Capillary blood flow during severe hemodilution observed by a noninvasive transcutaneous technique using flash epi-illumination.
Capillary red blood cell (RBC) flow in the skin of rat tail during an extreme hemodilution with albumin was microscopically observed with a completely noninvasive transcutaneous technique using flash epi-illumination. This illumination with a filter (center wavelength, 550 nm) caused RBC to become darker and contrast well with the background tissue since the light was absorbed by hemoglobin inside the RBC. The recorded videotape showed a clear image of RBC without tailing because of flash (strobe light) illumination, and this allowed accurate analysis of the RBC flow rate and capillary hematocrit. During hemodilution up to a 50% level of blood exchange, the functional capillary density remained unchanged and it started to decline significantly at the 60% level of blood exchange and reached 37 +/- 32% of the basal value at the 80% level of blood exchange. The RBC flow rates monotonously increased up to 294 +/- 110% of the basal value at the 60% level of blood exchange, which was in contrast to the abdominal aortic blood flow increase to 148 +/- 20%. Capillary hematocrit did not appear to fall in the same proportion as the systemic hematocrit, which coincided with the previous observations. These results indicate that microhemodynamic properties during hemodilution can be transcutaneously analyzed with this new technique without surgical preparation of the skin.


Gastric intramural PCO2 during peritonitis and shock.
To define whether increases in gastric intramural tissue CO2 and H+ increase during experimentally induced peritonitis with circulatory shock as they do under conditions of hemorrhagic shock and cardiac arrest. Peritonitis was induced in Sprague-Dawley rats by cecal ligation and fecal spillage. Over an interval of 260 +/- 20 min in 5 animals, there was a progressive reduction in mean aortic pressure from 153 +/- 12 to 40 +/- 20 mm Hg and a decline in cardiac index from 429 +/- 135 to 178 +/- 7 ml/min. This was associated with increases in gastric intramural [H+] from 34 +/- 5 to 217 +/- 93 mmol/L (p = 0.001). Arterial blood lactate content concurrently increased from 0.9 +/- 0.1 to 4.6 +/- 0.7 mmol/L (p = 0.001). Only a late increase in gastric intramural PCO2 from 45 +/- 5 to 128 +/- 38 mm Hg (p = 0.01) was observed. In contrast to the gastric acid base changes that accompany hemorrhagic shock, in which there is an early and prominent increase in both PCO2 and [H+] in close relationship to decreases in cardiac output and arterial pressure, there was a prominent increase in gastric [H+] but only a delayed rise in gastric intramural PCO2. Arterial blood lactate and central venous oxygen saturation were earlier indicators of perfusion failure. Since the bicarbonate concentration in the stomach wall was substantially greater than that of simultaneously measured arterial blood, this has bearing on the current clinical method of gastric tonometry which assumes that arterial blood bicarbonate is equivalent to gastric wall bicarbonate.


Atmospheric temperature measurements at altitudes of 5-30 km with a double-grating-based pure rotational Raman lidar.
A pure rotational Raman (PRR) lidar based on a second-harmonic generation Nd:YAG laser is built for measuring the atmospheric temperature at altitudes of 5-30 km. A double-grating polychromator is designed to extract the wanted PRR signals and suppress the elastically backscattered light. Measured examples present the overall lidar performance. For the 1-h integrated lidar temperature profiles, the 1σ statistical uncertainty is less than 0.5 K up to ∼17 km, while it does not exceed 2 K at altitudes of 17-26.3 km. Based on 38 nights of high-quality lidar temperature data, the temperature variability is studied. It is found that the variability differs between the nights with inversion layer and those without it. On the nights without inversion layer, the local hour-to-hour temperature variability was mostly less than 1 K at altitudes of 5-17 km. At altitudes of 17-23 km, it grew to 1.2-2.4 K. On the nights with inversion layer, in the middle and upper troposphere, the significant variability was found to occur only at the inversion-layer altitudes. At other tropospheric altitudes off the inversion layer, the variability was generally less than 1 K. The statistical results indicate that the temperature variability mostly was stronger in the presence of inversion layer than in its absence.


Thromboxane-dependent coronary vasoconstriction in obese mice: Role of peroxynitrite.
Obesity leads to chronic oxidative stress promoting the development of cardiovascular diseases including coronary artery disease and endothelial dysfunction. Increased reactive oxygen species production associated with obesity might lead to endothelial dysfunction through cyclooxygenase (COX) pathway. We evaluated arachidonic acid (AA)-dependent coronary vascular responses and explored COX metabolism in obese C57BL/6 mice. In response to arachidonic acid (AA), isolated hearts from obese mice showed increased vasoconstriction compared with control mice. Released thromboxane (TX) A2 during AA-induced vasoconstriction phase was increased in heart perfusates from obese mice. Indomethacin and 1-benzylimidazole, both reduced vasoconstriction response in control and obese mice. Vasoconstriction response to TXA2 mimetic analog U46619 was 2.7 higher in obese mice. Obesity increased COX-2, TXS and TX receptor protein expression as well as oxidative stress evaluated by nitrotyrosine and peroxynitrite levels, compared with control mice. Obese mice treated with FeTMPyP, a peroxynitrite scavenger, reversed all these parameters to control levels. These data suggest that alterations in COX pathway may be associated with increased generation of free radicals, including peroxynitrite, that result from the oxidative stress observed in obesity.


Covert orienting of attention in macaques. II. Contributions of parietal cortex.
1. To understand some of the contributions of parietal cortex to the dynamics of visual spatial attention, we recorded from cortical cells of monkeys performing attentional tasks. We studied 484 neurons in the intraparietal sulcus and adjacent gyral tissue of two monkeys. We measured phasic responses to peripheral visual stimuli while the monkeys attended toward or away from the stimuli or when attention was not controlled. Neurons were tested while the monkeys gazed at a spot of light (simple fixation task), actively attended to a foveal target (foveal attention task), performed a reaction time task (cued reaction time task), made saccadic eye movements to visual targets (saccade task), or responded to a repetitious peripheral target (probability task). 2. In a previous paper we demonstrated that monkeys, like humans, responded more quickly to visual targets when the targets followed briefly flashed visual cues (validly cued targets) (Bowman et al. 1993). It has been hypothesized that the cue attracts attention to its locus and results in faster reaction times (Posner 1980). In the present physiological studies, visual cues consistently excited these neurons when they were flashed in the receptive field. Such activity might signal a shift of attention. Visual targets that fell within the receptive field and that immediately followed the cue evoked relatively weak responses. This response was due to a relative refractory period. 3. Next we tested attentional processes in these tasks that were independent of the visual response to the cue. We placed the cue outside of the receptive field and the target within the receptive field. We found that 23% of these cells had a significant decrease in their firing rate to validly cued targets in their receptive fields under these conditions. Strong responses were evoked by the same target when the cue was flashed in the opposite hemifield (invalidly cued targets). Thus this group of neurons responded best when attention was directed toward the opposite hemifield. 4. For another group of parietal cells (13%) there was an enhanced response to targets in the visual receptive field when the cue was in the same hemifield. For the remaining 64% of the cells there was no significant modulation in this task. 5. The cued reaction time task involved exogenous control of attention; the sensory cue gave spatial and temporal direction to attention. We used several other tasks to test for endogenous control of attention.(ABSTRACT TRUNCATED AT 400 WORDS)


Hearing loss and treatment in young Down's syndrome children.
Twenty-four home-reared Down's syndrome children aged 9-32 months were assessed by trained audiologists on three separate occasions (summer, autumn and spring 1977-1978). Distraction test procedures were used; all failed to pass the screening test and 80-85% registered as having moderate to profound losses. Seventy-five per cent were categorized as having a conductive loss and some improvements were found over the test sessions as a result of surgical and decongestant treatment. Approximately 50% of the infants had been passed on similar screening procedures by the local health services. The results are discussed in relation to language development and service needs.


Active Surfaces Formed in Liquid Crystal Polymer Networks.
There is an increasing interest in animating materials to develop dynamic surfaces. These dynamic surfaces can be utilized for advanced applications, including switchable wetting, friction, and lubrication. Dynamic surfaces can also improve existing technologies, for example, by integrating self-cleaning surfaces on solar cells. In this Spotlight on Applications, we describe our most recent advances in liquid crystal polymer network (LCN) dynamic surfaces, focusing on substrate-based topographies and dynamic porous networks. We discuss our latest insights in the mechanisms of deformation with the "free volume" principle. We illustrate the scope of LCN technology through various examples of photo-/electropatterning, free-volume channeling, oscillating/programmable network distortion, and porous LCNs. Finally, we close by discussing prominent applications of LCNs and their outlook.


Clonal status and clinicopathological features of Langerhans cell histiocytosis.
Some studies have demonstrated that Langerhans cell histiocytosis (LCH) is a neoplastic hyperplasia of Langerhans cells, however some researchers consider that clonality should be assessed in more patients with LCH, both at disease presentation and during the disease course. Monoclonality is a major characteristic of most tumours, whereas normal tissue and reactive hyperplasia are polyclonal. To elucidate the nature of Langerhans cells further, the present study investigated the clinicopathological features and clonality of three cases of LCH in female patients using laser microdissection and a clonality assay, based on X-chromosomal inactivation mosaicism in somatic tissues and polymorphism of the androgen receptor gene. The results indicated that LCH was composed of Langerhans cells with a characteristic morphological appearance, eosinophils, giant cells, neutrophils and foamy cells. Immunohistochemically, the Langerhans cells were positive for CD1a, S-100 protein and vimentin. The clonality assay demonstrated that the Langerhans cells formed a monoclonal population, showing that LCH is neoplastic. We conclude that LCH is characterized by clonal proliferation, although additional studies with larger sample sizes are required to prove this conclusively.


Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers.
The catalytic subunit of human telomerase (hTERT) is known to be expressed in a variety of malignant tumours, including hepatocellular carcinoma (HCC). We studied hTERT expression in regenerative and precancerous lesions arising in cirrhosis. As shown by in situ hybridisation, hTERT mRNA was absent in normal liver, but present in varying numbers of hepatocytes and HCC cells of diseased livers, as well as in biliary epithelial cells, lymphocytes, sinusoidal-lining cells and tumour endothelial cells. RT-PCR for two hTERT transcript regions demonstrated hTERT expression in 11 out of 15 cirrhotic liver samples, in 20 out of 21 large regenerative nodules/low-grade dysplastic nodules, in 5 out of 5 high-grade dysplastic nodules, and in 4 out of 4 HCCs. The beta-splice variant was identified in all hTERT-positive cases, while the corresponding full-length transcript was found only in 13 out of 29 positive large nodular lesions and in 4 out of 11 positive cirrhotic samples. The full-length transcript was always found in the presence of the beta-splice variant, usually in low relative levels, and tended to correlate with telomerase activity in the samples, while the beta-splice variant did not. This study shows that hTERT re-expression takes place both in hepatic regeneration occurring in cirrhosis and in the early steps of hepatocarcinogenesis, and involves mainly the beta-splice variant of this molecule. Additional regulatory mechanisms may be required for the expression of the full-length hTERT transcript.


Developmental changes of rhesus monkeys in response to separation from the mother.
The development of separation response behaviors in infant rhesus macaques across the first 6 months of life was assessed. Seventeen infants underwent a neonatal assessment at 7, 14, 21, and 30 days of age which included a brief period of social isolation. At 3 and 6 months of age these same monkeys and four additional subjects were again subjected to a period of brief social isolation and also exposed to a novel environment with their sedated mother. Results indicate a developmental increase followed by a steady decline in the frequency of separation vocalizations. A modest relationship between early-infancy locomotor profiles and separation responses was also observed at several time points suggesting a possible relationship between these measures. However, stable inter-individual measures of separation distress did not emerge until late in the infantile period. This could suggest that high levels of maternal contact-seeking behavior early in infancy are context specific and not a reliable index of enduring temperament.


Reflections on the use of FPAR as a research methodology for sex worker (and key populations) research.
In this paper, we share some personal reflections of straddling different research roles in a doctoral study entitled Queering Sex Work and Mobility in South Africa. We highlight the importance of using a Feminist Participatory Action Research (FPAR) methodology when conducting studies with migrant and mobile sex workers as it offers participants an opportunity to express their lived realities and embodied knowledge(s) beyond linguistic barriers. Through our reflections, we demonstrate that marginalised communities can become co-creators in knowledge production processes, not just the givers of stories (aka 'poverty porn') but integral members of the research team who actively contribute towards the conceptualisation, data collection, analysis, publishing and distribution of scholarship.


Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence.
The opportunistic human fungal pathogen Cryptococcus neoformans has tremendous impact on global health, causing 181,000 deaths annually. Current treatment options are limited, and the frequent development of drug resistance exacerbates the challenge of managing invasive cryptococcal infections. In diverse fungal pathogens, the essential molecular chaperone Hsp90 governs fungal survival, drug resistance, and virulence. Therefore, targeting this chaperone has emerged as a promising approach to combat fungal infections. However, the role of Hsp90 in supporting C. neoformans pathogenesis remains largely elusive due to a lack of genetic characterization. To help dissect the functions of Hsp90 in C. neoformans, we generated a conditional expression strain in which HSP90 is under control of the copper-repressible promoter CTR4-2. Addition of copper to culture medium depleted Hsp90 transcript and protein levels in this strain, resulting in compromised fungal growth at host temperature; increased sensitivity to stressors, including the azole class of antifungals; altered C. neoformans morphology; and impaired melanin production. Finally, leveraging the fact that copper concentrations vary widely in different mouse tissues, we demonstrated attenuated virulence for the CTR4-2p-HSP90 mutant specifically in an inhalation model of Cryptococcus infection. During invasion and establishment of infection in this mouse model, the pathogen is exposed to the relatively high copper concentrations found in the lung as compared to blood. Overall, this work generates a tractable genetic system to study the role of Hsp90 in supporting the pathogenicity of C. neoformans and provides proof-of-principle that targeting Hsp90 holds great promise as a strategy to control cryptococcal infection.


Native, but not genetically inactivated, pertussis toxin protects mice against experimental allergic encephalomyelitis.
Treatment of SJL mice with 400 ng Bordetella pertussis toxin (PT) either in saline or emulsified in incomplete Freund's adjuvant protected the mice against experimental autoimmune encephalomyelitis (EAE) induced 28 days later by a synthetic peptide of myelin proteolipid protein (PLP139-151) in complete Freund's adjuvant. However, treatment with a genetically inactivated pertussis toxin in which the catalytic and NAD-binding sites of the ADP-ribosyltransferase subunit were modified by site-directed mutagenesis was without effect. In vitro, lymphocyte proliferation was considerably enhanced by both the native and the inactivated toxin, at concentrations of 0.1-1 microgram/ml. However, strong inhibition of proliferation was also observed with the native toxin only, at concentrations that were two to three orders of magnitude lower than that required for the mitogenic effect (0.1-1 ng/ml). The inhibition of proliferation was detectable in the case of high-background proliferation, after stimulation with antigen (PLP139-151) or purified protein derivative of Mycobacterium tuberculosis), or with anti-CD3 monoclonal antibody, but not after stimulation with concanavalin A or phorbol esters and Ca2+ ionophore. These results suggest that the inhibitory effect of PT operates by interfering selectively with a T cell receptor-dependent signaling pathway. The biological significance of the in vitro inhibitory effect of PT was demonstrated by a considerable decrease and/or delay in the ability of lymphocytes grown with PLP139-151 and low concentrations of PT to transfer EAE to naive recipients.


How Copepods Can Eat Toxins Without Getting Sick: Gut Bacteria Help Zooplankton to Feed in Cyanobacteria Blooms.
Toxin-producing cyanobacteria can be harmful to aquatic biota, although some grazers utilize them with often beneficial effects on their growth and reproduction. It is commonly assumed that gut microbiota facilitates host adaptation to the diet; however, the evidence for adaptation mechanisms is scarce. Here, we investigated the abundance of mlrA genes in the gut of the Baltic copepods Acartia bifilosa and Eurytemora affinis during cyanobacteria bloom season (August) and outside it (February). The mlrA genes are unique to microcystin and nodularin degraders, thus indicating the capacity to break down these toxins by the microbiota. The mlrA genes were expressed in the copepod gut year-round, being >10-fold higher in the summer than in the winter populations. Moreover, they were significantly more abundant in Eurytemora than Acartia. To understand the ecological implications of this variability, we conducted feeding experiments using summer- and winter-collected copepods to examine if/how the mlrA abundance in the microbiota affect: (1) uptake of toxic Nodularia spumigena, (2) uptake of a non-toxic algal food offered in mixtures with N. spumigena, and (3) concomitant growth potential in the copepods. The findings provide empirical evidence that the occurrence of mlrA genes in the copepod microbiome facilitates nutrient uptake and growth when feeding on phytoplankton mixtures containing nodularin-producing cyanobacteria; thus, providing an adaptation mechanism to the cyanobacteria blooms.


Aberrant MEG multi-frequency phase temporal synchronization predicts conversion from mild cognitive impairment-to-Alzheimer's disease.
Many neuroimaging studies focus on a frequency-specific or a multi-frequency network analysis showing that functional brain networks are disrupted in patients with Alzheimer's disease (AD). Although those studies enriched our knowledge of the impact of AD in brain's functionality, our goal is to test the effectiveness of combining neuroimaging with network neuroscience to predict with high accuracy subjects with mild cognitive impairment (MCI) that will convert to AD. In this study, eyes-closed resting-state magnetoencephalography (MEG) recordings from 27 stable MCI (sMCI) and 27 progressive MCI (pMCI) from two scan sessions (baseline and follow-up after approximately 3 years) were projected via beamforming onto an atlas-based set of regions of interest (ROIs). Dynamic functional connectivity networks were constructed independently for the five classical frequency bands while a multivariate phase-based coupling metric was adopted. Thus, computing the distance between the fluctuation of functional strength of every pair of ROIs between the two conditions with dynamic time wrapping (DTW), a large set of features was extracted. A machine learning algorithm revealed 30 DTW-based features in the five frequency bands that can distinguish the sMCI from pMCI with absolute accuracy (100%). Further analysis of the selected links revealed that most of the connected ROIs were part of the default mode network (DMN), the cingulo-opercular (CO), the fronto-parietal and the sensorimotor network. Overall, our dynamic network multi-frequency analysis approach provides an effective framework of constructing a sensitive MEG-based connectome biomarker for the prediction of conversion from MCI to Alzheimer's disease.


Efficiency of 22 online databases in the search for physicochemical, toxicological and ecotoxicological information on chemicals.
The objective of this study was to evaluate the efficiency of 22 free online databases that could be used for an exhaustive search of physicochemical, toxicological and/or ecotoxicological information about various chemicals. Twenty-two databases with free access on the Internet were referenced. We then selected 27 major physicochemical, toxicological and ecotoxicological criteria and 14 compounds belonging to seven different chemical classes which were used to interrogate all the databases. Two indices were successively calculated to evaluate the efficiency with taking or not taking account of their specialization. More than 50% of the 22 databases 'knew' all of the 14 chemicals, but the quantity of information provided is very different from one to the other and most are poorly documented. Two categories clearly appear with specialized and non-specialized databases. The HSDB database is the most efficient general database to be searched first, because it is well documented for most of the 27 criteria. However, some specialized databases (i.e. EXTOXNET, SOLVEDB, etc.) must be searched secondarily to find additional information.


Health effects of migration: U.S. Chinese in and outside the Chinatown.
Previous studies on the health effects of migration at the international level have seldom been directed to those concentrated in segregated enclaves. This study hypothesizes that in spite of the known deviations in certain demographic and socioeconomic characteristics of Chinatown (San Francisco-New York City) residents from the US Chinese population, no consistent relationship seems to exist between these attributes and health risks, as reflected in the mortality levels of the 2 populations. A convergence in mortality was observed for a noticeable number of causes of deaths, with but a few disease-cause sets of non-convergence with statistical significance. The study results were interpreted in terms of varying degrees of acculturation experience.


Short communication: Variations in major mineral contents of Mediterranean buffalo milk and application of Fourier-transform infrared spectroscopy for their prediction.
The aims of this study were (1) to assess variability in the major mineral components of buffalo milk, (2) to estimate the effect of certain environmental sources of variation on the major minerals during lactation, and (3) to investigate the possibility of using Fourier-transform infrared (FTIR) spectroscopy as an indirect, noninvasive tool for routine prediction of the mineral content of buffalo milk. A total of 173 buffaloes reared in 5 herds were sampled once during the morning milking. Milk samples were analyzed for Ca, P, K, and Mg contents within 3h of sample collection using inductively coupled plasma optical emission spectrometry. A Milkoscan FT2 (Foss, Hillerød, Denmark) was used to acquire milk spectra over the spectral range from 5,000 to 900 wavenumber/cm. Prediction models were built using a partial least square approach, and cross-validation was used to assess the prediction accuracy of FTIR. Prediction models were validated using a 4-fold random cross-validation, thus dividing the calibration-test set in 4 folds, using one of them to check the results (prediction models) and the remaining 3 to develop the calibration models. Buffalo milk minerals averaged 162, 117, 86, and 14.4mg/dL of milk for Ca, P, K, and Mg, respectively. Herd and days in milk were the most important sources of variation in the traits investigated. Parity slightly affected only Ca content. Coefficients of determination of cross-validation between the FTIR-predicted and the measured values were 0.71, 0.70, and 0.72 for Ca, Mg, and P, respectively, whereas prediction accuracy was lower for K (0.55). Our findings reveal FTIR to be an unsuitable tool when milk mineral content needs to be predicted with high accuracy. Predictions may play a role as indicator traits in selective breeding (if the additive genetic correlation between FTIR predictions and measures of milk minerals is high enough) or in monitoring the milk of buffalo populations for dairy industry purposes.


A descriptive analysis of casualties evacuated from the Africa area of operations.
The United States (US) military has expanded its area of operations into Africa. This medically immature theater is spread across a large region where prolonged field care (PFC) events are likely to occur. We describe trauma cases reported in the Africa Command (AFRICOM) area of operations to date within the Department of Defense Trauma Registry (DODTR). We queried the DODTR for all subjects evacuated from the AFRICOM area of operations from January 2002 to June 2017. There were 49 subjects in the registry during our time frame from AFRICOM. Most of the evacuations came from Djibouti (53%). The median age was 29 years, most evacuees being male (92%). Non-battle injuries accounted for most of the injuries (82%), and most were US military (90%). All battle injuries were gunshot wounds (GSW). Composite injury scores were low (median 4, IQR 4-9.5). All subjects survived to hospital discharge. GSWs (22%) and sports injuries (24%) accounted for most evacuations. Serious injuries most frequently involved the extremities (18%) and the thorax (12%). The most frequent major injuries were open fractures (22%) and abdominal injuries (10%). The most frequent facility-based interventions performed were wound debridement (29%) and fracture/joint dislocation reduction (22%). Based on this dataset, most of the injuries from AFRICOM were non-battle injuries. All battle injuries were GSWs. Our study highlights the differences in casualty care needs in this region which contrast the primary explosive-based injuries seen within United States Central Command (CENTCOM) operations. The limitations of this dataset highlight the potential value of a Joint Trauma Service (JTS) data collection mandate and resource support for units within this region to facilitate targeted improvements in medical care.


Comparative chloroplast genomes: insights into the evolution of the chloroplast genome of Camellia sinensis and the phylogeny of Camellia.
Chloroplast genome resources can provide useful information for the evolution of plant species. Tea plant (Camellia sinensis) is among the most economically valuable member of Camellia. Here, we determined the chloroplast genome of the first natural triploid Chinary type tea ('Wuyi narcissus' cultivar of Camellia sinensis var. sinensis, CWN) and conducted the genome comparison with the diploid Chinary type tea (Camellia sinensis var. sinensis, CSS) and two types of diploid Assamica type teas (Camellia sinensis var. assamica: Chinese Assamica type tea, CSA and Indian Assamica type tea, CIA). Further, the evolutionary mechanism of the chloroplast genome of Camellia sinensis and the relationships of Camellia species based on chloroplast genome were discussed. Comparative analysis showed the evolutionary dynamics of chloroplast genome of Camellia sinensis were the repeats and insertion-deletions (indels), and distribution of the repeats, indels and substitutions were significantly correlated. Chinese tea and Indian tea had significant differences in the structural characteristic and the codon usage of the chloroplast genome. Analysis of sequence characterized amplified region (SCAR) using sequences of the intergenic spacers (trnE/trnT) showed none of 292 different Camellia sinensis cultivars had similar sequence characteristic to triploid CWN, but the other four Camellia species did. Estimations of the divergence time showed that CIA diverged from the common ancestor of two Assamica type teas about 6.2 Mya (CI: 4.4-8.1 Mya). CSS and CSA diverged to each other about 0.8 Mya (CI: 0.4-1.5 Mya). Moreover, phylogenetic clustering was not exactly consistent with the current taxonomy of Camellia. The repeat-induced and indel-induced mutations were two important dynamics contributed to the diversification of the chloroplast genome in Camellia sinensis, which were not mutually exclusive. Chinese tea and Indian tea might have undergone different selection pressures. Chloroplast transfer occurred during the polyploid evolution in Camellia sinensis. In addition, our results supported the three different domestication origins of Chinary type tea, Chinese Assamica type tea and Indian Assamica type tea. And, the current classification of some Camellia species might need to be further discussed.


A New Perspective on Thyroid Hormones: Crosstalk with Reproductive Hormones in Females.
Accumulating evidence has shown that thyroid hormones (THs) are vital for female reproductive system homeostasis. THs regulate the reproductive functions through thyroid hormone receptors (THRs)-mediated genomic- and integrin-receptor-associated nongenomic mechanisms, depending on TH ligand status and DNA level, as well as transcription and extra-nuclear signaling transduction activities. These processes involve the binding of THs to intracellular THRs and steroid hormone receptors or membrane receptors and the recruitment of hormone-response elements. In addition, THs and other reproductive hormones can activate common signaling pathways due to their structural similarity and shared DNA consensus sequences among thyroid, peptide, and protein hormones and their receptors, thus constituting a complex and reciprocal interaction network. Moreover, THs not only indirectly affect the synthesis, secretion, and action of reproductive hormones, but are also regulated by these hormones at the same time. This crosstalk may be one of the pivotal factors regulating female reproductive behavior and hormone-related diseases, including tumors. Elucidating the interaction mechanism among the aforementioned hormones will contribute to apprehending the etiology of female reproductive diseases, shedding new light on the treatment of gynecological disorders.


Peripheral contrast sensitivity for dynamic sinusoidal gratings in early glaucoma.
Automated contrast thresholds were established for dynamic, 2 reversals per sec phase-shifted, sinusoidal gratings in a 5 degrees circular test field centred 7.5 degrees from the fixation point in six positions in the visual field in 16 patients (age 56-76 years) with clinically established (optic disc or nerve fibre layer damage) early glaucoma, without visual field defects. For reference, contrast thresholds were also obtained in 16 sex-matched and age-matched controls. For all three spatial frequencies, thresholds were raised in the glaucoma group (0.5 c/deg: p = 0.0034-0.041, 2 positions n.s.; 1.0 c/deg: p = 0.0093-0.049, 1 position n.s.; 2.0 c/deg: p = 0.0011-0.041, 1 position n.s.). Deficiencies did not correlate to glaucoma type (simplex vs capsular), intraocular pressure level at examination, visual acuity, or local therapy (beta-blockers vs miotics). In the glaucoma group, there was a general loss of contrast sensitivity in all six positions tested in the visual field, reflected in roughly similar threshold elevations. Losses appeared slightly greater in the lower hemi-field. Definite contrast threshold elevations from the early glaucomatous process were established in this group of glaucoma patients without visual field defects. However, the method was considered to be of less value in glaucoma detection for individual subjects, due to the large overlap in threshold values between glaucoma patients and controls.


Development of a field test for evaluating aerobic fitness in middle-aged adults: validity of a 15-m incremental shuttle walk and run test.
The purpose of this study was to develop a standardized and externally paced field test (15-m Incremental Shuttle Walk and Run Test [15mISWRT]), incorporating an incremental and progressive structure, to assess aerobic fitness in middle-aged adults. 68 middle-aged men performed three tests in random order between one to two week intervals: 15-m ISWRT, cardiopulmonary exercise test (CPX), and 1500-m fast walk. Variables evaluated were 15-m ISWRT performance (distance completed), VO2max measured by CPX, 1500-m fast walk performance (walking time), and HR response in 15-m ISWRT and 1500-m fast walk. Validity of the 15-m ISWRT was tested by comparing the associations among the 15-m ISWRT performance, VO2max and the 1500-m fast walk performance. Changes in HR response during the 15-m ISWRT and the 1500-m fast walk were also compared. Correlations between each variable were as follows: the correlation between 15- m ISWRT performance and VO2max was very high, r = 0.86 (p < 0.01), the correlation between the 1500-m fast walk and VO2max was r = -0.51 (p < 0.01). HR response during the 15-m ISWRT gently increased initially, whereas HR response during the 1500-m fast walk rapidly increased from the start. In conclusion, our findings indicate that the 15-m ISWRT is valid and safe for evaluating VO2max in middle-aged adults. Key pointsThe 15-m ISWRT is valid and safe for evaluating VO2max in middle-aged adults.In comparison with the 1500-m fast walk, the 15-m ISWRT may be a more favourable field-based assessment of aerobic fitness in the middle-aged adults.The 15-m ISWRT could become a valid means for evaluating aerobic fitness as an alternative to CPX in institutions and situations where CPX is difficult to implement.


Associations of Immune Genetic Variability with Gulf War Illness in 1990-1991 Gulf War Veterans from the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.
Gulf War illness (GWI) encompasses a constellation of persistent debilitating symptoms associated with significant changes in central nervous system (CNS) and immune functioning. Currently, there is no validated biomarker for GWI risk susceptibility. Given the impact of immune responses linked to GWI symptomology, genetic variability that causes persistent inflammatory/immune alterations may be key. This Boston University-based Gulf War Illness Consortium (GWIC) study investigated the impact of single nucleotide polymorphisms (SNPs) in variants of immune and pain genetic markers IL1B, IL2, IL6, IL6R, IL10, TNF, TGF, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, COMT and OPRM1 on GWI occurrence in a Caucasian subset of Gulf War (GW) veterans with (cases, n = 170) and without (controls, n = 34) GWI. Logistic regression modeling created a prediction model of GWI risk that associated genetic variability in TGF (rs1800469, p = 0.009), IL6R (rs8192284, p = 0.004) and TLR4 (rs4986791, p = 0.013) with GWI occurrence. This prediction model was specific and sensitive, with a receiver operator characteristic area under the curve of 71.4%. This is the first report of immune genetic variability being predictive of GWI and warrants validation in larger independent cohorts. Future reports will present interactions of these genetic risk factors with other characteristics of GW service.


Loss of ERbeta expression as a common step in estrogen-dependent tumor progression.
The characterization of estrogen receptor beta (ERbeta) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERbeta expression in cancer as compared with benign tumors or normal tissues, whereas ERalpha expression persists. The loss of ERbeta expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERalpha target genes by ERbeta or ERbeta-specific gene induction could explain that ERbeta has a differential effect on proliferation as compared with ERalpha. ERbeta may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERalpha and ERbeta expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.


Active destruction of defective ribosomes by a ubiquitin ligase involved in DNA repair.
Progression of DNA replication forks through damaged DNA requires a ubiquitin ligase comprised of the cullin Rtt101, the RING finger protein Hrt1, and the adaptor protein Mms1. Rtt101 and Mms1 were implicated recently by Fujii and colleagues (pp. 963-974) in the degradation of catalytically inactive mutant 25S ribosomal RNAS (rRNAs) in mature 60S ribosomal subunits, a process that requires ubiquitin and is accompanied by ubiquitination of 60S components. It now seems likely that the same ubiquitin ligase is enlisted to deal with defective rRNA and damaged DNA.


Correlation of radiographic patellofemoral indices with tibial tubercle transfer distance in Fulkerson osteotomy procedures.
A laterally tracking patella is commonly seen in patients with chronic recurrent lateral patellar dislocations. Clinical appearance of the J-sign occurs when the patella is congruent with the trochlear groove in flexion and moves over the lateral border of the femoral condyle as the lower leg reaches complete extension. A Fulkerson osteotomy procedure corrects this maltracking of the patella by medially transferring the tibial tubercle. There are many radiographic patellofemoral indices that can be used describe this incongruence about the patelloformal joint. The current literature supports the use of the tibial tubercle-trochlear groove (TT-TG) index in determining the appropriate amount medialization of the extensor mechanism. However there is little agreement in how far to transfer the tibial tubercle to best achieve maximum patello-femoral congruency. It is the senior author's belief that lateral patellar edge (LPE) measure on voluntary quadriceps active hyperextension MRI scan has the strongest correlation with final operative tibial tubercle transfer distance needed to achieve maximum patellofemoral congruency. The purpose of this study was to show that the voluntary quadriceps active hyperextension MRI measurement of lateral patellar edge (LPE) has the strongest correlation with tibial tubercle transfer distance required to achieve maxium patellofemoral congruency intraoperatively in the terminal 30 degrees of active knee extension compared to all other patellofemoral indices measured on axial MRI scans with the knee in voluntary active knee extension to 30 degrees of flexion, passive full extension, and voluntary quadriceps active hyperextension. Retrospective case series via review of the electronic medical record. Forty-three Fulkerson osteotomy patient charts were reviewed retrospectively. Three different pre-operative axial MRI views were then examined and measured for Tibial Tubercle-Trochlear Groove (tt-tg), lateral patellar edge (LPE), bisect offset (BSO), and lateral patellar displacement (LPD). Each patient had three MRIs: one with the knee resting in extension, one in voluntary quadriceps active hyperextension, and one in voluntary quadriceps active 30 degree flexion. Statistics were then calculated using Statistical Package for the Social Sciences (SPSS) (IBM corp). Tibial tubercle transfer distances required to achieve congruency intraoperatively correlated moderately (0.500-0.300) and were statistically significant (alpha .050) for passive extension MRI measurement of TT-TG (Pearson--0.403, alpha 0.010) and LPD (Pearson .362, alpha 0.022); voluntary quadriceps active hyperextension TT-TG (Pearson 0.487, alpha, 0.001); voluntary quadriceps active flexion TT-TG (Pearson .548, alpha< 0.001), LPE (Pearson .332, alpha 0.029), and LPD (Pearson 0.446 alpha .003). The hypothesis that voluntary quadriceps active hyperextension MRI LPE measurement best correlated with tibial tubercle transfer distance was incorrect. The data collected showed correlation and statistical significance for voluntary quadriceps active flexion LPE with required tibal tubercle transfer distance (Pearson 0.34, alpha 0.026). The MRI measurement that best correlated with tibial tubercle transfer distance was voluntary quadriceps active flexion measure of TT-TG (Pearson .556, alpha< 0.001).


Crystallization of Poly(ε-caprolactone) in Poly(vinylidene fluoride)/Poly(ε-caprolactone) Blend.
The crystallization behavior of poly(ε-caprolactone) (PCL) in a poly(vinylidene fluoride) (PVDF)/PCL blend as well as on a highly orientated PVDF substrate was studied by means of POM, DSC and TEM. The results show that the miscibility of the PVDF/PCL blend and the spherulitic morphology of PVDF varies with the blend ratio. For all the compositions, the pre-existing PVDF crystals accelerated the crystallization of PCL because the PVDF exhibits very strong nucleation ability toward PCL as reflected by the occurrence of heteroepitaxy and the transcrystallization of PBA on the PVDF substrate. This is associated with the perfect lattice matching between the PBA and PVDF crystals.


[Clinical and psychological features in patients with incident and recurrent cases of benign paroxysmal positional vertigo].
To assess the clinical and psychological features in patients with incident and recurrent posterior canal BPPV. The study included 47 patients (mean age 49.1±10.9 years; 12.8% of men and 87.2% of women) with idiopathic BPPV, posterior canal. According to the anamnesis, the patients were divided into two groups: 27 (57.4%) patients with incident BPPV (iBPPV) and 20 (42.6%) patients with recurrent BPPV (rBPPV). All patients were treated with repositioning Epley and/or Semont maneuvers until resolution of canalolithiasis. After that, clinical and psychological testing was immediately carried out, including short version of Vertigo Symptom Scale (VSS), Dizziness Handicap Inventory (DHI), Visual analogue scale (VAS) for fear of vertigo spells, Depersonalization-Derealization Inventory (DDI), Social Readjustment Rating Scale (SRRS) of Holmes and Rahe, Anxiety Sensitivity Index (ASI), Generalized Anxiety Disorder Scale (GAD-7) and Patient Health Questionnaire (PHQ). Patients with rBPPV compared with iBPPV had more severe symptoms of dizziness according to DHI (p=0.02) due to a functional and emotional subscales, as well as a more pronounced feeling of fear according to VAS (p=0.01). The data obtained on the remaining scales and questionnaires did not show statistically significant differences between the groups. The revealed results may indicate a greater predisposition of patients with rBPPV to the development of a special kind of mental disorders - functional dizziness or persistent postural-perceptual dizziness, which requires additional study and development of preventive measures.


Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes.
Aim: To investigate the degree by which epigenetic signatures in children from mothers with gestational diabetes mellitus (GDM) are influenced by environmental factors. Methods: We profiled the DNA methylation signature of blood from lean, obese and GDM mothers and their respective newborns. Results: DNA methylation profiles of mothers showed high similarity across groups, while newborns from GDM mothers showed a marked distinct epigenetic profile compared with newborns of both lean and obese mothers. Analysis of variance in DNA methylation levels between newborns showed higher variance in the GDM group. Conclusion: Our results suggest that environmental factors, rather than direct transmission of epigenetic marks from the mother, are involved in establishing the epigenetic signature associated with GDM.


Diagnostic Utility of Neuregulin for Acute Coronary Syndrome.
The purpose of this study was to determine the diagnostic test characteristics of serum neuregulin-1β (NRG-1β) for the detection of acute coronary syndrome (ACS). We recruited emergency department patients presenting with signs and symptoms prompting an evaluation for ACS. Serum troponin and neuregulin-1β levels were compared between those who had a final discharge diagnosis of myocardial infarction (STEMI and NSTEMI) and those who did not, as well as those who more broadly had a final discharge diagnosis of ACS (STEMI, NSTEMI, and unstable angina). Of 319 study participants, 11% had evidence of myocardial infarction, and 19.7% had a final diagnosis of ACS. Patients with MI had median neuregulin levels of 0.16 ng/mL (IQR [0.16-24.54]). Compared to the median of those without MI, 1.46 ng/mL (IQR [0.16-15.02]), there was no significant difference in the distribution of results (P = 0.63). Median neuregulin levels for patients with ACS were 0.65 ng/mL (IQR [0.16-24.54]). There was no statistical significance compared to those without ACS who had a median of 1.40 ng/mL (IQR [0.16-14.19]) (P = 0.95). Neuregulin did not perform successfully as a biomarker for acute MI or ACS in the emergency department.


Hyperchloremic metabolic acidosis due to saline absorption during laser enucleation of the prostate: a case report.
Recent technological advancements have enabled the use of electrolyte solutions such as saline or buffered electrolyte solution during transurethral resection or laser enucleation of the prostate. However, saline absorption may cause hyperchloremic metabolic acidosis. A male in his late seventies underwent holmium laser enucleation of the prostate under a combination of subarachnoid block and general anesthesia. Intraoperatively, abdominal distension prompted the attending anesthesiologist to consider the possibility of SGA malposition, and the trachea was intubated. Oropharyngeal and neck edema was observed, and laboratory examination revealed considerable acidosis with hyperchloremia. Further evaluation confirmed the absorption of a large amount of saline into the circulation via the perforated bladder. Application of the simplified Stewart approach clearly suggested that hyperchloremia was the principal cause of metabolic acidosis. The dilution of albumin attenuated acidosis. Absorption of normal saline during laser enucleation of prostate caused hyperchloremic metabolic acidosis and airway edema.


Total cotinine in plasma: a stable biomarker for exposure to tobacco smoke.
Determination of plasma cotinine concentration is the predominant assay employed to quantify smoking and exposure to environmental tobacco smoke in epidemiological studies. However, cotinine is biotransformed into secondary metabolites. This pilot study determined plasma concentrations of cotinine, cotinine glucuronide, 3-hydroxycotinine, and 3-hydroxycotinine glucuronide. Total cotinine concentration was determined by summation of all four metabolites. The goals of this study were (1) to explore the stability and validity of total cotinine concentration as a measure of tobacco smoking and as a measure of exposure to environmental tobacco smoke in nonsmokers, (2) to explore the stability of plasma concentrations of each of the four nicotine metabolites in smokers by performing a.m. and p.m. measures, and (3) to explore the stability of indices of glucuronidation as measures of possible markers for enzymatic activity. The subject sample included 76 white volunteers (32% smokers and 68% nonsmokers). Plasma total cotinine concentration appeared to be very stable, suggesting that total cotinine concentration may be a good measure for epidemiological studies employing a single plasma sample. Moreover, plasma total cotinine concentration also reflected exposure to environmental tobacco smoke more accurately than did plasma cotinine concentration, which would have not identified 27% of passive smokers. 3-Hydroxycotinine glucuronide and 3-hydroxycotinine plasma concentrations were almost as stable as cotinine concentrations. However, cotinine glucuronide and its indices of glucuronidation were unstable, suggesting that cotinine glucuronide undergoes deconjugation. New studies of total cotinine in plasma using more than two blood collections during the day are needed to definitively establish that it is a stable biomarker for epidemiological studies.


Predictive value of ventricular premature beats for subsequent ischaemic heart disease in apparently healthy subjects.
From 1978 to 1980, 260 healthy subjects, 40-79 years of age, underwent 24 h ambulatory electrocardiography in order to determine the prevalence and complexity of ventricular premature beats (VPBs) in adults without apparent heart disease. The number of types of VPBs seem in 5% or less were considered 'abnormal' and the present follow-up study undertaken in order to assess the significance of such 'abnormal' VPBs as predictors of subsequent ischaemic heart disease (IHD). Information concerning cardiac events within the follow-up period was available in 237 subjects. Nine were lost to follow-up and 24 refused clinical examination. IHD was documented in 13 (eight myocardial infarction, five angina pectoris). 'Abnormal' VPBs occurred in six out of 13 (46%) who later developed IHD compared to only 24 out of 213 (11%) without IHD (P less than 0.001). The presence of either more than 900 VPBs 24 h-1 or ventricular tachycardia of more than three beats, identified five out of 13 patients with IHD (sensitivity 38%), whereas 210 out of 213 with no evidence of IHD at follow-up were identified (specificity 98%). Four out of seven who initially had more than 900 VPBs 24 h-1 had IHD on follow-up. Our results have demonstrated a strong positive association between 'abnormal' VPBs observed in a random 24-h electrocardiographic recording of apparently healthy subjects 40-79 years of age and subsequent IHD. They also suggest that a 24-h ECG may be useful for the assessment of coronary risk even in asymptomatic subjects.


Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment.
The aim was to survey the range of cerebral injury and abnormalities of cerebral development in infants born between 23 and 30 weeks' gestation using serial MRI scans of the brain from birth, and to correlate those findings with neurodevelopmental outcome after 18 months corrected age. Between January 1997 and November 2000, consecutive infants born at < 30 weeks' gestational age underwent serial MRI brain scans from birth until term-equivalent age. Infants were monitored after 18 months of age, corrected for prematurity, with the Griffiths Mental Development Scales and neurologic assessment. A total of 327 MRI scans were obtained from 119 surviving infants born at 23 to 30 weeks of gestation. Four infants had major destructive brain lesions, and tissue loss was seen at term for the 2 survivors. Fifty-one infants had early hemorrhage; 50% of infants with term scans after intraventricular hemorrhage had ventricular dilation. Twenty-six infants had punctate white matter lesions on early scans; these persisted for 33% of infants assessed at term. Early scans showed cerebellar hemorrhagic lesions for 8 infants and basal ganglia abnormalities for 17. At term, 53% of infants without previous hemorrhage had ventricular dilation and 80% of infants had diffuse excessive high signal intensity within the white matter on T2-weighted scans. Complete follow-up data were available for 66% of infants. Adverse outcomes were associated with major destructive lesions, diffuse excessive high signal intensity within the white matter, cerebellar hemorrhage, and ventricular dilation after intraventricular hemorrhage but not with punctate white matter lesions, hemorrhage, or ventricular dilation without intraventricular hemorrhage. Diffuse white matter abnormalities and post-hemorrhagic ventricular dilation are common at term and seem to correlate with reduced developmental quotients. Early lesions, except for cerebellar hemorrhage and major destructive lesions, do not show clear relationships with outcomes.


A Similarity Heuristic in Children's Possibility Judgments.
Children often judge that strange and improbable events are impossible, but the mechanisms behind their reasoning remain unclear. This article (N = 250) provides evidence that young children use a similarity heuristic that compares potential events to similar known events to determine whether events are possible. Experiment 1 shows that 5- to 6-year-olds who hear about improbable events go on to judge that similar improbable events can happen. Experiment 2 shows that 5- to 6-year-olds more often affirm that improbable events can happen if told about related improbable events than if told about unrelated ones. Finally, Experiment 3 shows that 5- to 6-year-olds affirm the possibility of improbable events related to known events, but deny that related impossible events can happen.


Distributed suppression of stimulated Raman scattering in an Yb-doped filter-fiber amplifier.
Suppression of stimulated Raman scattering (SRS) is demonstrated in a cladding-pumped fiber amplifier. The Yb-doped amplifier fiber design incorporates a high-index ring that resonantly couples SRS wavelengths out of the gain material, thus filtering the gain. Modeling shows that fiber asymmetry plays an important role in the filtering spectrum.


A non-diaphragm type small shock tube for application to a molecular beam source.
A non-diaphragm type small shock tube was developed for application to a molecular beam source, which can generate beams in the energy range from 1 to several electron volts and beams containing dissociated species such as atomic oxygen. Since repetitive high-frequency operation is indispensable for rapid signal acquisition in beam scattering experiments, the dimensions of the shock tube were miniaturized to reduce the evacuation time between shots. The designed shock tube is 2-4 mm in diameter and can operate at 0.5 Hz. Moreover, a high shock Mach number at the tube end is required for high-energy molecular beam generation. To reduce the shock attenuation caused by the wall boundary layer, which becomes significant in small-diameter tubes, we developed a high-speed response valve employing the current-loop mechanism. The response time of this mechanism is about 100 μs, which is shorter than the rupture time of conventional diaphragms. We show that the current-loop valve generates shock waves with shorter formation distances (about 200-300 mm) than those of conventional shock tubes. In addition, the converging geometry efficiently accelerates shock wave in the small-diameter tubes. The optimal geometry of the shock tube yields shock Mach number around 7, which indicates that the translation energy of molecular beams can exceed 1 eV even in the presence of the real gas effect.


MYB80 homologues in Arabidopsis, cotton and Brassica: regulation and functional conservation in tapetal and pollen development.
The Arabidopsis AtMYB80 transcription factor regulates genes involved in pollen development and controls the timing of tapetal programmed cell death (PCD). Downregulation of AtMYB80 expression precedes tapetal degradation. Inhibition of AtMYB80 expression results in complete male sterility. Full-length AtMYB80 homologs have been isolated in wheat, rice, barley and canola (C genome). The complete sequences of MYB80 genes from the Brassica. napus (A gene), B. juncea (A gene), B. oleracea (C gene) and the two orthologs from cotton (Gossypium hirsutum) were determined. The deduced amino acid sequences possess a highly conserved MYB domain, 44-amino acid region and 18-amino acid C-terminal sequence. The cotton MYB80 protein can fully restore fertility of the atmyb80 mutant, while removal of the 44 amino acid sequence abolishes its function. Two conserved MYB cis-elements in the AtMYB80 promoter are required for downregulation of MYB80 expression in anthers, apparently via negative auto-regulation. In cotton, tapetal degradation occurs at a slightly earlier stage of anther development than in Arabidopsis, consistent with an earlier increase and subsequent downregulation in GhMYB80 expression. The MYB80 homologs fused with the EAR repressor motif have been shown to induce male sterility in Arabidopsis. Constructs were designed to maximize the level of male sterility. MYB80 genes are conserved in structure and function in all monocot and dicot species so far examined. Expression patterns of MYB80 in these species are also highly similar. The reversible male sterility system developed in Arabidopsis by manipulating MYB80 expression should be applicable to all major crops.


Spatial localization of ligand binding sites from electron current density surfaces calculated from NMR chemical shift perturbations.
Rapid, accurate structure determination of protein-ligand complexes is an essential component in structure-based drug design. We have developed a method that uses NMR protein chemical shift perturbations to spatially localize a ligand when it is complexed with a protein. Chemical shift perturbations on the protein arise primarily from the close proximity of electron current density from the ligand. In our approach the location of the center of the electron current density for a ligand aromatic ring was approximated by a point-dipole, and dot densities were used to represent ligand positions that are allowed by the experimental data. The dot density is increased in the region of space that is consistent for the most data. A surface can be formed in regions of the highest dot density that correlates to the center of the ligand aromatic ring. These surfaces allow for the rapid evaluation of ligand binding, which is demonstrated on a model system and on real data from HCV NS3 protease and HCV NS3 helicase, where the location of ligand binding can be compared to that obtained from difference electron density from X-ray crystallography.


The Introduction and Development of the H-index for Imaging Utilizers: A Novel Metric for Quantifying Utilization of Emergency Department Imaging.
The objective was to develop a novel metric for quantifying patient-level utilization of emergency department (ED) imaging. Using 2009 to 2015 Truven Health MarketScan commercial claims and encounters database, all ED visits and associated imaging services were identified. To measure imaging resource intensity, total imaging relative value units (RVUs) were calculated for each patient per ED visit. An individual's annual imaging h-index is defined as the largest number, h, such that h ED visits by that individual in a given year is associated with total medical imaging RVUs of a value of at least h. Over 7 years, in a sample of 86,506,362 privately insured individuals (232,919,808 person-years) in all 50 states and the District of Columbia, 38,973,716 ED visits were identified. A total of 9.5% of person-years had one ED visit and 2.7% had two or more (the remainder had none). From 2009 to 2015, the percentage of ED patients undergoing imaging increased from 25.1% to 34.6%. Individuals with two or more ED visits each associated with two or more imaging RVUs (ED imaging h-index ≥ 2) comprised 0.2% of the sample and 1.4% of ED visitors; however, they accounted for 4.0% of ED visits and the use of 18.6% of imaging resources. From 2009 to 2015, imaging resource allocation for such patients increased from 16.5% to 21.0%. The ED imaging h-index allows identification of patients who undergo significant ED imaging, based on a single-digit patient-specific metric that incorporates both annual ED visit number and medical imaging resource intensity per visit. While ED patients with an ED imaging h-index ≥ 2 represented a minuscule fraction of privately insured individuals, they were associated with one-fifth of all ED imaging resources.


Source of reaction-diffusion coupling in confined systems due to temperature inhomogeneities.
Diffusion is often accompanied by a reaction or sorption which can induce temperature inhomogeneities. Monte Carlo simulations of Lennard-Jones atoms in zeolite NaCaA are reported with a hot zone presumed to be created by a reaction. Our simulations show that localized hot regions can alter both the kinetic and transport properties. Further, enhancement of the diffusion constant is greater for larger barrier height, a surprising result of considerable significance to many chemical and biological processes. We find an unanticipated coupling between reaction and diffusion due to the presence of hot zone in addition to that which normally exists via concentration.


Validation of DIGIROP models and decision support tool for prediction of treatment for retinopathy of prematurity on a contemporary Swedish cohort.
Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce vision loss. A prediction model for severe ROP requiring treatment that might sensitively and specifically identify infants that develop severe ROP, DIGIROP-Birth, was developed using birth characteristics. DIGIROP-Screen additionally incorporates first signs of ROP in different models over time. The aim was to validate DIGIROP-Birth, DIGIROP-Screen and their decision support tool on a contemporary Swedish cohort. Data were retrieved from the Swedish national registry for ROP (2018-2019) and two Swedish regions (2020), including 1082 infants born at gestational age (GA) 24 to <31 weeks. The predictors were GA at birth, sex, standardised birth weight and age at the first sign of ROP. The outcome was ROP treatment. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) with 95% CI were described. For DIGIROP-Birth, the AUC was 0.93 (95% CI 0.90 to 0.95); for DIGIROP-Screen, it ranged between 0.93 and 0.97. The specificity was 49.9% (95% CI 46.7 to 53.0) and the sensitivity was 96.5% (95% CI 87.9 to 99.6) for the tool applied at birth. For DIGIROP-Screen, the cumulative specificity ranged between 50.0% and 78.7%. One infant with Beckwith-Wiedemann syndrome who fulfilled criteria for ROP treatment and had no missed/incomplete examinations was incorrectly flagged as not needing screening. DIGIROP-Birth and DIGIROP-Screen showed high predictive ability in a contemporary Swedish cohort. At birth, 50% of the infants born at 24 to <31 weeks of gestation were predicted to have low risk of severe ROP and could potentially be released from ROP screening examinations. All routinely screened treated infants, excluding those screened for clinical indications of severe illness, were correctly flagged as needing ROP screening.


Model for melting of confined DNA.
When DNA molecules are heated they denature. This occurs locally so that loops of molten single DNA strands form, connected by intact double-stranded DNA pieces. The properties of this "melting" transition have been intensively investigated. Recently there has been a surge of interest in this question, in part caused by experiments determining the properties of partially bound DNA confined to nanochannels. But how does such confinement affect the melting transition? To answer this question we introduce and solve a model predicting how confinement affects the melting transition for a simple model system by first disregarding the effect of self-avoidance. We find that the transition is smoother for narrower channels. By means of Monte Carlo simulations we then show that a model incorporating self-avoidance shows qualitatively the same behavior and that the effect of confinement is stronger than in the ideal case.


Thyroid-stimulating antibody mimics thyrotropin in its ability to desensitize the adenosine 3',5'-monophosphate response to acute stimulation in continuously cultured rat thyroid cells (FRT-L5).
TSH preincubation induces refractoriness to further stimulation of cAMP accumulation by the hormone in cultured thyroid cells. The question of whether the thyroid-stimulating antibodies (TSAb) present in sera of patients with Graves' disease have the same desensitizing effect as TSH was evaluated in this study using a differentiated strain of rat thyroid cells (FRT-L5) which requires TSH for growth and develops refractoriness to acute TSH stimulation of cAMP accumulation. Cells cultured for 4-5 days in medium deprived of TSH recovered responsiveness to TSH and TSAb. Refractoriness to TSH was reinduced in these cells by a 24-h preincubation with 250 microU/ml TSH. The addition of 100 microM KI or 100 microM methimazole to the medium together with TSH did not modify TSH-induced refractoriness. Four different TSAb preparations all induced refractoriness to TSH-stimulated cAMP accumulation. TSAb preincubation induced refractoriness to acute TSAb as well as TSH-stimulated cAMP accumulation. TSAb-induced desensitization was dose dependent and required prolonged (8-24 h) exposure to TSAb. Furthermore, the desensitization induced by TSAb as well as that caused by TSH were significantly inhibited by cycloheximide, indicating the need for de novo protein synthesis. In conclusion, TSAb mimics TSH in the induction of refractoriness in FRT-L5 cells.


Primary Bilateral High-Grade Vesicoureteral Reflux in Children: Management Perspective.
Objective Vesicoureteral reflux (VUR) is a common finding in the pediatric population with the risk of repeated infections and renal damage. There is little is known about the natural history of primary bilateral high-grade reflux. Herein we present our experience in the management of primary high-grade bilateral VUR and the long-term outcome of renal function in this specific group of patients. Materials and methods We retrospectively evaluated all patients with congenital bilateral VUR between 2006 and 2014. Records were reviewed for patient age at diagnosis, antenatal history, clinical presentation, the grade of VUR on voiding cystourethrogram (VCUG), presence of scars on dimercaptosuccinic acid (DMSA) scan, indications for surgical intervention, and surgical approaches. Clinical and radiological outcomes of this subgroup of patients were assessed. Results A total of 67 patients with bilateral VUR were identified, of whom 31 (20 boys and 11 girls) had primary high-grade (grade IV and V) bilateral VUR. The mean age at diagnosis was seven months. DMSA scans showed renal scars in 19 patients (61%) and eight of them were bilateral. Surgical intervention was necessary for 81% of patients with a success rate of 58% after endoscopic correction and 100% after reimplantation. Chronic kidney disease (CKD) developed in 13 patients (42%) after a mean follow-up of eight years. Conclusions Primary bilateral high-grade VUR carries a high rate of surgical intervention. The endoscopic correction has an acceptable success rate and efficient long-term outcome. Nevertheless, a significant proportion of patients progresses to CKD even after VUR management.


[Lens changes following intraocular tamponade in vitrectomy. Linear densitometric image analysis of Scheimpflug photographs 6 months after operation].
A complication arising from vitrectomy is the formation of cataract. As a result of an intra- and postoperative tamponade chosen (BSS, air, SF6-gas, silicon oil) the size and frequency of the cataract varies accordingly. 6 months after vitrectomy Scheimpflug photography and microdensitometric evaluation of the negatives were performed on 30 pairs of phacic eyes showing changes in the transparency of the lens. Following silicon oil tamponade a significant deterioration of transparency (t-test) was observed in the lens nucleus of the operated eye; in the area of the lens in front of the nucleus a marked but not significant deterioration of transparency was discovered following both silicon oil and SF6-gas tamponade. In the case of the area in front of the nucleus following SF6-gas tamponade as well as the whole of the lens following BSS or air tamponade a small but not at all significant difference in lens transparency was apparent after comparison of the operated to the non-operated eyes.


Interior structure of neptune: comparison with uranus.
Measurements of rotation rates and gravitational harmonics of Neptune made with the Voyager 2 spacecraft allow tighter constraints on models of the planet's interior. Shock measurements of material that may match the composition of Neptune, the so-calied planetary ;;ice,'' have been carried out to pressures exceeding 200 gigapascals (2 megabars). Comparison of shock data with inferred pressure-density profiles for both Uranus and Neptune shows substantial similarity through most of the mass of both planets. Analysis of the effect of Neptune's strong differential rotation on its gravitational harmonics indicates that differential rotation involves only the outermost few percent of Neptune's mass.


Genome-wide characterization of Mariner-like transposons and their derived MITEs in the Whitefly Bemisia tabaci (Hemiptera: Aleyrodidae).
The whitefly, Bemisia tabaci is a hemipteran pest of vegetable crops vectoring a broad category of viruses. Currently, this insect pest showed a high adaptability and resistance to almost all the chemical compounds commonly used for its control. In many cases, transposable elements (TEs) contributed to the evolution of host genomic plasticity. This study focuses on the annotation of Mariner-like elements (MLEs) and their derived Miniature Inverted repeat Transposable Elements (MITEs) in the genome of B. tabaci. Two full-length MLEs belonging to mauritiana and irritans subfamilies were detected and named Btmar1.1 and Btmar2.1, respectively. Additionally, 548 defective MLE sequences clustering mainly into 19 different Mariner lineages of mauritiana and irritans subfamilies were identified. Each subfamily showed a significant variation in MLE copy number and size. Furthermore, 71 MITEs were identified as MLEs derivatives that could be mobilized via the potentially active transposases encoded by Btmar 1.1 and Btmar2.1. The vast majority of sequences detected in the whitefly genome present unusual terminal inverted repeats (TIRs) of up to 400 bp in length. However, some exceptions are sequences without TIRs. This feature of the MLEs and their derived MITEs in B. tabaci genome that distinguishes them from all the other MLEs so far described in insects, which have TIRs size ranging from 20 to 40 bp. Overall, our study provides an overview of MLEs, especially those with large TIRs, and their related MITEs, as well as diversity of their families, which will provide a better understanding of the evolution and adaptation of the whitefly genome.


Fertile inventions: new contraceptive techniques.
Research into contraception is producing new techniques that involve everything from vaccinations to nasal sprays. Steroids are the basis of the conventional contraceptive pill and much current research is on alternative ways of introducing the same drugs into the woman's reproductive system. Norplant is 1 approach. It involves implanting 6 tiny silicone-rubber tubes just beneath the skin of a woman's underarm. The tubes contain a drug, widely used as an ingredient of the contraceptive pill, which is slowly released from the tubes over a period of 5 years. It is understandable that much contraceptive research is focused on the womb. The brain, however, seems a strange place to be concerned with when trying to prevent conception. But it is the brain that controls a woman's ovulation by sending signals to the reproductive system via the pituitary gland. And now it is possible to synthesize chemicals which, when given in the form of a nasal spray, will inhibit ovulation by mimicking the brain's signals to the pituitary gland. It may even be possible to develop drugs which act directly on parts of the brain itself--a prospect we should be aware of, whether we would approve of it or not. There has been such an explosion of knowledge of the neural transmission systems that this may not be so far-fetched as it sounds. Research in China tends to concentrate more on naturally occurring substances--like a new form of female sterilization which involves not anesthetics or surgery but a substance called "mucilage"--1 of the ingredients of birds-nest soup. If mucilage is passed through the cervix into the fallopian tubes it causes them to block up and so prevents the passage of the ovum. There is a Western "high-tech" alternative to this, called methylcyanoacrylate--you might be more familiar with it as "superglue" or "crazy glue." Used carelessly it can stick your fingers together, but this tendency to join human tissues can be more productively used to block up the fallopian tubes. The Chinese are also looking at another natural substance as the basis of the possible "male pill." This is gossypol which occurs in cottonseed. A major reason why most research has been focused on contraception for women is that men present problems of quite a different order of magnitude. While a woman only ovulates once every 28 days or so, male sperm are produced continuously, with 200-400 million of them in each ejaculation. But drugs based on gossypol, which seems to have the effect of reducing the sperm count, may be the answer. Under the auspices of the World Health Organization, research on gossypol and other plants with contraceptive potential is now going on over all the world. Some 350 have been put under the microscope so far and about 30 look worth pursuing.


Clinical indications for calcium channel blockers.
Ca2+ channel blocking agents have proven to be one of the most exciting groups of drugs for management of many cardiovascular diseases and as potentially first-line agents for treatment of angina pectoris and hypertension. Unlike beta blockers, they can directly relax coronary and peripheral arteries and, therefore, reduce total peripheral resistance and improve tissue perfusion. Ca2+ channel blockers are drugs of choice for patients with Prinzmetal's angina and should be first-line drugs for mixed angina, and can be used alone or with beta blockers for classic angina. These drugs as a group have many potential clinical indications, especially in diseases in which vascular or smooth muscle spasm seems to cause the disease. Although all three Ca2+ channel blockers have a common mechanism of action, their cardiac and hemodynamic effects are different, nifedipine being the least depressant to cardiac function. In choosing the right agent, careful consideration should be given to the patient's characteristics in order to derive maximum benefit with minimal risks.


Complete genome sequence of the fenitrothion-degrading Burkholderia sp. strain YI23.
Burkholderia species are ubiquitous in soil environments. Many Burkholderia species isolated from various environments have the potential to biodegrade man-made chemicals. Burkholderia sp. strain YI23 was isolated from a golf course soil and identified as a fenitrothion-degrading bacterium. In this study, we report the complete genome sequence of Burkholderia sp. strain YI23.


Gap junctions and connexin hemichannels both contribute to the electrical properties of retinal pigment epithelium.
Gap junctions are intercellular channels that permit the transfer of ions and small molecules between adjacent cells. These cellular junctions are particularly dense in the retinal pigment epithelium (RPE), and their contribution to many retinal diseases has been recognized. While gap junctions have been implicated in several aspects of RPE physiology, their role in shaping the electrical properties of these cells has not been characterized in mammals. The role of gap junctions in the electrical properties of the RPE is particularly important considering the growing appreciation of RPE as excitable cells containing various voltage-gated channels. We used a whole-cell patch clamp to measure the electrical characteristics and connectivity between RPE cells, both in cultures derived from human embryonic stem cells and in the intact RPE monolayers from mouse eyes. We found that the pharmacological blockade of gap junctions eliminated electrical coupling between RPE cells, and that the blockade of gap junctions or Cx43 hemichannels significantly increased their input resistance. These results demonstrate that gap junctions function in the RPE not only as a means of molecular transport but also as a regulator of electrical excitability.


Generation and measurement of subpicosecond electron beam pulses.
The generation and measurement of subpicosecond electron beam pulses by the transverse-longitudinal combination gate system is described. The temporal property of the pulse gate is analyzed with the help of the longitudinal emittance diagram. Close agreement has been obtained between the calculated pulse width and the observed one which was measured by the Lissajous's figure method. A beam pulse of 0.2 ps (FWHM) was produced.


Mutant alleles of Arabidopsis RADIALLY SWOLLEN 4 and 7 reduce growth anisotropy without altering the transverse orientation of cortical microtubules or cellulose microfibrils.
The anisotropic growth of plant cells depends on cell walls having anisotropic mechanical properties, which are hypothesized to arise from aligned cellulose microfibrils. To test this hypothesis and to identify genes involved in controlling plant shape, we isolated mutants in Arabidopsis thaliana in which the degree of anisotropic expansion of the root is reduced. We report here the characterization of mutants at two new loci, RADIALLY SWOLLEN 4 (RSW4) and RSW7. The radial swelling phenotype is temperature sensitive, being moderate (rsw7) or negligible (rsw4) at the permissive temperature, 19 degrees C, and pronounced at the restrictive temperature, 30 degrees C. After transfer to 30 degrees C, the primary root's elongation rate decreases and diameter increases, with all tissues swelling radially. Swelling is accompanied by ectopic cell production but swelling is not reduced when the extra cell production is eliminated chemically. A double mutant was generated, whose roots swell constitutively and more than either parent. Based on analytical determination of acid-insoluble glucose, the amount of cellulose was normal in rsw4 and slightly elevated in rsw7. The orientation of cortical microtubules was examined with immunofluorescence in whole mounts and in semi-thin plastic sections, and the orientation of microfibrils was examined with field-emission scanning electron microscopy and quantitative polarized-light microscopy. In the swollen regions of both mutants, cortical microtubules and cellulose microfibrils are neither depleted nor disoriented. Thus, oriented microtubules and microfibrils themselves are insufficient to limit radial expansion; to build a wall with high mechanical anisotropy, additional factors are required, supplied in part by RSW4 and RSW7.


The family of toxin-related ecto-ADP-ribosyltransferases in humans and the mouse.
ADP-ribosyltransferases including toxins secreted by Vibrio cholera, Pseudomonas aerurginosa, and other pathogenic bacteria inactivate the function of human target proteins by attaching ADP-ribose onto a critical amino acid residue. Cross-species polymerase chain reaction (PCR) and database mining identified the orthologs of these ADP-ribosylating toxins in humans and the mouse. The human genome contains four functional toxin-related ADP-ribosyltransferase genes (ARTs) and two related intron-containing pseudogenes; the mouse has six functional orthologs. The human and mouse ART genes map to chromosomal regions with conserved linkage synteny. The individual ART genes reveal highly restricted expression patterns, which are largely conserved in humans and the mouse. We confirmed the predicted extracellular location of the ART proteins by expressing recombinant ARTs in insect cells. Two human and four mouse ARTs contain the active site motif (R-S-EXE) typical of arginine-specific ADP-ribosyltransferases and exhibit the predicted enzyme activities. Two other human ARTs and their murine orthologues deviate in the active site motif and lack detectable enzyme activity. Conceivably, these ARTs may have acquired a new specificity or function. The position-sensitive iterative database search program PSI-BLAST connected the mammalian ARTs with most known bacterial ADP-ribosylating toxins. In contrast, no related open reading frames occur in the four completed genomes of lower eucaryotes (yeast, worm, fly, and mustard weed). Interestingly, these organisms also lack genes for ADP-ribosylhydrolases, the enzymes that reverse protein ADP-ribosylation. This suggests that the two enzyme families that catalyze reversible mono-ADP-ribosylation either were lost from the genomes of these nonchordata eucaryotes or were subject to horizontal gene transfer between kingdoms.


Neutral endopeptidase and angiotensin-converting enzyme -- key enzymes terminating the action of neuroendocrine mediators.
Zinc-metalloproteases, such as neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), effectively control the bioavailability of peptide mediators released from sensory nerves, immune and skin cells during the cutaneous response to endogenous or exogenous noxious stimuli. Functional inactivation of NEP or ACE by transient inhibition or permanent genomic deletion results in a relative abundance of substance P (SP) and bradykinin (BK); this augments murine allergic contact dermatitis (ACD) by affecting ACD sensitization and elicitation, which involves neurokinin 1 receptors (NK1), BK receptors (B2) and an intact cutaneous sensory nervous system. Present evidence suggests that increased SP via NK(1) is capable of boosting important functions of SP- and NK1-expressing dendritic cells (DCs) and T cells (TCs) in an auto- or paracrine manner, which promotes ACD antigen sensitization. Moreover, skin inflammation or wounding in vivo, as well as treatment of epidermal and dermal cells by UV light and inflammatory mediators in vitro, regulates NEP and ACE expression and activity. Likewise, NEP and ACE are capable of processing neuroendocrine hormones, such as adrenocorticotropin and alpha-melanocyte-stimulating hormone. Thus, present data indicate that ACE and NEP, via proteolytic cleavage of peptide mediators and growth factors, represent important control factors for the inflammatory response in skin disorders such as psoriasis or allergic inflammation, but may also be capable of affecting pigmentation, cell survival, wound healing and tissue regeneration.


Healing of diabetes and vascular ulcers on switching from peritoneal dialysis to hemodialysis.
Vascular complications are the main problem in diabetic patients and can be worsened by continuous ambulatorial peritoneal dialysis (CAPD). A 46-year old woman with a family history of diabetes progressively developed hyperglycemia and subsequently lower limb ulcers after beginning CAPD. Hypertonic bags were required to control fluid balance. On account of the severe and painful ulcers, the patient was changed to hemodialysis. Within a few weeks her diabetes improved and the vascular ulcers healed completely.


Potential energy landscape equation of state.
Depth, number, and shape of the basins of the potential energy landscape are the key ingredients of the inherent structure thermodynamic formalism introduced by Stillinger and Weber [F. H. Stillinger and T. A. Weber, Phys. Rev. A 25, 978 (1982)]. Within this formalism, an equation of state based only on the volume dependence of these landscape properties is derived. Vibrational and configurational contributions to pressure are sorted out in a transparent way. Predictions are successfully compared with data from extensive molecular dynamics simulations of a simple model for the fragile liquid orthoterphenyl.


Measurement of intracompartmental pressure: a comparison of the slit catheter, side-ported needle, and simple needle.
An experimental model of acute compartment syndrome involving the anterolateral compartment of the hindlimb in dogs was used to compare three methods of measurement of intracompartmental pressure: the simple-needle technique, use of the slit catheter, and use of the side-ported needle. No statistical difference was found between the values obtained with the slit catheter and those obtained with the side-ported needle; the mean difference was 1.4 millimeters of mercury throughout the range of compartment pressures that were measured. The side-ported needle appeared to be as accurate as the slit catheter for the measurement of compartment pressures (p = 0.355, 1-beta = 0.9). The values obtained with use of the simple needle were consistently higher than those obtained with the other two methods (p < 0.001): an average of 18.3 millimeters of mercury higher than the values measured with the slit catheter and 19.3 millimeters of mercury higher than those measured with the side-ported needle. Clinically, the side-ported needle or the slit catheter can be used to obtain accurate measurements of compartment pressure. Use of the simple 18-gauge needle is not recommended for this purpose.


Survival Effects of Cytoreductive Surgery for Refractory Patients after Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer.
Salvage second-line chemotherapy is usually recommended for patients with advanced epithelial ovarian cancer (AEOC) who develop progressive disease (PD) after neoadjuvant chemotherapy (NAC). Herein, we investigated the role of cytoreductive surgery (CRS) for such patients. We retrospectively reviewed the medical records of 36 patients with AEOC who developed PD after receiving NAC at two tertiary academic centers with different treatment strategies between 2001 and 2016. Patients who developed PD after NAC were consistently treated with CRS at one hospital (group A; n=13) and second-line chemotherapy at another (group B; n=23). The clinical characteristics and treatment outcomes were compared between the groups. Overall survival (OS) was longer in group A than in group B (19.4 months vs. 7.9 months; p=0.011). High-grade serous histology was associated with longer OS than non-high-grade serous types. In group A, optimal surgery resection (<1 cm) was achieved after CRS in 6 patients (46%). Multivariate analysis showed that the treatment option was the only independent predictive factor for OS (hazard ratio, 2.30; 95% confidence interval, 1.02-5.17; p=0.044). CRS may result in a survival benefit even in patients with AEOC who develop PD after NAC.


[Early diagnosis, therapy, and long-term follow up of dementia].
Since the start of long term care insurance and the availability of cholinesterase inhibitor as a prescription drug in Japan, detection and diagnosis of dementia in the early stage of the disease has become an important issue. Neuropsychological screening and imaging tools usually employed for diagnosis are insufficient. The use of diagnostic criteria to designate early stage patients is still controversial. Several disease entities, including mild cognitive impairment (MCI) and age-associated memory impairment (AAMI), are not clearly defined in Japan. To study the prognosis of early stage dementia, it is important to define the diagnostic criteria. Clear identification and diagnosis of early stage dementia is important to support patients and their family members. The early detection of dementia and cognitive decline has other important aspects. One is the implication of disease diagnosis in the community; people often hesitate to use the name dementia in the early stage, even when the patients fulfill the criteria for dementia. Another aspect is the longer term follow up of the patients after early detection. For these purposes, it will become more important to emphasize a team approach consisting of medical doctors, nurses, neuropsychologists, clinical psychologists, occupational therapists and socialteam workers.


Low-density lipoprotein from active SLE patients is more atherogenic to endothelial cells than low-density lipoprotein from the same patients during remission.
SLE patients have an enhanced risk of atherosclerosis and cardiovascular disease. However, the increased prevalence of cardiovascular disease is not fully explained by traditional Framingham cardiovascular risk factors. Specific features of low-density lipoprotein (LDL) particles, other than plasma concentration, may induce accelerated atherosclerosis at early stages in these patients. Thus, we aimed to explore the impact of LDL from both active and inactive SLE patients on human aortic endothelial cells. Human aortic endothelial cells were stimulated with the same concentration of LDL particles isolated from pooled serum that was collected from 13 SLE patients during both active and inactive states. Gene expression and cell migration assays were performed. Circulating LDL particles obtained from healthy volunteers and SLE patients in both remission and flare states were comparable in terms of number, cholesterol and triglyceride content, and net electric charge. Stimulation of cells with LDL from active SLE patients induced the expression of vascular cell adhesion molecule 1 (∼2.0-fold, P < 0.05), monocyte chemoattractant protein 1 (∼2.0-fold, P < 0.05) and matrix metallopeptidase 2 (∼1.6-fold, P < 0.01) compared with cells stimulated with LDL from inactive SLE patients. Additionally, LDL extracted from active patients increased cell migration in a wound-healing assay (1.4-fold, P < 0.05). Our data show that, at the same LDL concentration, LDL from active SLE patients had increased proatherogenic effects on endothelial cells compared with LDL from the same patients when in an inactive or remission state.


Sr2Cu2TeO6Br2: honeycomb layers of copper(II) ions.
Single crystals of distrontium(II) dicopper(II) tellurium(VI) hexaoxide dibromide, Sr2Cu2TeO6Br2, were synthesized via solid state/gas phase reactions in sealed evacuated silica tubes. The building units are irregular SrO4Br3 polyhedra (a new type of coordination polyhedron around Sr(II)), CuO5 square pyramids and TeO6 octahedra. The CuO5 square pyramids and the TeO6 octahedra together form layers in the bc plane bridged by Sr atoms. The Cu atoms are arranged to form puckered honeycomb layers. The Te atom lies on an inversion centre.


Radiolytic cyclization of stem-and-loop structured oligodeoxynucleotide with neighboring arrangement of α,ω-bis-disulfides.
Upon X-ray irradiation of hypoxic aqueous solution, modified oligodeoxynucleotides (ODNs) bearing a pair of disulfides at both ends of the strand that forms a stem-and-loop structure with a neighboring arrangement of α,ω-bis-disulfides underwent efficient cyclization via an intramolecular exchange reaction at the disulfide moieties with a multiple turnover process. Mechanistic studies revealed that hydrogen atoms generated in the radiolysis of water are key active species initiating a chain reaction to produce cyclic ODN disulfides, in which addition of hydrogen atom results in dissociation of the original disulfide bond to generate a thiyl radical intermediate as the chain carrier for the succeeding disulfide exchange into cyclization. The properties were also assessed for the resultant cyclic ODN disulfide that has several favorable features for use in the transcriptional decoy strategy. The cyclic ODN disulfides produced by the present radiolytic method showed high thermal stability, resistance to nuclease, and high binding activity to a representative transcriptional factor of nuclear factor κB.


In Vitro Growth Inhibitory Activities of Natural Products from Irciniid Sponges against Cancer Cells: A Comparative Study.
Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reported in vitro bioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. The in vitro growth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources.


Highly linear selective cobalt-catalyzed addition of aryl imines to styrenes: reversing intrinsic regioselectivity by ligand elaboration.
Highly linear selective, imine-directed hydroarylation of styrene has been achieved with cobalt-based catalytic systems featuring bis(2,4-dimethoxyphenyl)(phenyl)phosphine and either 2-methoxypyridine or DBU as a ligand and a Lewis base additive, respectively, thus affording a variety of 1,2-diarylethanes (bibenzyls) in good yields under mild reaction conditions. The triarylphosphine controls the regioselectivity, while the Lewis base significantly accelerates the reaction. Ligand screening and deuterium-labeling studies provide implications about the roles of the ligand and the Lewis base in the crucial C-C reductive elimination step.


The Michigan Arthroplasty Registry Collaborative Quality Initiative Experience: Improving the Quality of Care in Michigan.
The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) is a regional quality improvement effort that is focused on hip and knee arthroplasty. From its inception in 2012, MARCQI has grown to include data from 66 hospitals and surgery centers, and contains over 209,000 fully abstracted cases in its database. Using high-quality risk-standardized outcomes data, MARCQI drives quality improvement through a collaborative and nonpunitive structure. Quality improvement initiatives have included transfusion reduction, infection prevention, venous thromboembolism reduction, and reduction of discharge to nursing homes. In addition, MARCQI focuses on postmarket surveillance of implants by computing revision-risk estimates based on the cases that were registered prior to the end of 2016. This paper describes the impact of MARCQI on the quality of hip and knee arthroplasty care in the state of Michigan since its inception in 2012, and it briefly summarizes the recently released 5-year report.


Asbestos-induced visceral pleural fibrosis reduces pulmonary compliance.
To determine the nature of respiratory functional impairment caused by asbestos-induced visceral pleural fibrosis (VPF) and to discover which pulmonary physiological variable best reveals it, we examined 59 asbestos-exposed construction workers having asbestos-related changes on chest radiographs. Computed tomography scans of the thorax were also performed. Visceral pleural fibrosis was diagnosed in 29 subjects: seven had only VPF, 17 had VPF and pleural plaques, and five had VPF, plaques, and asbestosis. In subjects without VPF, 23 had plaques, six had plaques and asbestosis, and one had only minor fibrotic parenchymal changes insufficient for a diagnosis of asbestosis. Flow-volume spirometry, body plethysmography, static and dynamic compliance, and pulmonary diffusing capacity for carbon monoxide were measured. The subjects with VPF had significantly lower static (p = 0.005) and dynamic (p = 0.007) compliance values than those without. Other respiratory function variables failed to show any significant differences. We conclude that the measurement of static and dynamic compliance is a useful method in assessing pulmonary function impairment caused by visceral pleural fibrosis.