The electron microscopic features of sinus histiocytosis with massive lymphadenopathy: a study of 11 cases.
Eleven cases of sinus histiocytosis with massive lymphadenopathy (SHML) involving lymph nodes were studied electron microscopically. Histiocytes were the most conspicuous element of the infiltrate. They could be divided into small and large forms, although transitions were apparent among them. Most of the small histiocytes were located in the medullary cords. The large histiocytes were predominantly seen within sinuses and were subdivided into two types on the basis of their appearance. The most distinctive feature of these histiocytes was the presence of lymphocytes, plasma cells, and neutrophils within their cytoplasm. Other cells present in the infiltrate were lymphocytes, plasma cells, and occasional neutrophils and mast cells. Blood vessels were prominent throughout. Virus particles, bacteria, and Langerhans' granules were consistently absent. No morphologic clues were provided by this study as to the etiology of this disorder.


Rapid prototyping technology for cranioplasty: A case series.
Cranial vault defects may be acquired or congenital in origin. Rehabilitation of these patients often poses challenge to the operating team and prosthodontist. Polymethylmethacrylate is a commonly used alloplastic graft material which is used for the fabrication of cranial prosthesis. Nowadays, with the advancement in the bioengineering, custom-made template and cranial prosthesis can be made by rapid prototyping technology (RPT) by patient three-dimensional (3D) computed tomography (CT) scan images. This series of two cases explained two different techniques for the rehabilitation of the patient with frontotemporoparietal cranial defect. Case 1 had a history of cerebrovascular accident, followed by decompression craniotomy which led to frontotemporoparietal defect of the left side. This defect area was associated with the cerebrospinal fluid accumulation which made delineation of underlying bony margins difficult and interfered with conventional impression procedures. Case 2 had a road traffic accident which led to intracerebral hemorrhage followed by decompression craniotomy which resulted in frontotemporoparietal defect of the right side. The patient had a poor neuromuscular control which impedes with the upright posture of the head during impression making of the defect area. Therefore, these cases were planned to rehabilitate by RPT. In these techniques, the prosthesis was made using custom-made skull template produced by RPT, using the data of 3D-CT scan images. This technique resulted in the prosthesis with good esthetics and better fit of the prosthesis. The contours of the prosthesis were replicated in the same manner as compared to the contralateral side. RPT is an additive manufacturing technology which is now used in the field of dentistry too. This technique is easy to use; fabricate prosthesis with high precision is less time-consuming and has fewer chances of error.


Corticosteroids in liver disease: studies on the biological conversion of prednisone to prednisolone and plasma protein binding.
The conversion of prednisone to the biologically active corticosteroid prednisolone and the degree of plasma protein binding of prednisolone were studied in 22 patients with acute or chronic liver disease and in eight control subjects. In patients whose disease was active at the time of study, as judged by elevated serum levels of bilirubin and transaminase, significantly higher levels of plasma prednisolone were obtained after prednisolone administration than after equivalent doses of prednisone. In addition, the amount of unbound drug in the plasma was higher in patients with active disease. There was a significant correlation between the extent of plasma protein binding of prednisolone and the serum albumin concentration. Azathioprine did not affect the plasma binding of prednisolone in vitro. The plasma half-life of prednisolone was prolonged in two of three patients with chronic liver disease studied. These results suggest that in patients with acute hepatitis or active chronic liver disease there is impairment of reduction of the 11-oxo group of prednisone, and also impaired ring A reduction of prednisolone. Thus, incomplete conversion of prednisone to prednisolone occurs, which is a necessary step for biological activity; on the other hand there is also impairment of prednisolone degradation. These, together with low serum albumin concentrations which are associated with higher levels of circulating unbound prednisolone, result in quite different levels of biologically active corticosteroids compared with equivalent doses of prednisone or prednisolone in subjects without liver disease. The findings have important practical implications for the use of corticosteroids in patients with active liver disease.


Factors associated with critical care nurses' acute stress disorder after patient death.
In intensive care units, patient death can have a negative psychological influence on the patient's nurse. However, how the frequency of events and factors contributed to acute stress among nurses remains unknown. The objective of this study was to explore the prevalence of and the factors affecting acute stress disorder among intensive care unit nurses after their patient death. Nurses from five adult intensive care units whose patient had died during the nurses' working shift were recruited from July 2018 to April 2019. Bryant's Acute Stress Disorder Scale, the Beck Anxiety Inventory, and the Beck Depression Inventory-II were used to measure acute stress, depression, and anxiety. Descriptive statistics, chi-square tests, independent sample t-tests, and stepwise logistic regression were used for data analysis. In total, 119 nurses were enrolled. Nearly one in three nurses (29.4%) had suffered from acute stress disorder after their patient had died. Nurses experienced a higher risk of acute stress disorder when their patients underwent cardiopulmonary resuscitation before death (odds ratio [OR] = 13.75, 95% confidence interval [CI]: 2.59-72.95), when their patients died unexpectedly (OR = 4.88, 95% CI: 1.16-20.56), and when they experienced verbal abuse from the patient family at the patient death (OR = 4.61, 95% CI: 1.18-18.05) compared with their counterparts. Intensive care unit nurses often experience acute stress disorder after their patient death. The nurses of patients who underwent cardiopulmonary resuscitation before death and/or who died unexpectedly and/or nurses who were subjected to verbal abuse by the patient's family were at higher risk of acute stress disorder. A comprehensive program aimed at improving the knowledge, skills, and resilience of nurses is needed.


Establishment of culture conditions for survival of Histomonas meleagridis in transit.
Fresh ceca samples from turkeys in North Carolina infected with Histomonas meleagridis were collected at necropsy, inoculated into warmed Dwyers medium, and sent by overnight courier to our laboratory at The University of Georgia. Further incubation at 40 C yielded positive cultures from all four samples. PCR and DNA sequencing confirmed the presence of H. meleagridis. To further establish conditions for survival in transit, we infected turkeys with H. meleagridis, euthanatized the birds 10 days postinfection, and allowed carcasses to incubate at room temperature for either 2 or 24 hr. After incubation, samples of cecal contents (0.5 g) were placed in Dwyers medium and held at 4, 25, or 30 C for 6, 18, 24, 48, 72, 96, or 120 hr, simulating holding conditions during transit. Samples were placed in a 40 C incubator at the specified times and examined daily for histomonad growth by light microscopy. Positive histomonad growth was detected from cecal samples obtained from the 2-hr incubated carcass and from cultures held at 30 C for 6, 18, 24, 48, and 72 hr. No growth was seen from cultures held at 25 or 4 C or at any temperature from the carcass allowed to incubate for 24 hr at room temperature. These results suggest that positive isolation can be made from field samples, provided that material is collected at warm temperatures and transported rapidly to the laboratory.


Alkaline phosphatase isoenzymes in mouse plasma detected by polyacrylamide-gel disk electrophoresis.
Plasma alkaline phosphatase (ALP) activity is frequently measured in toxicity studies. In the present study, we assessed the usefulness of a commercially available polyacrylamide-gel (PAG) disk electrophoresis kit used in humans (AlkPhor System, Jokoh Co., Ltd., Tokyo, Japan) for identifying plasma ALP isoenzymes in mice of the Crlj:CD1 strain (ICR mice), which are commonly used in toxicity studies. We also examined age-related changes in plasma ALP isoenzymes in ICR mice. Electrophoresis was performed according to the manufacturer's instructions. In order to identify the origin of each ALP isoenzyme, in addition to plasma samples, tissue ALP extracts from the liver, bone and small intestine were treated with neuraminidase, anti-small intestinal ALP antibody, ALP inhibitor levamisole and/or wheat germ agglutinin (WGA). The kit revealed that main plasma ALP isoenzyme in intact ICR mice was bone-derived one, and it tended to decrease with age. On the other hand, liver-derived ALP isoenzyme greatly increased in plasma of cholestasis model mice induced by bile duct ligation. This model mouse had also a large molecular ALP detected in the stacking gel. This ALP was thought to be of intestinal origin because its activity remained even after levamisole inhibition. In addition, a minimum sample volume for sufficient resolution of plasma ALP isoenzymes was only 14µl. The results of this study suggest that the present method is a useful tool for detecting plasma ALP isoenzymes in mice and that pre-treatment of plasma with neuraminidase and concomitant levamisole inhibition with another gel is applicable for the evaluation of organ toxicity.


The Orexin System and Hypertension.
In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar-Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.


Calculus detection calibration among dental hygiene faculty members utilizing dental endoscopy: a pilot study.
Dental and dental hygiene faculty members often do not provide consistent instruction in the clinical environment, especially in tasks requiring clinical judgment. From previous efforts to calibrate faculty members in calculus detection using typodonts, researchers have suggested using human subjects and emerging technology to improve consistency in clinical instruction. The purpose of this pilot study was to determine if a dental endoscopy-assisted training program would improve intra- and interrater reliability of dental hygiene faculty members in calculus detection. Training included an ODU 11/12 explorer, typodonts, and dental endoscopy. A convenience sample of six participants was recruited from the dental hygiene faculty at a California community college, and a two-group randomized experimental design was utilized. Intra- and interrater reliability was measured before and after calibration training. Pretest and posttest Kappa averages of all participants were compared using repeated measures (split-plot) ANOVA to determine the effectiveness of the calibration training on intra- and interrater reliability. The results showed that both kinds of reliability significantly improved for all participants and the training group improved significantly in interrater reliability from pretest to posttest. Calibration training was beneficial to these dental hygiene faculty members, especially those beginning with less than full agreement. This study suggests that calculus detection calibration training utilizing dental endoscopy can effectively improve interrater reliability of dental and dental hygiene clinical educators. Future studies should include human subjects, involve more participants at multiple locations, and determine whether improved rater reliability can be sustained over time.


Schizophreniform disorder: a diagnostic dilemma.
The DSM-III diagnostic criteria for schizophreniform disorder, mainly based on duration of symptoms, are insufficient to furnish a good treatment strategy. In recent literature, schizophreniform disorder has been grouped either with the schizophrenias or with the affective disorders. Scandinavian researchers have described two other groups of psychotic disorders that resemble schizophreniform disorder. These are the reactive psychosis and the cycloid psychosis. They were found to be different from the schizophrenias and the affective disorders. "Good prognosis" schizophrenia, which has been extensively studied and reported in the literature, is clinically very similar to schizophreniform disorder. The relatively consistent data collected in patients with good prognosis schizophrenia may provide the basis for the additional diagnostic criteria needed in DSM-III schizophreniform disorder.


Sixteen years of change in the global terrestrial human footprint and implications for biodiversity conservation.
Human pressures on the environment are changing spatially and temporally, with profound implications for the planet's biodiversity and human economies. Here we use recently available data on infrastructure, land cover and human access into natural areas to construct a globally standardized measure of the cumulative human footprint on the terrestrial environment at 1 km(2) resolution from 1993 to 2009. We note that while the human population has increased by 23% and the world economy has grown 153%, the human footprint has increased by just 9%. Still, 75% the planet's land surface is experiencing measurable human pressures. Moreover, pressures are perversely intense, widespread and rapidly intensifying in places with high biodiversity. Encouragingly, we discover decreases in environmental pressures in the wealthiest countries and those with strong control of corruption. Clearly the human footprint on Earth is changing, yet there are still opportunities for conservation gains.


Contribution of Ultra-Fine Bubbles to Promoting Effect on Propane Hydrate Formation.
To investigate experimentally how ultra-fine bubbles (UFBs) may promote hydrate formation, we examined the formation of propane (C3H8) hydrate from UFB-infused water solution using two preparation methods. In one method, we used C3H8-hydrate dissociated water, and in the other, C3H8-UFB-included water prepared with a generator. In both solutions, the initial conditions had a UFB number density of up to 109 mL-1. This number density decreased by only about a half when stored at room temperature for 2 days, indicating that enough amount of UFBs were stably present at least during the formation experiments. Compared to the case without UFBs, the nucleation probabilities within 50 h were ~1.3 times higher with the UFBs, and the induction times, the time period required for the bulk hydrate formation, were significantly shortened. These results confirmed that UFB-containing water promotes C3H8-hydrate formation. Combined with the UFB-stability experiments, we conclude that a high number density of UFBs in water contributes to the hydrate promoting effect. Also, consistent with previous research, the present study on C3H8 hydrates showed that the promoting effect would occur even in water that had not experienced any hydrate structures. Applying these findings to the debate over the promoting (or "memory") effect of gas hydrates, we argue that the gas dissolution hypothesis is the more likely explanation for the effect.


Mutations in topoisomerase IV and DNA gyrase of Staphylococcus aureus: novel pleiotropic effects on quinolone and coumarin activity.
Previous studies have shown that topoisomerase IV and DNA gyrase interact with quinolones and coumarins in different ways. The MICs of coumarins (novobiocin and coumermycin) for MT5, a Staphylococcus aureus nov mutant, are higher than those for wild-type strains. Sequencing the gyrB gene encoding one subunit of the DNA gyrase revealed the presence of a double mutation likely to be responsible for this resistance: at codon 102 (Ile to Ser) and at codon 144 (Arg to Ile). For single-step flqA mutant MT5224c9, previously selected on ciprofloxacin, the fluoroquinolone MIC was higher and the coumarin MIC was lower than those for its parent, MT5. Sequencing the grlB and grlA genes of topoisomerase IV of MT5224c9 showed a single Asn-470-to-Asp mutation in GrlB. Genetic outcrosses by transformation with chromosomal DNA and introduction of plasmids carrying either the wild-type or the mutated grlB gene indicated that this mutation causes both increased MICs of fluoroquinolones and decreased MICs of coumarins and that the mutant grlB allele is codominant for both phenotypes with multicopy alleles. Integration of these plasmids into the chromosome confirmed the codominance of fluoroquinolone resistance, but grlB+ appeared dominant over grlB (Asp-470) for coumarin resistance. Finally, the gyrA (Leu-84) mutation previously described as silent for fluoroquinolone resistance increased the MIC of nalidixic acid, a nonfluorinated quinolone. Combining the grlA (Phe-80) and grlB (Asp-470) mutations with this gyrA mutation also had differing effects. The findings indicate that alterations in topoisomerases may have pleiotropic effects on different classes of inhibitors as well as on inhibitors within the same class. A full understanding of drug action and resistance at the molecular level must take into account both inhibitor structure-activity relationships and the effects of different classes of topoisomerase mutants.


Tissue fatty acid composition of pigs fed different fat sources.
Dietary fat influences the physico-chemical properties of meat, and fatty acid (FA) composition may have implications on human health. The objectives of the experiment were to study tissue FA partitioning and the effect of dietary fat source on tissue FA composition. Seventy crossbred gilts (61.8 ± 5.2 kg BW average) were fed one of seven treatments: a diet containing a very low level of fat (no fat (NF)) and six fat-supplemented diets (10%: tallow (T), high-oleic sunflower oil (HOSF), sunflower oil (SFO), linseed oil (LO), fat blend (FB: 55% tallow, 35% SFO, 10% LO) and fish oil blend (FO: 40% fish oil, 60% LO). Differential tissue FA depositions were observed, with flare fat being the most saturated, followed by intermuscular, and subcutaneous being the least saturated. Monounsaturated fatty acid (MUFA) deposition showed an opposite tissue pattern. Subcutaneous fat showed the highest MUFAs, intermuscular fat showed intermediate values and flare fat showed the lowest MUFAs. Intramuscular polyunsaturated fatty acid (PUFA) content was less susceptible to dietary treatment modifications compared with other depots. Significant tissue FA modifications were observed due to dietary treatments, mainly in diets rich in PUFA. The saturated fatty acids (SFA) were high in NF-fed and low in HOSF-fed animals, MUFA were high in HOSF-fed and low in SFO-, LO- and FO-fed animals, while PUFA were high in SFO- and LO-fed and low in HOSF-, T- and NF-fed animals. Pigs fed LO and FB showed detectable levels of EPA, which depended on the linolenic content of the diet. The only effective way to increase tissue DHA contents was to add DHA in the diet through FO feeding. Araquidonic acid was high in SFO diets and low in LO and FB diets, and also high in intramuscular fat compared with other tissues. EPA and DHA were also high in intramuscular fat compared with other fat depots. The deposition of oleic and linoleic acids depended on the composition of dietary fat, as their deposition varied between diets, even at similar levels of intake of each FA. The NF diet resulted in the greatest proportion of SFAs (palmitic and stearic) of all treatments tested. SFAs were less susceptible to modification than MUFA in response to the different PUFA levels supplemented in the diet. T resulted in less fat deposition in some of the fat depots and more in others, suggesting that T could partition fat differently among fat depots.


Inhaled formoterol during one year in asthma: a comparison with salbutamol.
Eighteen patients, who had previously taken part in a 2 wk cross-over comparison between formoterol and salbutamol, now took part in a one year double-blind study comparing salbutamol 200 micrograms b.i.d. with formoterol 12 micrograms b.i.d. Additional doses were taken when needed and were recorded. Ten patients were started on formoterol and eight on salbutamol. After one month, the patients were allowed to shift to the alternative drug. Two patients withdrew from the study. At the end of the study, 13 of 16 patients were on formoterol, thus showing a long-lasting preference for this drug. Forced expiratory volume in one second (FEV1) dose-response curves for inhaled salbutamol were repeatedly recorded during the study, and no tachyphylaxis was found. One patient stopped taking inhaled steroids but continued taking formoterol and theophylline. He deteriorated with a decreased response to salbutamol. After re-introduction of inhaled steroids his condition improved. This case indicates that effective bronchodilator therapy may mask the deterioration of asthma.


Systematic analysis of the Capsicum ERF transcription factor family: identification of regulatory factors involved in the regulation of species-specific metabolites.
ERF transcription factors (TFs) belong to the Apetala2/Ethylene responsive Factor (AP2/ERF) TF family and play a vital role in plant growth and development processes. Capsorubin and capsaicinoids have relatively high economic and nutritional value, and they are specifically found in Capsicum. However, there is little understanding of how ERFs participate in the regulatory networks of capsorubin and capsaicinoids biosynthesis. In this study, a total of 142 ERFs were identified in the Capsicum annuum genome. Subsequent phylogenetic analysis allowed us to divide ERFs into DREB (dehydration responsive element binding proteins) and ERF subfamilies, and further classify them into 11 groups with several subgroups. Expression analysis of biosynthetic pathway genes and CaERFs facilitated the identification of candidate genes related to the regulation of capsorubin and capsaicinoids biosynthesis; the candidates were focused in cluster C9 and cluster C10, as well as cluster L3 and cluster L4, respectively. The expression patterns of CaERF82, CaERF97, CaERF66, CaERF107 and CaERF101, which were found in cluster C9 and cluster C10, were consistent with those of accumulating of carotenoids (β-carotene, zeaxanthin and capsorubin) in the pericarp. In cluster L3 and cluster L4, the expression patterns of CaERF102, CaERF53, CaERF111 and CaERF92 were similar to those of the accumulating capsaicinoids. Furthermore, CaERF92, CaERF102 and CaERF111 were found to be potentially involved in temperature-mediated capsaicinoids biosynthesis. This study will provide an extremely useful foundation for the study of candidate ERFs in the regulation of carotenoids and capsaicinoids biosynthesis in peppers.


The Double Layer Methodology and the Validation of Eigenbehavior Techniques Applied to Lifestyle Modeling.
A novel methodology, the double layer methodology (DLM), for modeling an individual's lifestyle and its relationships with health indicators is presented. The DLM is applied to model behavioral routines emerging from self-reports of daily diet and activities, annotated by 21 healthy subjects over 2 weeks. Unsupervised clustering on the first layer of the DLM separated our population into two groups. Using eigendecomposition techniques on the second layer of the DLM, we could find activity and diet routines, predict behaviors in a portion of the day (with an accuracy of 88% for diet and 66% for activity), determine between day and between individual similarities, and detect individual's belonging to a group based on behavior (with an accuracy up to 64%). We found that clustering based on health indicators was mapped back into activity behaviors, but not into diet behaviors. In addition, we showed the limitations of eigendecomposition for lifestyle applications, in particular when applied to noisy and sparse behavioral data such as dietary information. Finally, we proposed the use of the DLM for supporting adaptive and personalized recommender systems for stimulating behavior change.


Trends in occupational mortality among middle-aged men in Sweden 1961-1990.
Many European countries have in recent decades reported growing socioeconomic differentials in mortality. While these trends have usually paralleled high unemployment and increasing income disparities, Sweden had low unemployment and narrowing income differences. This study describes trends, 1961-1990, in total and cardiovascular mortality among men, 45-69 years of age, in major occupational classes in Sweden. From census data four cohorts were created from those enumerated in 1960, 1970, 1980 and 1985. Through record linkage with the Swedish cause of death registry the mortality in each cohort was followed for 5-10 years. Age-standardized mortality trends 1961-1990 were calculated for occupational groups, categorized according to sector of the economy. The increase in mortality among middle-aged men in Sweden 1965-1980 was mainly a result of increasing cardiovascular mortality among industrial workers and farmers. In the 1980s the trend for these groups changed into a last decrease in mortality similar to that for non-manual occupations for the whole period. Consequently the rate ratio for industrial workers in comparison with men having a professional/managerial type of occupation increased from 0.98 to 1.43. The slowest decrease is now found among unqualified occupations in services and transportation. While Sweden, during the period studied, had narrowing income differentials and low unemployment this result points to the importance of working conditions in understanding trends and distribution of male adult mortality.


Bone mineral content is lower in prepubertal HIV-infected children.
Total body bone mineral content (TBBMC) was measured by dual energy x-ray absorptiometry in a cross-sectional study of 51 prepubertal HIV-infected children and 262 healthy prepubertal children aged 4.2 to 14.7 years. The mean TBBMC +/- SD was lower in HIV-positive children than in HIV-negative controls (955 +/- 325 vs. 1,106 +/- 273 g, respectively; p =.0006). Reductions in TBBMC remained in the HIV-positive group after adjusting for age, sex, and race by analysis of covariance (p <.001). Differences in TBBMC between HIV-positive and HIV-negative groups persisted when height and weight were also accounted for in the analysis (p =.027). The magnitude of the difference in TBBMC between the groups increased with age. In the HIV-positive group, no associations were observed between TBBMC and use of a protease inhibitor, duration of treatment with antiretroviral medications, viral load, or CD4 cell count. TBBMC is decreased in HIV-infected children. As a result of compromised bone mineral accrual, HIV-infected children may be at increased risk for osteoporosis and related complications.


GB virus C E2 glycoprotein: expression in CHO cells, purification and characterization.
A 315 amino acid recombinant segment of the GB virus C (GBV-C) E2 envelope glycoprotein (E2-315) was expressed and secreted from CHO cells. E2-315 was purified by affinity chromatography using a monoclonal antibody directed to a FLAG sequence genetically engineered onto the C terminus of the recombinant protein. The secreted protein had a molecular mass of 48-56 kDa and was shown to be N-glycosylated. Amino acid sequencing confirmed the expected N-terminal sequence. Purified E2-315 was used to develop an ELISA for detection of E2 antibodies in human sera. Antibodies to GBV-C E2 appeared to be directed toward conformational epitopes since human sera reactivity was detected in ELISA using native E2-315, but it was extremely weak or non-existent with denatured E2 protein. The use of an ELISA which can detect human GBV-C E2 antibodies will be important in further understanding of the clinical significance and epidemiology of GBV-C.


Ethnicity, politics and inequality: post-tsunami humanitarian aid delivery in Ampara District, Sri Lanka.
The provision of humanitarian aid at times of disaster in multi-ethnic community settings may lead to conflict, tension and even the widening of the distance between various ethnic groups. That aid agencies distribute humanitarian aid directly to affected communities, to speed up recovery, may often lead to chaos and the intensification of ethnic sentiments. The new distribution mechanisms introduced for the delivery of tsunami aid in Ampara District, Sri Lanka, did not recognise local networks and the culture of the ethnically mixed community setting. This paper analyses post-tsunami aid distribution in Ampara and shows how such an extemporised effort in an ethnically cognisant context increased ethnic division, inequality and disorder, while marginalising the poor segments of the affected population. It recommends the inclusion of local networks in aid dissemination as a measure for improving ethnic neutrality and social harmony in disaster-hit multi-ethnic communities.


"Might" or "suggest"? No wording approach was clearly superior in conveying the strength of recommendation.
To compare different wording approaches for conveying the strength of health care recommendations. Participants were medical residents in Canada and the United States. We randomized them to one of three wording approaches, each expressing two strengths of recommendation, strong and weak: (1) "we recommend," "we suggest;" (2) "clinicians should," "clinicians might;" (3) "we recommend," "we conditionally recommend." Each participant received one strong and one weak recommendation. For each recommendation, they chose a hypothetical course of action; we judged whether their choice was appropriate for the strength of the recommendation. The response rate was 77% (341/441). Most participants, in response to strong recommendations, chose hypothetical courses of action appropriate for weak recommendations. None of the wording approaches was clearly superior in conveying the strength of a recommendation. However, different approaches appeared superior depending on the strength and direction (for or against an intervention) of the recommendation. No wording approach was clearly superior in conveying the strength of recommendation. Guideline developers need to make the connection between the wording and their intended strength explicit.


Lack of nontargeted effects in murine bone marrow after low-dose in vivo X irradiation.
Exposure to high doses of ionizing radiation unequivocally produces adverse health effects including malignancy. At low doses the situation is much less clear, because effects are generally too small to be estimated directly by epidemiology, and extrapolation of risk and establishment of international rules and standards rely on the linear no-threshold (LNT) concept. Claims that low doses are more damaging than would be expected from LNT have been made on the basis of in vitro studies of nontargeted bystander effects and genomic instability, but relevant investigations of primary cells and tissues are limited. Here we show that after low-dose low-LET in vivo radiation exposures in the 0-100-mGy range of murine bone marrow there is no evidence of a bystander effect, assessed by p53 pathway signaling, nor is there any evidence for longer-term chromosomal instability in the bone marrow at doses below 1000 mGy. The data are not consistent with speculations based on in vitro nontargeted effects that low-dose X radiation is more damaging than would be expected from linear extrapolation.


The relationship between microsatellite slippage mutation rate and the number of repeat units.
Microsatellite markers are widely used for genetic studies, but the relationship between microsatellite slippage mutation rate and the number of repeat units remains unclear. In this study, microsatellite distributions in the human genome are collected from public sequence databases. We observe that there is a threshold size for slippage mutations. We consider a model of microsatellite mutation consisting of point mutations and single stepwise slippage mutations. From two sets of equations based on two stochastic processes and equilibrium assumptions, we estimate microsatellite slippage mutation rates without assuming any relationship between microsatellite slippage mutation rate and the number of repeat units. We use the least squares method with constraints to estimate expansion and contraction mutation rates. The estimated slippage mutation rate increases exponentially as the number of repeat units increases. When slippage mutations happen, expansion occurs more frequently for short microsatellites and contraction occurs more frequently for long microsatellites. Our results agree with the length-dependent mutation pattern observed from experimental data, and they explain the scarcity of long microsatellites.


The methyltransferase domain of the Respiratory Syncytial Virus L protein catalyzes cap N7 and 2'-O-methylation.
Respiratory syncytial virus (RSV) is a negative sense single-stranded RNA virus and one of the main causes of severe lower respiratory tract infections in infants and young children. RSV RNA replication/transcription and capping are ensured by the viral Large (L) protein. The L protein contains a polymerase domain associated with a polyribonucleotidyl transferase domain in its N-terminus, and a methyltransferase (MTase) domain followed by the C-terminal domain (CTD) enriched in basic amino acids at its C-terminus. The MTase-CTD of Mononegavirales forms a clamp to accommodate RNA that is subsequently methylated on the cap structure and depending on the virus, on internal positions. These enzymatic activities are essential for efficient viral mRNA translation into proteins, and to prevent the recognition of uncapped viral RNA by innate immunity sensors. In this work, we demonstrated that the MTase-CTD of RSV, as well as the full-length L protein in complex with phosphoprotein (P), catalyzes the N7- and 2'-O-methylation of the cap structure of a short RNA sequence that corresponds to the 5' end of viral mRNA. Using different experimental systems, we showed that the RSV MTase-CTD methylates the cap structure with a preference for N7-methylation as first reaction. However, we did not observe cap-independent internal methylation, as recently evidenced for the Ebola virus MTase. We also found that at μM concentrations, sinefungin, a S-adenosylmethionine analogue, inhibits the MTase activity of the RSV L protein and of the MTase-CTD domain. Altogether, these results suggest that the RSV MTase domain specifically recognizes viral RNA decorated by a cap structure and catalyzes its methylation, which is required for translation and innate immune system subversion.


Characterizing Fentanyl Variability Using Population Pharmacokinetics in Pediatric Burn Patients.
Opioids are essential first line analgesics for pain management after burn injury. Opioid dosing remains challenging in burn patients, particularly in children, due to the immense variability in efficacy between patients. Opioid pharmacokinetics are altered in burned children, increasing variability and obviating dosing regimens extrapolated from adult-data. The present study aimed to characterize variability in fentanyl pharmacokinetics and identify significant contributors to variability in children with ≥10% total body surface area burn requiring fentanyl during routine wound care. We recorded patient demographics and clinical data. Blood samples were collected following fentanyl administration for pharmacokinetics at time 0, 30, 60, 120, and 240 minutes on day of admission and repeated on days 3 and 7. Serum fentanyl concentrations were quantified using tandem liquid chromatography mass spectrometry. Population analysis was used to estimate pharmacokinetics parameters. Fourteen patients, 1.2-17 years, with burns from 10-50.5% were included in analysis. A two-compartment model with body weight as a covariate best described fentanyl pharmacokinetics for the overall population. The population clearance and intercompartmental clearance were 7.19 and 2.16 L/hour, respectively, and the volume of distribution for the central and peripheral compartments was 4.01 and 25.1 L, respectively. Individual patient parameter estimates had extensive variability. This study confirmed the high variability in pediatric burn patient fentanyl pharmacokinetics and demonstrates similarities and differences to other populations reported in literature. Further research is needed with a larger number of patients to extensively investigate the impact of burns, genetic polymorphisms, and other factors on fentanyl efficacy and patient outcomes.


LACK OF INFLUENCE OF SUSPENDING MEDIA ON HEAT ACTIVATION OF BACILLUS SUBTILIS SPORES AND ABSENCE OF DEACTIVATION.
Bacillus subtilis strain 5230 endospores suspended in a variety of suspending media at a concentration of ca. 10(8) per ml were heated at 95 and 75 C. The effect of the heating at 75 C was measured by plate count, and was reported as the heat-activated decimal fraction of the total viable-spore population. Thermal inactivation at 95 C was influenced by the suspending medium. No effects on heat activation at 75 C were noted for suspending media containing glucose, xylose, ribose, NaCl, or sodium phosphate, nor was there any marked effect due to a change in pH from 5 to 8. The heat-activation response was retained during postheating storage at 5 C in water up to 215 days. Postheating storage in several suspending media for 7 days also indicated no deactivation.


Hepatotropic viruses: new insights in pathogenesis and treatment.
Hepatitis B virus (HBV) can be detected in peripheral blood mononuclear cells (PBMCs), mainly B lymphocytes and monocytes. The frequency of PBMC infection is higher in patients with ongoing HBV replication, but can persist for years after the complete resolution of an acute episode of hepatitis B. Infected PBMCs can act as reservoirs for the cell-to-cell transmission of the virus, and vertical transmission studies indicate that the HBV-infected PBMCs of mothers may act as a vector for intrauterine HBV infection. Recent data evaluated whether HBV occult infection could co-operate with HCV infection in the pathogenesis of mixed cryoglobulinemia (MC) and lymphoma and/or whether it may be implicated in the pathogenesis of MC and malignant diseases -B-cell non-Hodgkin's lymphoma (NHL) also independently from HCV. The treatment of chronic HBeAg-negative hepatitis B is intended to ensure the long-term suppression of HBV replication with the aim of halting the progression of liver damage and preventing the development of liver-related complications. This can be done by means of short-term "curative" treatment or long-term "suppressive" therapy. The first approach requires a 48-week course of peginterferon, which controls viral replication (HBV DNA <10.000 copies/ml) in 20-30% of patients; the second requires the long-term (possibly lifetime) administration of nucleoside and/or nucleotide analogues. As none of the currently available drugs alone suppresses viral replication (HBV DNA <200 copies/ml) for five years in all patients, some require a rescue therapy based on the addition of a non-cross-resistant drug, which should be given as early as possible ("on demand" combination therapy). However, the currently available anti-HBV analogues can easily suppress HBV replication for five years in most HBeAg-negative patients. As both strategies have their pros and cons, the best approach needs to be carefully evaluated on an individual basis.


Hierarchical Controller-Estimator for Coordination of Networked Euler-Lagrange Systems.
This paper proposes several hierarchical controller-estimator algorithms (HCEAs) to solve the coordination problem of networked Euler-Lagrange systems (NELSs) with sampled-data interactions and switching interaction topologies, where the cases with both discontinuous and continuous signals are successfully addressed in a unified framework. The HCEAs comprise two main layers (i.e., a control layer and an estimator layer) and one optional layer (i.e., a filter layer), in which the coordination problem is tackled in the main layers and the transient response can be optionally smoothed in the filter layer. For stabilizing the corresponding cascade closed-loop systems, several sufficient conditions on the upper bound of the aperiodic sampling intervals and the lower bound of the control parameters are established. In addition, the HCEAs are extended to address the task-space coordination problem of networked heterogeneous robotic systems, which shows the versatility of the HCEAs. Finally, comparison studies and simulation results are provided to demonstrate the effectiveness, significance, and advantages of the presented algorithms.


Invasive fusariosis.
SUMMARYInvasive fusariosis is a serious invasive fungal disease, affecting immunocompetent and, more frequently, immunocompromised patients. Localized disease is the typical clinical form in immunocompetent patients. Immunocompromised hosts at elevated risk of developing invasive fusariosis are patients with acute leukemia receiving chemotherapeutic regimens for remission induction, and those undergoing allogeneic hematopoietic cell transplant. In this setting, the infection is usually disseminated with positive blood cultures, multiple painful metastatic skin lesions, and lung involvement. Currently available antifungal agents have poor in vitro activity against Fusarium species, but a clear-cut correlation between in vitro activity and clinical effectiveness does not exist. The outcome of invasive fusariosis is largely dependent on the resolution of immunosuppression, especially neutrophil recovery in neutropenic patients.


Bryophyte cover and richness decline after 18 years of experimental warming in alpine Sweden.
Climate change is expected to affect alpine and Arctic tundra communities. Most previous long-term studies have focused on impacts on vascular plants, this study examined impacts of long-term warming on bryophyte communities. Experimental warming with open-top chambers (OTCs) was applied for 18 years to a mesic meadow and a dry heath alpine plant community. Species abundance was measured in 1995, 1999, 2001 and 2013. Species composition changed significantly from original communities in the heath, but remained similar in mesic meadow. Experimental warming increased beta diversity in the heath. Bryophyte cover and species richness both declined with long-term warming, while Simpson diversity showed no significant responses. Over the 18-year period, bryophyte cover in warmed plots decreased from 43 % to 11 % in heath and from 68 % to 35 % in meadow (75 % and 48 % decline, respectively, in original cover), while richness declined by 39 % and 26 %, respectively. Importantly, the decline in cover and richness first emerged after 7 years. Warming caused significant increase in litter in both plant communities. Deciduous shrub and litter cover had negative impact on bryophyte cover. We show that bryophyte species do not respond similarly to climate change. Total bryophyte cover declined in both heath and mesic meadow under experimental long-term warming (by 1.5-3 °C), driven by general declines in many species. Principal response curve, cover and richness results suggested that bryophytes in alpine heath are more susceptible to warming than in meadow, supporting the suggestion that bryophytes may be less resistant in drier environments than in wetter habitats. Species loss was slower than the decline in bryophyte abundance, and diversity remained similar in both communities. Increased deciduous shrub and litter cover led to decline in bryophyte cover. The non-linear response to warming over time underlines the importance of long-term experiments and monitoring.


Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate)), a peroxisome proliferator.
An increase in cytosolic epoxide hydrolase (cEH) activity occurs in the livers of mice treated with peroxisome proliferating-hypolipidemic-nongenotoxic carcinogens. As increases in activity of epoxide metabolizing enzymes may reflect the carcinogenic mechanism, a detailed comparison of the response of cEH, microsomal epoxide hydrolase (mEH), and cytosolic glutathione S-transferase (cGST) activities using the geometrical isomers trans- and cis-stilbene oxide as substrates has been performed in livers from mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate]. The maximal increase of cEH activity occurred at lower dietary doses of clofibrate (0.5%) and within a shorter time (5 days) than mEH and cGST (2%, 14 days) activity. After 14 days at 0.5% clofibrate, cEH, mEH, and cGST activities were 250, 175, and 165% and 290, 220, and 75% of control values in male and female mice, respectively. Withdrawal of clofibrate from the diet resulted in a reversion of activities to control values within 7 days. Clofibrate treatment shifted the apparent subcellular compartmentation of all three enzymatic activities with an increase in the ratio of soluble to particulate activity. In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred. Both the increase of cEH activity and the appearance of mEH-like activity in the cytosol are novel responses of epoxide metabolizing enzymes, which may be related to the novel cellular responses that follow clofibrate treatment, peroxisome proliferation, hypolipidemia, and nongenotoxic carcinogenesis.


Solubilization of proteins from bovine brain coated vesicles by protein perturbants and Triton X-100.
To identify integral and peripheral membrane proteins, highly purified coated vesicles from bovine brain were exposed to solutions of various pH, ionic strength, and concentrations of the nonionic detergent Triton X-100. At pH 10.0 or above most major proteins were liberated, but four minor polypeptides sedimented with the vesicles. From quantitative analysis of phospholipids in the pellet and extract, we determined that at a pH of up to 12 all phospholipids could be recovered in the pellet. Electron microscopic examination of coated vesicles at pH 12.0 showed all vesicles devoid of coat structures. Treatment with high ionic strength solutions (0-1.0 M KCl) at pH 6.5-8.5 also liberated all major proteins, except tubulin, which remained sedimentable. The addition of Triton X-100 to coated vesicles or to stripped vesicles from which 90% of the clathrin had been removed resulted in the release of four distinct polypeptides of approximate Mr 38,000, 29,000, 24,000 and 10,000. The 38,000-D polypeptide (pK approximately 5.0), which represents approximately 50% of the protein liberated by Triton X-100, appears to be a glycoprotein on the basis of its reaction with periodic acid-Schiff reagent. Extraction of 90% of the clathrin followed by extraction of 90% of the phospholipids with Triton X-100 produced a protein residue that remained sedimentable and consisted of structures that appeared to be shrunken stripped vesicles. Together our data indicate that most of the major polypeptides of brain coated vesicles behave as peripheral membrane proteins and at least four polypeptides behave as integral membrane proteins. By use of a monoclonal antibody, we have identified one of these polypeptides (38,000 mol wt) as a marker for a subpopulation of calf brain coated vesicles.


Nulliparity and duration of pregnancy in multiple gestation.
We sought to test the hypothesis that nulliparous women with multiple gestations would be more likely to have shorter gestational durations, a higher frequency of previable deliveries, and fewer pregnancy complications when compared with parous women. We reviewed the medical records of women who delivered a multiple gestation at 15 or more weeks at 2 institutions between January 1, 1990 and June 30, 2002 (n = 1,035). We recorded demographic data, medical complications, and pregnancy outcomes and analyzed these using paired t tests for continuous variables, chi(2) for categorical variables, and linear regression analysis for the effect of multiple variables on the primary outcome variable, gestational age at delivery. There was a statistically significant difference in mean gestational age at delivery (34 versus 34.9 weeks, P =.006) between the nulliparous and multiparous groups after excluding women with a history of previous preterm birth and/or midtrimester loss. There were no differences between groups in the likelihood of delivering before 20, 24, or 28 weeks. In linear regression analysis, ongoing fetal number (P <.001), premature rupture of membranes (PROM; P <.001), cerclage (P =.002), and death of 1 or more fetuses (P <.001) were associated with shorter gestation. Cesarean delivery was associated with longer gestation (P <.001). Nulliparous women were significantly more likely to have a pregnancy complicated by hypertension (20.8% versus 9.2%, P <.001), diabetes (7% versus 4%, P =.03), or PROM (24.4% versus 17.3%, P =.006). Nulliparous women with a multiple gestation deliver their pregnancies, on average, 0.9 weeks earlier than parous women and more frequently experience hypertension, diabetes, and PROM. They are not, however, more likely to deliver before 24 weeks of gestation.


Investigations on caffeine passage into the canine gastric juice.
Two caffeine boluses (5 and 10 mg/kg) were i.v. administered to four gastric fistula dogs. Gastric secretion was collected before and during pentagastrin stimulation (1, 2 and 4 micrograms/kg/h). Caffeine concentration in serum and gastric juice was determined by HPLC. Mean serum caffeine concentrations were clearly dose-dependent: 4.88 +/- 0.73 (n = 72) and 10.18 +/- 0.98 mg/l (n = 70). After each bolus, the time course of serum concentration was described by a single exponential, yielding an estimation of caffeine half-life: 310 +/- 46 (n = 9) and 453 +/- 59 min (n = 9), respectively. In both cases the same apparent volume of distribution: 0.87 +/- 0.02 l/kg (n = 9) was found. In gastric juice, caffeine concentration depended on the caffeine dose: 2.51 +/- 2.15 (n = 66) and 6.04 +/- 2.57 mg/l (n = 62); outputs were found to be linearly related to juice output, the slope being controlled by the caffeine dose. It was concluded that caffeine passage into gastric juice was governed by a solvent drag mechanism.


Illumination Adaptation in a Multi-Wavelength Opto-Electronic Patch Sensor.
In capturing high-quality photoplethysmographic signals, it is crucial to ensure that appropriate illumination intensities are used. The purpose of the study was to deliver controlled illumination intensities for a multi-wavelength opto-electronic patch sensor that has four separate arrays each consisting of four light-emitting diodes (LEDs), the wavelength of the light generated by each array being different. The study achieved the following: (1) a linear constant current source LED driver incorporating series negative feedback using an integrated operational amplifier circuit; (2) the fitting of a linear regression equation to provide rapid determination of the LEDs driver voltage; and (3) an algorithm for the automatic adjustment of the output voltage to ensure suitable LED illumination. The data from a single centrally-located photo detector, which is capable of capturing all four channels of back-light in a time-multiplexed manner, were used to monitor heart rate and blood oxygen saturation. This paper provides circuitry for driving the LEDs and describes an adaptive algorithm implemented on a microcontroller unit that monitors the quality of the photo detector signals received in order to control each of the individual currents being supplied to the LED arrays. The study demonstrated that the operation of the new circuitry in its ability to adapt LED illumination to the strength of the signal received and the performance of the adaptive system was compared with that of a non-adaptive approach.


Fine Iron Aerosols Are Internally Mixed with Nitrate in the Urban European Atmosphere.
Atmospheric iron aerosol is a bioavailable essential nutrient playing a role in oceanic productivity. Using aerosol time-of-flight mass spectrometry (ATOFMS), the particle size (0.3-1.5 μm), chemical composition and mixing state of Fe-containing particles collected at two European urban sites (London and Barcelona) were characterized. Out of the six particle types accounting for the entire Fe-aerosol population, that arising from long-range transport (LRT) of fine Fe-containing particles (Fe-LRT, 54-82% across the two sites) was predominant. This particle type was found to be internally mixed with nitrate and not with sulfate, and likely mostly associated with urban traffic activities. This is in profound contrast with previous studies carried out in Asia, where the majority of iron-containing particles are mixed with sulfate and are of coal combustion origin. Other minor fine iron aerosol sources included mineral dust (8-11%), traffic brake wear material (1-17%), shipping/oil (1-6%), biomass combustion (4-13%) and vegetative debris (1-3%). Overall, relative to anthropogenic Asian Fe-sulfate dust, anthropogenic European dust internally mixed with additional key nutrients such as nitrate is likely to play a different role in ocean global biogeochemical cycles.


Superionic Ag+ Conductor Ag17(CO3)3I11.
A new superionic Ag+ conductor with a nominal composition Ag17(CO3)3I11 (11AgI-3Ag2CO3) was found in the AgI-Ag2CO3 system. The conductor, which was formed at temperatures from 100 to 170 °C, is a metastable phase that gradually decomposes into AgI and Ag10(CO3)I4 over a period of a few weeks at room temperature (RT). A Ag+ ionic conductivity of 0.16 S/cm was measured at RT, and an activation energy of 0.33 eV was evaluated in the temperature range from -9 to 19 °C. Single-crystal X-ray analysis revealed that Ag17(CO3)3I11 crystallized in a rhombohedral unit cell with hexagonal parameters of a = 15.8831(6) Å and c = 30.0730(13) Å at -183 °C and space group R3c. The Ag atoms were distributed over 53 sites in the asymmetry unit, with a maximum occupancy of 0.33(8). The continuous distribution of the partially occupied Ag sites was associated with the conduction paths of the Ag+ ions in the structure.


LH responses to LHRH in perifused pituitary cell culture: sex differences in the rat.
The present experiments were designed to study male and female luteinizing hormone (LH) secretory patterns following pulsatile or continuous LH-releasing hormone (LHRH) administration using a perifused dispersed rat anterior pituitary cell culture system. In male cells, consistent LH responses were elicited by hourly LHRH pulses (30 pmol), whereas in the female cells (proestrus or diestrus I), a statistically significant (P less than or equal to 0.01) decrease in the LH secretion occurred with successive LHRH pulses. Proestrous cells secreted significantly (P less than or equal to 0.01) more LH than diestrous cells during the first 24 h but not after 48 h in culture. When exposed to a 6-h continuous infusion of LHRH (10 nM), male cells released LH in a single phase and female cells secreted LH in a biphasic pattern. These data suggest that significant sex differences exist in the rat LH secretory pattern elicited by LHRH in vitro.


Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury.
Vascular endothelial growth factor (VEGF) mRNA and protein expression are increased by hypoxia in a variety of cell types and organs. In the kidney, however, chronic hypoxia does not up-regulate VEGF mRNA. This suggests that VEGF may be regulated by unique mechanisms in the kidney. Unilateral ischemia was induced in rats by vascular cross-clamping (40 min) followed by reperfusion (0, 20, 40, and 80 min). The distribution of VEGF protein was determined by immunohistochemical staining and Western blotting. mRNA was detected by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining for VEGF was verified using two VEGF antibodies. To further substantiate the immunohistochemical findings, laser scanning confocal fluorescence microscopy was used to demonstrate the distribution of VEGF protein in rat renal tubular epithelial cells (NRK52-E) subjected to hypoxia (40 min) and re-oxygenation (0, 5, 20, 40 and 80 min). Normal kidneys showed diffuse immunohistochemical staining for VEGF in all tubules of the renal cortex and medulla. Following ischemia, staining demonstrated a prominent shift of cytoplasmic VEGF to the basolateral aspect of tubular cells with both VEGF antibodies. The distribution of cytoplasmic VEGF returned to normal following 40 and 80 minutes of reperfusion. Western blots of cytoplasmic samples from ischemic kidneys reperfused for 0 and 20 minutes showed decreased levels of VEGF164 compared with normal (P < 0.01). VEGF164 and VEGF188 levels in the membrane fraction showed no change. Northern blots and semiquantitative RT-PCR showed no significant up-regulation of VEGF mRNA or change in the splice pattern. NRK52-E cells subjected to hypoxia and re-oxygenation for 0 and 5 minutes showed increased staining for VEGF compared with normal, with prominent VEGF staining at the periphery of the cell, similar to the appearance in ischemic kidneys. VEGF staining became more diffuse with further re-oxygenation. Although synthesis of VEGF mRNA and protein is not increased during ischemia reperfusion injury, pre-existing VEGF in the tubular cell cytoplasm redistributes to the basolateral aspect of the cells. These data suggest that the kidney may have evolved unique patterns of VEGF regulation to cope with acute hypoxia.


Modeling the potential impact of host population survival on the evolution of M. tuberculosis latency.
Tuberculosis (TB) is an infectious disease with a peculiar feature: Upon infection with the causative agent, Mycobacterium Tuberculosis (MTB), most hosts enter a latent state during which no transmission of MTB to new hosts occurs. Only a fraction of latently infected hosts develop TB disease and can potentially infect new hosts. At first glance, this seems like a waste of transmission potential and therefore an evolutionary suboptimal strategy for MTB. It might be that the human immune response keeps MTB in check in most hosts, thereby preventing it from achieving its evolutionary optimum. Another possible explanation is that long latency and progression to disease in only a fraction of hosts are evolutionary beneficial to MTB by allowing it to persist better in small host populations. Given that MTB has co-evolved with human hosts for millenia or longer, it likely encountered small host populations for a large share of its evolutionary history and had to evolve strategies of persistence. Here, we use a mathematical model to show that indeed, MTB persistence is optimal for an intermediate duration of latency and level of activation. The predicted optimal level of activation is above the observed value, suggesting that human co-evolution has lead to host immunity, which keeps MTB below its evolutionary optimum.


Characterization of two independent, exposure-time dependent paclitaxel-resistant human ovarian carcinoma cell lines.
This experiment was conducted to address the question of whether acquired paclitaxel resistance is dependent upon whether it is given as a single brief exposure or as a long-term exposure. PX2 and PX24 were established from 2008 human ovarian cancer cells by 2-h single exposure or 24-h continuous exposure to paclitaxel. PX2 acquired paclitaxel resistance faster than PX24 by twofold. Drug resistant pattern was exposure-time dependent. In 2-h exposure, PX2 showed 53.86 ± 4.96 (mean ± standard deviation [SD]) fold paclitaxel resistance while PX24 showed 9.51 ± 1.01 fold resistance (P = 0.002). In 24-h exposure, PX2 showed 2.31 ± 0.3 fold paclitaxel resistance while PX24 showed 28.17 ± 0.98 fold resistance (P = 0.040). PX2 and PX24 acquired cross-resistance to docetaxel and SN38 and the resistance degrees were significantly higher in PX2 than PX24. They displayed approximately twofold cisplatin collateral sensitivity. PX24 also displayed sensitivity to other platinum drugs, oxaliplatin and ZD0473, whereas PX2 acquired significant resistance to both of them. Although differential tubulin-isotype expressions were noted among 2008, PX2 and PX24, they were not significant. In electron microscopy, prominent, densely stained lysosomes were observed more in the resistant cells than 2008. Two independent, exposure-time dependent paclitaxel-resistant human ovarian carcinoma cell lines were established. Understanding the characteristics of the differential resistance pattern could be clinically beneficial for the selection of second line chemotherapy for relapsed ovarian cancer.


Biocompatible micro-sized cell culture chamber for the detection of nanoparticle-induced IL8 promoter activity on a small cell population.
In most conventional in vitro toxicological assays, the response of a complete cell population is averaged, and therefore, single-cell responses are not detectable. Such averaging might result in misinterpretations when only individual cells within a population respond to a certain stimulus. Therefore, there is a need for non-invasive in vitro systems to verify the toxicity of nanoscale materials. In the present study, a micro-sized cell culture chamber with a silicon nitride membrane (0.16 mm2) was produced for cell cultivation and the detection of specific cell responses. The biocompatibility of the microcavity chip (MCC) was verified by studying adipogenic and neuronal differentiation. Thereafter, the suitability of the MCC to study the effects of nanoparticles on a small cell population was determined by using a green fluorescence protein-based reporter cell line. Interleukin-8 promoter (pIL8) induction, a marker of an inflammatory response, was used to monitor immune activation. The validation of the MCC-based method was performed using well-characterized gold and silver nanoparticles. The sensitivity of the new method was verified comparing the quantified pIL8 activation via MCC-based and standard techniques. The results proved the biocompatibility and the sensitivity of the microculture chamber, as well as a high optical quality due to the properties of Si3N4. The MCC-based method is suited for threshold- and time-dependent analysis of nanoparticle-induced IL8 promoter activity. This novel system can give dynamic information at the level of adherent single cells of a small cell population and presents a new non-invasive in vitro test method to assess the toxicity of nanomaterials and other compounds.PACS: 85.35.Be, 81.16.Nd, 87.18.Mp.


Validity and feasibility of a self-administered home vision examination in Yueqing, China: a cross-sectional study.
To investigate the validity and feasibility of a self-administered home vision examination programme in China. Cross-sectional study. Yueqing, China. A two-stage convenience sampling procedure was used to randomly select 600 households from 30 communities participating in the Yueqing Eye Study (YES). The aim of YES is to encourage home-based vision screening, reporting of visual acuity (VA) annually through social media and encouraging people to attend follow-up clinic appointments as a way to improve eye care access for adults with VA ≤+0.5 log of the minimum angle of resolution (logMAR). Household screeners (one per household) who tested other family members' VA completed a questionnaire on family structure, demographic information and knowledge about screening procedures. Other family members then underwent confirmatory VA testing by researchers. The completion rate of home-based VA screening, its sensitivity and specificity were used to evaluate validity. Factors that determined whether families participated in the self-VA screening were used to evaluate feasibility. 345 (66%) of the 523 (87.2%) households with valid data form their home-based vision examinations also were retested by researchers. There was no statistically significant difference in scores on the family-administerd or researcher-administerd VA test (VA≤+0.5 logMAR, p=0.607; VA >+0.5 logMAR, p=0.612). The sensitivity and specificity of home-based vision screening were 80.5% (95% CI 70.2% to 86.9%) and 95.1% (95% CI 92.6% to 96.8%), respectively. 14.7% (77/523) of tested respondents had VA ≤+0.5 logMAR. Predictors of performing home screening for VA remaining in regression models included higher economic status ('fair and above' vs 'poor': OR 1.74; 95% CI 1.08 to 2.76; p=0.022), age (<45 years vs ≥45 years: OR 0.46; 95% CI 0.25 to 0.85; p=0.014) and living in a nuclear (OR 5.17; 95% CI 2.86 to 9.36; p<0.001) or extended family (OR 8.37; 95% CI 4.93 to 14.20; p<0.001). Self-administered home vision screening is reliable and highly accepted by Chinese adults.


Evidence for deep-water production in the North Pacific Ocean during the early Cenozoic warm interval.
The deep-ocean circulation is responsible for a significant component of global heat transport. In the present mode of circulation, deep waters form in the North Atlantic and Southern oceans where surface water becomes sufficiently cold and dense to sink. Polar temperatures during the warmest climatic interval of the Cenozoic era (approximately 65 to 40 million years (Myr) ago) were significantly warmer than today, and this may have been a consequence of enhanced oceanic heat transport. However, understanding the relationship between deep-ocean circulation and ancient climate is complicated by differences in oceanic gateways, which affect where deep waters form and how they circulate. Here I report records of neodymium isotopes from two cores in the Pacific Ocean that indicate a shift in deep-water production from the Southern Ocean to the North Pacific approximately 65 Myr ago. The source of deep waters reverted back to the Southern Ocean 40 Myr ago. The relative timing of changes in the neodymium and oxygen isotope records indicates that changes in Cenozoic deep-water circulation patterns were the consequence, not the cause, of extreme Cenozoic warmth.


Cr2TiC2-based double MXenes: novel 2D bipolar antiferromagnetic semiconductor with gate-controllable spin orientation toward antiferromagnetic spintronics.
Antiferromagnetic (AF) spin devices could be one of the representative components for applications of spintronics thanks to the numerous advantages such as resistance to magnetic field perturbation, stray field-free operation, and ultrahigh device operation speed. However, detecting and manipulating the spin of AF materials is still a major challenge due to the absence of a net magnetic moment and spin degeneracy in the band structure. Bipolar antiferromagnetic semiconductors are promising solutions to these problems. Herein, using density functional theory calculations, we present asymmetrical functionalized double MXenes (Cr2TiC2FCl) that behave as a novel bipolar antiferromagnetic semiconductor (BAFS) with vanishing magnetism, in which the valence band and conduction band around the Fermi level exhibit opposite spin directions. Remarkably, gate voltage can manipulate the spin orientation of the AF Cr2TiC2FCl and lead to a transition from BAFS to half-metal antiferromagnets (HMAF). Moreover, the mixed functionalized double MXenes with various F/Cl concentrations show the BAFS feature due to the different chemical environment for the Cr atom. Our results presented herein open a new strategy towards AF spintronics and the realization of the AF spin field effect transistor.


Effects of tobacco and P. gingivalis on gingival fibroblasts.
Cigarette smoke condensate (CSC) is the particulate matter of cigarette smoke. Porphyromonas gingivalis (P. gingivalis) is an opportunistic pathogen involved in periodontitis. It was hypothesized that the combination of CSC and P. gingivalis would increase the collagen-degrading ability of human gingival fibroblasts (HGFs). In this study, HGFs were exposed to CSC, P. gingivalis supernatant, and CSC plus P. gingivalis supernatant. The collagen-degrading ability and protein/mRNA levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) of HGFs were examined. The combined treatment increased collagen degradation, protein levels of active forms of MMP-1, MMP-2, MMP-3, and MMP-14 in conditioned media, and the low-molecular-weight fragment of MMP-14 in membrane extracts, as well as mRNA levels of MMP-1, MMP-2, and MMP-14. In conclusion, the combined effects of CSC and P. gingivalis increased HGF-mediated collagen degradation by destroying the balance between MMPs and TIMPs at multiple levels.


[Effect of presowing treatment of spring wheat seeds with wheat germ agglutinin on the chlorophyll content, lectin activity in leaves and nitrogen-fixing capacity of rhizospheric microorganisms].
The response of spring wheat and rhizospheric nitrogen-fixing micro-organisms to the presowing treatment of seeds by wheat germ agglutinin was investigated in conditions of green house experiments. It was shown, that exogenous lectin induced the metabolic changes in plants and caused an increase in chlorophyll content and activity of endogenous lectins in the leaves, as well as enhanced accumulation of plants biomass and nitrogen-fixing capacity of the rhizospheric micro-organisms. These results evidence for the considerable role of exogenous lectin as a regulator of growth and development of plants and activity of the nitrogen-fixing microorganisms.


Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats.
Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT(2)R). However, the role of vascular AT(2)R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult (~17 weeks) and aged (~19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT(1)R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT(2)R antagonist, PD123319. In a separate group of animals, the specific MasR antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure (~15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT(2)R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT(2)R blockade or MasR blockade. At the same time, AT(2)R, MasR, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT(2)R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT(2)R and MasR.


Protocol for a pragmatic feasibility randomised controlled trial of peer coaching for adults with long-term conditions: PEER CONNECT.
Patients with low levels of knowledge, skills and confidence to manage their health and well-being (activation) are more likely to have unmet health needs, delay seeking healthcare and need emergency care. National Health Service England estimates that this may be applicable to 25%-40% of patients with long-term health conditions. Volunteer peer coaching may support people to increase their level of activation. This form of intervention may be particularly effective for people with low levels of activation. This single site, two-arm randomised controlled trial has been designed to assess the feasibility of conducting a definitive trial of volunteer peer health and well-being coaching for people with long-term health conditions (multiple sclerosis, rheumatic diseases or chronic pain) and low activation. Feasibility outcomes include recruitment and retention rates, and intervention adherence. We will measure patient activation, mental health and well-being as potential outcomes for a definitive trial. These outcomes will be summarised descriptively for each time point by allocated group and help to inform sample size calculation for the definitive trial. Criteria for progression to a full trial will be used. Ethical approval has been granted by the London - Surrey Research Ethics Committee, reference 21/LO/0715. Results from this feasibility trial will be shared directly with participants, presented at local, regional and national conferences and published in an open-access journal. ISRCTN12623577.


Ectopic calcification in β-thalassemia patients is associated with increased oxidative stress and lower MGP carboxylation.
A number of beta-thalassemia (β-thal) patients in the course of the disease exhibit ectopic calcification affecting skin, eyes and the cardiovascular system. Clinical and histopathological features have been described similar to those in pseudoxanthoma elasticum (PXE), although different genes are affected in the two diseases. Cultured dermal fibroblasts from β-thal patients with and without PXE-like clinical manifestations have been compared for parameters of redox balance and for the expression of proteins, which have been already associated with the pathologic mineralisation of soft connective tissues. Even though oxidative stress is a well-known condition of β-thal patients, our results indicate that the occurrence of mineralized elastin is associated with a more pronounced redox disequilibrium, as demonstrated by the intracellular increase of anion superoxide and of oxidized proteins and lipids. Moreover, fibroblasts from β-thal PXE-like patients are characterized by decreased availability of carboxylated matrix Gla protein (MGP), as well as by altered expression of proteins involved in the vitamin K-dependent carboxylation process. Results demonstrate that elastic fibre calcification is promoted when redox balance threshold levels are exceeded and the vitamin K-dependent carboxylation process is affected decreasing the activity of MGP, a well-known inhibitor of ectopic calcification. Furthermore, independently from the primary gene defect, these pathways are similarly involved in fibroblasts from PXE and from β-thal PXE-like patients as well as in other diseases leading to ectopic calcification, thus suggesting that can be used as markers of pathologic mineralisation.


Diabetes, prediabetes and cancer mortality.
We aimed to investigate the risk of cancer mortality in relation to the glucose tolerance status classified according to the 2 h OGTT. Data from 17 European population-based or occupational cohorts involved in the DECODE study comprising 26,460 men and 18,195 women aged 25-90 years were collaboratively analysed. The cohorts were recruited between 1966 and 2004 and followed for 5.9 to 36.8 years. Cox proportional hazards analysis with adjustment for cohort, age, BMI, total cholesterol, blood pressure and smoking status was used to estimate HRs for cancer mortality. Compared with people in the normal glucose category, multivariable adjusted HRs (95% CI) for cancer mortality were 1.13 (1.00, 1.28), 1.27 (1.02, 1.57) and 1.71 (1.35, 2.17) in men with prediabetes, previously undiagnosed diabetes and known diabetes, respectively; in women they were 1.11 (0.94, 1.30), 1.31 (1.00, 1.70) and 1.43 (1.01, 2.02), respectively. Significant increases in deaths from cancer of the stomach, colon-rectum and liver in men with prediabetes and diabetes, and deaths from cancers of the liver and pancreas in women with diabetes were also observed. In individuals without known diabetes, the HR (95% CI) for cancer mortality corresponding to a one standard deviation increase in fasting plasma glucose was 1.06 (1.02, 1.09) and in 2 h plasma glucose was 1.07 (1.03, 1.11). Diabetes and prediabetes were associated with an increased risk of cancer death, particularly death from liver cancer. Mortality from all cancers rose linearly with increasing glucose concentrations.


Advances in understanding the complex mechanisms of DNA interstrand cross-link repair.
DNA interstrand cross-links (ICLs) are lesions caused by a variety of endogenous metabolites, environmental exposures, and cancer chemotherapeutic agents that have two reactive groups. The common feature of these diverse lesions is that two nucleotides on opposite strands are covalently joined. ICLs prevent the separation of two DNA strands and therefore essential cellular processes including DNA replication and transcription. ICLs are mainly detected in S phase when a replication fork stalls at an ICL. Damage signaling and repair of ICLs are promoted by the Fanconi anemia pathway and numerous posttranslational modifications of DNA repair and chromatin structural proteins. ICLs are also detected and repaired in nonreplicating cells, although the mechanism is less clear. A unique feature of ICL repair is that both strands of DNA must be incised to completely remove the lesion. This is accomplished in sequential steps to prevent creating multiple double-strand breaks. Unhooking of an ICL from one strand is followed by translesion synthesis to fill the gap and create an intact duplex DNA, harboring a remnant of the ICL. Removal of the lesion from the second strand is likely accomplished by nucleotide excision repair. Inadequate repair of ICLs is particularly detrimental to rapidly dividing cells, explaining the bone marrow failure characteristic of Fanconi anemia and why cross-linking agents are efficacious in cancer therapy. Herein, recent advances in our understanding of ICLs and the biological responses they trigger are discussed.


Catching the phylogenic history through the ontogenic hourglass: a phylogenomic analysis of Drosophila body segmentation genes.
The phylogenetic information content of different developmental stages is a long-standing issue in the study of development and evolution. We performed phylogenetic analyses of 51 body segmentation genes in 12 species of Drosophila in order to investigate the impact of the mode of evolution of development on phylogeny inference. Previous studies of these genes in Drosophila using pairwise phenetic comparisons at the species group level revealed the presence of an "hourglass model" (HG), wherein mid-embryonic stages are the most evolutionarily constrained. We utilized two character-based approaches: taxonomic congruence using the relative consensus fork index (RCFI), in which phylogenies are inferred from each gene separately and compared with a total evidence tree (TET), and partitioned simultaneous analysis using several indices such as branch support (BS) and localized incongruence length difference (LILD) test. We also proposed a new index, the recapitulatory index (R), which divides the number of synapomorphies on the total number of informative characters in a data set. Polynomial adjustment of both BS and R indices showed strong support for the hourglass model regardless of the taxonomic level (species subgroup vs. subgenera), showing less phylogenetic information content for mid-developmental stages (mainly the zygotic segment polarity stage). Significant LILD scores were randomly distributed among developmental stages revealing the absence of differential selective constraints, but were significantly related to chromosomal location showing physical (linkage) impact on phylogenetic incongruence. RCFI was the most sensitive measure to taxonomic level, having a convex parabola at the species subgroup level in support of the hourglass model and a concave parabola at the subgeneric level in support of the adaptive penetrance model. This time-dependent discrepancy of best fit developmental model parallels previous conflicting results from the vertebrates. Because of the quasi-phenetic nature of this index, we argue that the discrepancy is due to the evolutionary rate heterogeneity of developmental genes rather than to fundamental differences among organisms. We suggest that simultaneous character-based analyses give better macroevolutionary support to the hourglass model of the developmental constraints on genome evolution than pairwise phenetic comparisons.


Meat quality, fatty acid composition and sensory evaluation of Cherry Valley, Spent Layer and Crossbred ducks.
The aim of this research was to compare meat quality characteristics of Cherry Valley (CV), Spent Layer (SL) and Crossbred (CB) ducks. Meat quality, proximate and fatty acid composition were measured in breast and thigh muscles from CV, SL and CB, as well as sensory evaluation of duck soup made from three breeds. The results showed SL contained a highest percentage of protein but lowest moisture than those of CV and intermediate CB (P < 0.05). The L* and b* value of SL ducks were lowest among three breeds (P < 0.05). The breast of SL had higher water-holding capacity compared to CV (P < 0.05), although CV was the most tender among the three breeds (P < 0.05). SL had lower contents of saturated fatty acid and higher contents of unsaturated fatty acids with a more acceptable P/S ratio of 0.57 and n-6/n-3 ratio of 1.52 (P < 0.05). Intramuscular fat and polyunsaturated fatty acids were involved in producing intense aroma and flavor of duck meats. Differences of color and tenderness in meats were attributed to values of L* and cooking loss of muscles. In conclusion, it would be suggested that SL was more suitable for producing duck soup among the three breeds.


Demonstration of colonies of Cowdria ruminantium in midgut epithelial cells of Amblyomma variegatum.
The development of colonies of Cowdria ruminantium was studied in midgut epithelial cells of adult Amblyomma variegatum that had become infected by feeding as nymphs on cattle with experimentally induced heart-water disease. Colonies were not observed in gut tissues obtained from nymphs during the feeding period, but were present in midgut epithelial cells of ticks obtained at 15 days after they were replete through molting to the adult stage. Colonies were small (1 to 10 micron) initially, but as tick development progressed, their diameter increased to as much as 60 micron. With electron microscopy, colonies were observed to be membrane bound and contained pleomorphic organisms that were reticulated. The organisms seemed to be dividing by binary fission. Many colonies contained a large, electron-dense inclusion that was morphologically similar to hemoglobin deposits found in the cytoplasm of midgut epithelial cells of recently fed ticks. Cowdria ruminantium was often observed adhered to these inclusions.


New tools for automated cryo-EM single-particle analysis in RELION-4.0.
We describe new tools for the processing of electron cryo-microscopy (cryo-EM) images in the fourth major release of the RELION software. In particular, we introduce VDAM, a variable-metric gradient descent algorithm with adaptive moments estimation, for image refinement; a convolutional neural network for unsupervised selection of 2D classes; and a flexible framework for the design and execution of multiple jobs in pre-defined workflows. In addition, we present a stand-alone utility called MDCatch that links the execution of jobs within this framework with metadata gathering during microscope data acquisition. The new tools are aimed at providing fast and robust procedures for unsupervised cryo-EM structure determination, with potential applications for on-the-fly processing and the development of flexible, high-throughput structure determination pipelines. We illustrate their potential on 12 publicly available cryo-EM data sets.


Systematic review of outbreaks of Pneumocystis jirovecii pneumonia: evidence that P. jirovecii is a transmissible organism and the implications for healthcare infection control.
Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity and mortality in immunocompromised patients. Several nosocomial outbreaks of PCP have been reported in human-immunodeficiency-virus-negative, immunocompromised patients. The primary route of P. jirovecii transmission has yet to be proven; however, these outbreaks of infection suggest either interhuman transmission or a common environmental source. To identify and evaluate all published clusters and outbreaks of PCP. The main objective was to compare the epidemiology of the outbreaks, with a particular focus on the evidence for different modes of transmission. PubMed and EMBASE were searched to identify all English-language articles describing PCP outbreaks or clusters between 1980 and March 2015. Data were extracted on the outbreak setting, features of the outbreak, application of molecular typing, results of epidemiological assessment and environmental sampling. Thirty outbreaks described in 29 articles were identified. Twenty-five (83%) of these outbreaks were described in patients who had undergone solid organ transplantation, primarily renal transplantation. All studies described a defined cohort of patients who shared some nosocomial facilities, including both inpatient and outpatient areas. Genotyping was undertaken in 16 (47%) studies. Cases with an identical genotype were demonstrated in all these studies. The findings of this review raise a number of concerns regarding the public health and infection control implications of infection with PCP. The evidence presented for nosocomial acquisition and possible person-to-person transmission of infection suggests the need for formal infection control policies.


Arabidopsis retrotransposon virus-like particles and their regulation by epigenetically activated small RNA.
In Arabidopsis, LTR retrotransposons are activated by mutations in the chromatin gene DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21- to 22-nt epigenetically activated siRNA (easiRNA) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. High-throughput short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR retrotransposons without the need for mapping transposition, as well as independent of genomic copy number. Linear replication intermediates of the functionally intact COPIA element EVADE revealed multiple central polypurine tracts (cPPTs), a feature shared with HIV in which cPPTs promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon "suicide" by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR retrotransposons and their control at transcriptional, post-transcriptional, and reverse transcriptional levels.


Association between gastrointestinal cancers and fingerprint patterns in the Iranian population.
Gastrointestinal cancers are malignant diseases with high mortality rate. Early diagnosis of patients could improve the results of treatment. Many studies used dermatoglyphics as a biomarker to predict the incidence of genetic diseases and cancers. This study assessed the association between gastrointestinal cancers and particular fingerprint patterns, which could be useful in early diagnosis of these malignancies. The study was conducted on 153 histopathologically confirmed gastrointestinal cancer patients and 299 healthy individuals. The fingerprints were taken by a specific method of rolling the subject's fingers or thumbs in ink. The data were analyzed for the significance using the chi-square test and the t-test. Odds ratio with 95% confidence intervals were calculated. Dermatoglyphic analysis showed that whorl and loop patterns significantly changed in the case group as compared to control. However, the odds ratio suggested that whorl pattern in 6 or more fingers might be a risk factor for developing gastrointestinal cancers. Our results showed that there is an association between fingerprint patterns and gastrointestinal cancers, and so, the dermatoglyphic analysis may aid in the early diagnosis of these cancers.


Treadmill interventions in children under six years of age at risk of neuromotor delay.
Delayed motor development may occur in children with Down syndrome, cerebral palsy, general developmental delay or children born preterm. It limits the child's exploration of the environment and can hinder cognitive and social-emotional development. Literature suggests that task-specific training, such as locomotor treadmill training, facilitates motor development. To assess the effectiveness of treadmill interventions on locomotor development in children with delayed ambulation or in pre-ambulatory children (or both), who are under six years of age and who are at risk for neuromotor delay. In May 2017, we searched CENTRAL, MEDLINE, Embase, six other databases and a number of trials registers. We also searched the reference lists of relevant studies and systematic reviews. We included randomised controlled trials (RCTs) and quasi-RCTs that evaluated the effect of treadmill intervention in the target population. Four authors independently extracted the data. Outcome parameters were structured according to the International Classification of Functioning, Disability and Health model. This is an update of a Cochrane review from 2011, which included five trials. This update includes seven studies on treadmill intervention in 175 children: 104 were allocated to treadmill groups, and 71 were controls. The studies varied in population (children with Down syndrome, cerebral palsy, developmental delay or at moderate risk for neuromotor delay); comparison type (treadmill versus no treadmill; treadmill with versus without orthoses; high- versus low-intensity training); study duration, and assessed outcomes. Due to the diversity of the studies, only data from five studies were used in meta-analyses for five outcomes: age of independent walking onset, overall gross motor function, gross motor function related to standing and walking, and gait velocity. GRADE assessments of quality of the evidence ranged from high to very low.The effects of treadmill intervention on independent walking onset compared to no treadmill intervention was population dependent, but showed no overall effect (mean difference (MD) -2.08, 95% confidence intervals (CI) -5.38 to 1.22, 2 studies, 58 children; moderate-quality evidence): 30 children with Down syndrome benefited from treadmill training (MD -4.00, 95% CI -6.96 to -1.04), but 28 children at moderate risk of developmental delay did not (MD -0.60, 95% CI -2.34 to 1.14). We found no evidence regarding walking onset in two studies that compared treadmill intervention with and without orthotics in 17 children (MD 0.10, 95% CI -5.96 to 6.16), and high- versus low-intensity treadmill interventions in 30 children with Down syndrome (MD -2.13, 95% -4.96 to 0.70).Treadmill intervention did not improve overall gross motor function (MD 0.88, 95% CI -4.54 to 6.30, 2 studies, 36 children; moderate-quality evidence) or gross motor skills related to standing (MD 5.41, 95% CI -1.64 to 12.43, 2 studies, 32 children; low-quality evidence), and had a negligible improvement in gross motor skills related to walking (MD 4.51, 95% CI 0.29 to 8.73, 2 studies, 32 children; low-quality evidence). It led to improved walking skills in 20 ambulatory children with developmental delay (MD 7.60, 95% CI 0.88 to 14.32, 1 study) and favourable gross motor skills in 12 children with cerebral palsy (MD 8.00, 95% CI 3.18 to 12.82). A study which compared treadmill intervention with and without orthotics in 17 children with Down syndrome suggested that adding orthotics might hinder overall gross motor progress (MD -8.40, 95% CI -14.55 to -2.25).Overall, treadmill intervention showed a very small increase in walking speed compared to no treadmill intervention (MD 0.23, 95% CI 0.08 to 0.37, 2 studies, 32 children; high-quality evidence). Treadmill intervention increased walking speed in 20 ambulatory children with developmental delay (MD 0.25, 95% CI 0.08 to 0.42), but not in 12 children with cerebral palsy (MD 0.18, 95% CI -0.09 to 0.45). This update of the review from 2011 provides additional evidence of the efficacy of treadmill intervention for certain groups of children up to six years of age, but power to find significant results still remains limited. The current findings indicate that treadmill intervention may accelerate the development of independent walking in children with Down syndrome and may accelerate motor skill attainment in children with cerebral palsy and general developmental delay. Future research should first confirm these findings with larger and better designed studies, especially for infants with cerebral palsy and developmental delay. Once efficacy is established, research should examine the optimal dosage of treadmill intervention in these populations.


Measuring patient experience of diagnostic care and acceptability of testing.
A positive patient experience has been long recognised as a key feature of a high-quality health service, however, often assessment of patient experience excludes diagnostic care. Experience of diagnostic services and the acceptability of diagnostic tests are often conflated, with lack of clarity about when and how either should be measured. These problems contrast with the growth in the development and marketing of new tests and investigation strategies. Building on the appraisal of current practice, we propose that the experience of diagnostic services and the acceptability of tests should be assessed separately, and describe distinct components of each. Such evaluations will enhance the delivery of patient-centred care, and facilitate patient choice.


An exploratory study of associations between sleep timing variability and cardiometabolic health in middle-aged adults with type 2 diabetes mellitus.
Sleep is increasingly recognised as an important risk factor for metabolic disease, and as an important influence on severity in established metabolic disease. Recent evidence suggests that sleep timing variability (the day-to-day fluctuations of sleep timing) may be an important factor in metabolic diseases such as type 2 diabetes mellitus. In the current study, we explore the associations between measures of sleep timing variability and cardiometabolic measures in a group of healthy middle-aged adults with and without type 2 diabetes mellitus. Healthy controls (N = 27) and adults with well-controlled uncomplicated type 2 diabetes mellitus (N = 30) wore actiwatches for an average of 9 days for objective assessment of sleep timing parameters, and also underwent a detailed clinical assessment. We found greater self-reported social jetlag in the diabetes group, but no groupwise differences in measures of sleep timing variability. In the diabetes patients, HbA1c levels were inversely correlated with variability in the time of sleep onset and midsleep, and with sleep duration. HOMA-IR did not correlate with any sleep timing variability measure, nor were there associations between sleep timing variability and other metabolic biomarkers (cholesterol, LDL, HDL, triglycerides and uric acid). Systolic blood pressure was inversely correlated with actigraphically defined social jetlag in both the control and diabetes groups. The results of this study indicate associations between sleep timing variability and HbA1c, but the direction of these relationships is at variance with some other recent reports. Our results indicate a need for future hypothesis-testing studies to further explore the impact of sleep timing variance on metabolic health.


Use of Real-World Evidence in Regulatory Decisions for Traditional Chinese Medicine: Current Status and Future Directions.
Traditional Chinese medicine (TCM) is a valuable resource unique to China with a long history of human use and clinical practice, which can be analyzed to generate real-world evidence (RWE). The Chinese government has been actively promoting regulatory reform that is in line with the characteristics of TCM, optimizing the clinical evidence system for TCM, and exploring the important role of RWE in supporting the development of new drugs and regulatory decision-making for TCM. This article aims to provide a comprehensive review of the use of RWE in regulatory decisions for TCM. Based on the characteristics of TCM, this study focuses on the application scenarios, challenges, and opportunities of RWE in TCM. And some suggestions are put forward to promote the wider application of RWE in TCM development and supervision.