Mobile phone-based surveillance for animal disease in rural communities: implications for detection of zoonoses spillover.
Improving the speed of outbreak detection and reporting at the community level are critical in managing the threat of emerging infectious diseases, many of which are zoonotic. The widespread use of mobile phones, including in rural areas, constitutes a potentially effective tool for real-time surveillance of infectious diseases. Using longitudinal data from a disease surveillance system implemented in 1500 households in rural Kenya, we test the effectiveness of mobile phone animal syndromic surveillance by comparing it with routine household animal health surveys, determine the individual and household correlates of its use and examine the broader implications for surveillance of zoonotic diseases. A total of 20 340 animal and death events were reported from the community through the two surveillance systems, half of which were confirmed as valid disease events. The probability of an event being valid was 2.1 times greater for the phone-based system, compared with the household visits. Illness events were 15 times (95% CI 12.8, 17.1) more likely to be reported through the phone system compared to routine household visits, but not death events (OR 0.1 (95% CI 0.09, 0.11)). Disease syndromes with severe presentations were more likely to be reported through the phone system. While controlling for herd and flock sizes owned, phone ownership was not a determinant of using the phone-based surveillance system, but the lack of a formal education, and having additional sources of income besides farming were associated with decreased likelihood of reporting through the phone system. Our study suggests that a phone-based surveillance system will be effective at detecting outbreaks of diseases such as Rift Valley fever that present with severe clinical signs in animal populations, but in the absence of additional reporting incentives, it may miss early outbreaks of diseases such as avian influenza that present primarily with mortality. This article is part of the theme issue 'Dynamic and integrative approaches to understanding pathogen spillover'.


Alcohol and coronary heart disease.
The data on two questions are reviewed: does heavy alcohol intake increase the risk of coronary heart disease (CHD)? And, is moderate intake protective? Identified alcoholics and problem drinkers have an increased risk of CHD, and in Britain there is a correlation among 22 towns, between the proportion of heavy drinkers in a town and CHD mortality. Of seven longitudinal studies reviewed, one shows heavy drinkers to have an increased CHD incidence. An inverse association between alcohol consumption and CHD mortality is seen in international comparisons and in time trends in the USA. Of six case-control studies reviewed from England and the USA, all show an inverse association between CHD and alcohol consumption which persists after control for other risk factors. Longitudinal studies, in Japanese-Americans, white American men and women, British civil servants, Puerto Ricans, Yugoslavs and Australians, all show moderate drinkers to have a lower CHD risk than abstainers. Abstainers are likely to differ from moderate drinkers in a number of ways. To date it has not proved possible to show that any of these differences account for the higher CHD risk of abstainers. The apparent protective effect is not large (RR = 0.5) but the consistency of the association and the existence of plausible mechanisms increase the likelihood that the negative association is causal. However, if alcohol intake were to increase in the population the social and medical consequences would be large. An increased intake is therefore not recommended as a community measure for CHD prevention.


Translating stem and progenitor cell biology to the clinic: barriers and opportunities.
Stem cells are the natural units of embryonic generation, and also adult regeneration, of a variety of tissues. Recently, the list of tissues that use the model of differentiation from stem to progenitor to mature cell has increased from blood to include a variety of tissues, including both central and peripheral nervous systems and skeletal muscle; it is also possible that all organs and tissues are derived from, and still contain, stem cells. Because the number and activities of stem cells and their progeny are homeostatically regulated, clinical stem cell transplantation could greatly add to the physician's armamentarium against degenerative diseases.


Prostaglandin-E2 is produced by adult human epidermal melanocytes in response to UVB in a melanogenesis-independent manner.
Excessive ultraviolet radiation (UVR) exposure induces erythema, mediated in part by prostaglandin-E(2) (PGE(2)). While keratinocytes are a major PGE(2) source, epidermal melanocytes (EM) also express PGE(2)-production machinery. It is unclear whether EM-produced PGE(2) contributes to UVR-induced skin inflammation, and whether this is correlated with melanogenesis. Epidermal melanocytes were cultured from skin phototype-1 and -4 donors, followed by assessment of PGE(2) production and melanogenesis. Epidermal melanocytes expressed cytoplasmic phospholipase-A(2), cyclooxygenase-1, cytoplasmic prostaglandin-E synthase and microsomal prostaglandin-E synthase-1, -2. Epidermal melanocytes produced PGE(2) under basal conditions, which increased further after arachidonic acid stimulation. Epidermal melanocytes expressed cyclooxygenase-2 (COX-2) mRNA and a selective COX-2 inhibitor (NS-398) reduced PGE(2) production. Ultraviolet B-induced PGE(2) production was positively correlated with skin phototype-1, despite variability between individual EM donors. By contrast, there was no correlation between PGE(2) production by EM and their melanogenic status. Thus, EM may contribute to UVR-induced erythema, with role of donor skin phototype more important than their melanogenic status.


Spontaneous pneumothorax: comparison of simple drainage, talc pleurodesis, and tetracycline pleurodesis.
From 1978 to 1985 96 patients with their first spontaneous pneumothorax were randomised into three groups, receiving either treatment with simple drainage (34 patients), drainage with tetracycline pleurodesis (33 patients), or drainage with talc pleurodesis (29 patients). There were 58 men and 38 women, aged 18-88 years. There was no significant difference between the three groups in the mean time in hospital or the period for which the drains were retained. The incidence of infection, persistent pneumothorax, and relapse while in hospital was also similar for the three groups. At follow-up in 1987-89 patients could be accounted for, with an average follow-up period of 4.6 years. The incidence of recurrence was 36% in the simple drainage group, 13% in the tetracycline pleurodesis group, and 8% in the talc pleurodesis group. The difference between the talc and simple drainage groups was significant. None of the methods caused severe short or long term side effects or changes in the follow-up chest radiograph. Thoracoscopy, performed on admission in 85 patients, showed normal appearances in 73 patients and small cysts in 12. The thoracoscopic findings were of no value in predicting recurrence. Talc pleurodesis resulted in a significantly lower recurrence rate than simple drainage, tetracycline pleurodesis having intermediate efficacy.


Understanding environmental sounds in sentence context.
There is debate about how individuals use context to successfully predict and recognize words. One view argues that context supports neural predictions that make use of the speech motor system, whereas other views argue for a sensory or conceptual level of prediction. While environmental sounds can convey clear referential meaning, they are not linguistic signals, and are thus neither produced with the vocal tract nor typically encountered in sentence context. We compared the effect of spoken sentence context on recognition and comprehension of spoken words versus nonspeech, environmental sounds. In Experiment 1, sentence context decreased the amount of signal needed for recognition of spoken words and environmental sounds in similar fashion. In Experiment 2, listeners judged sentence meaning in both high and low contextually constraining sentence frames, when the final word was present or replaced with a matching environmental sound. Results showed that sentence constraint affected decision time similarly for speech and nonspeech, such that high constraint sentences (i.e., frame plus completion) were processed faster than low constraint sentences for speech and nonspeech. Linguistic context facilitates the recognition and understanding of nonspeech sounds in much the same way as for spoken words. This argues against a simple form of a speech-motor explanation of predictive coding in spoken language understanding, and suggests support for conceptual-level predictions.


Can the tricyanomethanide anion improve CO2 absorption by acetate-based ionic liquids?
Carbon dioxide absorption by mixtures of two ionic liquids with a common cation-1-butyl-3-methylimidazolium acetate, [C4C1Im][OAc], and 1-butyl-3-methylimidazolium tricyanomethanide, [C4C1Im][C(CN)3]-was determined experimentally at pressures below atmospheric pressure as a function of temperature between 303 K and 343 K, and at 303 K as a function of pressure up to 10 bar. It is observed that the absorption of carbon dioxide decreases with increasing tricyanomethanide anion concentration and with increasing temperature, showing a maximum of 0.4 mole fraction of carbon dioxide in pure [C4C1Im][OAc] at 303 K. At this temperature, the CO2 absorption in the mixtures [C4C1Im][OAc](1-x)[C(CN)3]x is approximately the mole-fraction average of that in the pure ionic liquids. By applying an appropriate thermodynamic treatment, after identification of the species in solution, it was possible to calculate both the equilibrium constant, Keq, and Henry's law constant, KH, in the different mixtures studied thus obtaining an insight into the relative contribution of chemical and physical absorption of the gas. It is shown that chemical sorption proceeds through a 1 : 2 stoichiometry between CO2 and acetate-based ionic liquid. The presence of the C(CN)3- anion does not significantly affect the chemical reaction of the gas with the solvent (Keq = 75 ± 2 at 303 K) but leads to lower Henry's law constants (from KH = 77.8 ± 0.6 bar to KH = 49.5 ± 0.5 bar at 303 K), thus pointing towards larger physical absorption of the gas. The tricyanomethanide anion considerably improves the mass transfer by increasing the fluidity of the absorbent as proven by the larger diffusivities of all the ions when the concentration of the C(CN)3- anion increases in the mixtures.


Impact of migration and acculturation on prevalence of type 2 diabetes and related eye complications in Indians living in a newly urbanised society.
Health of migrants is a major public health challenge faced by governments and policy makers. Asian Indians are among the fastest growing migration groups across Asia and the world, but the impact of migration and acculturation on diabetes and diabetes-related eye complications among Indians living in urban Asia remains unclear. We evaluated the influence of migration and acculturation (i.e., migration status and length of residence) on the prevalence of type-2 diabetes mellitus (T2DM) and diabetes-related eye complications (diabetic retinopathy (DR) and cataract), among first-generation (defined as participant born in India with both parents born in India, n = 781) and second-generation (participants born in Singapore with both parents born in India, n = 1,112) Indian immigrants from a population-based study of Adult Indians in Singapore. Diabetes was defined as HbA1c≥6.5%, use of diabetic medication or a physician diagnosis of diabetes. Retinal and lens photographs were graded for the presence of DR and cataract. Compared to first generation immigrants, second generation immigrants had a higher age- and gender-standardized prevalence of T2DM (34.4% versus 29.0%, p<0.001), and, in those with T2DM, higher age- and gender-standardized prevalence of DR (31.7% versus 24.8%, p<0.001), nuclear cataract (13.6% versus 11.6%, p<0.001), and posterior sub-capsular cataract (6.4% versus 4.6%, p<0.001). Among first generation migrants, longer length of residence was associated with significantly younger age of diagnosis of diabetes and greater likelihood of having T2DM and diabetes-related eye complications. Second generation immigrant Indians and longer length of residence are associated with higher prevalence of diabetes and diabetes-related complications (i.e., DR and cataract) among migrant Indians living in Singapore. These data highlight potential worldwide impacts of migration patterns on the risk and burden of diabetes.


Properties of a cytochrome c-enriched light particulate fraction isolated from the photosynthetic bacterium Rhodopseudomonas spheroides.
Differential centrifugation of suspensions of French-press-disrupted Rhodopseudomonas spheroides yielded a light particulate fraction that was different in many properties from the bulk membrane fraction. It was enriched in cytochrome c and had a low cytochrome b content. When prepared from photosynthetically grown cells this fraction had a very low specific bacteriochlorophyll content. The cytochrome c of the light particles differed in absorption maxima at 77K from cytochrome c2 attached to membranes; there was pronounced splitting of the alpha-band, as is found in cytochrome c2 free in solution. Potentiometric titration at A552--A540 showed the presence of two components that fitted an n = 1 titration; one component had a midpoint redox potential of +345mV, like cytochrome c2 in solution, and the second had E0' at pH 7.0 of +110 mV, and they were present in a ratio of approx. 2:3. Difference spectroscopy at 77K showed that the spectra of the two components were very similar. More of a CO-binding component was present in particles from photosynthetically grown cells. Light membranes purified by centrifugation on gradients of 5--60% (w/w) sucrose retained the two c cytochromes; they contained no detectable succinate-cytochrome c reductase or bacteriochlorophyll and very little ubiquinone, but they contained NADH-cytochrome c reductase and some phosphate. Electrophoresis on sodium dodecyl sulphate/polyacrylamide gels showed that the light membranes of aerobically and photosynthetically grown cells were very similar and differed greatly from other membrane fractions of R. spheroides.


A comprehensive analysis and immunobiology of autoimmune neurological syndromes during the Zika virus outbreak in Cúcuta, Colombia.
We have focused on the epidemiology and immunobiology of Zika virus (ZIKV) infection and factors associated with the development of Guillain-Barré syndrome (GBS) and other neurological syndromes in Cúcuta, the capital of North Santander department, Colombia. Data of patients with ZIKV disease reported to the national population-based surveillance system were used to calculate the basic reproduction number (R0) and the attack rates (ARs) as well as to develop epidemiological maps. Patients with neurological syndromes were contacted and their diagnoses were confirmed. A case-control study in which 29 patients with GBS associated with ZIKV compared with 74-matched control patients with ZIKV infection alone was undertaken. Antibodies against arboviruses and other infections that may trigger GBS were evaluated. The estimated value of R0 ranged between 2.68 (95% CI 2.54-2.67) to 4.57 (95% CI 4.18-5.01). The sex-specific ARs were 1306 per 100,000 females, and 552 per 100,000 males. A non-linear interaction between age and gender on the ARs was observed. The incidence of GBS in Cúcuta increased 4.41 times secondary to ZIKV infection. The lag time between ZIKV infection and neurological symptoms was 7 days (interquartile range 2-14.5). Patients with GBS appeared to represent a lower socioeconomic status and were living near to environmentally contaminated areas. All GBS patients were positive for IgG antibodies against both ZIKV and Dengue virus, and 69% were positive for Chikungunya virus. Noteworthy, GBS was associated with a previous infection with M. pneumoniae (OR: 3.95; 95% CI 1.44-13.01; p = 0.006). No differences in antibody levels against C. jejuni, Epstein-Barr virus and cytomegalovirus were observed. High rates of cranial nerves involvement and dysautonomia were present in 82% and 75.9%, respectively. Intensive care unit (ICU) admission was necessary in 69% of the GBS patients. Most of the patients disclosed a high disability condition (Hughes grade 4). Dysautonomia was the main risk factor of poor GBS prognosis (i.e., ICU admission and disability). Thirteen patients were diagnosed with other neurological syndromes different to GBS (6 with transverse myelitis, 3 with encephalitis, 3 with peripheral facial palsy and one with thoraco-lumbosacral myelopathy). Our data confirm an increased transmission of ZIKV in Cúcuta, and provide support to the view that severe neurological syndromes are related to ZIKV disease. The complex ways by which previous infections and socioeconomic status interact to increase the risk of GBS in people infected by ZIKV should be further investigated.


New approach to Gutenberg-Richter scaling.
We introduce a new model for an earthquake fault system that is composed of noninteracting simple lattice models with different levels of damage denoted by q. The undamaged lattice models (q=0) have Gutenberg-Richter scaling with a cumulative exponent β=1/2, whereas the damaged models do not have well defined scaling. However, if we consider the "fault system" consisting of all models, damaged and undamaged, we get excellent scaling with the exponent depending on the relative frequency with which faults with a particular amount of damage occur in the fault system. This paradigm combines the idea that Gutenberg-Richter scaling is associated with an underlying critical point with the notion that the structure of a fault system also affects the statistical distribution of earthquakes. In addition, it provides a framework in which the variation, from one tectonic region to another, of the scaling exponent, or b value, can be understood.


Rapid repeat pregnancy among unmarried, African American adolescent parent couples.
This article describes rapid repeat pregnancy (RRP), getting pregnant or giving birth again within 24 months of giving birth, in a group of unmarried, low-income, African American first-time, adolescent parent couples from the perspectives of their kinship systems, that is, the adolescent parents and their parents or parental figures. RRP has been associated with prematurity, low birth weight, inadequate prenatal care, school dropout, increased potential for poverty, and prolonged welfare dependence. There were 21 RRPs among 24 kinship systems: 9 adolescent males who fathered RRPs with new partners and also reported having been denied access to their study babies; 6 adolescent mothers with new partners, who also reported intimate partner violence with the study adolescent father; and 6 study adolescent parent couples, whose paternal family reported doubts about the paternity of the study babies. Adolescent fathers should be offered the same child care and contraceptive information routinely offered to adolescent mothers.


The cross correlation function of partially coherent vortex beam.
This work presents theoretical analysis on the cross correlation function (CCF) of partially coherent vortex beam (PCVB), where the relation of the number of the rings of CCF dislocations and orbital angular momentum (OAM) of PCVB is analyzed in detail. It is shown that rings of CCF dislocations do not always exist, and depend on the coherence length, the order of PCVB and location of observation plane, although the CCF indicates topological charge to some degree. Comprehensive analysis of the CCF of PCVB and numerical simulations all validate such phenomenon.


Ginsenoside Rg1 nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction.
Diabetic cerebral infarction is with poorer prognosis and high rates of mortality. Ginsenoside Rg1 (Rg1) has a wide variety of therapeutic values for central nervous system (CNS) diseases for the neuron protective effects. However, the blood-brain barrier (BBB) restricts Rg1 in reaching the CNS. In this study, we investigated the therapeutic effects of Rg1 nanoparticle (PHRO, fabricated with γ-PGA, L-PAE (H), Rg1, and OX26 antibody), targeting transferrin receptor, on the diabetes rats complicated with diabetic cerebral infarction in vitro and in vivo. Dynamic light scattering analysis shows the average particle size of PHRO was 79±18 nm and the polydispersity index =0.18. The transmission electron microscope images showed that all NPs were spherical in shape with diameters of 89±23 nm. PHRO released Rg1 with sustained release manner and could promote the migration of cerebrovascular endothelial cells and tube formation and even penetrated the BBB in vitro. PHRO could penetrate the BBB with high concentration in brain tissue to reduce the cerebral infarction volume and promote neuronal recovery in vivo. PHRO was promising to be a clinical treatment of diabetes mellitus with cerebral infarction.


Reliability of normalisation methods for EMG analysis of neck muscles.
Acceptable reliability of normalisation contractions in electromyography (EMG) is paramount for testing conducted over a number of days or if normal laboratory strength testing equipment is unavailable. This study examined the reliability of maximal voluntary isometric contractions (MVIC) and sub-maximal (60%) isometric contractions for use in neck muscle EMG studies. Surface EMG was recorded bilaterally from eight sites around the neck at C4/5 level from five healthy male subjects. Subjects performed MVIC and sub-maximal normalisation contractions using an isokinetic dynamometer (ID) and a portable cable dynamometer with attached strain gauge (PCD) in addition to a MVIC against a manual resistance (MR). Subjects were tested in flexion, extension, left and right lateral bending and were retested by the same tester within a two-week period. Intra class correlation co-efficients (ICC) were calculated for each testing method and contraction direction and a mean ICC was calculated across all contraction directions. All normalisation methods produced excellent within-day reliability (mean ICC >0.80) but only the MVICs using the ID and PCD had acceptable reliability when assessed between-days. This study confirmed the validity of using MVICs elicited using the ID and PCD as reliable reference contractions for the normalisation of neck EMG.


Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia.
Three patients diagnosed with acute myeloid leukemia (AML) with reciprocal 21q22/RUNX1(AML1) translocations involving chromosomes 1 and 4 were studied. Three novel RUNX1 translocation partner genes on 1q21.2 (ZNF687), 1p35 (YTHDF2), and 4q31.3 (SH3D19) were identified using a panhandle polymerase chain reaction and the 3' rapid amplification of cDNA ends method. The translocation events occurred between exons 3 and 7 of the RUNX1 gene. The partner gene breakpoints localized to the region in the partner gene with the highest Alu density, suggesting that Alus may contribute to the recombination events. Two out of three of the cases retained RUNX1's entire RUNT domain in the translocation, and RUNX1 mutations were absent in the fusion transcripts, confirmed by reverse transcription-polymerase chain reaction and sequencing analysis. SH3D19 encodes a cytoplasmic protein EBP known to suppress RAS-induced cellular transformation, which can be inhibited by nuclear recruitment. The t(4;21) created a hybrid RUNX1-EBP protein retaining RUNX1's DNA binding domain, which may result in nuclear localization of the chimeric protein and inhibition of EBP's RAS-suppressive functions. Future studies would be useful to further characterize these novel fusion protein products.


Tdrd1 acts as a molecular scaffold for Piwi proteins and piRNA targets in zebrafish.
Piwi proteins function in an RNAi-like pathway that silences transposons. Piwi-associated RNAs, also known as piRNAs, act as a guide to identify Piwi targets. The tudor domain-containing protein Tdrd1 has been linked to this pathway but its function has thus far remained unclear. We show that zebrafish Tdrd1 is required for efficient Piwi-pathway activity and proper nuage formation. Furthermore, we find that Tdrd1 binds both zebrafish Piwi proteins, Ziwi and Zili, and reveals sequence specificity in the interaction between Tdrd1 tudor domains and symmetrically dimethylated arginines (sDMAs) in Zili. Finally, we show that Tdrd1 complexes contain piRNAs and RNA molecules that are longer than piRNAs. We name these longer transcripts Tdrd1-associated transcripts (TATs). TATs likely represent cleaved Piwi pathway targets and may serve as piRNA biogenesis intermediates. Altogether, our data suggest that Tdrd1 acts as a molecular scaffold for Piwi proteins, bound through specific tudor domain-sDMA interactions, piRNAs and piRNA targets.


Effects of small intestinal glucose load on blood pressure, splanchnic blood flow, glycemia, and GLP-1 release in healthy older subjects.
Postprandial hypotension is an important problem, particularly in the elderly. The fall in blood pressure is dependent on small intestinal glucose delivery and, possibly, changes in splanchnic blood flow, the release of glucagon-like peptide-1 (GLP-1), and sympathetic nerve activity. We aimed to determine in healthy older subjects, the effects of variations in small intestinal glucose load on blood pressure, superior mesenteric artery flow, GLP-1, and noradrenaline. Twelve subjects (6 male, 6 female; ages 65-76 yr) were studied on four separate occasions, in double-blind, randomized order. On each day, subjects were intubated via an anesthetized nostril, with a nasoduodenal catheter, and received an intraduodenal infusion of either saline (0.9%) or glucose at a rate of 1, 2, or 3 kcal/min (G1, G2, G3, respectively), for 60 min (t = 0-60 min). Between t = 0 and 60 min, there were falls in systolic and diastolic blood pressure following G2 and G3 (P = 0.003 and P < 0.001, respectively), but no change during saline or G1. Superior mesenteric artery flow increased slightly during G1 (P = 0.01) and substantially during G2 (P < 0.001) and G3 (P < 0.001), but not during saline. The GLP-1 response to G3 was much greater (P < 0.001) than to G2 and G1. Noradrenaline increased (P < 0.05) only during G3. In conclusion, in healthy older subjects the duodenal glucose load needs to be > 1 kcal/min to elicit a significant fall in blood pressure, while the response may be maximal when the rate is 2 kcal/min. These observations have implications for the therapeutic strategies to manage postprandial hypotension by modulating gastric emptying.


Ultra-deep, long-read nanopore sequencing of mock microbial community standards.
Long sequencing reads are information-rich: aiding de novo assembly and reference mapping, and consequently have great potential for the study of microbial communities. However, the best approaches for analysis of long-read metagenomic data are unknown. Additionally, rigorous evaluation of bioinformatics tools is hindered by a lack of long-read data from validated samples with known composition. We sequenced 2 commercially available mock communities containing 10 microbial species (ZymoBIOMICS Microbial Community Standards) with Oxford Nanopore GridION and PromethION. Both communities and the 10 individual species isolates were also sequenced with Illumina technology. We generated 14 and 16 gigabase pairs from 2 GridION flowcells and 150 and 153 gigabase pairs from 2 PromethION flowcells for the evenly distributed and log-distributed communities, respectively. Read length N50 ranged between 5.3 and 5.4 kilobase pairs over the 4 sequencing runs. Basecalls and corresponding signal data are made available (4.2 TB in total). Alignment to Illumina-sequenced isolates demonstrated the expected microbial species at anticipated abundances, with the limit of detection for the lowest abundance species below 50 cells (GridION). De novo assembly of metagenomes recovered long contiguous sequences without the need for pre-processing techniques such as binning. We present ultra-deep, long-read nanopore datasets from a well-defined mock community. These datasets will be useful for those developing bioinformatics methods for long-read metagenomics and for the validation and comparison of current laboratory and software pipelines.


The nematic phases of bent-core liquid crystals.
Over the last ten years, the nematic phases of liquid crystals formed from bent-core structures have provoked considerable research because of their remarkable properties. This Minireview summarises some recent measurements of the physical properties of these systems, as well as describing some new data. We concentrate on oxadiazole-based materials as exemplars of this class of nematogens, but also describe some other bent-core systems. The influence of molecular structure on the stability of the nematic phase is described, together with progress in reducing the nematic transition temperatures by modifications to the molecular structure. The physical properties of bent-core nematic materials have proven difficult to study, but patterns are emerging regarding their optical and dielectric properties. Recent breakthroughs in understanding the elastic and flexoelectric behaviour are summarised. Finally, some exemplars of unusual electric field behaviour are described.


[How deaf people cope in routine and emergency situations - suggested paths for thought and action].
Oeaf people have unique characteristics and needs. There is a limited amount of research regarding the needs of deaf people, and no studies were found concerning deaf people in emergency situations. The absence of the sense of hearing in deaf people is only one component of the complexity of their world. Many factors contribute to this complexity, but the most striking is the means of communication between the deaf and the hearing person and vice versa. Changes during emergency situations present a challenge for hearing individuals, and even more so, for deaf people. Deaf individuals experience difficulty in obtaining and transmitting information, accessing care and more. These difficulties often result in the dependency of the deaf person on others. The State of Israel enacted laws targeted to facilitate the access of individuals with disabilities in general, and deaf people in particular, to public services. In emergencies, the Home Front Command and the Ministry of Social Welfare distribute pagers to the deaf population, as a device to communicate warning alerts. However, these devices do not fulfil the need for accessible care, bi-directional flow of information, and additional needs that arise during times of emergency. The deaf population is a cultural minority, whose needs in emergency situations are unknown. Familiarity with the deaf population is the first step towards improving treatment and communication that are apt for this population. This paper reviews what is known in the literature about this topic and presents an attempt to bridge the gap of knowledge and barriers to communication between the deaf population and


Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment.
Cytokines and alcohol share a common modulation of inflammation and hormones as well as being implicated in multiple diseases, but the mechanisms are poorly understood. The purpose of this study was to investigate the interaction of liver, serum and brain cytokines as well as whether ethanol would potentiate endotoxin (Lipopolysaccharide, LPS) responses once ethanol had cleared. Male C57BL/6J mice were treated intragastrically with water (control) or ethanol (5 g/kg, i.g., 25% ethanol, w/v), with volumes matched, for 1 day or daily for 10 days. Mice were then injected intraperitoneally with saline (control) or LPS (3 mg/kg, i.p.) in saline 24 hrs after the last dose of ethanol. Gene expression and protein synthesis of proinflammatory cytokines and anti-inflammatory cytokine, oxidative enzymes, microglial activation and inhibition of neurogenesis were examined using real-time PCR, ELISA, and immunohistochemistry. LPS increased proinflammatory cytokines (TNFalpha, MCP-1, IL-1beta) several fold in liver, brain and serum at 1 hr. Ethanol is known to increase liver cytokines and alter the risk of multiple chronic diseases. Ten daily doses of ethanol increased brain and liver TNFalpha, and pretreatment with ethanol potentiated LPS-induced increases in TNFalpha, MCP-1, IL-1beta in liver, serum and brain. Proinflammatory cytokine levels in liver and serum returned to basal levels within a day, whereas brain proinflammatory cytokines remained elevated for long periods. IL-10, an anti-inflammatory cytokine, is reduced in brain by ethanol and LPS, while brain proinflammatory cytokines remain increased, whereas liver IL-10 is increased when proinflammatory cytokines have returned to control levels. Activation of brain microglia indicated by morphological changes, reduced neurogenesis and increased brain expression of COX-2 and gp91phox NADPH oxidase subunit mRNA were found in the 10 daily doses of ethanol-pretreated LPS group. Acute increases in serum cytokines induce long lasting increases in brain proinflammatory cytokines. Ten daily doses of ethanol exposure results in persistent alterations of cytokines and significantly increases the magnitude and duration of central and peripheral proinflammatory cytokines and microglial activation. Ethanol induced differential anti-inflammatory cytokine IL-10 responses in liver and brain could cause long lasting disruption of cytokine cascades that could contribute to protection or increased risk of multiple chronic diseases.


Post-incident review after restraint in mental health care -a potential for knowledge development, recovery promotion and restraint prevention. A scoping review.
Use of physical restraint is a common practice in mental healthcare, but is controversial due to risk of physical and psychological harm to patients and creating ethical dilemmas for care providers. Post-incident review (PIR), that involve patient and care providers after restraints, have been deployed to prevent harm and to reduce restraint use. However, this intervention has an unclear scientific knowledge base. Thus, the aim of this scoping review was to explore the current knowledge of PIR and to assess to what extent PIR can minimize restraint-related use and harm, support care providers in handling professional and ethical dilemmas, and improve the quality of care in mental healthcare. Systematic searches in the MEDLINE, PsychInfo, Cinahl, Sociological Abstracts and Web of Science databases were carried out. The search terms were derived from the population, intervention and settings. Twelve studies were included, six quantitative, four qualitative and two mixed methods. The studies were from Sweden, United Kingdom, Canada and United States. The studies' design and quality varied, and PIR s' were conducted differently. Five studies explored PIR s' as a separate intervention after restraint use, in the other studies, PIR s' were described as one of several components in restraint reduction programs. Outcomes seemed promising, but no significant outcome were related to using PIR alone. Patients and care providers reported PIR to: 1) be an opportunity to review restraint events, they would not have had otherwise, and 2) promote patients' personal recovery processes, and 3) stimulate professional reflection on organizational development and care. Scientific literature directly addressing PIR s' after restraint use is lacking. However, results indicate that PIR may contribute to more professional and ethical practice regarding restraint promotion and the way restraint is executed. The practice of PIR varied, so a specific manual cannot be recommended. More research on PIR use and consequences is needed, especially PIR's potential to contribute to restraint prevention in mental healthcare.


Development and implementation of guidelines in allergic rhinitis – an ARIA-GA2LEN paper.
The links between asthma and rhinitis are well characterized. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines stress the importance of these links and provide guidance for their prevention and treatment. Despite effective treatments being available, too few patients receive appropriate medical care for both diseases. Most patients with rhinitis and asthma consult primary care physicians and therefore these physicians are encouraged to understand and use ARIA guidelines. Patients should also be informed about these guidelines to raise their awareness of optimal care and increase control of the two related diseases. To apply these guidelines, clinicians and patients need to understand how and why the recommendations were made. The goal of the ARIA guidelines is to provide recommendations about the best management options for most patients in most situations. These recommendations should be based on the best available evidence. Making recommendations requires the assessment of the quality of available evidence, deciding on the balance between benefits and downsides, consideration of patients' values and preferences, and, if applicable, resource implications. Guidelines must be updated as new management options become available or important new evidence emerges. Transparent reporting of guidelines facilitates understanding and acceptance, but implementation strategies need to be improved.


A Benchmark for Homomeric Enzyme Active Site Structure Prediction Highlights the Importance of Accurate Modeling of Protein Symmetry.
Accurate prediction and modeling of an enzyme's active site are critical for engineering efforts as well as providing insight into an enzyme's naturally occurring function. Previous efforts demonstrated that the integration of constraints enforcing strict geometric orientations between catalytic residues significantly improved the modeling accuracy for the active sites of monomeric enzymes. In this study, a similar approach was explored to evaluate the effect on the active sites of homomeric enzymes. A benchmark of 17 homomeric enzymes with known structures and a bound ligand relevant to the established chemistry were identified from the protein data bank. The enzymes identified span multiple classes as well as symmetries. Unlike what was observed for the monomeric enzymes, upon the application of catalytic geometric constraints, there was no significant improvement observed in modeling accuracy for either the active site of the protein structure or the accuracy of the subsequently docked ligand. Upon further analysis, it is apparent that the symmetric interface being modeled is inaccurate and prevented the active sites from being modeled at atomic-level accuracy. This is consistent with the challenge others have identified in being able to predict de novo protein symmetry. To further improve the accuracy of active site modeling for homomeric proteins, new methodologies to accurately model the symmetric interfaces of these complexes are needed.


Steady-state cerebral glucose concentrations and transport in the human brain.
Understanding the mechanism of brain glucose transport across the blood-brain barrier is of importance to understanding brain energy metabolism. The specific kinetics of glucose transport have been generally described using standard Michaelis-Menten kinetics. These models predict that the steady-state glucose concentration approaches an upper limit in the human brain when the plasma glucose level is well above the Michaelis-Menten constant for half-maximal transport, Kt. In experiments where steady-state plasma glucose content was varied from 4 to 30 mM, the brain glucose level was a linear function of plasma glucose concentration. At plasma concentrations nearing 30 mM, the brain glucose level approached 9 mM, which was significantly higher than predicted from the previously reported Kt of approximately 4 mM (p < 0.05). The high brain glucose concentration measured in the human brain suggests that ablumenal brain glucose may compete with lumenal glucose for transport. We developed a model based on a reversible Michaelis-Menten kinetic formulation of unidirectional transport rates. Fitting this model to brain glucose level as a function of plasma glucose level gave a substantially lower Kt of 0.6 +/- 2.0 mM, which was consistent with the previously reported millimolar Km of GLUT-1 in erythrocyte model systems. Previously reported and reanalyzed quantification provided consistent kinetic parameters. We conclude that cerebral glucose transport is most consistently described when using reversible Michaelis-Menten kinetics.


Treatment of renal artery embolism.
Renal artery embolectomy was performed on four patients. There was no operative mortality. Four of the five affected kidneys were salvaged. The most common initial symptom was flank pain. The literature from 1970 to 1982 was reviewed to determine the current operative mortality (11%) and frequency of kidney salvage (67% to 90%) with surgery or anticoagulation. Newer treatment modalities, including intraarterially injected low-dose streptokinase and percutaneous transluminal angioplasty, have also proved useful. The addition of these newer methods, combined with the fact that kidneys can frequently be salvaged after prolonged periods of acute renal artery occlusion, led to the development of a clinical algorithm for treatment. With this algorithm, surgical embolectomy was reserved for patients with total renal parenchymal compromise caused by emboli, whose conditions failed to respond to less invasive treatment modes.


Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes.
Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.


Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats.
Prior work has shown that d-amphetamine (AMPH) treatment or voluntary exercise improves cognitive functions after traumatic brain injury (TBI). In addition, voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF). The current study was conducted to determine how AMPH and exercise treatments, either alone or in combination, affect molecular events that may underlie recovery following controlled cortical impact (CCI) injury in rats. We also determined if these treatments reduced injury-induced oxidative stress. Following a CCI or sham injury, rats received AMPH (1 mg/kg/day) or saline treatment via an ALZET pump and were housed with or without access to a running wheel for 7 days. CCI rats ran significantly less than sham controls, but exercise level was not altered by drug treatment. On day 7 the hippocampus ipsilateral to injury was harvested and BDNF, synapsin I and phosphorylated (P) -synapsin I proteins were quantified. Exercise or AMPH alone significantly increased BDNF protein in sham and CCI rats, but this effect was lost with the combined treatment. In sham-injured rats synapsin I increased significantly after AMPH or exercise, but did not increase after combined treatment. Synapsin levels, including the P-synapsin/total synapsin ratio, were reduced from sham controls in the saline-treated CCI groups, with or without exercise. AMPH treatment significantly increased the P-synapsin/total synapsin ratio after CCI, an effect that was attenuated by combining AMPH with exercise. Exercise or AMPH treatment alone significantly decreased hippocampal carbonyl groups on oxidized proteins in the CCI rats, compared with saline-treated sedentary counterparts, but this reduction in a marker of oxidative stress was not found with the combination of exercise and AMPH treatment. These results indicate that, whereas exercise or AMPH treatment alone may induce plasticity and reduce oxidative stress after TBI, combining these treatments may cancel each other's therapeutic effects.


The efficacy of licorice root extract in decreasing transaminase activities in non-alcoholic fatty liver disease: a randomized controlled clinical trial.
This study was performed to investigate the effects of licorice on non-alcoholic fatty liver disease (NAFLD). In this double blind randomized clinical trial, 66 patients were divided into case and control groups. All patients had elevated liver enzymes and had increased liver echogenicity (lipid accumulation) on sonography. The case group was treated with one capsule containing 2 g aqueous licorice root extract per day for 2 months while the control group was treated in the same manner with a placebo. Weight, body mass index (BMI) and liver transaminase levels were measured for each patient before and after the study. In the case group, the mean alanine aminotransferase (ALT) level decreased from 64.09 to 51.27 IU/mL and the aspartate aminotransferase (AST) level decreased from 58.18 to 49.45 IU/mL, which were statistically significant (p < 0.001 and p < 0.001). But in the control group, a drop in the ALT and AST levels was not statistically significant. The BMI difference before and after the study was not statistically significant in both groups. Despite the significant drop in liver enzymes following administration of licorice root extract, it is recommended that further studies that include histological examination are necessary.


Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex.
Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.


Improving the humification and phosphorus flow during swine manure composting: A trial for enhancing the beneficial applications of hazardous biowastes.
Improving the recovery of organic matter and phosphorus (P) from hazardous biowastes such as swine manure using acidic substrates (ASs) in conjunction with aerobic composting is of great interest. This work aimed to investigate the effects of ASs on the humification and/or P migration as well as on microbial succession during the swine manure composting, employing multivariate and multiscale approaches. Adding ASs, derived from wood vinegar and humic acid, increased the degree of humification and thermal stability of the compost. The 31P nuclear magnetic resonance spectroscopy and X-ray absorption near-edge structure analyses demonstrated compost P was in the form of struvite crystals, Ca/Al-P phases, and Poly-P (all inorganic P species) as well as inositol hexakisphosphate and Mono-P (organophosphorus species). However, the efficiency of P recovery could be improved by generating more struvite by adding the ASs. The flows among nutrient pools resulted from the diversity in the dominant microbial communities in different composting phases after introducing the ASs and appearance of Bacillus spp. in all phases. These results demonstrate the potential value of ASs for regulating and/or improving nutrients flow during the composting of hazardous biowastes for producing higher quality compost, which may maximize their beneficial benefits and applications.


Glucose metabolism in Neisseria gonorrhoeae.
The metabolism of glucose was examined in several clinical isolates of Neisseria gonorrhoeae. Radiorespirometric studies revealed that growing cells metabolized glucose by a combination on the Entner-Doudoroff and pentose phosphate pathways. A portion of the glyceraldehyde-3-phosphate formed via the Entner-Doudoroff pathway was recycled by conversion to glucose-6-phosphate. Subsequent catabolism of this glucose-6-phosphate by either the Entner-Doudoroff or pentose phosphate pathways yielded CO(2) from the original C6 of glucose. Enzyme analyses confirmed the presence of all enzymes of the Entner-Doudoroff, pentose phosphate, and Embden-Meyerhof-Parnas pathways. There was always a high specific activity of glucose-6-phosphate dehydrogenase (EC 18.104.22.168) relative to that of 6-phosphogluconate dehydrogenase (EC 18.104.22.168). The glucose-6-phosphate dehydrogenase utilized either nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide as electron acceptor. Acetate was the only detectable nongaseous end product of glucose metabolism. Following the disappearance of glucose, acetate was metabolized by the tricarboxylic acid cycle as evidenced by the preferential oxidation of [1-(14)C]acetate over that of [2-(14)C]acetate. When an aerobically grown log-phase culture was subjected to anaerobic conditions, lactate and acetate were formed from glucose. Radiorespirometric studies showed that under these conditions, glucose was dissimilated entirely by the Entner-Doudoroff pathway. Further studies determined that this anaerobic dissimilation of glucose was not growth dependent.


Cluster-based MOFs with accelerated chemical conversion of CO2 through C-C bond formation.
Investigations on metal-organic frameworks (MOFs) as direct catalysts have been well documented, but direct catalysis of the chemical conversion of terminal alkynes and CO2 as chemical feedstock by MOFs into valuable chemical products has never been reported. We report here two cluster-based MOFs I and II assembled from a multinuclear Gd-cluster and Cu-cluster, displaying high thermal and solvent stabilities. I and II as heterogeneous catalysts possess active catalytic centers [Cu12I12] and [Cu3I2], respectively, exhibiting excellent catalytic performance in the carboxylation reactions of CO2 with 14 kinds of terminal alkynes under 1 atm and mild conditions. For the first time catalysis of the carboxylation reaction of terminal alkynes with CO2 by MOF materials without any cocatalyst/additive is reported. This work not only reduces greenhouse gas emission but also provides highly valuable materials, opening a wide space in seeking recoverable catalysts to accelerate the chemical conversion of CO2.


Effects of alendronate on osteoporosis treatment and levels of related cytokines.
Alendronate regulates the activity of osteoclasts and healing of osteoporosis. This study investigated the effect of alendronate on bone healing and changes in the levels of cytokines. Bilateral ovaries of 10 adult female rabbits were removed surgically in aseptic condition to establish the animal model of osteoporosis. Five rabbits in group A were treated with alendronate (1.15 mg·kg-1·week-1) once a week by a stomach tube, whereas the remaining 5 in group B were treated with physiological saline. The success of the animal model establishment and the efficacy of alendronate treatment were evaluated by the sports ability score and the Basso, Beattie, and Bresnahan (BBB) score; the healing degree of osteoporosis was determined by X-ray analysis and measurement of biomechanical properties; the changes in the levels of related cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. Treatment improved dyskinesia of the animals in group A than that in group B, with significant improvement occurring in the 4th week of treatment. The BBB score of the group A animals revealed movements similar to normal, but that of the group B animals exhibited significant motor disturbance (P < 0.01). X-ray examination showed that with time, the X-ray ratings increased. Measurement of the biomechanical properties further showed that alendronate had a positive effect on osteoporosis healing. The results of ELISA and immunohistochemistry showed that the levels of ALP, BMP-2, bFGF, and IGF-1 were upregulated in group A. In conclusion, alendronate accelerated osteoporosis healing probably via certain cytokine-related mechanism.


Multivalent Binding and Biomimetic Cell Rolling Improves the Sensitivity and Specificity of Circulating Tumor Cell Capture.
Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in patients with cancer undergoing radiotherapy treatment.Experimental Design: Patients with histologically confirmed primary carcinoma undergoing radiotherapy, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to five time points, including before radiotherapy, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of radiotherapy. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR.Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45-/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before radiotherapy to 32 CTCs/mL at completion of radiotherapy (P = 0.001). CTCs declined throughout radiotherapy in patients with complete clinical and/or radiographic response, in contrast with an elevation in CTCs at mid or post-radiotherapy in the two patients with known pathologic residual disease.Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared with multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment. Clin Cancer Res; 24(11); 2539-47. ©2018 AACR.


The characterization of γH2AX and p53 as biomarkers of genotoxic stress in a rainbow trout (Oncorhynchus mykiss) brain cell line.
Rainbow trout cell cultures were exposed to three genotoxicants and examined for effects on γH2AX and p53 levels by western blotting and on cell viability using the indicator dyes Alamar Blue (AB) for energy metabolism and 5'-carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM) for plasma membrane integrity. Bleomycin induced γH2AX and p53 in a dose- and time-dependent manner and had little cytotoxic effect. However, induction was first seen at 0.3 μM for γH2AX but not until 16.5 μM for p53. Methyl methanesulfonate (MMS) increased H2AX phosphorylation but diminished p53 levels as the dose was increased from 908 μM up to 2724 μM. Over this dose range cell viability was progressively lost. 4-nitroquinoline N-oxide (NQO) induced both γH2AX and p53, beginning at 62.5 nM, which was also the concentration at which cell viability began to decline. As the NQO concentration increased further, elevated γH2AX was detected at up to 2.0 μM, while p53 was elevated up to 1.0 μM. Therefore, H2AX phosphorylation was superior to p53 levels as a marker of DNA damage caused by genotoxicants that act by introducing double-stranded DNA breaks (bleomycin), alkyl groups (MMS), and quinoline adducts (NQO).


Cellular basis for bimatoprost effects on human conventional outflow.
Bimatoprost is a widely used ocular hypotensive agent to treat glaucoma. It lowers intraocular pressure in humans by increasing both pressure-independent (uveoscleral) and pressure-dependent (conventional) aqueous humor outflow. The present study specifically examines bimatoprost effects on the cells that populate human outflow tissues. The authors tested for prostamide receptor activation in primary cultures of human trabecular meshwork (TM), Schlemm's canal (SC), and ciliary smooth muscle (CSM) cells using cellular dielectric spectroscopy (CDS). The authors observed that bimatoprost produced an immediate and concentration-dependent increase in cell monolayer impedance for TM, SC, and CSM cells with EC(50) values of 4.3, 1.2, and 1.7 nM, respectively; corresponding to decreased cell contractility. Notably, in TM, SC, and CSM cells, bimatoprost was approximately equipotent to the selective FP receptor agonists fluprostenol and 17-phenyl PGF(2α). Bimatoprost effects were insensitive to cholera toxin and pertussis toxin but were abolished by phorbol 12-myristate 13-acetate pretreatment, suggesting Gq-involvement in cell signaling. The effects of bimatoprost on TM and SC cells were inhibited by the prostamide receptor antagonist AGN211334, with IC(50) values of 1.2 and 3.3 μM, respectively. Interestingly, AGN211334 behaved as an apparent inverse agonist in CDS assays involving TM cells but as a neutral prostamide antagonist with SC cells. Taken together, results suggest that bimatoprost specifically activates receptors in both cell types of the human conventional outflow pathway to modify intraocular pressure. However, only TM cell monolayers appear to have autocrine, or agonist-independent, receptor signaling that is sensitive to a prostamide receptor antagonist.


Improved prediction of proximal femoral fracture load using nonlinear finite element models.
Hip fracture, which is often due to osteoporosis or other conditions affecting bone strength, can lead to permanent disability, pneumonia, pulmonary embolism, and/or death. Great effort has been directed toward developing noninvasive methods for evaluating proximal femoral strength (fracture load), with the goal of assessing fracture risk. Previously, computed tomographic scan-based, linear finite element (FE) models were used to estimate proximal femoral fracture loads ex vivo in two load configurations, one approximating joint loading during single-limb stance and the other simulating impact from a fall. Measured and computed fracture loads were correlated (stance, r=0.867; fall, r=0.949). However, precision for the stance configuration was insufficient to identify subjects with below average fracture loads reliably. The present study examined whether, for this configuration, nonlinear FE models could be used to identify these subjects. These models were found to predict fracture load within +/-2.0 kN (r=0.962). This level of precision is sufficient to identify 97.5% of femora with fracture loads 1.3 standard deviations below the mean as having below average fracture loads. Accordingly, 20% of subjects with below average fracture loads, i.e. those with the lowest fracture loads and likely to be at greatest risk of fracture, would be correctly identified with at least 97.5% reliability. This FE modeling method will be a powerful tool for studies of hip fracture.


The When and Where of Working Memory Dysfunction in Early-Onset Schizophrenia-A Functional Magnetic Resonance Imaging Study.
Behavioral evidence indicates that working memory (WM) in schizophrenia is already impaired at the encoding stage. However, the neurophysiological basis of this primary deficit remains poorly understood. Using event-related fMRI, we assessed differences in brain activation and functional connectivity during the encoding, maintenance and retrieval stages of a visual WM task with 3 levels of memory load in 17 adolescents with early-onset schizophrenia (EOS) and 17 matched controls. The amount of information patients could store in WM was reduced at all memory load levels. During encoding, activation in left ventrolateral prefrontal cortex (VLPFC) and extrastriate visual cortex, which in controls positively correlated with the amount of stored information, was reduced in patients. Additionally, patients showed disturbed functional connectivity between prefrontal and visual areas. During retrieval, right inferior VLPFC hyperactivation was correlated with hypoactivation of left VLPFC in patients during encoding. Visual WM encoding is disturbed by a failure to adequately engage a visual-prefrontal network critical for the transfer of perceptual information into WM. Prefrontal hyperactivation appears to be a secondary consequence of this primary deficit. Isolating the component processes of WM can lead to more specific neurophysiological markers for translational efforts seeking to improve the treatment of cognitive dysfunction in schizophrenia.


Flexible Cross-Modal Hashing.
Hashing has been widely adopted for large-scale data retrieval in many domains due to its low storage cost and high retrieval speed. Existing cross-modal hashing methods optimistically assume that the correspondence between training samples across modalities is readily available. This assumption is unrealistic in practical applications. In addition, existing methods generally require the same number of samples across different modalities, which restricts their flexibility. We propose a flexible cross-modal hashing approach (FlexCMH) to learn effective hashing codes from weakly paired data, whose correspondence across modalities is partially (or even totally) unknown. FlexCMH first introduces a clustering-based matching strategy to explore the structure of each cluster and, thus, to find the potential correspondence between clusters (and samples therein) across modalities. To reduce the impact of an incomplete correspondence, it jointly optimizes the potential correspondence, the cross-modal hashing functions derived from the correspondence, and a hashing quantitative loss in a unified objective function. An alternative optimization technique is also proposed to coordinate the correspondence and hash functions and reinforce the reciprocal effects of the two objectives. Experiments on public multimodal data sets show that FlexCMH achieves significantly better results than state-of-the-art methods, and it, indeed, offers a high degree of flexibility for practical cross-modal hashing tasks.


Major and minor depression in Parkinson's disease: a neuropsychological investigation.
Previous studies have failed to distinguish the differential contribution of major and minor depression to cognitive impairment in patients with idiopathic Parkinson's disease (PD). This study was aimed at investigating the relationships among major depression (MD), minor depression (MiD) and neuropsychological deficits in PD. Eighty-three patients suffering from PD participated in the study. MD and MiD were diagnosed by means of a structured interview (SCID-I) based on the DSM-IV criteria, and severity of depression was evaluated by the Beck Depression Inventory. For the neuropsychological assessment, we used standardized scales that measure verbal and visual episodic memory, working memory, executive functions, abstract reasoning and visual-spatial and language abilities. MD patients performed worse than PD patients without depression on two long-term verbal episodic memory tasks, on an abstract reasoning task and on three measures of executive functioning. The MiD patients' performances on the same tests fell between those of the other two groups of PD patients but did not show significant differences. Our results indicate that MD in PD is associated with a qualitatively specific neuropsychological profile that may be related to an alteration of prefrontal and limbic cortical areas. Moreover, the same data suggest that in these patients MiD and MD may represent a gradual continuum associated with increasing cognitive deficits.


Linkage disequilibrium and the genetic distance in livestock populations: the impact of inbreeding.
Genome-wide linkage disequilibrium (LD) is subject to intensive investigation in human and livestock populations since it can potentially reveal aspects of a population history, permit to date them and help in fine-gene mapping. The most commonly used measure of LD between multiallelic loci is the coefficient D'. Data based on D' were recently published in humans, livestock and model animals. However, the properties of this coefficient are not well understood. Its sampling distribution and variance has received recent attention, but its expected behaviour with respect to genetic or physical distance remains unknown. Using stochastic simulations of populations having a finite size, we show that D' fits an exponential function having two parameters of simple biological interpretation: the residual value (rs) towards which D' tends as the genetic distance increases and the distance R at which this value is reached. Properties of this model are evaluated as a function of the inbreeding coefficient (F). It was found that R and rs increase when F increases. The proposed model offers opportunities to better understand the patterns and the origins of LD in different populations and along different chromosomes.


Hydrogen gas inhalation protects against cutaneous ischaemia/reperfusion injury in a mouse model of pressure ulcer.
Pressure ulcer formation depends on various factors among which repetitive ischaemia/reperfusion(I/R) injury plays a vital role. Molecular hydrogen (H2 ) was reported to have protective effects on I/R injuries of various internal organs. In this study, we investigated the effects of H2 inhalation on pressure ulcer and the underlying mechanisms. H2 inhalation significantly reduced wound area, 8-oxo-dG level (oxidative DNA damage) and cell apoptosis rates in skin lesions. H2 remarkably decreased ROS accumulation and enhanced antioxidant enzymes activities by up-regulating expression of Nrf2 and its downstream components in wound tissue and/or H2 O2 -treated endothelia. Meanwhile, H2 inhibited the overexpression of MCP-1, E-selectin, P-selectin and ICAM-1 in oxidant-induced endothelia and reduced inflammatory cells infiltration and proinflammatory cytokines (TNF-α, IL-1, IL-6 and IL-8) production in the wound. Furthermore, H2 promoted the expression of pro-healing factors (IL-22, TGF-β, VEGF and IGF1) and inhibited the production of MMP9 in wound tissue in parallel with acceleration of cutaneous collagen synthesis. Taken together, these data indicated that H2 inhalation suppressed the formation of pressure ulcer in a mouse model. Molecular hydrogen has potentials as a novel and alternative therapy for severe pressure ulcer. The therapeutic effects of molecular hydrogen might be related to its antioxidant, anti-inflammatory, pro-healing actions.


Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials).
Interleukin (IL)-2 therapy leads to significant CD4 cell increases in HIV-infected patients. Since phase III trials are ongoing, studies supporting the long-term feasibility of this strategy are needed. We studied the long-term outcomes of 131 patients treated with IL-2 in two studies initiated either before (ANRS 048) or following (ANRS 079) the advent of HAART. At the last assessment (median follow-up 3.4 years), these patients experienced a gain of 428 cells/microl and a decrease in plasma HIV RNA to 1.70 log10 copies/ml. In both studies, high CD4 cell counts were maintained with a median of ten 5-day cycles of subcutaneous IL-2. Median time since the last cycle was 2 years. At last assessment, 59% of 048 patients maintained a non-HAART regimen. Detailed analysis at week 170 showed that median CD4 cell counts were 856 (048) and 964 (079) cells/microl. This corresponded to a gain from baseline of 515 (048) and 627 (079) cells/microl. The median viral load decreases from baseline and corresponded to 1.70 (048) and 1.88 (079) log10 copies/ml. Comparisons across the studies showed that CD4 gains and viral load changes were similar whether HAART or non-HAART was used. The frequency of cycling, but not CD4 cell counts, viral loads or antiviral regimen at baseline, was predictive of long-term CD4 gain (P = 0.03). Altogether, these observations support IL-2 as a long-term therapeutic strategy in HIV infection.


Cannabinoids and innate immunity: taking a toll on neuroinflammation.
The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS), and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids), have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs) that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.


Effect of interferon on growth and division cycle of Friend erythroleukemic murine cells in vitro.
The administration of appropriate doses of interferon to cultures of Friend leukemia cells causes a pronounced inhibition of cell growth. Several lines of evidence indicate that this effect is due to interferon itself, rather than to unknown contaminants of interferon preparations. Autoradiograph analysis of growth parameters of Friend leukemia cells during treatment with interferon demonstrates that the rate of entry into the S phase, the percent decline of unlabeled mitoses, and the mitotic indexes are significantly lower in interferon-treated cell cultures than in control untreated cultures when tritiated thymidine was added 12 h after the administration of interferon. These data indicate that fractions of interferon-treated cell population are delayed in both G1 and in G2 phases of the cell cycle. This was confirmed by exact measurements of the length of the various phases of the cycle. The interferon-induced inhibition of growth of Friend leukemia cells is reversible after removal of the compound. Autoradiograph data obtained from control cultures and from cultures previously treated with interferon that had been washed free of interferon and reseeded in interferon-free medium, demonstrate that during the first 12 h after removal of interferon, a large majority of the cells previously treated with interferon had a deranged flow into the S phase, a high number of unlabeled mitoses, and a low mitotic index. These data provide further evidence for the above-mentioned prolongations of G1 and G2 phases of the cell cycle. All growth parameters tested reverted to normal values within 12 h after washing out interferon.


An in vitro model of the glomerular capillary wall using electrospun collagen nanofibres in a bioartificial composite basement membrane.
The filtering unit of the kidney, the glomerulus, contains capillaries whose walls function as a biological sieve, the glomerular filtration barrier. This comprises layers of two specialised cells, glomerular endothelial cells (GEnC) and podocytes, separated by a basement membrane. Glomerular filtration barrier function, and dysfunction in disease, remains incompletely understood, partly due to difficulties in studying the relevant cell types in vitro. We have addressed this by generation of unique conditionally immortalised human GEnC and podocytes. However, because the glomerular filtration barrier functions as a whole, it is necessary to develop three dimensional co-culture models to maximise the benefit of the availability of these cells. Here we have developed the first two tri-layer models of the glomerular capillary wall. The first is based on tissue culture inserts and provides evidence of cell-cell interaction via soluble mediators. In the second model the synthetic support of the tissue culture insert is replaced with a novel composite bioartificial membrane. This consists of a nanofibre membrane containing collagen I, electrospun directly onto a micro-photoelectroformed fine nickel supporting mesh. GEnC and podocytes grew in monolayers on either side of the insert support or the novel membrane to form a tri-layer model recapitulating the human glomerular capillary in vitro. These models will advance the study of both the physiology of normal glomerular filtration and of its disruption in glomerular disease.


Protective role of magnesium in the neutralization by antibodies of Chlamydia trachomatis infectivity.
Neutralization of the infectivity of Chlamydia trachomatis was assessed by using polyclonal antisera and monoclonal antibodies (MAbs). Polyclonal antisera and a species-reactive MAb as well as a subspecies-specific MAb, both of which were directed toward the major outer membrane protein of C. trachomatis, reduced the number of chlamydial inclusion-forming units in an in vitro assay. Neutralization was dependent on the presence of complement. The species-specific MAb reacted with all 15 serovars by a microimmunofluorescence assay and a dot blot enzyme-linked immunosorbent assay with heat-treated elementary bodies. On the other hand, this same MAb reacted with all serovars, except those in the C complex, by the dot blot enzyme-linked immunosorbent assay with viable organisms and neutralized in vitro all 10 serovars tested, except those in the C complex. When neutralization assays were performed in a solution containing Mg2+, neutralization by both polyclonal antisera and MAbs was significantly reduced. A dose response to Mg2+ supplied as MgSO4 revealed that all concentrations tested from 50 to 800 microM had some effect. Concentrations of greater than or equal to 400 microM MgSO4 completely abolished neutralization at the lowest dilution of polyclonal antisera and species-reactive MAb tested. Although Mg2+ also blocked the neutralization effect of the subspecies-specific MAb, this neutralization was not as complete as that observed with the species-reactive MAb. Addition of Mg2+ to the assay over the initial 45 min of incubation of C. trachomatis with MAb and complement showed that the organisms could be rescued to some extent over the first 30 min of incubation, after which time neutralization of infectivity could not be reversed. C. trachomatis treated with Mg2+, the species-reactive MAb, and complement were lethal to mice in an in vivo toxicity and infectivity assay, whereas mice injected with organisms incubated with the same MAb and complement without Mg2+ survived.


Phosphorylation regulates NCC stability and transporter activity in vivo.
A T60M mutation in the thiazide-sensitive sodium chloride cotransporter (NCC) is common in patients with Gitelman's syndrome (GS). This mutation prevents Ste20-related proline and alanine-rich kinase (SPAK)/oxidative stress responsive kinase-1 (OSR1)-mediated phosphorylation of NCC and alters NCC transporter activity in vitro. Here, we examined the physiologic effects of NCC phosphorylation in vivo using a novel Ncc T58M (human T60M) knock-in mouse model. Ncc(T58M/T58M) mice exhibited typical features of GS with a blunted response to thiazide diuretics. Despite expressing normal levels of Ncc mRNA, these mice had lower levels of total Ncc and p-Ncc protein that did not change with a low-salt diet that increased p-Spak. In contrast to wild-type Ncc, which localized to the apical membrane of distal convoluted tubule cells, T58M Ncc localized primarily to the cytosolic region and caused an increase in late distal convoluted tubule volume. In MDCK cells, exogenous expression of phosphorylation-defective NCC mutants reduced total protein expression levels and membrane stability. Furthermore, our analysis found diminished total urine NCC excretion in a cohort of GS patients with homozygous NCC T60M mutations. When Wnk4(D561A/+) mice, a model of pseudohypoaldosteronism type II expressing an activated Spak/Osr1-Ncc, were crossed with Ncc(T58M/T58M) mice, total Ncc and p-Ncc protein levels decreased and the GS phenotype persisted over the hypertensive phenotype. Overall, these data suggest that SPAK-mediated phosphorylation of NCC at T60 regulates NCC stability and function, and defective phosphorylation at this residue corrects the phenotype of pseudohypoaldosteronism type II.


Compact Er:Yb:glass-laser-based supercontinuum source for high-resolution optical coherence tomography.
We present a low coherence light source by direct super-continuum generation from a diode-pumped, passively modelocked Er:Yb:glass-laser, which generates 198 fs transform-limited pulses with an average power of 100 mW at a repetition rate of 75 MHz. The pulse train is launched into a dispersion optimized highly nonlinear fiber for spectral broadening. The optical bandwidth spans from 1150 nm to 2400 nm, which is more than one octave. The potential for ultrahigh-resolution optical coherence tomography (OCT) is demonstrated by coherence measurements supporting an axial resolution of 3.5 microm in air.


MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.
We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10(-10), odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10(-11), OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3'UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R(2) = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3'UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10(-19), OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.


Neuroprotective activity of lavender oil on transient focal cerebral ischemia in mice.
The air-dried aerial parts of Lavandula angustifolia Mill, a traditional Uygur herbal drug, is used as resuscitation-inducing therapy to treat neurodisfunctions, such as stroke. This study was designed to assess the neuroprotective effects of lavender oil against ischemia/reperfusion (IR) injury in mice. Focal cerebral ischemia was induced by the intraluminal occlusion method with a nylon string. The neurodysfuntion was evaluated by neurological deficit and the infarct area was showed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The histopathological changes were observed by hematoxylin and eosin staining. The levels of mitochondria-generated reactive oxygen species (ROS), malondialdehyde (MDA) and carbonyl, the ratio of reduced glutathione (GSH)/glutathione disulfide (GSSG), the activities of superoxide dismutase (SOD), catalase (CAT) and glutathion peroxidase (GSH-Px) in brain tissue were measured to estimate the oxidative stress state. Neurological deficit, infarct size, histopathology changes and oxidative stress markers were evaluated after 22 h of reperfusion. In comparison with the model group, treatment with lavender oil significantly decreased neurological deficit scores, infarct size, the levels of MDA, carbonyl and ROS, and attenuated neuronal damage, upregulated SOD, CAT, GSH-Px activities and GSH/GSSG ratio. These results suggested that the neuroprotective effects of lavender oil against cerebral ischemia/reperfusion injury may be attributed to its antioxidant effects.


A comparative survey of the function, mechanism and control of cellular oscillators.
This review attempts to survey in a uniform manner the available evidence concerning the generation and behaviour of several well-investigated cellular oscillators. Members of two broad classifications are contrasted: (i) cytoplasmic oscillations, where the periodic phenomena is generated by an instability pathway and (ii) membrane oscillators in which a membrane potential rhythm is generated at the membrane. Interactions between the cytoplasmic and membrane compartments are considered and the effects of these interactions on oscillatory behaviour is discussed. Because of their biological importance and the greater body of experimental results, particular attention is directed to a study of membrane potential oscillations. These systems can be approximately classified in two groups: (i) systems in which a periodic potential results from oscillatory changes in permeability and (ii) systems in which potential oscillations result from the periodic activity of an electrogenic pump. The examples considered include the glycolytic oscillator, oscillations in vein contraction in the slime mould Physarum polycephalum, rhythmic aggregation in Dictyostelium discoideum, neural oscillators, the periodic potential in Purkinje fibres and the sino-atrial node and rhythmic behaviour in smooth muscle. Questions considered include the generation of periodic activity, the modulation of the oscillation by drugs and other metabolic and membrane effectors and the question of the functional role of these oscillations.


Homologous Use of Allogeneic Umbilical Cord Tissue to Reduce Knee Pain and Improve Knee Function.
To determine if knee pain subjects who received cryopreserved umbilical cord tissue (UCT) injected into knee joints experience less knee pain, better function, decreased physical limitations, and reduction of medications (opiates, NSAIDs, and acetaminophen) over a 24 week period, Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and medication usage data were recorded for 30 consenting human knee pain subjects receiving UCT at a single site in the United States. Subject profile information was gathered and analyzed to gain insight into the effects of age, sex, and BMI on improvement over time. Mean resting VAS scores and mean VAS scores with activity improved over 24 weeks (from 1.95 to 0.83 and from 6.28 to 2.87, respectively, p < 0.001). There was no strong evidence of a correlation between sex and VAS scores. There were statistically significant correlations for BMI vs. pre-injection VAS with activity scores and Age vs. pre-injection VAS with activity scores (r = 0.402, p = 0.028 and r = 0.434, p = 0.017, respectively). Mean WOMAC scores improved from 44.7 to 18.5 over 24 weeks (p < 0.001). 77.8% of patients who used medications at the beginning of the study reduced or eliminated medication use. The analysis demonstrates that injections with UCT decrease pain, improve physical function, and allow for less medication use for at least 24 weeks.


[Edward Blyth (1810-1873). Father of the Indian ornitology].
Edward Blyth was born on 23 December 1810. When he was ayoung man he took an interest with the zoology which became his life's passion. As a young naturalist he was a conscientious observer of the nature and a man gifted with a superb memory. Unfortunately his career was not successful in London because of the conflict with the younger of the Gray brothers. Facing the prospect of no employment in The British Museum, Blyth decided to leave England for Calcutta where he was offered a post of a museum curator. The English naturalist spent in India the years from 1841 to 1862. During that time he greatly enriched the zoological collection of the museum and consequently the place had much more visitors. Regarding his private life he got married in 1854 to Elisabeth Mary Turner Hodges. Undoubtedly the next four year were the happiest in Blyth's life. After his wife's death Blyth's health condition deteriorated. The ongoing conflicts he kept having while the first stay in India and constant struggle to improve his financial status made him decide to return to England. Blyth left India in 1862. After coming back to his homeland he continued the naturalistic passions. Nevertheless Blyth was constantly troubled by the financial problems. Also, his health, both mental and physical, systematically deteriorated. Finally the death came on 27 December 1873, in London. Blyth tried in vain to gain the recognition and join the scientific establishment of the 19th century England. Constant lack of satisfactory income and often problems with health prevented the ornithologist to be fully devote to his passion. The aim of this article is to highlight some of the most important and interesting events of Blyth's life. Moreover, another objective is to popularise Blyth and his work since he was one of the greatest naturalists of that time.


Role of routine preoperative lymphoscintigraphy in sentinel node biopsy for breast cancer.
Sentinel node biopsy (SNB) is rapidly emerging as the preferred technique for nodal staging in breast cancer. When radioactive colloid is used, a preoperative lymphoscintiscan is obtained to ease sentinel lymph node (SN) identification. This study evaluates whether preoperative lymphoscintigraphy adds diagnostic accuracy to offset the additional time and cost required. 823 breast cancer patients underwent SNB based on lymphoscintigraphy, intraoperative gamma probe detection, and blue dye mapping using 99 mTc-nanocolloid and Patent Blue V injected peritumourally. The SNB was followed by standard axillary treatment at the same operation. Preoperative lymphoscintigraphy was performed around 3 h after the radioisotope injection. Preoperative lymphoscintigraphy revealed SNs in 593 (72%) of the 823 patients imaged. SN visualisation on lymphoscintigraphy was less successful in large tumours and tumours involving the upper outer quadrant of the breast (P=0.046, P<0.001, respectively). Lymphoscintigraphy showed internal mammary sentinel nodes in 9% (62/707) patients. The SN was identified intraoperatively in 98% (581) patients who had SN visualised on preoperative lymphoscintigraphy, with a false-negative rate of 7%. In patients who did not have SN visualised on preoperative lymphoscintigraphy, the SN was identified at operation in 90% (204) patients, with a false-negative rate of 7%. The SN identification rate was significantly higher in patients with SN visualised on preoperative lymphoscintigraphy (P<0.001). SN identification rate intraoperatively using the gamma probe was significantly higher in the SN visualised group compared with the SN non-visualised group (95% vs. 68%; chi square (1 degrees of freedom (df)) P<0.001. There was no statistically significant difference in the false-negative rate and the operative time between the two groups. A mean of 2.3 (standard deviation (SD) 1.3) SNs per patient were removed in patients with SN visualised on preoperative lymphoscintigraphy compared with 1.8 (SD 1.2) in patients with no SN visualised on lymphoscintigraphy (P<0.001). Although SN visualisation on preoperative lymphoscintigraphy significantly improved the intraoperative SN localisation rate, SN was successfully identified in 90% of patients with no SN visualisation on lymphoscintigraphy. Given the time and cost required to perform routine preoperative lymphoscintigraphy, these data suggest that it may not be necessary in all cases. It may be valuable for surgeons in the learning phase to shorten the learning curve and in patients who have increased risk of intraoperative failed localisation (obese or old patients). A negative preoperative lymphoscintiscan predicts the inability to localise with the hand-held gamma probe. Therefore, if the SN is not visualised on lymphoscintigraphy then the addition of intraoperative blue dye is recommended to increase the likelihood of SN identification.


Improved similarity measures for small sets of spike trains.
Multiple measures have been developed to quantify the similarity between two spike trains. These measures have been used for the quantification of the mismatch between neuron models and experiments as well as for the classification of neuronal responses in neuroprosthetic devices and electrophysiological experiments. Frequently only a few spike trains are available in each class. We derive analytical expressions for the small-sample bias present when comparing estimators of the time-dependent firing intensity. We then exploit analogies between the comparison of firing intensities and previously used spike train metrics and show that improved spike train measures can be successfully used for fitting neuron models to experimental data, for comparisons of spike trains, and classification of spike train data. In classification tasks, the improved similarity measures can increase the recovered information. We demonstrate that when similarity measures are used for fitting mathematical models, all previous methods systematically underestimate the noise. Finally, we show a striking implication of this deterministic bias by reevaluating the results of the single-neuron prediction challenge.


A multicentre sero-behavioural survey for hepatitis B and C, HIV and HTLV among people who inject drugs in Germany using respondent driven sampling.
People who inject drugs are at high risk for hepatitis B, hepatitis C and HIV. HTLV was reported by neighboring countries to be prevalent in this population, but the situation for Germany is unclear. To generate seroprevalence and related behavioural data and to enhance prevention efforts against these infections for drug users in Germany, a multicentre sero- and behavioural survey was initiated. People who inject drugs are not well reached by services for testing and counselling for blood-borne infections in Germany. An interventional part of the study is intended to prove feasibility and acceptance of testing and counselling in low-threshold drop-in settings. Between May 2011 and March 2015, eligible participants (persons having injected drugs within the last 12 months, aged 16 years+, and living in the study city) are recruited by respondent driven sampling, using low-threshold drop-in facilities as study-sites in eight German cities with large drug scenes. Calculated sample size is 2,033 participants. Capillary blood samples collected as dried blood spots are anonymously tested for serological and molecular markers of hepatitis B and C, HIV, and HTLV I and II. A detailed face-to-face-interview about hepatitis- and HIV-related knowledge, former testing, imprisonment, sexual and injecting risk behaviour is conducted with participants. Staff is trained to offer pre- and post-test-counselling of blood-borne infections and HIV rapid testing to participants. We chose respondent driven sampling for recruitment of participants to improve representativeness of results. Persons, who are not reached by the facility where the study is conducted, are aimed to be included by recruitment through their personal social network of injecting drug users. To reduce differential biases in the questions on knowledge of transmission and prevention of infections, we present true statements on hepatitis B, C and HIV, their possible routes of transmission and measures of prevention to participants. Participants are told that the statements are true and are asked to answer if they knew this fact already or if it is new to them. In case of knowledge gaps they are offered free targeted counselling as well as free HIV rapid testing and post-test counselling of HIV and hepatitis test results.


Efficacy of Gingocap as compared to pyridoxine in the treatment of nausea and vomiting during pregnancy.
Nausea and vomiting is the common problem disturbing almost 80% of the females in initial three months of conception and later sometime throughout pregnancy. To find out the efficacy and safety of herbal coded test drug Gingocap in comparison with the control drug Pyridoxine, a randomized clinical case control study was conducted at the OPD of Yusra Medical Centre, Karachi and Amir Habib Medical Center and Maternity Home, Karachi. After administration of test and control drug the frequency of nausea and vomiting was noted after every 2 weeks on 2nd, 4th, 6th and 8th weeks during 60 days of the course of study. The percentage of reduction of nausea and vomiting symptoms from the baseline in cases treated with test Gingocap compared to control drug Pyridoxine was recorded. Overall 35 and 30 patients were administered Gingocap and Pyridoxine between 6-16 weeks conception respectively. The data analyzed through T-test using SPSS version 18.0. It was concluded that Gingocap has the potential to relieve the symptoms of nausea and vomiting and exhibited no side effects and this drug was acceptable by maximum number of the patients.


Individual variation and lateral asymmetry of the rat primary somatosensory cortex.
We have evaluated the interindividual variability and lateral symmetry of a major cortical area by comparing the primary somatosensory cortex (S1) of adult rats. Our choice of the rat was dictated by the accuracy with which one can measure S1 and its component representations in the rodent brain; the importance of such measurements lies in understanding the rules that govern the allocation of cortical space and, ultimately, the consequences of differential allocation for behavior. With respect to interindividual differences, the major somatic representations in S1 are surprisingly variable in size. The area of the whiskerpad representation, for example, ranged from 3.72 to 6.84 mm2 in a sample of 53 rats; other components of S1 showed comparable differences among animals. With respect to lateral symmetry, the average area of each major representation was similar for the right and left hemispheres; thus, we found no consistent bias in the size of S1 or its elements in the sample as a whole. Within individual animals, however, the sizes of the major somatic representations were often quite different in the two hemispheres. The magnitude of the lateral differences averaged 7.9 +/- 0.8% (mean +/- SEM) for the whisker pad representation, 11.6 +/- 1.3% for the upper lip, 15.4 +/- 1.6% for the furry buccal pad, 13.9 +/- 1.4% for the lower jaw, and 13.3 +/- 1.2% for the forepaw. These results show that the amount of cortical space allocated to corresponding functions in individual rats--or in the two hemispheres of a particular rat--are often different. Such variations are likely to be reflected in somatosensory performance.