Antimicrobial activity of Micromeria nervosa from the Palestinian area.
Organic and aqueous solvent extracts and fractions of Micromeria nervosa (Desf.) Benth. (Labiatae) were investigated for antimicrobial activities on several microorganisms including bacteria and yeast. The different extracts differed significantly in their antimicrobial activities with the ethanolic extract being most active, followed by ethyl acetate and petroleum ether extracts. The least active extract was the aqueous. No significant difference between the different test microorganisms in their susceptibility to different extracts, with Candida albicans being the most susceptible to ethanolic extract giving 1.5 times the effect of nystatin. One of the main active ingredients of M. nervosa was isolated and identified as carvacrol. No significant difference in antimicrobial activity was found between carvacrol and its isomer thymol. The most susceptible test microorganism was Proteus vulgaris to carvacrol, and P. vulgaris and C. albicans to thymol. The least susceptible bacterium to both fractions was Pseudomonas aeruginosa. Minimum inhibitory concentration (MIC) and minimum bactericidal or fungicidal concentrations (MBC or MFC) were determined for both compounds.


Co-administration of routine paediatric vaccines in England often deviates from the immunisation schedule.
Vaccine co-administration can facilitate the introduction of new vaccines in immunisation schedules and improve coverage. We analysed real life data to quantify the extent of routine paediatric vaccine co-administrations as recommended and as never recommended in the immunisation schedule in England, and assessed factors for recommended and never recommended vaccine co-administrations. Immunisation data for all scheduled routine paediatric vaccines between 2008 and 2018 was obtained from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We included 6'257'828 doses administered to 1'005'827 children. Twenty-one percent of vaccines were given separately, 79% were co-administered. Sixty-four percent of vaccines scheduled for co-administration were co-administered as recommended while 15% were administered separately. Among all vaccine co-administrations, 75% happened as recommended in the schedule, 4% were never recommended, while 21% deviated from the schedule. Vaccine co-administration according to the schedule varied greatly between vaccines. Forty-eight percent of English children received at least one of their vaccine co-administrations not as recommended in the immunisation schedule, with 19% of children receiving none of their co-administered vaccines as recommended. Late administration of one or more vaccines increased the odds for deviated co-administrations (OR 1.60) and strongly increased the odds for never recommended co-administrations (OR 5.34). Differences between genders, NHS regions, and IMD quintiles were statistically significant but small. Suboptimal co-administration rates for routine paediatric vaccines are a missed opportunity and should be optimised by concerted public health action.


Patterns of Medical Cannabis Use among Cancer Patients from a Medical Cannabis Dispensary in New York State.
Background: Research on the patterns of use of medical cannabis among cancer patients is lacking. Objective: To describe patterns of medical cannabis use by patients with cancer, and how patterns differ from patients without cancer. Design/Measurements: We performed secondary data analysis using data from a medical cannabis licensee in New York State, analyzing demographic information, qualifying conditions, and symptoms, and the medical cannabis product used, including tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios. Setting/Subjects: Adults age ≥18 who used New York State medical cannabis licensee products between January 2016 and December 2017. Results: There were a total of 11,590 individuals with 1990 (17.2%) having cancer who used at least one cannabis product. Patients with cancer using cannabis were older and more likely to be female. The most common qualifying symptom for both cancer and noncancer patients was severe or chronic pain. Cancer patients were more likely to use the sublingual tincture form of cannabis (n = 1098, 55.2%), while noncancer patients were more likely to use the vaporization form (n = 4222, 44.0%). Over time, across all patients, there was an increase in the THC daily dose by a factor of 0.20 mg/week, yielding a corresponding increase in the THC:CBD daily ratio. Compared with noncancer patients, these trends were not different in the cancer group for THC daily dose, but there were less pronounced increases in the THC:CBD daily ratio over time among cancer patients. Conclusions: Our study found some key differences in demographics and medical cannabis product use between patients with cancer and without cancer.


Severe vivax malaria: a prospective exploration at a tertiary healthcare centre in Southwestern India.
Plasmodium vivax is recognized to cause severe malaria and mortality. We aimed to determine the proportion of disease severity, the spectrum of complications, underlying non-infectious comorbidities and predictors of severity in monoinfection P. vivax malaria among adults at a tertiary healthcare centre in Southwestern India. A prospective cohort study was conducted among microscopically confirmed monoinfection P. vivax acute malaria patients aged, ≥18 years. Cases with pregnancy and concomitant febrile illnesses including mixed malaria were excluded. Cases were distinguished as either 'severe' or 'non-severe' P. vivax malaria as per the definitions laid by the World Health Organization. Of total 511 acute P. vivax cases studied, 23.9% (122/511) had severe malaria. The proportion of severity did not vary between microscopy alone and additional nPCR proved monoinfection P. vivax subgroups. There was no significant difference (p = 0.296) in the occurrence of non-infectious comorbidities among non-severe (9.0%, 35/389) and severe (12.3%, 15/122) vivax groups. Multiple complications despite early parasite clearance resulted in delayed casualty in two cases, indicating overall case fatality rate of 3/1000 cases. Age >40 years, rising respiratory rate, total bilirubin, serum creatinine and falling hemoglobin were the independent predictors of disease severity in this vivax malaria cohort. Total and direct bilirubin and serum urea had good discriminatory performance for severe vivax malaria. Total bilirubin should be considered as an important prognostic marker while managing P. vivax malaria. Patients with multiple complications must be treated cautiously as there may be delayed deterioration leading to mortality despite parasite clearance.


HIV-occlusive vascular disease.
To evaluate peripheral arterial occlusive disease in HIV-infected patients regarding clinical presentation and outcome of surgical intervention. Prospective clinical survey. Routine voluntary testing for HIV/AIDS was performed in all patients presenting to our vascular unit. HIV+ patients were enrolled in a registry and followed up prospectively. We identified 154 HIV+ patients, of whom 91 (59%) presented with occlusive disease. There were 71 males and 20 females with a mean age of 44.2 years. The usual risk factors for atherosclerosis were present, but the incidence was less than reported in the classic atherosclerosis population. More than 90% of the patients presented with advanced stage vascular disease (Fontaine III/IV), which explains the high rate (31.9%) of primary amputation. Eighty-seven patients presented with lower-limb ischaemia, 2 patients with upper-limb ischaemia and 2 patients with symptomatic carotid artery stenosis. Seventy-eight procedures were performed on 72 patients, with a perioperative mortality of 6.95%. The limb salvage rate for femoro-popliteal bypass procedures was poor (36.1%), resulting in a high incidence of secondary amputations and prolonged hospital stay. Long-term mortality for the operated patients was 20% over a mean follow-up period of 15.4 months. Hypo-albuminaemia was found to be an important predictor of outcome. Patients presenting with HIV-associated peripheral arterial disease should be carefully selected for intervention, taking into consideration nutritional and immune status, stage of the vascular disease and selecting the appropriate procedure.


The i-TTM model for ab initio-based ion-water interaction potentials. II. Alkali metal ion-water potential energy functions.
A new set of i-TTM potential energy functions describing the interactions between alkali metal ions and water molecules is reported. Following our previous study on halide ion-water interactions [J. Phys. Chem. B, 2016, 120, 1822], the new i-TTM potentials are derived from fits to CCSD(T) reference energies and, by construction, are compatible with the MB-pol many-body potential, which has been shown to accurately predict the properties of water from the gas to the condensed phase. Within the i-TTM formalism, two-body repulsion, electrostatic, and dispersion energies are treated explicitly, while many-body effects are represented by classical induction. The accuracy of the new i-TTM potentials is assessed through extensive comparisons with results obtained from different ab initio methods, including CCSD(T), CCSD(T)-F12b, DF-MP2, and several DFT models, as well as from polarizable force fields for M+(H2O)n clusters with M+ = Li+, Na+, K+, Rb+, and Cs+, and n = 1-4.


Visual marking across eye blinks.
Visual search for a conjunction target can be made efficient by presenting one initial set of distractors as a preview, prior to the onset of the other items in the search display Watson & Humphreys (Psychological Review 104:90-122, 1997). However, this "preview advantage" is lost if the initial items are offset for a brief period before onsetting again with the search display Kunar, Humphreys, & Smith (Psychological Science 14:181-185, 2003). Researchers have long disputed whether the preview advantage reflects a process of internally coding and suppressing the old items or of the onset of the new items capturing attention Donk & Theeuwes (Perception & Psychophysics 63:891-900, 2001). In this study, we assessed whether an internally driven blink (in which participants close their eyes) acts in the same manner as an external blink produced by offsetting and then onsetting the preview. In the novel blink conditions, participants searched feature, conjunction, and preview displays after being cued to blink their eyes. The search displays were presented during the eye blink, and so were immediately available once participants opened their eyes. Having participants make an eye blink generally slowed search but had no effect on the search slopes. In contrast, imposing an externally driven blink disrupted preview search. The data indicated that visual attention can compensate for internally driven blinks, and this does not lead to the loss of the representations of distractors across time. Moreover, efficient preview search occurred when the search items had no abrupt onsets, demonstrating that onsets of new search items are not critical for the preview benefit.


Hormonal, metabolic, and inflammatory profiles and endometrial cancer risk within the EPIC cohort--a factor analysis.
A "Western" lifestyle characterized by physical inactivity and excess weight is associated with a number of metabolic and hormonal dysregulations, including increased circulating estrogen levels, hyperinsulinemia, hyperglycemia, and chronic inflammation. The same hormonal and metabolic axes might mediate the association between this lifestyle and the development of endometrial cancer. Using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC), a prospective cohort study carried out in 10 European countries during 1992-2000, we conducted a factor analysis to delineate important components that summarize the variation explained by a set of biomarkers and to examine their association with endometrial cancer risk. Prediagnostic levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, sex hormone-binding globulin, estrone, estradiol, C-peptide, insulin-like growth factor-binding proteins 1 and 2, adiponectin, high- and low-density lipoprotein cholesterol, glucose, triglycerides, tumor necrosis factor (TNF) α, soluble TNF receptors 1 and 2, C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist were measured in 233 incident endometrial cancer cases and 446 matched controls. Factor analysis identified 3 components associated with postmenopausal endometrial cancer risk that could be labeled "insulin resistance/metabolic syndrome," "steroids," and "inflammation" factors. A fourth component, "lipids," was not significantly associated with endometrial cancer. In conclusion, besides the well-known associations of risk with sex hormones and insulin-regulated physiological axes, our data further support the hypothesis that inflammation factors play a role in endometrial carcinogenesis.


Sudden cardiac death athletes: a systematic review.
Previous events evidence that sudden cardiac death (SCD) in athletes is still a reality and it keeps challenging cardiologists. Considering the importance of SCD in athletes and the requisite for an update of this matter, we endeavored to describe SCD in athletes. The Medline (via PubMed) and SciELO databases were searched using the subject keywords "sudden death, athletes and mortality". The incidence of SCD is expected at one case for each 200,000 young athletes per year. Overall it is resulted of complex dealings of factors such as arrhythmogenic substrate, regulator and triggers factors. In great part of deaths caused by heart disease in athletes younger than 35 years old investigations evidence cardiac congenital abnormalities. Athletes above 35 years old possibly die due to impairments of coronary heart disease, frequently caused by atherosclerosis. Myocardial ischemia and myocardial infarction are responsible for the most cases of SCD above this age (80%). Pre-participatory athletes' evaluation helps to recognize situations that may put the athlete's life in risk including cardiovascular diseases. In summary, cardiologic examinations of athletes' pre-competition routine is an important way to minimize the risk of SCD.


Fluid and electrolyte balance during 24-hour fluid and/or energy restriction.
Weight categorized athletes use a variety of techniques to induce rapid weight loss (RWL) in the days leading up to weigh in. This study examined the fluid and electrolyte balance responses to 24-hr fluid restriction (FR), energy restriction (ER) and fluid and energy restriction (F+ER) compared with a control trial (C), which are commonly used techniques to induce RWL in weight category sports. Twelve subjects (six male, six female) received adequate energy and water (C) intake, adequate energy and restricted water (~10% of C; FR) intake, restricted energy (~25% of C) and adequate water (ER) intake or restricted energy (~25% of C) and restricted (~10% of C) water intake (F+ER) in a randomized counterbalanced order. Subjects visited the laboratory at 0 hr, 12 hr, and 24 hr for blood and urine sample collection. Total body mass loss was 0.33% (C), 1.88% (FR), 1.97% (ER), and 2.44% (F+ER). Plasma volume was reduced at 24 hr during FR, ER, and F+ER, while serum osmolality was increased at 24 hr for FR and F+ER and was greater at 24 hr for FR compared with all other trials. Negative balances of sodium, potassium, and chloride developed during ER and F+ER but not during C and FR. These results demonstrate that 24 hr fluid and/ or energy restriction significantly reduces body mass and plasma volume, but has a disparate effect on serum osmolality, resulting in hypertonic hypohydration during FR and isotonic hypohydration during ER. These findings might be explained by the difference in electrolyte balance between the trials.


The accumulation of deficits with age and possible invariants of aging.
This paper extends a method of apprising health status to a broad range of ages from adolescence to old age. The "frailty index" is based on the accumulation of deficits (symptoms, signs, disease classifications) as analyzed in the National Population Health Survey, a representative Canadian population sample (n = 81,859). The accumulation of deficits has both an age-independent (background) component and an age-dependent (exponential) component, akin to the well-known Gompertz-Makeham model for the risk of mortality. While women accumulate more deficits than men of the same age, on average, their rate of accumulation is lower, so the difference in the level of deficits between men and women decreases with age. Two possible invariants of the process of accumulation of deficits were found: (1) the age at which the average proportion of deficits coincides for men and women is 94 years, which closely matches the species-specific lifespan in humans (95 +/- 2); (2) the value of the frailty index (proportion of deficits), which corresponds to that age (0.18). The similarity between mortality kinetics and the accumulation of deficits (frailty kinetics), and the coincidence of the time parameters in the frailty and mortality models make it possible to express mortality risk in terms of accumulated deficits. This provides a simple and accessible tool that might have potential in a number of biomedical applications.


A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers.
The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1; best p = 5.5 × 10-8) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p = 5.9 × 10-9). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p = 4.0 × 10-10. RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p = 2.2 × 10-14), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.


Participating in diagnostic experience: adults with neuropsychiatric disorders.
Abstract Knowledge regarding neuropsychiatric disabilities has increased in recent years, resulting in an increasing number of adults requesting neuropsychiatric evaluation. The aim of this qualitative study was to describe adult clients' experiences of participating actively in a supportive assessment process in which they received a diagnosis of either autism spectrum disorder (ASD) and/or attention-deficit hyperactivity disorder (ADHD) and then received follow-up counselling, guidance, and compensatory resources that were immediate and directly integrated into the diagnostic experience. The Occupational Performance History Interview - Second Version (OPHI-II) was selected because it is client-centred. It measures how a significant life event affects a person's occupational identity, occupational competence, and interaction with the environment. The OPHI-II was administered to capture 15 participants' experiences of being diagnosed with ASD and/or ADHD as the significant life event of focus. Three categories were formed by using qualitative content analysis: (i) strengthened occupational identity; (ii) compensatory support enhances occupational competence, and (iii) effects of the social environment on relationships. Findings indicated that the diagnostic experience had transformative effects on participants' occupational identities, occupational competence, and ability to self-advocate for increased understanding and resources within their environments. The implications of these findings and future research are discussed.


A comparison of the surgical outcomes among patients with HBV-positive, HCV-positive, and non-B non-C hepatocellular carcinoma: a nationwide study of 11,950 patients.
To compare the prognostic factors and outcomes after hepatic resection among patients with hepatitis B virus (HBV)-positive, hepatitis C virus (HCV)-positive, and negative for hepatitis B surface antigen and hepatitis C antibody, so-called "NBNC"-hepatocellular carcinoma (HCC) using the data from a nationwide survey. The incidence of NBNC-HCC is rapidly increasing in Japan. A total of 11,950 patients with HBV-HCC (n = 2194), HCV-HCC (n = 7018), or NBNC-HCC (n = 2738) who underwent a curative hepatic resection were enrolled in this study. The clinicopathological features were compared among the groups. The significant prognostic variables determined by univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. Liver function in the HCV-HCC group was significantly worse than that in the HBV-HCC and NBNC-HCC groups. The NBNC-HCC group had significantly more advanced HCC than the HCV-HCC group. The 5-year overall survival rates after hepatectomy in the HBV-HCC, HCV-HCC, and NBNC-HCC groups were 65%, 59%, and 68%, respectively. The 5-year recurrence-free survival (RFS) rates in these 3 groups were 41%, 31%, and 47%, respectively. Stratifying the RFS rates according to the TNM stage showed that the NBNC-HCC group had a significantly better prognosis than the HBV-HCC group in stages II, III, and IVA, and a significantly better prognosis than the HCV-HCC group in stages I and II. Multivariate analysis revealed a significantly better RFS rate in the NBNC-HCC group. The findings of this nationwide survey indicated that patients with NBNC-HCC had a significantly lower risk of HCC recurrence than those with HBV-HCC and HCV-HCC.


Adolescence: a growth period conductive to alienation.
This paper clarifies the relationship of alienation to the period of adolescence by developing a portrait of the alienated and the at-risk adolescent. Current research on adolescent alienation follows two converging themes, the socio-psychological, where deviant behavior is viewed as evidence of adolescent estrangement from self and society, and the sociological, where alienation is divided into a series of dimensions for empirical assessment. These two perspectives converge to describe the alienated adolescent. The alienated adolescent is disruptive, rebukes authority, drops out of school or becomes a passive participant, is prone to suicide, abuses drugs and alcohol, and rejects the norms established by family, school, and society in general. Adolescence is a high-risk period wherein the adolescent experiences multiple environments which exacerbates higher levels of alienation. These environments include disorganized or disruptive families, schools that encourage students to become passive participants in the learning process, and a high-pressured pace of life. To lessen the at-risk nature of adolescents toward alienation, society can take steps to humanize their environment. These steps include the intergenerational integration of adolescents, their assimilation into responsible societal activities, providing them with a sense of meaning, and enfranchisement into the decision-making process.


Urinary incontinence: can weight loss treat urinary incontinence in obese women?
New research confirms that weight loss is an effective first-line intervention for overweight or obese women with urinary incontinence. Such patients should be encouraged to lose weight, but must also be given access to a full range of treatment options.


Direct measurement of the rates and barriers on forward and reverse diffusions of intramolecular collision in overhang oligonucleotides.
The dynamics of end-to-interior (Type I) and end-to-end (Type II) collisions in a dangling overhang anchored on a double-stranded DNA (dsDNA) was studied by monitoring the fluorescence quenching of tetramethylrhodamine (TMR) by guanosine residues through combining photoinduced electron transfer (PET) with fluorescence correlation spectroscopy (FCS) at different temperatures. TMR and guanosine residues are separated by a double helix with dangling bases ranging from 2 to 16. By analyzing the FCS data, we obtained the forward and reverse intrachain diffusion rate constants and respective barriers. For both Type I and Type II collisions, the intrachain diffusion rates followed the scaling law of the Gaussian chain model. Especially, the reverse intrachain diffusion rate was insensitive to the base length of separation. Both the activation enthalpy and activation entropy of the forward and reverse diffusions were length independent. The comparison between Type I and Type II collisions shows that the collision rate of end-to-interior is slower than that of end-to-end. The phenomenon is further checked in detail by a series of dangling DNA with the same separation length but different tail lengths (Type III).


Notch signaling from tumor cells: a new mechanism of angiogenesis.
Notch signaling is an evolutionarily conserved pathway and plays key roles in embryonic vascular development and angiogenesis. Multiple components of the Notch pathway are expressed in vasculature, and mice deficient for a variety of these components display embryonic lethality with vascular remodeling defects. Alteration of Notch signaling in various endothelial cells generates profound effects on angiogenesis in vitro. New evidence shows that Notch signaling from tumor cells is able to activate endothelial cells and trigger tumor angiogenesis in vitro and in a xenograft mouse tumor model. Selective interruption of Notch signaling within tumors may provide an antiangiogenic strategy.


Validating a GPS-based approach to detect health facility visits against maternal response to prompted recall survey.
Common approaches to measure health behaviors rely on participant responses and are subject to bias. Technology-based alternatives, particularly using GPS, address these biases while opening new channels for research. This study describes the development and implementation of a GPS-based approach to detect health facility visits in rural Pune district, India. Participants were mothers of under-five year old children within the Vadu Demographic Surveillance area. Participants received GPS-enabled smartphones pre-installed with a location-aware application to continuously record and transmit participant location data to a central server. Data were analyzed to identify health facility visits according to a parameter-based approach, optimal thresholds of which were calibrated through a simulation exercise. Lists of GPS-detected health facility visits were generated at each of six follow-up home visits and reviewed with participants through prompted recall survey, confirming visits which were correctly identified. Detected visits were analyzed using logistic regression to explore factors associated with the identification of false positive GPS-detected visits. We enrolled 200 participants and completed 1098 follow-up visits over the six-month study period. Prompted recall surveys were completed for 694 follow-up visits with one or more GPS-detected health facility visits. While the approach performed well during calibration (positive predictive value (PPV) 78%), performance was poor when applied to participant data. Only 440 of 22 251 detected visits were confirmed (PPV 2%). False positives increased as participants spent more time in areas of high health facility density (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.62-3.25). Visits detected at facilities other than hospitals and clinics were also more likely to be false positives (OR = 2.78, 95% CI = 1.65-4.67) as were visits detected to facilities nearby participant homes, with the likelihood decreasing as distance increased (OR = 0.89, 95% CI = 0.82-0.97). Visit duration was not associated with confirmation status. The optimal parameter combination for health facility visits simulated by field workers substantially overestimated health visits from participant GPS data. This study provides useful insights into the challenges in detecting health facility visits where providers are numerous, highly clustered within urban centers and located near residential areas of the population which they serve.


Unstable laser resonators with super-Gaussian mirrors.
A new class of tapered reflectivity mirrors with a super-Gaussian profile R infinity exp(-kr(n)) is introduced, and a geometrical-optics approach for analysis and design of unstable resonators made with these mirrors is presented. A super-Gaussian mirror, built by a special evaporation technique, has been tested in an unstable resonator of a pulsed Nd:YAG laser, demonstrating its effectiveness in generating diffraction-limited beams.


Migration patterns of dendritic cells in the mouse. Traffic from the blood, and T cell-dependent and -independent entry to lymphoid tissues.
Dendritic cells (DC) are critical accessory cells for primary immune responses and they may be important stimulators of transplantation reactions, but little is known of their traffic into the tissues. We have studied the migration of purified splenic DC and T lymphocytes, labeled with 111Indium-tropolone, in syngeneic and allogeneic mice. First we demonstrate that DC can migrate from the blood into some lymphoid and nonlymphoid tissues. Immediately after intravenous administration, radio-labeled DC were sequestered in the lungs, but they actively migrated into the liver and spleen and reached equilibrium levels between 3 and 24 h after transfer. At least half of the radiolabel accumulated in the liver, but the spleen was the principal site of DC localization in terms of specific activity (radiolabel per weight of tissue). DC were unable to enter Peyer's patches, or mesenteric and other peripheral lymph nodes from the bloodstream. This was also true in splenectomized recipients, where the otherwise spleen-seeking DC were quantitatively diverted to the liver. In contrast, T cells homed readily to the spleen and lymph nodes of normal mice and increased numbers were present in these tissues in splenectomized mice. Thus, unlike T cells, DC cannot recirculate from blood to lymph via the nodes. We then show that migration of DC from the blood into the spleen is dependent on the presence of T cells: DC did not enter the spleens of nude mice, but when they were reconstituted with T cells the numbers entering the spleen resembled those in euthymic mice. In nude mice, as in splenectomized recipients, the DC that would normally enter the spleen were quantitatively diverted to the liver. These findings suggest that there is a spleen-liver equilibrium for DC, that may be akin to that existing between spleen and lymph node for T cells. Finally, we followed the traffic of radiolabeled DC via the afferent lymphatics after subcutaneous footpad inoculation. DC accumulated in the popliteal nodes but did not migrate further to the inguinal nodes. There was no difference between euthymic and nude mice, showing that unlike traffic to the spleen, this route probably does not require T cells. These migration patterns were not affected by major histocompatibility barriers, and were only seen with viable, but not glutaraldehyde-fixed, DC.(ABSTRACT TRUNCATED AT 400 WORDS)


Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterised by circulating anti-mitochondrial antibodies (AMA) as well as disease specific anti-nuclear antibodies (ANA), cholestatic liver biochemistry, and characteristic histology. The disease primarily affects middle-aged females, and its incidence is apparently increasing worldwide. Epidemiological studies have indicated several risk factors for the development of PBC, with family history of PBC, recurrent urinary tract infection, and smoking being the most widely cited. Smoking has been implicated as a risk factor in several autoimmune diseases, including the liver, by complex mechanisms involving the endocrine and immunological systems to name a few. Studies of smoking in liver disease have also shown that smoking may progress the disease towards fibrosis and subsequent cirrhosis. This review will examine the literature surrounding smoking as a risk factor for PBC, as well as a potential factor in the progression of fibrosis in PBC patients.


Assessing glucose uptake through the yeast hexose transporter 1 (Hxt1).
The transport of glucose across the plasma membrane is mediated by members of the glucose transporter family. In this study, we investigated glucose uptake through the yeast hexose transporter 1 (Hxt1) by measuring incorporation of 2-NBDG, a non-metabolizable, fluorescent glucose analog, into the yeast Saccharomyces cerevisiae. We find that 2-NBDG is not incorporated into the hxt null strain lacking all glucose transporter genes and that this defect is rescued by expression of wild type Hxt1, but not of Hxt1 with mutations at the putative glucose-binding residues, inferred from the alignment of yeast and human glucose transporter sequences. Similarly, the growth defect of the hxt null strain on glucose is fully complemented by expression of wild type Hxt1, but not of the mutant Hxt1 proteins. Thus, 2-NBDG, like glucose, is likely to be transported into the yeast cells through the glucose transport system. Hxt1 is internalized and targeted to the vacuole for degradation in response to glucose starvation. Among the mutant Hxt1 proteins, Hxt1N370A and HXT1W473A are resistant to such degradation. Hxt1N370A, in particular, is able to neither uptake 2-NBDG nor restore the growth defect of the hxt null strain on glucose. These results demonstrate 2-NBDG as a fluorescent probe for glucose uptake in the yeast cells and identify N370 as a critical residue for the stability and function of Hxt1.


Mindfulness-based cancer recovery and supportive-expressive therapy maintain telomere length relative to controls in distressed breast cancer survivors.
Group psychosocial interventions including mindfulness-based cancer recovery (MBCR) and supportive-expressive group therapy (SET) can help breast cancer survivors decrease distress and influence cortisol levels. Although telomere length (TL) has been associated with breast cancer prognosis, the impact of these two interventions on TL has not been studied to date. The objective of the current study was to compare the effects of MBCR and SET with a minimal intervention control condition (a 1-day stress management seminar) on TL in distressed breast cancer survivors in a randomized controlled trial. MBCR focused on training in mindfulness meditation and gentle Hatha yoga whereas SET focused on emotional expression and group support. The primary outcome measure was relative TL, the telomere/single-copy gene ratio, assessed before and after each intervention. Secondary outcomes were self-reported mood and stress symptoms. Eighty-eight distressed breast cancer survivors with a diagnosis of stage I to III cancer (using the American Joint Committee on Cancer (AJCC) TNM staging system) who had completed treatment at least 3 months prior participated. Using analyses of covariance on a per-protocol sample, there were no differences noted between the MBCR and SET groups with regard to the telomere/single-copy gene ratio, but a trend effect was observed between the combined intervention group and controls (F [1,84], 3.82; P = .054; η(2) = .043); TL in the intervention group was maintained whereas it was found to decrease for control participants. There were no associations noted between changes in TL and changes in mood or stress scores over time. Psychosocial interventions providing stress reduction and emotional support resulted in trends toward TL maintenance in distressed breast cancer survivors, compared with decreases in usual care.


Robustly estimating the flow direction of information in complex physical systems.
We propose a new measure (phase-slope index) to estimate the direction of information flux in multivariate time series. This measure (a) is insensitive to mixtures of independent sources, (b) gives meaningful results even if the phase spectrum is not linear, and (c) properly weights contributions from different frequencies. These properties are shown in extended simulations and contrasted to Granger causality which yields highly significant false detections for mixtures of independent sources. An application to electroencephalography data (eyes-closed condition) reveals a clear front-to-back information flow.


Two rhizobial strains, Mesorhizobium loti MAFF303099 and Bradyrhizobium japonicum USDA110, encode haloalkane dehalogenases with novel structures and substrate specificities.
Haloalkane dehalogenases are key enzymes for the degradation of halogenated aliphatic pollutants. Two rhizobial strains, Mesorhizobium loti MAFF303099 and Bradyrhizobium japonicum USDA110, have open reading frames (ORFs), mlr5434 and blr1087, respectively, that encode putative haloalkane dehalogenase homologues. The crude extracts of Escherichia coli strains expressing mlr5434 and blr1087 showed the ability to dehalogenate 18 halogenated compounds, indicating that these ORFs indeed encode haloalkane dehalogenases. Therefore, these ORFs were referred to as dmlA (dehalogenase from Mesorhizobium loti) and dbjA (dehalogenase from Bradyrhizobium japonicum), respectively. The principal component analysis of the substrate specificities of various haloalkane dehalogenases clearly showed that DbjA and DmlA constitute a novel substrate specificity class with extraordinarily high activity towards beta-methylated compounds. Comparison of the circular dichroism spectra of DbjA and other dehalogenases strongly suggested that DbjA contains more alpha-helices than the other dehalogenases. The dehalogenase activity of resting cells and Northern blot analyses both revealed that the dmlA and dbjA genes were expressed under normal culture conditions in MAFF303099 and USDA110 strain cells, respectively.


Emergent Issues in Directly-Funded Care: Canadian Perspectives.
Direct Funding (DF) provides individuals with a budget to arrange their own home care instead of receiving publicly arranged services. DF programs have evolved in a number of countries since the 1970s. In Canada, while small-scale DF programs have existed since the early 1970s, the research on these programs remains limited. Responding to gaps identified by an umbrella review and using a health equity framework, this research extends the knowledge base on DF programs from a Canadian perspective through an environmental scan. The research asks: What are the features of DF programs across Canada? What are the emerging issues related to program design and policy development? The study employed a qualitative environmental scan design, gathering data through questionnaires and semi-structured interviews (n = 23). The findings include a summary table describing features of 20 programs and two interview themes: a lack of information on DF workers and concerns about the growing role of home care agencies. This study has the potential to contribute to long-term health equity monitoring research. The findings suggest that as DF expands in Canada, promoting hiring from personal networks may address inequities in rural access to home care services and improve social outcomes for linguistic, cultural, and sexual minorities. However, the findings underscore a need to monitor access to DF programs by people of lower-socioeconomic backgrounds in Canada and discourage policy design that requires independent self-management, which disadvantages people with compromised decision-making capacities.


New insights into the pathology of acute respiratory failure.
The purpose of this review is to provide a historical perspective and to analyze the recent advances in the understanding of the cellular and tissue pathology of acute respiratory failure, specifically of the acute respiratory distress syndrome. The scope of mechanisms involved in acute lung injury and acute respiratory distress syndrome is far too great to do it justice in a single review. Therefore, this review will focus only on recent advances in the understanding of the morphologic changes that occur in acute lung injury, acute respiratory distress syndrome, and ventilator-induced lung injury. The use of fluorescent labels brought a novel method to identify and quantify cell wounding in the whole organ animal model of ventilator-induced lung injury. Real-time in vivo microscopy demonstrated the injurious effects of alveolar instability in the pathogenesis of ventilator-induced lung injury. Lipid tether mechanics, using laser tweezers, have advanced the understanding of the mechanical properties of the plasma membrane in response to mechanical stress. New animal injury models have brought forward new insights into the pathogenesis and structural abnormalities seen in acute respiratory distress syndrome. Apoptosis and epithelial wounding and repair have been examined in novel methods, and new mechanisms in lung edema formation have been proposed. New mechanisms in the pathology of acute respiratory failure have shifted the focus to lung mechanics, tissue damage, remodeling, and the systemic effects derived from the mechanical stress imposed by the ventilator in patients with adult respiratory distress syndrome.


Changes in quality of care and quality of life of outpatients with advanced cancer after a regional palliative care intervention program.
A recent mixed-methods study to evaluate the effects of a comprehensive regional palliative care program, the Japan Outreach Palliative Care Trial of the Integrated Model study, achieved broad positive outcomes at a regional level. This is a secondary analysis of patient outcomes. The primary aims were to explore: 1) the changes in domains of patient-reported quality of care and quality of life after interventions, and 2) the changes in quality of care and quality of life of patients with different characteristics (i.e., performance status, age, and anticancer treatment). A region-representative sample of metastatic/locally advanced cancer patients in outpatient settings participated in questionnaire surveys before and after regional intervention. Responses were obtained from 859 of 1880 and 857 of 2123 in the pre- and postintervention surveys, respectively. All subdomain scores of the quality of care, except for help with decision making, significantly improved in the postintervention survey. The percentages of the patients who reported that improvement was necessary decreased from 13% to 5.0%. Although there were no or only a marginally significant difference in total and subdomain scores of quality of life between preintervention and postintervention surveys, the subgroups of patients with a poor performance status and those receiving no anticancer treatment achieved a significant improvement in the quality of life. Although average changes in patient-reported outcomes were relatively small in the total sample of patients, the intervention seemed to provide tangible benefits for the patients with poor general conditions. A future regional intervention trial should include patient outcomes in those with a poor general condition to evaluate the net effects of the program.


Influence of core stability exercise on lumbar vertebral instability in patients presented with chronic low back pain: A randomized clinical trial.
Excessive lumbar vertebrae translation and rotation in sagittal plane has been attributed as an associated factor of lumbar segmental instability (LSI) and low back pain (LBP). Reduction of these abnormalities improves back pain. The aim of this study was to investigate the effect of core stability exercise on the translation and rotation of lumbar vertebrae in sagittal plane in patients with nonspecific chronic LBP (NSCLBP). In this randomized clinical trial, 30 patients with NSCLBP due to LSI were included. The participants were randomly divided into two groups of treatment and control. The treatment group received general exercises plus core stability exercise for 8 weeks whereas; the control group received only general exercises. The magnitude of translation (mm) and rotation (deg) of lumbar vertebrae in the sagittal plane was determined by radiography in flexion and extension at baseline and after intervention. The primary outcome measures were to determine the mean changes from baseline in translation and rotation of the lumbar vertebrae in the sagittal plane after 8 weeks of intervention in each group. The secondary outcome was to compare the two groups in regard to translation and rotation of the lumbar vertebrae at the end of the study period. Data were analyzed using paired t-test and independent t-test. Thirty patients aged 18-40 years old with clinical diagnosis of NSCLBP entered the study. Compared with baseline values, mean value of translation and rotation of the lumbar vertebra reduced significantly in both groups (P<0.05), except L3 translation in the control group. At the endpoint, mean translation value of L4 (P=0.04) and L5 (P=0.001) and rotation of the L5 (P=0.01) in the treatment group was significantly lower than the control group. These findings indicate that in patients presented with NSCLBP due to lumbar segmental instability, core stability exercises plus general exercises are more efficient than general exercises alone in the improvement of excessive lumbar vertebrae translation and rotation.


Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.
The human organic anion transporting polypeptide-C (OATP-C) (gene SLC21A6) is a liver-specific transporter importantly involved in the hepatocellular uptake of a variety of endogenous and foreign chemicals. In this study, we demonstrate the presence of multiple functionally relevant single-nucleotide polymorphisms (SNPs) in OATP-C in a population of African- and European-Americans. Moreover, examination of 14 nonsynonymous polymorphisms indicated that genotypic frequencies were dependent on race. Functional assessment of 16 OATP-C alleles in vitro revealed that several variants exhibited markedly reduced uptake of the OATP-C substrates estrone sulfate and estradiol 17beta-d-glucuronide. Specifically, alterations in transport were associated with SNPs that introduce amino acid changes within the transmembrane-spanning domains (T217C (Phe-73 --> Leu), T245C (Val-82 --> Ala), T521C (Val-174 --> Ala), and T1058C (Ile-353 --> Thr)) and also with those that modify extracellular loop 5 (A1294G (Asn-432 --> Asp), A1385G (Asp-462 --> Gly), and A1463C (Gly-488 --> Ala)). Cell surface biotinylation experiments indicated that the altered transport activity of some OATP-C variants was due, in part, to decreased plasma membrane expression. Given the relatively high genotypic frequency of the T521C (14%) transition in European-Americans and the G1463C (9%) transversion in African-Americans, SNPs in OATP-C may represent a heretofore unrecognized factor influencing drug disposition.


Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi.
Heterologous expression of multi-gene biosynthetic pathways in eukaryotic hosts is limited by highly regulated individual monocistrons. Dissimilar to prokaryotes, each eukaryotic gene is strictly controlled by its own regulatory elements, such as promoter and terminator. Consequently, parallel transcription can occur only when a group of genes is synchronously activated. A strategy to circumvent this limitation is the concerted expression of multiple genes as a polycistron. By exploiting the "stop-carry on" mechanism of picornaviruses, we have designed a sophisticated, yet easy-to-assemble vector system to heterologously express multiple genes under the control of a single promoter. For facile selection of correctly transformed colonies by basic fluorescence microscopy, our vector includes a split gene for a fluorescent reporter protein. This method was successfully applied to produce the psychotropic mushroom alkaloid psilocybin in high yields by heterologous expression of the entire biosynthetic gene cluster in the mould Aspergillus nidulans.


Trading spaces: computation, representation, and the limits of uninformed learning.
Some regularities enjoy only an attenuated existence in a body of training data. These are regularities whose statistical visibility depends on some systematic recoding of the data. The space of possible recoding is, however, infinitely large--it is the space of applicable Turing machines. As a result, mappings that pivot on such attenuated regularities cannot, in general, be found by brute-force search. The class of problems that present such mappings we call the class of "type-2 problems." Type-1 problems, by contrast, present tractable problems of search insofar as the relevant regularities can be found by sampling the input data as originally coded. Type-2 problems, we suggest, present neither rare nor pathological cases. They are rife in biologically realistic settings and in domains ranging from simple animat (simulated animal or autonomous robot) behaviors to language acquisition. Not only are such problems rife--they are standardly solved! This presents a puzzle. How, given the statistical intractability of these type-2 cases, does nature turn the trick? One answer, which we do not pursue, is to suppose that evolution gifts us with exactly the right set of recording biases so as to reduce specific type-2 problems to (tractable) type-1 mappings. Such a heavy-duty nativism is no doubt sometimes plausible. But we believe there are other, more general mechanisms also at work. Such mechanisms provide general (not task-specific) strategies for managing problems of type-2 complexity. Several such mechanisms are investigated. At the heart of each is a fundamental poly--namely, the maximal exploitation of states of representation already achieved by prior, simpler (type-1) learning so as to reduce the amount of subsequent computational search. Such exploitation both characterizes and helps make unitary sense of a diverse range of mechanisms. These include simple incremental learning (Elman 1993), modular connectionism (Jacobs et al. 1991), and the developmental hypothesis of "representational redescription" (Karmiloff-Smith 1979; 1992). In addition, the most distinctive features of human cognition--language and culture--may themselves be viewed as adaptations enabling this representation/computation trade-off to be pursued on an even grander scale.


Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a condition associated with high morbidity, mortality and cost to the community. Patients often report symptomatic improvement with long acting beta-2 agonists (LABAs) and anticholinergic bronchodilator medications, both of which are recommended in COPD guidelines. These medications have different mechanisms of action and therefore theoretically could have an additive effect when combined. As these medications are prescribed in COPD as long term therapy, it is important to assemble reliable evidence on their relative and additive effects. To compare the relative efficacy and safety of regular long term use (at least four weeks) of ipratropium bromide and LABA in patients with stable COPD. Comparisons were made between single agents and in combination versus LABAs alone. We searched the Cochrane Airways Group Specialised Register of Trials (August 2005) and reference lists of articles. We also contacted drug companies for relevant trial data. All randomised controlled trials comparing treatment for at least four weeks with an anticholinergic agent (ipratropium bromide) alone or in combination with LABA versus LABA alone, delivered via metered dose inhaler or nebuliser, in non-asthmatic adult subjects with stable COPD. Three review authors independently performed data extraction and study quality assessment. We contacted study authors and pharmaceutical companies for missing data. Seven studies met the inclusion criteria of the review (2652 participants). Monotherapy comparison (six studies): There was a significantly greater change in favour of salmeterol in morning PEF and FEV1. There were no significant differences in quality of life, exacerbations, or symptoms. Formoterol appeared to confer some benefits over ipratropium treatment in terms of morning peak flow. Combination comparison (three studies): There was a significant improvement in post-bronchodilator lung function, supplemental short-acting beta-agonist use and HRQL in favour of combination therapy compared with salmeterol alone. The available data from the trials suggest that there is little difference between regular long term use of IpB alone and salmeterol if the aim is to improve COPD symptoms and exercise tolerance. However, salmeterol was more effective in improving lung function variables. In terms of post-bronchodilator lung function, combination therapy conferred modest benefits and a significant improvement in HRQL, and reduced supplemental short-acting beta-agonist requirement, although this effect was not consistent. Additional studies are needed to assess the relative effects of combining therapies, using validated subjective measurements, and should consider concordance and the convenience of people having to use different inhaler devices.


Surgery without scars: report of transluminal cholecystectomy in a human being.
Natural orifice transluminal endoscopic surgery (NOTES) provides the potential for performance of incisionless operations. This would break the physical barrier between bodily trauma and surgery, representing an epical revolution in surgery. Our group at IRCAD-EITS (Institut de Recherche contre les Cancers de l'Appareil Digestif [Institute of Digestive Cancer Research]-European Institute of TeleSurgery) has been actively involved in the development of NOTES since 2004 with a dedicated project created to develop feasibility and survival studies and new endoscopic technology. NOTES cholecystectomy in a woman via a transvaginal approach. University hospital. Patient The patient was a 30-year-old woman with symptomatic cholelithiasis. The procedure was carried out by a multidisciplinary team using a standard double-channel flexible videogastroscope and standard endoscopic instruments. The placement of a 2-mm needle port, mandatory to insufflate carbon dioxide and to monitor the pneumoperitoneum, was helpful for further retraction of the gallbladder. At no stage of the procedure was there need for laparoscopic assistance. All of the principles of cholecystectomy were strictly adhered to. The postoperative course was uneventful. The patient had no postoperative pain and no scars, and was discharged on the second postoperative day. Transluminal surgery is feasible and safe. NOTES, a radical shift in the practice and philosophy of interventional treatment, is becoming established and is enormously advantageous to the patient. With its invisible mending and tremendous potential, NOTES might be the next surgical evolution.


Strength of evidence for density dependence in abundance time series of 1198 species.
Population limitation is a fundamental tenet of ecology, but the relative roles of exogenous and endogenous mechanisms remain unquantified for most species. Here we used multi-model inference (MMI), a form of model averaging, based on information theory (Akaike's Information Criterion) to evaluate the relative strength of evidence for density-dependent and density-independent population dynamical models in long-term abundance time series of 1198 species. We also compared the MMI results to more classic methods for detecting density dependence: Neyman-Pearson hypothesis-testing and best-model selection using the Bayesian Information Criterion or cross-validation. Using MMI on our large database, we show that density dependence is a pervasive feature of population dynamics (median MMI support for density dependence = 74.7-92.2%), and that this holds across widely different taxa. The weight of evidence for density dependence varied among species but increased consistently, with the number of generations monitored. Best-model selection methods yielded similar results to MMI (a density-dependent model was favored in 66.2-93.9% of species time series), while the hypothesis-testing methods detected density dependence less frequently (32.6-49.8%). There were no obvious differences in the prevalence of density dependence across major taxonomic groups under any of the statistical methods used. These results underscore the value of using multiple modes of analysis to quantify the relative empirical support for a set of working hypotheses that encompass a range of realistic population dynamical behaviors.


Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation.
We have evaluated the possibility that the action of voluntary exercise on the regulation of brain-derived neurotrophic factor (BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of epigenetic regulation. We focused the studies on the Bdnf promoter IV, as this region is highly responsive to neuronal activity. We have found that exercise stimulates DNA demethylation in Bdnf promoter IV, and elevates levels of activated methyl-CpG-binding protein 2, as well as BDNF mRNA and protein in the rat hippocampus. Chromatin immunoprecipitation assay showed that exercise increases acetylation of histone H3, and protein assessment showed that exercise elevates the ratio of acetylated :total for histone H3 but had no effects on histone H4 levels. Exercise also reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of the Bdnf gene [N.M. Tsankova et al. (2006)Nat. Neurosci., 9, 519-525], but did not affect histone deacetylase 9. Exercise elevated the phosphorylated forms of calcium/calmodulin-dependent protein kinase II and cAMP response element binding protein, implicated in the pathways by which neural activity influences the epigenetic regulation of gene transcription, i.e. Bdnf. These results showing the influence of exercise on the remodeling of chromatin containing the Bdnf gene emphasize the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reported information about the impact of a behavior, inherently involved in the daily human routine, on the epigenome opens exciting new directions and therapeutic opportunities in the war against neurological and psychiatric disorders.


Pica and refractory iron deficiency anaemia: a case report.
Iron deficiency is the most common cause of anaemia worldwide. Pica, the ingestion of substances that are inappropriate for consumption, is associated with iron deficiency and may be under-diagnosed. A 34-year-old woman presented with iron deficiency anaemia refractory to treatment for more than a decade. The clinical presentation, endoscopic findings and laboratory investigations were consistent with pica. Subsequent geophysical analysis confirmed that the ingested material was kaolin, a negatively charged silicate. Prolonged unexplained iron deficiency anaemia should prompt clinicians to remember and inquire about pica. In our patient, this would have averted numerous unnecessary investigations and prevented a decade-long suffering.


Halobaculum roseum sp. nov., isolated from underground salt deposits.
Two extremely halophilic archaea, strains D90T and D93, were isolated from underground salt deposits of Yunnan salt mine, China. Both strains were pleomorphic or short rods, non-motile, Gram-negative and required 1.7 M NaCl for growth, with optimum at 3.4 M. Mg2+ was not required for growth. Multiple copies of the 16S rRNA gene were obtained for both strains. Sequence similarity analysis of 16S rRNA genes revealed that strains D90T and D93 were closely related to Halobaculum magnesiiphilum MGY-184T and Halobaculum gomorrense DSM 9297T with the sequence similarity between 96.2-98.1 %. The sequence similarity of the rpoB' gene between strain D90T and Halobaculum gomorrenseJCM 9908T was 94.1 %. The DNA G+C contents of strains D90T and D93 were 65.9 and 67.6 mol%, respectively. The major polar lipids of both strains were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and glycolipid. The DNA-DNA relatedness value between strains D90T and D93 was 90.1±0.5 %, while that between strain D90T and Halobaculum gomorrenseJCM 9908T was 30.0±0.7 %. The comparison of physiological and biochemical characteristics, including the requirements of NaCl, Mg2+, pH, etc., differentiated strains D90T and D93 from Halobaculum magnesiiphilum MGY-184T and Halobaculum gomorrenseJCM 9908T. Therefore, strains D90T and D93 represent a novel species of the genus Halobaculum, for which the name Halobaculum roseum sp. nov. is proposed. The type strain is D90T (=CGMCC 1.15501T=JCM 31273T).


Total hip replacement: the case for noncemented femoral fixation because of age.
Both noncemented fixation and improved cemented fixation of total hip replacements emerged to counteract the clinical and radiographic failures of early cemented procedures. A randomized clinical trial comparing a second-generation cemented with a second-generation noncemented total hip replacement demonstrated that in the medium term both implants allow excellent, disease-specific, global and functional capacity outcome measures. No significant differences existed between the cemented and noncemented implants in terms of these parameters or revision rate. Cost-to-utility analyses of both types of replacements revealed that total hip replacement is one of the most cost-effective medical interventions. Noncemented total hip replacements seem as efficacious as cemented devices in patients younger than 70 years.


Generation of cDNA probes directed by amino acid sequence: cloning of urate oxidase.
Urate oxidase (E.C. 188.8.131.52) catalyzes the oxidation of uric acid to allantoin in most mammals except humans and certain primates. The amino-terminal amino acid sequence for porcine urate oxidase was determined and used in a novel procedure for generating complementary DNA (cDNA) probes to this amino acid sequence. The procedure is based on the polymerase chain reaction and utilizes mixed oligonucleotide primers complementary to the reverse translation products of an amino acid sequence. This rapid and simple cDNA cloning procedure is generally applicable and requires only a partial amino acid sequence. A cDNA probe developed by this procedure was used to isolate a full-length porcine urate oxidase cDNA and to demonstrate the presence of homologous genomic sequences in humans.


Quantitative and sensitive detection of GNAS mutations causing mccune-albright syndrome with next generation sequencing.
Somatic activating GNAS mutations cause McCune-Albright syndrome (MAS). Owing to low mutation abundance, mutant-specific enrichment procedures, such as the peptide nucleic acid (PNA) method, are required to detect mutations in peripheral blood. Next generation sequencing (NGS) can analyze millions of PCR amplicons independently, thus it is expected to detect low-abundance GNAS mutations quantitatively. In the present study, we aimed to develop an NGS-based method to detect low-abundance somatic GNAS mutations. PCR amplicons encompassing exons 8 and 9 of GNAS, in which most activating mutations occur, were sequenced on the MiSeq instrument. As expected, our NGS-based method could sequence the GNAS locus with very high read depth (approximately 100,000) and low error rate. A serial dilution study with use of cloned mutant and wildtype DNA samples showed a linear correlation between dilution and measured mutation abundance, indicating the reliability of quantification of the mutation. Using the serially diluted samples, the detection limits of three mutation detection methods (the PNA method, NGS, and combinatory use of PNA and NGS [PNA-NGS]) were determined. The lowest detectable mutation abundance was 1% for the PNA method, 0.03% for NGS and 0.01% for PNA-NGS. Finally, we analyzed 16 MAS patient-derived leukocytic DNA samples with the three methods, and compared the mutation detection rate of them. Mutation detection rate of the PNA method, NGS and PNA-NGS in 16 patient-derived peripheral blood samples were 56%, 63% and 75%, respectively. In conclusion, NGS can detect somatic activating GNAS mutations quantitatively and sensitively from peripheral blood samples. At present, the PNA-NGS method is likely the most sensitive method to detect low-abundance GNAS mutation.


Accuracy assessment of diploid consensus sequences.
If the origins of fragments are known in genome sequencing projects, it is straightforward to reconstruct diploid consensus sequences. In reality, however, this is not true. Although there are proposed methods to reconstruct haplotypes from genome sequencing projects, an accuracy assessment is required to evaluate the confidence of the estimated diploid consensus sequences. In this paper, we define the confidence score of diploid consensus sequences. It requires the calculation of the likelihood of an assembly. To calculate the likelihood, we propose a linear time algorithm with respect to the number of polymorphic sites. The likelihood calculation and confidence score are used for further improvements of haplotype estimation in two directions. One direction is that low-scored phases are disconnected. The other direction is that, instead of using nominal frequency 1/2, the haplotype frequency is estimated to reflect the actual contribution of each haplotype. Our method was evaluated on the simulated data whose polymorphism rate (1.2 percent) was based on Ciona intestinalis. As a result, the high accuracy of our algorithm was indicated: The true positive rate of the haplotype estimation was greater than 97 percent.


Red Wine and Pomegranate Extracts Suppress Cured Meat Promotion of Colonic Mucin-Depleted Foci in Carcinogen-Induced Rats.
Processed meat intake is carcinogenic to humans. We have shown that intake of a workshop-made cured meat with erythorbate promotes colon carcinogenesis in rats. We speculated that polyphenols could inhibit this effect by limitation of endogenous lipid peroxidation and nitrosation. Polyphenol-rich plant extracts were added to the workshop-made cured meat and given for 14 days to rats and 100 days to azoxymethane-induced rats to evaluate the inhibition of preneoplastic lesions. Colons of 100-d study were scored for precancerous lesions (mucin-depleted foci, MDF), and biochemical end points of peroxidation and nitrosation were measured in urinary and fecal samples. In comparison with cured meat-fed rats, dried red wine, pomegranate extract, α-tocopherol added at one dose to cured meat and withdrawal of erythorbate significantly decreased the number of MDF per colon (but white grape and rosemary extracts did not). This protection was associated with the full suppression of fecal excretion of nitrosyl iron, suggesting that this nitroso compound might be a promoter of carcinogenesis. At optimized concentrations, the incorporation of these plant extracts in cured meat might reduce the risk of colorectal cancer associated with processed meat consumption.


Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications.
Autoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest. We aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective. The functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed. An analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.


Differential mechanisms of adenosine- and ATPγS-induced microvascular endothelial barrier strengthening.
Maintenance of the endothelial cell (EC) barrier is critical to vascular homeostasis and a loss of barrier integrity results in increased vascular permeability. While the mechanisms that govern increased EC permeability have been under intense investigation over the past several decades, the processes regulating the preservation/restoration of the EC barrier remain poorly understood. Herein we show that the extracellular purines, adenosine (Ado) and adenosine 5'-[γ-thio]-triphosphate (ATPγS) can strengthen the barrier function of human lung microvascular EC (HLMVEC). This ability involves protein kinase A (PKA) activation and decreases in myosin light chain 20 (MLC20) phosphorylation secondary to the involvement of MLC phosphatase (MLCP). In contrast to Ado, ATPγS-induced PKA activation is accompanied by a modest, but significant decrease in cyclic adenosine monophosphate (cAMP) levels supporting the existence of an unconventional cAMP-independent pathway of PKA activation. Furthermore, ATPγS-induced EC barrier strengthening does not involve the Rap guanine nucleotide exchange factor 3 (EPAC1) which is directly activated by cAMP but is instead dependent upon PKA-anchor protein 2 (AKAP2) expression. We also found that AKAP2 can directly interact with the myosin phosphatase-targeting protein MYPT1 and that depletion of AKAP2 abolished ATPγS-induced increases in transendothelial electrical resistance. Ado-induced strengthening of the HLMVEC barrier required the coordinated activation of PKA and EPAC1 in a cAMP-dependent manner. In summary, ATPγS-induced enhancement of the EC barrier is EPAC1-independent and is instead mediated by activation of PKA which is then guided by AKAP2, in a cAMP-independent mechanism, to activate MLCP which dephosphorylates MLC20 resulting in reduced EC contraction and preservation.


Calcareous sponge genomes reveal complex evolution of α-carbonic anhydrases and two key biomineralization enzymes.
Calcium carbonate biominerals form often complex and beautiful skeletal elements, including coral exoskeletons and mollusc shells. Although the ability to generate these carbonate structures was apparently gained independently during animal evolution, it sometimes involves the same gene families. One of the best-studied of these gene families comprises the α- carbonic anhydrases (CAs), which catalyse the reversible transformation of CO2 to HCO3 - and fulfill many physiological functions. Among Porifera -the oldest animal phylum with the ability to produce skeletal elements- only the class of calcareous sponges can build calcitic spicules, which are the extracellular products of specialized cells, the sclerocytes. Little is known about the molecular mechanisms of their synthesis, but inhibition studies suggest an essential role of CAs. In order to gain insight into the evolution and function of CAs in biomineralization of a basal metazoan species, we determined the diversity and expression of CAs in the calcareous sponges Sycon ciliatum and Leucosolenia complicata by means of genomic screening, RNA-Seq and RNA in situ hybridization expression analysis. Active biomineralization was located with calcein-staining. We found that the CA repertoires of two calcareous sponge species are strikingly more complex than those of other sponges. By characterizing their expression patterns, we could link two CAs (one intracellular and one extracellular) to the process of calcite spicule formation in both studied species. The extracellular biomineralizing CAs seem to be of paralogous origin, a finding that advises caution against assuming functional conservation of biomineralizing genes based upon orthology assessment alone. Additionally, calcareous sponges possess acatalytic CAs related to human CAs X and XI, suggesting an ancient origin of these proteins. Phylogenetic analyses including CAs from genomes of all non-bilaterian phyla suggest multiple gene losses and duplications and presence of several CAs in the last common ancestor of metazoans. We identified two key biomineralization enzymes from the CA-family in calcareous sponges and propose their possible interaction in spicule formation. The complex evolutionary history of the CA family is driven by frequent gene diversification and losses. These evolutionary patterns likely facilitated the numerous events of independent recruitment of CAs into biomineralization within Metazoa.


Preventing cold-related morbidity and mortality in a changing climate.
Winter weather patterns are anticipated to become more variable with increasing average global temperatures. Research shows that excess morbidity and mortality occurs during cold weather periods. We critically reviewed evidence relating temperature variability, health outcomes, and adaptation strategies to cold weather. Health outcomes included cardiovascular-, respiratory-, cerebrovascular-, and all-cause morbidity and mortality. Individual and contextual risk factors were assessed to highlight associations between individual- and neighborhood-level characteristics that contribute to a person's vulnerability to variability in cold weather events. Epidemiologic studies indicate that the populations most vulnerable to variations in cold winter weather are the elderly, rural and, generally, populations living in moderate winter climates. Fortunately, cold-related morbidity and mortality are preventable and strategies exist for protecting populations from these adverse health outcomes. We present a range of adaptation strategies that can be implemented at the individual, building, and neighborhood level to protect vulnerable populations from cold-related morbidity and mortality. The existing research justifies the need for increased outreach to individuals and communities for education on protective adaptations in cold weather. We propose that future climate change adaptation research couple building energy and thermal comfort models with epidemiological data to evaluate and quantify the impacts of adaptation strategies.


Expression analysis of HMGB1 in histological samples of malignant pleural mesothelioma.
High mobility group box 1 (HMGB1) is a chromatin structural protein, expressed ubiquitously in the nuclei of mammalian cells. When transported extracellularly, it acts as a tumour suppressor and oncogenic protein. In malignant pleural mesothelioma (MPM), high serum levels of HMGB1 have been related to a poor prognosis. Conversely, the significance of HMGB1 expression in MPM tissues is still unclear. Biopsy samples from 170 patients with MPM were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to evaluate HMGB1 protein and gene expression. The expression level of HMGB1 protein was scored using a semiquantitative system that sums the intensity (0-3) and the percentage (from 0 to 4) of positively stained cells in nuclei, cytoplasm and in both. The final score was considered as high (>3) or low (<3) expression. Gene expression levels were calculated using the ΔΔCt method. High expression levels of HMGB1 as total (P = 0.0011) and cytoplasmic score (P = 0.0462) were related to a worse disease-specific survival (DSS) in the entire cohort and in the clinicopathological subgroups. No significant correlation was found between HMGB1 gene expression and DSS. These findings indicate that HMGB1 may be a useful prognostic biomarker in MPM when detected by immunohistochemistry. Conversely, as it is also expressed in normal and reactive mesothelial cells, HMGB1 cannot be considered a diagnostic biomarker in histological samples of mesothelioma.


The plant-growth-promoting rhizobacterium Paenibacillus polymyxa induces changes in Arabidopsis thaliana gene expression: a possible connection between biotic and abiotic stress responses.
This paper addresses changes in plant gene expression induced by inoculation with plant-growth-promoting rhizobacteria (PGPR). A gnotobiotic system was established with Arabidopsis thaliana as model plant, and isolates of Paenibacillus polymyxa as PGPR. Subsequent challenge by either the pathogen Erwinia carotovora (biotic stress) or induction of drought (abiotic stress) indicated that inoculated plants were more resistant than control plants. With RNA differential display on parallel RNA preparations from P. polymyxa-treated or untreated plants, changes in gene expression were investigated. From a small number of candidate sequences obtained by this approach, one mRNA segment showed a strong inoculation-dependent increase in abundance. The corresponding gene was identified as ERD15, previously identified to be drought stress responsive. Quantification of mRNA levels of several stress-responsive genes indicated that P. polymyxa induced mild biotic stress. This suggests that genes and/or gene classes associated with plant defenses against abiotic and biotic stress may be co-regulated. Implications of the effects of PGPR on the induction of plant defense pathways are discussed.


Functional variations in the ultrastructure of the thyroid gland in malnourished infant monkeys.
Healthy male pigtail monkeys (Macaca nemestrina) were procured at the age of 6-9 months, and fed either a 20 percent casein diet or a diet containing 2 percent casein as the sole source of protein. After 3-5 months, the malnourished monkeys developed many features usually associated with the clinical syndrome of marasmic kwashiorkor as seen in socioeconomically underpriviledged societies. Ultrastructural evaluation of thyroid gland revealed that dietary protein-calorie deficiency produced marked reduction in follicular cell height, conspicuous decrease in the number of apical filamentous microvilli, and a relative scarcity of the apical microvesicles as well as other pale staining colloid vesicles compared to findings on control glands. The electron-dense lysosomelike granules did not appear particularly affected, although in some sections they seemed to have increased in number and were located mainly in the basal portion of the cells, These electron-dense granules often displayed marked lack of homogeneity in regard to their structure in the malnourished glands. Most of these morphologic alterations have been noted frequently in thyroid glands of hypophysectomized animals, or in glands suppressed by the administration of thyroxine, and are therefore highly indicative of thyroid hypofuction in this animal prototype of human protein-calorie malnutrition.


Comparative studies of differential gene calling using RNA-Seq data.
With its massive amount of data, gene-expression profiling by RNA-Seq has many advantanges compared with microarray experiments. RNA-Seq analysis, however, is fundamentally different from microarray data analysis. Techniques developed for analyzing microarray data thus cannot be directly applicable for the digital gene expression data. Several statistical methods have been developed for identifying differentially expressed genes specifically from RNA-Seq data over the past few years. In this study, we examined the performance of differential gene-calling methods using RNA-Seq data in practical situations. We focused on two representative methods: one parametric method, DESeq, and one nonparametric method, NOISeq. We examined their performance using both simulated and real datasets. Our simulation followed the RNA-Seq process and produced more realistic short read data. Both DESeq and NOISeq identified over-expressed genes more correctly than under-expressed genes. While DESeq was more likely to call longer genes as differentially expressed than shorter ones, NOISeq did not have such bias. When the underlying variation increased, both methods showed higher rates of false positives. When replicates were not available in the experiments, both methods showed lower rates of true positives and higher rates of false positives. The level of variation clearly affected the performance of both methods, showing the importance of understanding the variation in the data as well as having replications in RNA-Seq experiments. We showed that it is possible to obtain improved differential gene-calling results by combining the results obtained by the two methods. We suggested strategies to use these two methods individually or combined according to the characteristics of the data.


Effect of hydrogen bonds on polarizability of a water molecule in (H2O)(N) (N = 6, 10, 20) isomers.
Polarizabilities of the low-lying isomers of (H(2)O)(N) (N = 6, 10, 20) clusters were computed by using Density Functional Theory. The global polarizabilities of the water isomers were found to depend mainly on the total number of water molecules rather than their cluster structures. We show that this result hides in fact a strong heterogeneity of the molecular polarizability within the different isomers. The global polarizability of a cluster was divided into a sum of molecular contributions by using the Hirshfeld partitioning scheme. We reveal that the value of the local polarizability of a molecule in the cluster is correlated with the number and type of the hydrogen bonds (HB) the molecule forms. Consequently, the molecules located in the interior of the cluster, which usually form more HBs, have smaller molecular polarizabilities than the molecules at the surface, which form less HBs. The contribution of intermolecular interaction to the global polarizability was analyzed by decomposing the cluster polarizability into intra- and inter-molecular contributions. The former measures the polarization within the molecular basin against the external electric field, while the latter is described as the sum of polarizability caused by charge flow through the HBs. These two contributions vary with the cluster size: the intermolecular contribution decreases with the cluster size on the contrary of the intramolecular contribution which increases.


Region-selective self-assembly of functionalized carbon allotropes from solution.
Approaches for the selective self-assembly of functionalized carbon allotropes from solution are developed and validated for 0D-fullerenes, 1D-carbon nanotubes and 2D-graphene. By choosing the right molecular interaction of self-assembled monolayers (serving the surface) with the functionalization features of carbon materials, which provide the solubility but also serve the driving force for assembly, we demonstrate a region-selective and self-terminating assembly of the materials. Active layers of the carbon allotropes can be selectively deposited in the channel region of thin-film transistor (TFT) devices by this approach. As an example for a 0D system, molecules of C60 functionalized octadecylphosphonic acids are used to realize self-assembled monolayer field-effect transistors (SAMFETs) based on a selective molecular exchange reaction of stearic acid in the channel region. For noncovalently functionalized single-walled carbon nanotubes (SWCNTs) and graphene oxide (GO) flakes, the electrostatic Coulomb interactions between the functional groups of the carbon allotropes and the charged head groups of a SAM dielectric layer are utilized to implement the selective deposition.


Microtubular Dysfunction and Male Infertility.
Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and sperm motility process, microtubules ascertain functional capacity of sperm. Also, microtubule based structures such as axoneme and manchette are crucial for sperm head and tail formation. This review (a) presents a concise, yet detailed structural overview of the microtubules, (b) analyses the role of microtubule structures in various male reproductive functions, and (c) presents the association of microtubular dysfunctions with male infertility. Considering the immense importance of microtubule structures in the formation and maintenance of physiological functions of sperm cells, this review serves as a scientific trigger in stimulating further male infertility research in this direction.


Effects of the antibiotic ionophore X-537A on contractility and ionic exchange in rabbit ventricular myocardium.
The effects of the ionophore X-537A on mechanical function and on ionic exchange were studied in the isolated, arterially perfused rabbit interventricular septum. X-537A produced an initial positive inotropic response which was, however, transient in this preparation and appeared to be dependent on an effect of the ionophore on catecholamines. The positive inotropy gave way to a progressive decline in force development which was unrelated to the action of catecholamines and was not accompanied by the development of contracture. Isotope uptake experiments revealed that coincident with this decline in force development there was a continuous net loss of tissue K+ and a net gain of Na+. X-537A (5 micronM) perfused for 20 minutes resulted in a net K+ loss of 50.2 +/- 4.6 mmol/kg dry weight and a net Na+ gain of 74.0 +/- 4.5 mmol/kg dry weight. Isotope washout experiments confirmed that the entire net loss of K+ could be accounted for by increased K+ efflux. X-537A did not alter Na+ efflux nor did it have any detectable effect on 45Ca exchange of the perfused septum in which the ability to detect net movements is at a level of approximately +/- 550 micron mol/kg dry weight. On removal of the ionophore the decline in force development ceased and reversed to near control levels and the progressive ionic changes ceased. However, despite the near total recovery of contractile function the Na+ and K+ levels remained at values little different from those reached at the termination of X-537A perfusion. In addition, after removal of the ionophore, we found that K+ exchange rate remained significantly less than control and, furthermore, a kinetic inhomogeneity of tissue K+ was observed. The results emphasize a dissociation between cellular Na+ and K+ content and function following the ionic perturbations induced by the ionophore.


Polymorphisms in P450 CYP1B1 affect the conversion of estradiol to the potentially carcinogenic metabolite 4-hydroxyestradiol.
Most drug metabolizing cytochrome P450s (P450) are predominantly expressed in the liver. In contrast, human CYP1B1 is an extrahepatic P450 which is overexpressed in many tumours and has been strongly implicated in the activation of carcinogens. Rare allelic variants of the CYP1B1 gene which encode an inactive protein have been identified. However, four polymorphisms which most likely do not abolish functionality have been described. In this report, we have characterized the functional consequences of these. A CYP1B1 cDNA, identical to a cDNA published previously, served as a template to introduce allelic changes either separately or in combination. The resulting effects on CYP1B1 activity were determined in membranes isolated from Escherichia coli which coexpressed CYP1B1 together with P450 reductase. None of the allelic changes affected the CYP1B1 expression level. The allelic changes Arg48 to Gly, Ala19 to Ser and Asn453 to Ser had little influence on the Vmax and the Km of the CYP1B1 mediated 2- and 4-hydroxylation of estradiol. In contrast, the Km of these metabolic pathways was increased at least three-fold by the allelic change Va432 to Leu or by simultaneously changing Val432 to Leu and Asn453 to Ser. However, these alterations had little effect on the kinetic parameters of other CYP1B1 mediated reactions such as the epoxidation of (-)-trans-(7R,8R)-benzo[a]pyrene 7,8-dihydrodiol as determined by (r-7,t-8,t-9,c-10)-benzo[a]pyrene tetraol formation, or such as the O-dealkylation of ethoxyresorufin and the 1'-hydroxylation of bufuralol. Molecular modelling suggests that amino acid residue 432 of CYP1B1 may be involved in the interaction between CYP1B1 and P450 reductase. Since 4-hydroxyestradiol has been implicated in hormonal carcinogenesis and CYP1B1 is expressed in target tissues, the data presented demonstrate that polymorphisms in CYP1B1 have the potential to affect disease susceptibility.


Walls are thin 1 (WAT1), an Arabidopsis homolog of Medicago truncatula NODULIN21, is a tonoplast-localized protein required for secondary wall formation in fibers.
By combining Zinnia elegans in vitro tracheary element genomics with reverse genetics in Arabidopsis, we have identified a new upstream component of secondary wall formation in xylary and interfascicular fibers. Walls are thin 1 (WAT1), an Arabidopsis thaliana homolog of Medicago truncatula NODULIN 21 (MtN21), encodes a plant-specific, predicted integral membrane protein, and is a member of the plant drug/metabolite exporter (P-DME) family (transporter classification number: TC 2.A.7.3). Although WAT1 is ubiquitously expressed throughout the plant, its expression is preferentially associated with vascular tissues, including developing xylem vessels and fibers. WAT1:GFP fusion protein analysis demonstrated that WAT1 is localized to the tonoplast. Analysis of wat1 mutants revealed two cell wall-related phenotypes in stems: a defect in cell elongation, resulting in a dwarfed habit and little to no secondary cell walls in fibers. Secondary walls of vessel elements were unaffected by the mutation. The secondary wall phenotype was supported by comparative transcriptomic and metabolomic analyses of wat1 and wild-type stems, as many transcripts and metabolites involved in secondary wall formation were reduced in abundance. Unexpectedly, these experiments also revealed a modification in tryptophan (Trp) and auxin metabolism that might contribute to the wat1 phenotype. Together, our data demonstrate an essential role for the WAT1 tonoplast protein in the control of secondary cell wall formation in fibers.


Influence of enteric infections on response to oral poliovirus vaccine: a systematic review and meta-analysis.
The impaired immunogenicity of oral poliovirus vaccine (OPV) in low-income countries has been apparent since the early field trials of this vaccine. Infection with enteropathogens at the time of vaccination may contribute to this phenomenon. However, the relative influence of these infections on OPV performance remains uncertain. We conducted a systematic review to examine the impact of concurrent enteric infections on OPV response. Using random-effects models, we assessed the effects of nonpolio enteroviruses (NPEVs) and diarrhea on the odds of seroconversion and/or vaccine virus shedding. We identified 25 trials in which OPV outcomes were compared according to the presence or absence of enteric infections, the majority of which (n = 17) reported only on NPEVs. Concurrent NPEVs significantly reduced the odds of per-dose seroconversion for type 1 poliovirus (odds ratio [OR] 0.44, 95% confidence interval 0.23-0.84), but not type 2 (OR 0.53 [0.19-1.46]) or type 3 (OR 0.56 [0.27-1.12]). A similar reduction, significant for type 1 poliovirus (OR 0.50 [0.28-0.89]), was observed in the odds of vaccine virus shedding among NPEV-infected individuals. Concurrent diarrhea significantly inhibited per-dose seroconversion overall (OR 0.61 [0.38-0.87]). Our findings are consistent with an inhibitory effect of concurrent enteric infections on OPV response.


Metal-on-metal bearings and hypersensitivity in patients with artificial hip joints. A clinical and histomorphological study.
Some patients who have a total hip replacement with a second-generation metal-on-metal articulation have persistent or early recurrence of preoperative symptoms. Characteristic histological changes in the periprosthetic tissues suggested the development of an immunological response. Therefore, in order to determine the relevance of these symptoms, we performed a study of the clinical data and periprosthetic tissues associated with endoprostheses with a metal-on metal articulation that had been retrieved at revision. Periprosthetic tissues as well as the clinical data on the patients were obtained from the first nineteen consecutive revisions performed at the treating hospitals. At the time of the revision, fourteen patients had the metal-on-metal articulation exchanged for either an alumina-ceramic or a metal-on-polyethylene articulation. Five patients received another second-generation metal-on-metal total joint replacement. Five-micrometer sections were prepared from the tissue samples, were stained with routine and immunohistochemical methods, and were examined histologically. Histological specimens from three groups of patients, two of which were treated with non-metal-on-metal implants, served as controls. The majority of patients had persistence of their preoperative pain or early recurrence of the pain after the original total hip replacement, and often a pronounced hip joint effusion had developed after the original replacement. Radiographic follow-up showed the development of radiolucent lines in five hips and of osteolysis in another seven hips. At the revision surgery, both the cup and the stem were found to be well fixed in nine patients. The characteristic histological features were diffuse and perivascular infiltrates of T and B lymphocytes and plasma cells, high endothelial venules, massive fibrin exudation, accumulation of macrophages with droplike inclusions, and infiltrates of eosinophilic granulocytes and necrosis. Only a few metal particles were detected. Immunohistochemical analysis demonstrated that the cellular reaction was still active. The patients who received another second-generation metal-on-metal articulation at the time of the revision had no decrease in symptoms. In the control group of tissues obtained at revisions of endoprostheses without cobalt, chromium, or nickel articulations, there were no similar signs of immune reactions. These histological findings support the possibility of a lymphocyte-dominated immunological response. Although the prevalence of this reaction is low, the persistence or early reappearance of symptoms, including a marked joint effusion and the development of osteolysis, after primary implantation may suggest the possibility of such a reaction.