O-3262, again like O-2093 and unlike O-2247 and O-2248, significantly inhibited limb spasticity in mice with CREAE. These data confirm the potential utility of selective AEA uptake inhibitors as anti-spasticity drugs in MS and, given the very subtle chemical differences between potent and weak inhibitors of uptake, support further the existence of a specific mechanism for this process.


Comparison of hemagglutinating pili of Haemophilus influenzae type b with similar structures of nontypeable H. influenzae.
Thirty-eight clinical isolates of nontypeable Haemophilus influenzae were tested for the presence of hemagglutinating pili similar to those of H. influenzae type b (Hib) that mediate buccal epithelial cell adherence. Four endogenously hemagglutinating (HA+) strains were identified, and eight additional HA+ variants were obtained from HA- strains by erythrocyte enrichment. All 12 HA+ nontypeable H. influenzae isolates bound antisera directed against denatured pilins of Hib, but none bound antisera against assembled native pili of Hib. In erythrocyte- and buccal-cell-binding assays, HA+ nontypeable H. influenzae binding was reduced compared with HA+ Hib binding and was not significantly different from HA- nontypeable H. influenzae binding. Both HA- and HA+ nontypeable H. influenzae binding was increased over binding of HA- Hib. HA+ nontypeable H. influenzae strains agglutinated adult erythrocytes that possess the Anton antigen, which is thought to be the receptor for Hib pili, and did not agglutinate cord or Lu(a-b-) dominant erythrocytes, which lack the Anton antigen. Electron microscopy of HA- and HA+ variants of three nontypeable H. influenzae strains showed few or no surface appendages on the HA- organisms, but piluslike structures were seen on many organisms from two HA+ nontypeable H. influenzae strains and on a few organisms from one strain. Thus, nontypeable H. influenzae appears to possess structures that are immunologically similar to the pilins that make up the hemagglutinating pili of Hib. However, nontypeable H. influenzae appears to also possess mechanisms for erythrocyte and buccal cell adherence that are not directly correlated with the presence of a hemagglutinating pilus.


Post-traumatic myelopathy following flopping high jump: a pilot case of spinal manipulation.
To present the first case of spinal cord injury from high jump and the first pilot case of spinal manipulation for post-traumatic myelopathy. An 11-yr-old tetraplegic boy was admitted to the hospital, where he had a thorough neurological examination, including myelogram, EEG and skull and spinal X rays, with normal findings. The author revealed subtle subluxations on plain X-ray films. Triceps hyperreflexia was detected bilaterally. Bilateral patella and ankle clonus with hyperreflexia, basic and excess spasticity, and bilateral extensor plantar responses were noted in the lower limbs. A clinical diagnosis of early post-traumatic incomplete spastic tetraplegia below C7 was made. He did not respond to 3 months of orthodox conservative hospital management, including steroid therapy. Spinal manipulation of the lower cervical and upper thoracic spine was performed in a private chiropractic clinic for 2 wk. He apparently recovered after 3 months of spinal manipulation. On recent examination, he has virtually completely recovered. He still suffers from hand muscle atrophy, hyperreflexia of the triceps and ankle reflex and bilateral positive Babinski reflex; ankle and patellar clonus are almost absent. The early response and long-term (9-yr follow-up) benefits of spinal manipulation to the early delayed traumatic myelopathy of this patient suggest spinal cord ischemia as its pathophysiology. Mechanisms of post-traumatic myelopathy are postulated. Biomechanical mechanisms of spinal manipulation for neurological recovery of post-traumatic myelopathy and/or radiculopathy are advanced. Further pilot spinal manipulation by experienced chiropractors after adequate anti-edematous (steroid) therapy is recommended for selected patients with post-traumatic myelopathy and/or radiculopathy, especially in a multidisciplinary spinal injury unit.


Biosynthesis of complement C1 inhibitor by Hep G2 cells. Reactivity of different glycosylated forms of the inhibitor with C1s.
The biosynthesis of C1 Inh (C1 inhibitor) was studied in a human hepatoma cell line (Hep G2) by metabolic labelling, immunoprecipitation with anti-(C1 Inh) serum, analysis on SDS/polyacrylamide gel slabs and fluorography. Two forms of C1 Inh are secreted by Hep G2: a minor form of Mr 90,000 and a major form of Mr approximately 100,000. The latter form is also found in small amounts intracellularly in co-existence with an 80,000-Mr form. Accumulation of the 80,000-Mr C1 Inh is favoured when the cells are labelled at 23 degrees C instead of 37 degrees C or when they are treated with monensin. In the presence of tunicamycin, a compound that blocks the formation of N-asparagine-linked oligosaccharide chains, a decrease in Mr of both secreted and intracellular major forms is observed, indicating that secreted and intracellular C1 Inh contain N-linked oligosaccharide units. The 100,000 Mr secreted C1 Inh is sensitive to endoglycosidase F but resistant to endoglycosidase H, and it incorporates [3H]galactose, [3H]glucosamine and [3H]galactosamine, indicating the presence of both N-linked oligosaccharides of the complex type and O-linked oligosaccharides. The intracellular C1 Inh contains N-linked oligosaccharide units of the high-mannose type as demonstrated by endoglycosidase H-sensitivity. The functional activity of C1 Inh during its biosynthesis was tested by studying its reactivity towards C1s. Both secreted and intracellular C1 Inh form covalent-like complexes with purified plasma C1s. The underglycosylated C1 Inh secreted in presence of tunicamycin is still reactive with purified C1s. These results clearly show that sugars are not essential for this inhibitory activity of C1 Inh.