Differences in gene expression profiles in early and late stage rhodesiense HAT individuals in Malawi.
T. b. rhodesiense is the causative agent of Rhodesian human African trypanosomiasis (r-HAT) in Malawi. Clinical presentation of r-HAT in Malawi varies between foci and differs from East African HAT clinical phenotypes. The purpose of this study was to gain more insights into the transcriptomic profiles of patients with early stage 1 and late stage 2 HAT disease in Malawi. Whole blood from individuals infected with T. b. rhodesiense was used for RNA-Seq. Control samples were from healthy trypanosome negative individuals matched on sex, age range, and disease foci. Illumina sequence FASTQ reads were aligned to the GRCh38 release 84 human genome sequence using HiSat2 and differential analysis was done in R Studio using the DESeq2 package. XGR, ExpressAnalyst and InnateDB algorithms were used for functional annotation and gene enrichment analysis of significant differentially expressed genes. RNA-seq was done on 23 r-HAT case samples and 28 healthy controls with 7 controls excluded for downstream analysis as outliers. A total of 4519 genes were significant differentially expressed (p adjusted <0.05) in individuals with early stage 1 r-HAT disease (n = 12) and 1824 genes in individuals with late stage 2 r-HAT disease (n = 11) compared to controls. Enrichment of innate immune response genes through neutrophil activation was identified in individuals with both early and late stages of the disease. Additionally, lipid metabolism genes were enriched in late stage 2 disease. We further identified uniquely upregulated genes (log2 Fold Change 1.4-2.0) in stage 1 (ZNF354C) and stage 2 (TCN1 and MAGI3) blood. Our data add to the current understanding of the human transcriptome profiles during T. b. rhodesiense infection. We further identified biological pathways and transcripts enriched than were enriched during stage 1 and stage 2 r-HAT. Lastly, we have identified transcripts which should be explored in future research whether they have potential of being used in combination with other markers for staging or r-HAT.


A Systematic Meta-analysis of Immune Signatures in Patients With Acute Chikungunya Virus Infection.
Individuals infected with chikungunya virus (CHIKV) normally exhibit a variety of clinical manifestations during the acute phase of infection. However, studies in different patient cohorts have revealed that disease manifestations vary in frequency. Disease profiles between patients with acute CHIKV-infection and febrile patients without CHIKV were compared and examined to determine whether any clinical presentations were associated with the clinical outcome of CHIKV infection. Circulatory immune mediators profiles were then characterized and compared with data from 14 independent patient cohort studies. The particular immune mediator signature that defines acute CHIKV infection was determined. Our findings revealed a specific pattern of clinical presentations of joint-specific arthralgia from this CHIKV cohort. More importantly, we identified an immune mediator signature dominated by proinflammatory cytokines, which include interferon α and γ and interleukin 2, 2R, 6, 7, 12, 15, 17, and 18, across different patient cohorts of CHIKV load associated with arthralgia. To our knowledge, this is the first study that associated levels of CHIKV load with arthralgia as an indicator of acute CHIKV infection. Importantly, our findings also revealed specific immune mediator signatures that can be used to better define CHIKV infection.


Policies of the Office of Population Censuses and Surveys. Philosophy and constraints.
The Medical Division of the Office of Population Censuses and Surveys (OPCS) organizes and indexes general systems of records for medical research and administration. The main sources of records are the census, registrations of births and of deaths, hospital discharge records, registered cases of cancer and of congenital malformations, surveys by the Social Surveys Division, and samples of records in general practice. Results take the form of regularly published series of statistics and commentaries and of studies in depth, often by scientists in the National Health Service (NHS), and research institutions which are encouraged to use the systems for prospective and retrospective surveys. The surveys are facilitated by the central registry where a note of every death in the country is attached to the relevant record (and the causes of death are available). Recent developments include studies of records of general practitioners; the causes of deaths among immigrants in England and Wales; the fertility, migration, and mortality of a cohort of about 1 percent of the population. The publication policy of OPCS is described.


Comparison of the hypotensive and other ocular effects of prostaglandins E2 and F2 alpha on cat and rhesus monkey eyes.
It is generally accepted that exogenous or endogenous prostaglandins (PGs) can give rise to acute increases in intraocular pressure (IOP) and to the development of flare and other signs of uveitis. It was recently shown, however, that low doses of PGE2 and/or PGF2 alpha topically applied to rabbit or owl monkey eyes significantly reduce IOP. The present experiments show that topical application of 10 to 500 micrograms of PGE2 also causes a highly significant IOP reduction in cat eyes lasting up to 48 hr with little or no development of flare or miosis, whereas similar application of PGF2 alpha causes, in addition to an IOP reduction, the development of profound pupillary constriction. Topical application of either PGF2 alpha or PGE2 to the eyes of rhesus monkeys also causes significant dose-dependent reduction in IOP. The hypotensive response in the rhesus monkey is not associated with detectable flare or consistent pupillary constriction, although at higher PG doses, hypotension tends to be preceded in both species by a brief (15 to 30 min) hypertensive phase. It is concluded that the eyes of different species show different patterns of IOP, miotic, and flare responses to topically applied PGs, the only consistent effect being a reduction in IOP. In some species, most notably in primates, a reduction in IOP is the predominant effect of PGs. Thus, PGs or their analogues may provide a new approach to the clinical control of IOP and the treatment of glaucoma.


Identification of the active mechanism of aminoglycoside entry in V. cholerae through characterization of sRNA ctrR, regulating carbohydrate utilization and transport.
The possible active entry of aminoglycosides in bacterial cells has been debated since the development of this antibiotic family. Here we report the identification of their active transport mechanism in Vibrio species. We combined genome-wide transcriptional analysis and fitness screens to identify alterations driven by treatment of V. cholerae with sub-minimum inhibitory concentrations (sub-MIC) of the aminoglycoside tobramycin. RNA-seq data showed downregulation of the small non-coding RNA ncRNA586 during such treatment, while Tn-seq revealed that inactivation of this sRNA was associated with improved fitness in the presence of tobramycin. This sRNA is located near sugar transport genes and previous work on a homologous region in Vibrio tasmaniensis suggested that this sRNA stabilizes gene transcripts for carbohydrate transport and utilization, as well as phage receptors. The role for ncRNA586, hereafter named ctrR, in the transport of both carbohydrates and aminoglycosides, was further investigated. Flow cytometry on cells treated with a fluorescent aminoglycoside confirmed the role of ctrR and of carbohydrate transporters in differential aminoglycoside entry. Despite sequence diversity, ctrR showed functional conservation across the Vibrionales. This system in directly modulated by carbon sources, suggesting regulation by carbon catabolite repression, a widely conserved mechanism in Gram-negative bacteria, priming future research on aminoglycoside uptake by sugar transporters in other bacterial species.


A predominance of the T cell receptor V gamma 2/V delta 2 subset in human mycobacteria-responsive T cells suggests germline gene encoded recognition.
Little is known about the nature of Ag recognition by the TCR-gamma delta. The recent observation that gamma delta T cells preferentially recognize mycobacterial Ag provides a model to examine the molecular basis of gamma delta-TCR recognition. Here, examination of the Mycobacteria-stimulated peripheral blood T cells with TCR-specific mAb revealed a predominance of T cells bearing V gamma 2/V delta 2 gene products. PCR cloning and sequence analysis of the TCR chains demonstrated extensive junctional diversity indicating that the response was polyclonal. The marked in vitro gamma delta T cell response to Mycobacteria was also detected in newborns before encounters with foreign Ag and exclusively involved the same V-gene usage observed in adults. Together, these results suggest that a major mechanism of gamma delta T cell reactivity involves recognition mediated by germline-encoded segments of the TCR.


Lidocaine for preventing postoperative sore throat.
Sore throat is a common side-effect of general anaesthesia and is reported by between 30% and 70% of patients after tracheal intubation. The likelihood of a sore throat varies with the type, diameter, and cuff pressure of the endotracheal tube used. If intubation is essential, it may be helpful to give drugs prophylactically to alleviate postoperative sore throat. Local anaesthetics and steroids have been used for this purpose. This review was originally published in 2009 and was updated in 2015. The objective of this review was to evaluate the efficacy and any harm caused by topical and systemic lidocaine used prophylactically to prevent postoperative sore throat in adults undergoing general anaesthesia with endotracheal intubation. We searched CENTRAL (The Cochrane Library 2013, Issue 9), MEDLINE (January 1966 to October 2013), and EMBASE (1980 to October 2013). We also contacted manufacturers and researchers in the field. The original search was undertaken in June 2007. We reran the search in February 2015 and found four studies of interest. We will deal with those studies when we next update the review. We included randomized controlled trials (RCTs) of topical and systemic prophylactic lidocaine therapy versus control (using air or saline) that reported on the risk and severity of postoperative sore throat as an outcome. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information, such as the risk of any adverse effects. We included 19 studies involving 1940 participants in this updated review. Of those 1940 participants, 952 received topical or systemic lidocaine therapy and 795 were allocated to the control groups. Topical and systemic lidocaine therapy appeared to reduce the risk of postoperative sore throat (16 studies, 1774 participants, risk ratio (RR) was 0.64 (95% confidence interval (CI) 0.48 to 0.85), the quality of the evidence was low), although when only high-quality trials were included (eight studies, 814 participants) the effect was no longer significant (RR 0.71, 95% CI 0.47 to 1.09). Lidocaine given systemically in two studies (320 participants) did not reveal evidence of an effect (RR 0.44, 95% CI 0.19 to 1.05 ). The severity of sore throat as measured on a visual-analogue scale (VAS) was reduced by lidocaine therapy (six trials, 611 participants, (mean difference (MD) -10.80, 95% CI -14.63 to -6.98). The adverse effects of lidocaine were not reported in these studies, though toxicity is generally rare. In our revised systematic review, although the results of included studies show generally positive results, they should be interpreted carefully. The effect size of lidocaine appeared to be affected by study quality; drug concentration; route of administration; management of cuff pressure during anaesthesia; the included population; and the type of outcome measured.


Neural activity in prefrontal cortex during copying geometrical shapes. I. Single cells encode shape, sequence, and metric parameters.
In drawing a copy of a geometrical shape, a sequence of movements must be produced to represent the sides of the object in the proper spatial relationship. We investigated neural mechanisms of this process by training monkeys to draw (using a joystick) copies of geometrical shapes (triangles, squares, trapezoids and inverted triangles) presented on a video monitor while recording single cell activity in prefrontal cortex. The drawing trajectories monkeys produced were divided into a series of discrete segments, varying in direction and length. We performed a stepwise multiple linear regression analysis to identify those copy parameters significantly influencing cell activity. The copied shape (e.g., triangle, square) and the serial position of the segment within each trajectory were the most prevalent effects (in 46% and 43% of cells, respectively), followed by segment direction (32%) and length (16%). Effects of temporal factors (maximum segment speed and time to maximum segment speed) were less frequent. These results demonstrate that prefrontal neurons encode several spatial and sequence variables that define copy trajectories. We also found that specific groupings of significant effects tended to occur together in single neurons. Specifically, single neurons simultaneously processed the serial position of a segment within each trajectory along with the corresponding spatial (but not temporal) attributes of that segment (i.e., direction and length), as well as with the overall shape to which the segments belong. Finally, we discovered that relationships between neural activity and segment serial position were systematic in many instances, described by monotonically increasing and decreasing functions, as well as parabolic functions. These findings indicate that, within the copying task, the serial segment position is a key factor for neural activity in the periprincipalis area of the prefrontal cortex.


Meta-analysis of the reduction of antibiotic-sensitive and antibiotic-resistant Escherichia coli as a result of low- and medium-pressure UV lamps.
It is vital that harmful bacteria are removed from water and wastewater treatment plants to prevent human/environmental exposure. This paper examines the log reduction of antibiotic-sensitive (AS) and antibiotic-resistant (AR) Escherichia coli (E. coli) as a result of low-pressure (LP) and medium-pressure (MP) UV lamps. A meta-analysis was performed and a mixed-effect model was created in which 303 data points on the log reduction of E. coli from UV treatment were collected. The results show that in order to achieve a 6 log reduction using an MP lamp, on average a UV level of 7.3 mJ/cm2 for AS E. coli and 7.5 mJ/cm2 for AR E. coli were required. Using an LP lamp, a UV level of 8.1 mJ/cm2 for AS E. coli and 8.4 mJ/cm2 for AR E. coli were required. The results show there is no significant difference between the inactivation of AR and AS E. coli at different UV levels. The model predicts that AR or AS E. coli will be inactivated at UV levels lower than the recommended UV operation conditions (40 mJ/cm2), but it is important to use this UV level to inactivate other harmful microorganisms.


Positive affect promotes engagement in care after HIV diagnosis.
Revised Stress and Coping Theory proposes that positive affect serves adaptive functions, and its beneficial effects are heightened during stressful periods. This study examined the prospective relationship between positive affect and engagement in care during the 18 months after a HIV seropositive diagnosis. The Coping, HIV, and Affect Interview (CHAI) cohort study enrolled 153 individuals who had recently received a HIV seropositive diagnosis. Using logistic and linear regression, baseline positive affect was examined as a predictor of linkage to HIV care, antiretroviral therapy (ART) persistence (i.e., starting ART and remaining on it during subsequent follow-up assessments), and mean log₁₀ HIV viral load over follow-up. After controlling for education, T-helper (CD4+) count, HIV viral load, and negative affect, higher baseline positive affect independently predicted increased odds of linkage to HIV care at 3 months postdiagnosis (adjusted OR [AOR] = 1.10; 95% CI = 1.01-1.21) and ART persistence over the 18-month follow-up period (AOR = 1.08; 95% CI = 1.01-1.16). Positive affect was not directly associated with lower mean HIV viral load over follow-up. However, one standard deviation higher positive affect indirectly predicted 6.7% lower HIV viral load via greater odds of ART persistence (βindirect = -0.18, p < .05). Greater positive affect predicts linkage to HIV care and ART persistence. ART persistence, in turn, is associated with lower HIV viral load. Clinical research is needed to examine whether interventions designed to enhance positive affect can boost the effectiveness of HIV treatment as prevention.


A comparative study of patients' activities and interactions in a stroke unit before and after reconstruction-The significance of the built environment.
Early mobilization and rehabilitation, multidisciplinary stroke expertise and comprehensive therapies are fundamental in a stroke unit. To achieve effective and safe stroke care, the physical environment in modern stroke units should facilitate the delivery of evidence-based care. Therefore, the purpose of this study was to explore patients' activities and interactions in a stroke unit before the reconstruction of the physical environment, while in a temporary location and after reconstruction. This case study examined a stroke unit as an integrated whole. The data were collected using a behavioral mapping technique at three different time points: in the original unit, in the temporary unit and in the new unit. A total of 59 patients were included. The analysis included field notes from observations of the physical environment and examples from planning and design documents. The findings indicated that in the new unit, the patients spent more time in their rooms, were less active, and had fewer interactions with staff and family than the patients in the original unit. The reconstruction involved a change from a primarily multi-bed room design to single-room accommodations. In the new unit, the patients' lounge was located in a far corner of the unit with a smaller entrance than the patients' lounge in the old unit, which was located at the end of a corridor with a noticeable entrance. Changes in the design of the stroke unit may have influenced the patients' activities and interactions. This study raises the question of how the physical environment should be designed in the future to facilitate the delivery of health care and improve outcomes for stroke patients. This research is based on a case study, and although the results should be interpreted with caution, we strongly recommend that environmental considerations be included in future stroke guidelines.


Bryo-Activities: A Review on How Bryophytes Are Contributing to the Arsenal of Natural Bioactive Compounds against Fungi.
Usually regarded as less evolved than their more recently diverged vascular sisters, which currently dominate vegetation landscape, bryophytes seem having nothing to envy to the defensive arsenal of other plants, since they had acquired a suite of chemical traits that allowed them to adapt and persist on land. In fact, these closest modern relatives of the ancestors to the earliest terrestrial plants proved to be marvelous chemists, as they traditionally were a popular remedy among tribal people all over the world, that exploit their pharmacological properties to cure the most different diseases. The phytochemistry of bryophytes exhibits a stunning assortment of biologically active compounds such as lipids, proteins, steroids, organic acids, alcohols, aliphatic and aromatic compounds, polyphenols, terpenoids, acetogenins and phenylquinones, thus it is not surprising that substances obtained from various species belonging to such ancestral plants are widely employed as antitumor, antipyretic, insecticidal and antimicrobial. This review explores in particular the antifungal potential of the three Bryophyta divisions-mosses (Musci), hornworts (Anthocerotae) and liverworts (Hepaticae)-to be used as a sources of interesting bioactive constituents for both pharmaceutical and agricultural areas, providing an updated overview of the latest relevant insights.


Circulating biomarkers in glaucoma, age-related macular degeneration, and diabetic retinopathy.
Biomarkers to predict the altering physiological conditions over the period leading toward the ocular disorders are of major importance in therapeutics. Isolation and validation of the biomarkers specific to ocular diseases are a challenging task. Glaucoma is a neurodegenerative disease of the eye where the correlation of biomarkers in circulating fluid may be made specific for the eye. However, conditions such as wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR), circulating biomarkers might be having some degree of overlap with other conditions like cancer where a common factor such as angiogenesis is involved. Diabetes, a systemic disorder affecting the target organs such as eye, kidney, heart, and nervous system can be predicted using common circulating biomarkers. However, these markers need to be validated along with various stages of disease progression to enable the possibility of targeted pharmacological interventions apart from good glycemic control alone. This review compiles the attempts made to correlate such circulating biomarkers in the ocular conditions such as glaucoma, AMD, and DR in the search for a surrogate marker for diagnostic and prognostic value. To make biomarkers for the common convenience, genetic markers are excluded from this review.


Bayesian inference of selection in a heterogeneous environment from genetic time-series data.
Evolutionary geneticists have sought to characterize the causes and molecular targets of selection in natural populations for many years. Although this research programme has been somewhat successful, most statistical methods employed were designed to detect consistent, weak to moderate selection. In contrast, phenotypic studies in nature show that selection varies in time and that individual bouts of selection can be strong. Measurements of the genomic consequences of such fluctuating selection could help test and refine hypotheses concerning the causes of ecological specialization and the maintenance of genetic variation in populations. Herein, I proposed a Bayesian nonhomogeneous hidden Markov model to estimate effective population sizes and quantify variable selection in heterogeneous environments from genetic time-series data. The model is described and then evaluated using a series of simulated data, including cases where selection occurs on a trait with a simple or polygenic molecular basis. The proposed method accurately distinguished neutral loci from non-neutral loci under strong selection, but not from those under weak selection. Selection coefficients were accurately estimated when selection was constant or when the fitness values of genotypes varied linearly with the environment, but these estimates were less accurate when fitness was polygenic or the relationship between the environment and the fitness of genotypes was nonlinear. Past studies of temporal evolutionary dynamics in laboratory populations have been remarkably successful. The proposed method makes similar analyses of genetic time-series data from natural populations more feasible and thereby could help answer fundamental questions about the causes and consequences of evolution in the wild.


Synthesis and anticonvulsant activity of new kojic acid derivatives.
A series of new 3-hydroxy-6-hydroxymethyl-2-substituted 4H-pyran-4-one derivatives were synthesized as potential anticonvulsant compounds. Mannich compounds were prepared by the reaction of appropriate substituted piperazine derivatives with kojic acid and formaline. The structure of the synthesized compounds was confirmed using the elementary analysis results and spectroscopic techniques such as IR, 1H-NMR and ESI-MS. Anticonvulsant activities of the synthesized compounds were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet) induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed according to procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies, 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 11) against MES seizures and 3-hydroxy-6-hydroxymethyl-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4H-pyran-4-one (compound 7) against scMet seizures were determined to be the most active compounds at all doses without neurotoxicity.


Increased sequence diversity coverage improves detection of HIV-specific T cell responses.
The accurate identification of HIV-specific T cell responses is important for determining the relationship between immune response, viral control, and disease progression. HIV-specific immune responses are usually measured using peptide sets based on consensus sequences, which frequently miss responses to regions where test set and infecting virus differ. In this study, we report the design of a peptide test set with significantly increased coverage of HIV sequence diversity by including alternative amino acids at variable positions during the peptide synthesis step. In an IFN-gamma ELISpot assay, these "toggled" peptides detected HIV-specific CD4(+) and CD8(+) T cell responses of significantly higher breadth and magnitude than matched consensus peptides. The observed increases were explained by a closer match of the toggled peptides to the autologous viral sequence. Toggled peptides therefore afford a cost-effective and significantly more complete view of the host immune response to HIV and are directly applicable to other variable pathogens.


Estrogen receptor-related receptors in the killifish Fundulus heteroclitus: diversity, expression, and estrogen responsiveness.
The estrogen receptor-related receptors (ERRs) are a group of nuclear receptors that were originally identified on the basis of sequence similarity to the estrogen receptors. The three mammalian ERR genes have been implicated in diverse physiological processes ranging from placental development to maintenance of bone density, but the diversity, function, and regulation of ERRs in non-mammalian species are not well understood. In this study, we report the cloning of four ERR cDNAs from the Atlantic killifish, Fundulus heteroclitus, along with adult tissue expression and estrogen responsiveness. Phylogenetic analysis indicates that F. heteroclitus (Fh)ERRalpha is an ortholog of the single ERRalpha identified in mammals, pufferfish, and zebrafish. FhERRbetaa and FhERRbetab are co-orthologs of the mammalian ERRbeta. Phylogenetic placement of the fourth killifish ERR gene, tentatively identified as FhERRgammab, is less clear. The four ERRs showed distinct, partially overlapping mRNA expression patterns in adult tissues. FhERRalpha was broadly expressed. FhERRbetaa was expressed at apparently low levels in eye, brain, and ovary. FhERRbetab was expressed more broadly in liver, gonad, eye, brain, and kidney. FhERRgammab was expressed in multiple tissues including gill, heart, kidney, and eye. Distinct expression patterns of FhERRbetaa and FhERRbetab are consistent with subfunctionalization of the ERRbeta paralogs. Induction of ERRalpha mRNA by exogenous estrogen exposure has been reported in some mammalian tissues. In adult male killifish, ERR expression did not significantly change following estradiol injection, but showed a trend toward a slight induction (three- to five-fold) of ERRalpha expression in heart. In a second, more targeted experiment, expression of ERRalpha in adult female killifish was downregulated 2.5-fold in the heart following estradiol injection. In summary, our results indicate that killifish contain additional ERR genes relative to mammals, including ERRbeta paralogs. In addition, regulation of ERRalpha expression in killifish apparently differs from regulation in mammals. Together, these features may facilitate determination of both conserved and specialized ERR gene functions.


Age at hip fracture and life expectancy in Denmark - Secular trends over two decades.
Recent improvements in the health of the oldest old coexist with a decline in hip fracture rates, in particular in women. We speculated that increased longevity with decreasing hip fracture rates would result in a delay in hip fracture. We conducted an analysis of time trends in the age at hip fracture, by type and gender, for the past two decades using national data. We used data from the Danish Hospital Discharge Register (1996-2017) to analyse the age distribution of femoral neck (FN) and pertrochanteric fractures (PT), allowing only the first fracture at each of these two sites to contribute to the analysis in each calendar year. Demographics for the background population at risk including life expectancy tabulations, were also obtained. The average age at FN fracture in women increased slowly but significantly by 0.035years - or 12.8 days - per calendar year [0.035, 95% CI (0.016; 0.054), p<0.001], resulting in an increase from 79.6 to 80.4 years. There were no significant changes in the age at FN fracture in men or the age at PT fracture in women and men. Further, increases in life expectancy were considerably faster than any change observed in the age at hip fracture. In 1996, the average age at FN or PT fracture exceeded the average life expectancy in both men and women whereas the opposite was the case from 2009 and onwards in men and 2015 and onwards in women. This study demonstrates a significant change in the demographics of hip fractures in Denmark over the past two decades. We observed a significant increase in the age at FN fracture in women but not in men, with no significant increase in the age at IT fracture and PT fracture. This developed much more slowly, however, than the increase in life expectancy in both sexes observed over the same period of time. Taken together, these changes resulted in a large decrease in the female to male incidence rate ratio from 2.6 and 2.5 (FN and PT, respectively) to 1.9 and 1.7.Additional effort is required to prevent hip fractures to ensure that the increasing life expectancy is matched by a similar increase in hip-fracture free life expectancy.


Pharmacokinetics of perindopril: therapeutic consequences.
Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half-life of over 30 hours, associated with sustained inhibition of ACE. During repeated dosing, there is little accumulation of the drug and no evidence of increased hemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: (1) Binding of perindoprilat to ACE prolongs the hemodynamic effect, giving the option of once daily administration. (2) Despite the long terminal elimination half-life of the drug, significant accumulation is not a problem during chronic treatment. (3) Increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used. (4) Further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.


Antagonistic role of vertebral translation against vertebral rotation in the spontaneous postoperative modulation of the anterior chest wall contour in thoracic idiopathic scoliosis.
A computed tomography study. To identify the best scoliotic deformity components that show impact upon the spontaneous postoperative modulation of the deformed anterior chest wall contour in right convex thoracic adolescent idiopathic scoliosis. Spontaneous postoperative aggravation of the anterior concave costal projection was a common occurrence in adolescent idiopathic scoliosis, yet the risk factors that effectively bridged the gap between what the surgeons did in the interior and how the rib cages reacted on the exterior were still open to debate. Pre- and postoperative computed tomographic scans of 77 patients with right convex thoracic adolescent idiopathic scoliosis were retrieved and analyzed. According to the postoperative variation of anterior chest wall angle (CWA), the patients were divided into 2 groups with either aggravated or improved CWA. Multiple scoliotic deformity parameters and their surgical correction rates were evaluated, correlated, and then compared between the 2 groups. Moreover, patients with apex located at T9 were isolated and evaluated independently. A logistic regression analysis was used to determine the independent predictors of the spontaneous postoperative modulation of the anterior chest wall contour. The surgical correction rate of Cobb angle (supine), the rotational angle with respect to the sagittal plane (RAsag angle), the rotational angle with respect to the anterior midline of the body (RAml angle), the angle of lateral deviation of the apical vertebrae from the midline (MLdev angle), the posterior hemithorax ratio, the vertebral translation (VT), and the thoracic rotation averaged 64.6%, 19.5%, 30.8%, 39.2%, 15.0%, 41.2%, and 28.7%, respectively. Ratio of aggravated anterior chest wall contour was the highest at the T7 apex group (84.6%) as compared with T8 apex group (47.1%), T9 apex group (19.5%), and T10 apex group (0.0%). The preoperative CWA was significantly lower in the aggravated CWA group when compared with the improved group (2.1 ± 1.8°vs. 6.6 ± 2.4°, P < 0.001). Besides, in the aggravated CWA group, significantly greater surgical correction of VT and lesser correction of RAsag angle were demonstrated when compared with the improved CWA group (VT: 53.0% vs. 34.8%, P = 0.001; RAsag: 2.5% vs. 28.7%, P = 0.000). In the T9 subgroup, remarkably different correction rate of VT and RAsag were similarly observed (VT: 54.9% vs. 35.3%, P = 0.046; RAsag: 4.9% vs. 23.5%, P = 0.034). In terms of other deformity parameters, no significantly different correction rate was consistently detected. In the logistic regression analysis, apex location, CWA, and correction rate of RAsag were demonstrated to be independent factors predictive of the alteration of chest wall contour. In addition to the smaller preoperative CWA and higher apex location, lesser correction of vertebral rotation, if accompanied by great surgical correction of apical VT, could also largely result in a poor postoperative anterior chest wall contour.


Species Adulteration in the Herbal Trade: Causes, Consequences and Mitigation.
The global economy of the international trade of herbal products has been increasing by 15% annually, with the raw material for most herbal products being sourced from South and Southeast Asian countries. In India, of the 8000 species of medicinal plants harvested from the wild, approximately 960 are in the active trade. With increasing international trade in herbal medicinal products, there is also increasing concern about the widespread adulteration and species admixtures in the raw herbal trade. The adverse consequences of such species adulteration on the health and safety of consumers have only recently begun to be recognised and documented. We provide a comprehensive review of the nature and magnitude of species adulteration in the raw herbal trade, and identify the underlying drivers that might lead to such adulteration. We also discuss the possible biological and chemical equivalence of species that are used as adulterants and substitutes, and the consequences thereof to consumer health and safety, and propose a framework for the development of a herbal trade authentication service that can help regulate the herbal trade market.


Comparison of the 2,2'-azinobis-3-ethylbenzotiazo-line-6-sulfonic acid (ABTS) and ferric reducing anti-oxidant power (FRAP) methods to asses the total antioxidant capacity in extracts of fruit and vegetables.
A comparison was made on the use of two spectrophotometric methods, the ferric reducing antioxidant power (FRAP) method and the 2,2'-azinobis-3-ethylbenzotiazoline-6-sulfonic acid (ABTS) method, for the measurement of the total antioxidant capacity (TAC) of plant foods. The correlations of TAC measured by the two methods were highly significant in both water-soluble (r2= 0.90) and water-insoluble extracts (r2= 0.98) from 13 strawberry samples. Also a corresponding comparison of TAC in extracts from 14 plant species showed high correlation coefficients, r2= 0.98 for water-soluble extracts and r2= 0.88 for water-insoluble extracts. The ratio of TAC values obtained with the two methods (ABTS/FRAP) varied between 0.7 and 3.3 for different plant extracts indicating that they contained antioxidants with varying reactivity in the two methods. TACs in six pure antioxidant substances were ranked in the following order by both methods: quercetin > ferulic acid > catechin > rutin > caffeic acid > Trolox = chlorogenic acid. The two methods showed similar TAC values for quercetin, rutin, caffeic acid and chlorogenic acid while ferulic acid and catechin gave higher results with the ABTS method than with the FRAP method, and such differences probably explain the varying ratios of ABTS/FRAP obtained in foods. Regarding storage TAC in water-soluble strawberry extracts stored at -20 or -80 degrees C was stable for at least five months while storage at 4 degrees C decreased the TAC value with 40% during five weeks of storage. The study showed that both the ABTS and FRAP methods can be used for convenient monitoring of the antioxidant capacities in fruit and vegetables, and that different antioxidants had varying reactivity in the two methods.


Associations of parental and child food and exercise aversion with child food intake and physical activity.
The interplay between parental and child food and physical activity aversion, briefly defined as fear or avoidance of novelty or breaking from routine, may explain such child behaviors as inadequate food consumption and physical activity. Two studies were conducted to investigate the associations between child and parental food and physical activity aversion (child self-reported aversion, parental-reported aversion, and parental perceptions of child aversion) and child food intake and physical activity. Parent-child dyads participated in 2 longitudinal studies. Study 1 (food aversion; the baseline [T1] and the 10-month follow-up [T2]) enrolled 924 dyads (1,848 individuals; 54.3% girls, aged 5-11 years old, 88.9% mothers). Study 2 (physical activity aversion; the baseline [T1] and the 7- to 8-month follow-up [T2]) enrolled 879 dyads (1,758 individuals; 52.4% girls, aged 5-11 years old, 83.2% mothers). There was no overlap between the samples enrolled in the two studies. Dyads completed self-report measures; child and parental body weight and height (for calculation of body mass index [BMI] as covariates/potential moderators) were measured objectively. Mediation analyses with 2 sequential mediators were performed. The association between self-reported parental food aversion (T1) and child fruit and vegetable intake (T2) was mediated sequentially by parental perception of child food aversion (T1) and self-reported child food aversion (T2). The same pattern of associations was found for physical activity aversion. Child BMI did not moderate the hypothesized associations. High levels of parental and child aversion operated sequentially in explaining lower levels of child fruit and vegetable intake and physical activity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Integration of carbon and nitrogen metabolism with energy production is crucial to light acclimation in the cyanobacterium Synechocystis.
Light drives the production of chemical energy and reducing equivalents in photosynthetic organisms required for the assimilation of essential nutrients. This process also generates strong oxidants and reductants that can be damaging to the cellular processes, especially during absorption of excess excitation energy. Cyanobacteria, like other oxygenic photosynthetic organisms, respond to increases in the excitation energy, such as during exposure of cells to high light (HL) by the reduction of antenna size and photosystem content. However, the mechanism of how Synechocystis sp. PCC 6803, a cyanobacterium, maintains redox homeostasis and coordinates various metabolic processes under HL stress remains poorly understood. In this study, we have utilized time series transcriptome data to elucidate the global responses of Synechocystis to HL. Identification of differentially regulated genes involved in the regulation, protection, and maintenance of redox homeostasis has offered important insights into the optimized response of Synechocystis to HL. Our results indicate a comprehensive integrated homeostatic interaction between energy production (photosynthesis) and energy consumption (assimilation of carbon and nitrogen). In addition, measurements of physiological parameters under different growth conditions showed that integration between the two processes is not a consequence of limitations in the external carbon and nitrogen levels available to the cells. We have also discovered the existence of a novel glycosylation pathway, to date known as an important nutrient sensor only in eukaryotes. Up-regulation of a gene encoding the rate-limiting enzyme in the hexosamine pathway suggests a regulatory role for protein glycosylation in Synechocystis under HL.


White matter hyperintensity burden and functional outcomes in acute ischemic stroke patients after mechanical thrombectomy: A systematic review and meta-analysis.
The influence of white matter hyperintensity (WMH) on clinical outcomes in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT) remains controversial. We performed a systematic review and meta-analysis to examine whether WMH burden is associated with clinical outcomes in AIS patients after MT. PubMed, Embase, and Web of Science were searched from inception to Sep 03, 2023. The registration number for PROSPERO is CRD42022340568. Studies reporting an association between the burden of WMH in AIS patients and clinical outcomes after MT were included in the meta-analysis. A random-effects model was used for meta-analysis. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Additionally, the presence of imprecise-study effects was evaluated using Egger's test and funnel plot. Fifteen studies with 3,456 patients were enrolled in this meta-analysis. Among AIS patients who underwent MT, moderate/severe WMH had higher odds of 90-day unfavorable functional outcomes (odds ratio [OR] 2.72, 95% confidence interval [CI] 2.14-3.44; I2 = 0.0%; 95% CI 0.0%-42.7%), 90-day mortality (OR 1.94, 95% CI 1.45-2.60; I2 = 19.5%; 95% CI 0.0%-65.2%) and futile recanalization (OR 2.99, 95% CI 1.42-6.28; I2 = 69.7%; 95% CI 0.0%-91.0%) compared with none/mild WMH. However, the two groups had no significant difference in successful recanalization, symptomatic hemorrhagic transformation, and hemorrhagic transformation. A subset analysis of patients from 3 articles showed that WMH volume was not significantly associated with these outcomes. A notable limitation is that this meta-analysis lacks direct adjustment for imbalances in important baseline covariates. Patients with moderate/severe WMH on baseline imaging are associated with substantially increased odds of 90-day unfavorable outcomes, futile recanalization, and 90-day mortality after MT. This association suggests that moderate/severe WMH may contribute to the prediction of clinical outcomes in AIS patients after MT.


[The initial experience of using fraxiparin in extracorporeal detoxication in clinical cardiology].
Procedures, connected with extracorporal blood circulation--hemodialysis, hemosorption and plasmapheresis--were used in complex of treatment in 30 patients with various cardiovascular diseases. As an anticoagulant in 8 patients was used the preparation of low molecular heparine (Fraxiparine) produced by "Sanofi" (France) firm, and in 22-heparin, produced by "Polfa" (Poland). Ascertained advantages of Fraxiparine versus heparin were: possibility of single injection of preparation, the reducing of total dose magnitude, which is needed for one curative act conduction, lowering by 70% approximately the hemorrhagic complications rate.


Left atrial geometric and functional remodeling in athletes.
The aim of this study was to evaluate left atrial (LA) volume and its changes with the phases of atrial filling, and to examine the effect of exercise capacity on these parameters. Using two-dimensional echocardiography, LA volumes were measured in 30 male endurance runners and 30 age-matched sedentary men (controls). Maximal oxygen consumption (VO2max) was measured using a metabolic chart during exercise. LA reservoir, pump, and conduit functions, kinetic energy and force were calculated. We found that athletes had higher LA volume and volume index (except the conduit volume), LA passive emptying fraction, and LA total emptying fraction compared to control subjects. We observed positive correlations between: VO2max and LA passive emptying fraction (r=0.49, p<0.05); VO2max and LA active emptying fraction (r=0.54, p<0.05); VO2max and LA kinetic energy (r=0.61, p<0.05); and VO2max and LA force (r=0.57, p<0.05). These findings suggest that atrial function reflects exercise capacity in athletes.


Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation?
Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75-1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81-1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52-1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Therefore, despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we do not recommend that POEs be incorporated into the clinical guidelines or advice for such carriers.


[Chronic whiplash syndrome--an overview].
In some countries a seemingly large number of patients suffer from chronic whiplash syndrome, whereas in other countries whiplash is not known or is considered to give only moderate symptoms over a brief period of time. In this paper, this discrepancy is accounted for by a biopsychosocial model, a central element of which is the existence of a large pool of spontaneously occurring symptoms in the population, among them head and neck pain. By the mechanisms of attribution, expectation ("nocebo") and reinforcement, common symptoms may be experienced by the patient as caused exclusively by a mild or moderate trauma. Inappropriate behaviour and harmful treatment may worsen and prolong symptoms. To this one should add the effects of conscious exaggeration of symptoms, under-performance in neuropsychological testing, and underreporting of pre-accident symptoms in a medico-legal context. When assessing litigation claims, it is emphasised that a causal relation between common whiplash injuries and chronic complaints has not been demonstrated; a causal relationship can be accepted in exceptional cases only if a set of minimal criteria are fulfilled.


[A case of persistent left superior vena cava with absent right superior vena cava found on the insertion of central venous catheter].
A 77-year-old man was scheduled to undergo the resection of hepatoma. After the induction of general anesthesia, a central venous (CV) catheter was inserted from the right internal jugular vein under the echographic observation. Then, we noticed that the size of the vein was smaller than usual, which caused a little difficulty in the insertion. The post-insertion chest X-ray showed unusual placement of the catheter's tip toward the left side of the trachea. Re-evaluation of preoperative CT revealed the persistent left superior vena cava (PLSVC) with absent right superior vena cava. Post-operative examination with echography of the neck showed that the left internal jugular vein was much greater than the right. When noticing a small right internal jugular vein in pre-procedure echography, existence of PLSVC should be considered, and meticulous CV catheterization is necessary for safety.


Human amnion epithelial cells modulate the inflammatory response to ventilation in preterm lambs.
Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs. Preterm lambs received intratracheal hAECs (90x106) or vehicle, prior to 2 h of mechanical ventilation. Within 5 min of ventilation onset, lambs also received intravenous hAECs (90x106) or vehicle. Lung histology, bronchoalveolar lavage (BAL) cell phenotypes, and cytokine profiles were examined after 2 h of ventilation, and in unventilated controls. Histological indices of lung injury were higher than control, in vehicle-treated ventilated lambs but not in hAEC-treated ventilated lambs. Ventilation-induced pulmonary leukocyte recruitment was greater in hAEC-treated lambs than in vehicle-treated lambs. Lung IL-1β and IL-6 mRNA expression was higher in vehicle- and hAEC-treated ventilated lambs than in controls but IL-8 mRNA levels were greater than control only in vehicle-treated ventilated lambs. Numbers of CD44+ and CD21+ lymphocytes and macrophages from the lungs were altered in vehicle- and hAEC-treated ventilated lambs. Numbers of CD8+ macrophages were lower in hAEC-treated ventilated lambs than in vehicle-treated ventilated lambs. Indices of systemic inflammation were not different between vehicle- and hAEC-treated lambs. Human amnion epithelial cells modulate the pulmonary inflammatory response to ventilation in preterm lambs, and reduce acute lung injury. Immunomodulatory effects of hAECs reduce lung injury in preterm neonates and may protect against longer-term respiratory disease.


Minimally-Invasive versus Conventional Repair of Spondylolysis in Athletes: A Review of Outcomes and Return to Play.
Spondylolysis from pars fracture is a common injury among young athletes, which can limit activity and cause chronic back pain. While current literature has examined the relative benefits of surgical and conservative management of these injuries, no study has yet compared outcomes between conventional direct repair of pars defects and modern minimally invasive procedures. The goals of surgery are pain resolution, return to play at previous levels of activity, and a shorter course of recovery. In this review, the authors have attempted to quantify any differences in outcome between patients treated with conventional or minimally invasive techniques. A literature search was performed of the PubMed database for relevant articles, excluding articles describing conservative management, traumatic injury, or high-grade spondylolisthesis. Articles included for review involved young athletes treated for symptomatic spondylolysis with either conventional or minimally invasive surgery. Two independent reviewers conducted the literature search and judged articles for inclusion. All studies were classified according to the North American Spine Society standards. Of the 116 results of our initial search, 16 articles were included with a total of 150 patients. Due to a paucity of operative details in older studies and inconsistencies in both clinical methods and reporting among most articles, little quantitative analysis was possible. However, patients in the minimally invasive group did have significantly higher rates of pain resolution (p<0.001). Short recovery times were also noted in this group. Both groups experienced low complication rates, and the majority of patients returned to previous levels of activity. Surgical repair of spondylolysis in young athletes is a safe and practical therapy. Current literature suggests that while conventional repair remains effective, minimally invasive procedures better clinical outcomes. We await further data to conduct a more thorough quantitative analysis of these techniques.


Risk and Protective Factors Associated With Health-Related Quality of Life of Parents With Mental Illness.
Purpose: Health-related quality of life (HRQoL) can be reduced in parents with mental illness (mental illness) who face the dual demands of disabling symptoms and their impact on family, social, and occupational life. This study aimed at analyzing the influence of various factors on HRQoL in parents with mental illness. Method: Baseline data of the German randomized controlled multicenter project CHIMPS (children of parents with mental illness) was used for analyses. The final sample consisted of n = 208 parents with mental illness and n = 197 children and adolescents aged 8-18 years. HRQoL was assessed with the EQ-5D. Results: Parents with mental illness reported significantly lower global and specific HRQoL than the German reference population. They were least satisfied with aspects that relate to anxiety and depression followed by usual activities, pain and discomfort. Better global HRQoL was primarily associated with self-reported physical and mental health, as well as adaptive coping behavior. Associations with mobility, self-care, usual activity, pain and discomfort, anxiety and depression were analyzed and discussed. Conclusions: HRQoL in parents with mental illness is reduced. Clinical interventions should focus on the alleviation of mental health symptoms and probably somatic symptoms and promote adaptive coping skills.


Neuropsychological functioning in end-stage renal disease.
To compare the neuropsychological functioning and behaviour of children with non-syndromic end-stage renal disease (ESRD) and sibling controls. The study was carried out at two tertiary care paediatric teaching hospitals, in Halifax and Vancouver, Canada. Children with ESRD were on a renal transplant waiting list and either pending dialysis or on dialysis therapy. Twenty two patient-sibling pairs were evaluated. Neuropsychological assessments consisting of measures of intelligence, academic achievement, memory, and motor abilities were carried out. Maternal ratings of behaviour and self-report rating of self-esteem were collected. The Verbal, Performance, and Full Scale IQs of patients with ESRD were significantly lower than the IQs of the sibling controls. The mean differences were 8.6, 11.7, and 10.9 points, respectively. ESRD patients also had significantly more difficulty on measures of fine motor coordination and ability to copy geometric designs than sibling controls. There were no differences between groups on measures of academic achievement, memory, behaviour, or self-esteem. Although children with ESRD exhibited mild deficits on measures of intelligence and some measures of motor abilities, their neuropsychological outcome was more favourable than earlier reports indicated.


Injuries in women's gymnastics. The state of the art.
This article takes a three-stage approach to the topic of injuries in women's gymnastics. In the first stage, we review the literature and summarize our current knowledge of injury rates, injuries in specific events, and anatomical location of injuries. In the second, we critically evaluate the relative contributions of these studies in terms of their generalizability, methods, and conceptual approaches. Finally, we present possible directions for future research in the area of women's gymnastic injuries.


Differential cell tropism of feline immunodeficiency virus molecular clones in vivo.
Independent studies have demonstrated different cell tropisms for molecular clones of feline immunodeficiency virus (FIV). In this report, we examined three clones, FIV-pF34, FIV-14, and FIV-pPPR, for replication in Crandell feline kidney (CrFK) cells, feline peripheral blood mononuclear cells (PBMC), and feline macrophage cultures. Importantly, cell tropism for these three clones was also examined in vivo. FIV-pF34 replication was efficient in CrFK cells but severely restricted in PBMC, whereas replication of FIV-pPPR was vigorous in PBMC but severely restricted in CrFK cells. FIV-14 replication was productive in both CrFK cells and PBMC. Interestingly, all three molecular clones replicated with similar efficiencies in primary feline monocyte-derived macrophages. In vivo, FIV-pF34 proved least efficient for establishing persistent infection, and proviral DNA when detectable, was localized predominately to nonlymphoid cell populations (macrophages). FIV-pPPR proved most efficient for induction of a persistent viremia in vivo, and proviral DNA was localized predominately in CD4(+) and CD8(+) lymphocyte subsets. FIV-14 inoculation of cats resulted in an infection characterized by seroconversion and localization of proviral DNA in CD4(+) lymphocytes only. Results of this study on diverse FIV molecular clones revealed that in vitro replication efficiency of an FIV isolate in PBMC directly correlated with replication efficiency in vivo, whereas proficiency for replication in macrophages in vitro was not predictive for replication potential in vivo. Also, infection of both CD4(+) and CD8(+) lymphocyte subsets was associated with higher virus load in vivo. Results of the studies on these three FIV clones, which exhibited differential cell tropism, indicated a correlation between in vitro and in vivo cell tropism and virus replication.


Ethical issues in expanding latent TB management in high burden countries.
Global efforts are being made to eliminate tuberculosis (TB) as a public health problem by 2030. These efforts are being thwarted by the challenge of effective management to minimise the progression of latent TB infection (LTBI) to TB, thereby interrupting the chain of transmission. Approximately 5%-10% LTBI cases eventually develop TB in their lifetime with the risk being higher in children, people living with HIV/AIDS (PLHIV), undernourished people, and patients with diabetes, chronic kidney disease, silicosis, and other comorbid conditions. Apart from operational barriers, complex ethical issues govern decision-making processes in either retaining current LTBI management practices or advocating implementation of the latest World Health Organization guidelines, which suggest extending treatment to vulnerable groups who have a higher risk of progression to TB. Newer LTBI treatment regimens have a diminished risk of toxicity that allays threats to patient safety. Public health justification for treating LTBI can also override patient autonomy, but the lack of a patient-centred approach is associated with poor adherence and treatment outcomes. Cost-effectiveness studies need to evaluate the gains and losses accruing from funding treatment of LTBI versus similar costs in nutritional interventions for managing undernutrition. Similarly, the impact of diverting resources available for management of the existing active TB control programmes to expanding LTBI treatment also needs to be assessed. In conclusion, a comprehensive LTBI treatment strategy built on the basis of high-quality evidence is the best way forward for resolving the ethical considerations at the heart of LTBI management in the developing world. Keywords: Tuberculosis; India; Latent TB; Medical ethics.


In vitro and in vivo enhancement of adipogenesis by Italian ryegrass (Lolium multiflorum) in 3T3-L1 cells and mice.
Adipogenesis is very much important in improving the quality of meat in animals. The aim of the present study was to investigate the in vitro and in vivo adipogenesis regulation properties of Lolium multiflorum on 3T3-L1 pre-adipocytes and mice. Chemical composition of petroleum ether extract of L. multiflorum (PET-LM) confirmed the presence of fatty acids, such as α-linolenic acid, docosahexaenoic acid, oleic acid, docosatetraenoic acid, and caprylic acid, as the major compounds. PET-LM treatment increased viability, lipid accumulation, lipolysis, cell cycle progression, and DNA synthesis in the cells. PET-LM treatment also augmented peroxysome proliferator activated receptor (PPAR)-γ2, CCAAT/enhancer binding protein-α, adiponectin, adipocyte binding protein, glucose transporter-4, fatty acid synthase, and sterol regulatory element binding protein-1 expression at mRNA and protein levels in differentiated adipocytes. In addition, mice administered with 200 mg/kg body weight PET-LM for 8 weeks showed greater body weight than control mice. These findings suggest that PET-LM facilitates adipogenesis by stimulating PPARγ-mediated signaling cascades in adipocytes which could be useful for quality meat development in animals.


Primary adrenal lymphoma: a systematic review.
Fewer than 200 cases of primary adrenal lymphoma (PAL) have been reported. We have systematically reviewed all 187 cases of PAL reported in the English literature until June 2013, from which we drew the following conclusions: PAL is typically a highly symptomatic and aggressive, metabolically hyperactive, hypovascular, hypoechoic (and heterogeneous on ultrasound), hypodense (with slight to moderate enhancement on computed tomography), high-grade lymphoma, primarily affecting elderly males and presenting with large bilateral adrenal masses. Most cases have adrenal insufficiency, B-symptoms, and elevated lactate dehydrogenase. Hepatosplenomegaly, lymphadenopathy, concurrent or prior immune dysregulation, and bone marrow involvement are uncommon. Epstein-Barr virus positivity is observed in more than half of cases and the disease is disseminated at presentation in 18 % of cases. The two most common WHO 2008-defined PAL subtypes are diffuse large B cell lymphoma (78 %) and peripheral T cell lymphoma (7 %). The prognosis of PAL has improved with the advent of rituximab-containing chemotherapeutic regimens. According to our results, administration of chemotherapy and adrenal insufficiency are significant independent predictors of prognosis.


Methodological aspects of ELISA analysis of thioredoxin 1 in human plasma and cerebrospinal fluid.
Thioredoxin-1 (Trx1) is a protein antioxidant involved in major cellular processes. Increased plasma levels of Trx1 have been associated with human diseases suggesting that Trx1 is a marker for oxidative stress with putative clinical use. However, the reported mean levels of Trx1 in the control cohorts vary a hundred-fold between studies (0.8-87 ng/ml), possibly due to methodological differences between the capture ELISA used in the different studies. The aim of this study was to investigate methodological aspects related to the ELISA measurement of Trx1. ELISAs utilizing different capture and detection combinations of antibodies to Trx1 and as well as recombinant human (rh) Trx1 standards from two sources were characterized. The different ELISAs were subsequently used to measure Trx1 in human plasma and cerebrospinal fluid samples (CSF) from healthy donors and from patients with various neurological diagnoses. The Trx1 standards differed in their content of monomeric and oligomeric Trx1, which affected the ELISAs composed of different antibody combinations. Thus, the levels of Trx1 determined in human plasma and CSF samples varied depending on the antibody used in the ELISAs and on the rhTrx1 standard. Furthermore, the relevance of preventing interference by heterophilic antibodies (HA) in human plasma and CSF was investigated. The addition of a HA blocking buffer to human samples drastically reduced the ELISA signals in many samples showing that HA are likely to cause false positive results unless they are blocked. In conclusion, the study shows that the design of a Trx1 ELISA in regards to antibodies and standards used has an impact on the measured Trx1 levels. Importantly, analyses of human plasma and CSF without preventing HA interference may obscure the obtained data. Overall, the results of this study are crucial for the improvement of future studies on the association of Trx1 levels with various diseases.


A pivotal role for pneumolysin in the immunopathogenesis, treatment and prevention of pneumococcal disease.
The pneumococcus remains an extremely important cause of morbidity and mortality worldwide. While the microorganism has a number of significant virulence mechanisms, many recent studies have focused on pneumolysin, which is recognised to be one of the most important virulence factors of the organism. The purpose of this manuscript is to review recent developments with respect to the role of pneumolysin in pneumococcal disease. It describes how the cytotoxic and other pro-inflammatory activities of this toxin contribute to disease pathogenesis and pathology, as well as various immunological and pharmacological strategies that may target these deleterious effects of the toxin.


STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment.
Although type I IFNs play critical roles in antiviral and antitumor activity, it remains to be elucidated how type I IFNs are produced in sterile conditions of the tumor microenvironment and directly affect tumor-infiltrating immune cells. Mouse de novo gliomas show increased expression of type I IFN messages, and in mice, CD11b(+) brain-infiltrating leukocytes (BIL) are the main source of type I IFNs that are induced partially in a STING (stimulator of IFN genes)-dependent manner. Consequently, glioma-bearing Sting(Gt) (/Gt) mice showed shorter survival and lower expression levels of Ifns compared with wild-type mice. Furthermore, BILs of Sting(Gt) (/Gt) mice showed increased CD11b(+) Gr-1(+) immature myeloid suppressor and CD25(+) Foxp3(+) regulatory T cells (Treg) and decreased IFNγ-producing CD8(+) T cells. CD4(+) and CD8(+) T cells that received direct type I IFN signals showed lesser degrees of regulatory activity and increased levels of antitumor activity, respectively. Finally, intratumoral administration of a STING agonist (cyclic diguanylate monophosphate; c-di-GMP) improved the survival of glioma-bearing mice associated with enhanced type I IFN signaling, Cxcl10 and Ccl5, and T-cell migration into the brain. In combination with subcutaneous OVA peptide vaccination, c-di-GMP increased OVA-specific cytotoxicity of BILs and prolonged their survival. These data demonstrate significant contributions of STING to antitumor immunity via enhancement of type I IFN signaling in the tumor microenvironment and suggest a potential use of STING agonists for the development of effective immunotherapy, such as the combination with antigen-specific vaccinations.


Learning causal networks with latent variables from multivariate information in genomic data.
Learning causal networks from large-scale genomic data remains challenging in absence of time series or controlled perturbation experiments. We report an information- theoretic method which learns a large class of causal or non-causal graphical models from purely observational data, while including the effects of unobserved latent variables, commonly found in many genomic datasets. Starting from a complete graph, the method iteratively removes dispensable edges, by uncovering significant information contributions from indirect paths, and assesses edge-specific confidences from randomization of available data. The remaining edges are then oriented based on the signature of causality in observational data. The approach and associated algorithm, miic, outperform earlier methods on a broad range of benchmark networks. Causal network reconstructions are presented at different biological size and time scales, from gene regulation in single cells to whole genome duplication in tumor development as well as long term evolution of vertebrates. Miic is publicly available at https://github.com/miicTeam/MIIC.


Analgesic and spasmolytic effects of dipyrone, hyoscine-N-butylbromide and a combination of the two in ponies.
The analgesic and spasmolytic effects of dipyrone (Novalgin) (2500 mg/100 kg bodyweight) hyoscine-N-butylbromide (Buscopan) (20 mg/100 kg bodyweight) and a combination of both drugs were evaluated in a balloon-induced model of colic, using five ponies with caecal fistulae. The drugs were given intravenously and 0.9 per cent sodium chloride solution (5 ml/100 kg bodyweight) was used as a control. The physiological saline solution and dipyrone had no effect on caecal contractions. After the injection of hyoscine-N-butylbromide and the drug combination caecal contractions ceased within 30 seconds and for 20 and 24 minutes, respectively (P less than 0.05). The results on pain relief were not statistically significant for any of the drugs. Dipyrone had a good analgesic effect in only two of the ponies, starting after eight to 10 minutes and lasting for 50 minutes. The drug combination relieved pain within 30 seconds after injection and the relief lasted for 50 minutes in three of the ponies and for 20 minutes in the other two. Hyoscine-N-butylbromide alone produced an analgesic effect within 30 seconds after injection which lasted for 20 minutes.


Algorithm for designing free-form imaging optics with nonrational B-spline surfaces.
The local control of B-spline surfaces has the potential to provide better surface representation for free-form imaging optics; however, it also makes B-spline surface optimization more challenging. To solve this problem, we, for the first time to the best of our knowledge, present an algorithm to design free-form imaging optics with nonrational B-spline surfaces. In this method, the local z-coordinates of a set of data points on B-spline surfaces are defined as independent variables, and the location of each ray point in the image plane is considered as a nonlinear function of these independent variables. By this mathematical consideration, a prescribed imaging system design with B-spline surfaces can be converted into an overdetermined system of nonlinear equations, and the least-squares solution to this nonlinear problem is found by using the Gauss-Newton method based on a ray-tracing technique. An off-axis two-mirror system is presented to demonstrate the elegance of this method in imaging system design with B-spline surfaces.


Methanolic extract of Cuminum cyminum inhibits ovariectomy-induced bone loss in rats.
Several animal and clinical studies have shown that phytoestrogens, plant-derived estrogenic compounds, can be useful in treating postmenopausal osteoporosis. Phytoestrogens and phytoestrogen-containing plants are currently under active investigation for their role in estrogen-related disorders. The present study deals with anti-osteoporotic evaluation of phytoestrogen-rich plant Cuminum cyminum, commonly known as cumin. Adult Sprague-Dawley rats were bilaterally ovariectomized (OVX) and randomly assigned to 3 groups (10 rats/group). Additional 10 animals were sham operated. OVX and sham control groups were orally administered with vehicle while the other two OVX groups were administered 0.15 mg/kg estradiol and 1 g/kg of methanolic extract of Cuminum cyminum fruits (MCC) in two divided doses for 10 weeks. At the end of the study blood, bones and uteri of the animals were collected. Serum was evaluated for calcium, phosphorus, alkaline phosphatase and tartarate resistant acid phosphatase. Bone density, ash density, mineral content and mechanical strength of bones were evaluated. Scanning electron microscopic (SEM) analysis of bones (tibia) was performed. Results were analyzed using ANOVA and Tukeys multiple comparison test. MCC (1 g/kg, p.o.) significantly reduced urinary calcium excretion and significantly increased calcium content and mechanical strength of bones in comparison to OVX control. It showed greater bone and ash densities and improved microarchitecture of bones in SEM analysis. Unlike estradiol it did not affect body weight gain and weight of atrophic uterus in OVX animals. MCC prevented ovariectomy-induced bone loss in rats with no anabolic effect on atrophic uterus. The osteoprotective effect was comparable with estradiol.


Dynamic assessment of the pupillary reflex in patients on high-dose opioids.
Background and aims Pupil size and reaction are influenced by opioids, an effect that is not considered to be affected by opioid tolerance. As clinicians have observed patients on high-dose opioids who exhibited seemingly normal pupil sizes, we wanted to dynamically assess the pupillary reflex in cancer patients on high-dose opioids. Methods We performed a dynamic assessment of the pupillary reflex in cancer patients on high-dose opioids and a control group of healthy volunteers using a portable, monocular, infrared pupillometer. We also performed a clinical examination and measured blood concentrations of opioids and their active metabolites. Results Sixty three patients who were on opioids for 2 months (median time) and on an oral morphine equivalent dose of 250 mg (median dose) were investigated. Most patients used more than one opioid. When correcting for age, pupil size in the group that had received no increase of opioid dose over the last 14 days was not significantly different from pupil size in the healthy volunteer group (p = 0.76), while the group that had increased the dose of opioids differed significantly from healthy volunteers (p = 0.006). We found no statistically significant correlation between total oral morphine equivalents and pupillary reactions or between blood opioid or opioid metabolite concentrations and baseline pupillary changes. Conclusion Pupillary changes do take place in patients on opioids. However, tolerance to these changes occurs when medication is not increased over time. Dynamic pupillometry can give additional information about the degree of tolerance to opioids. Implications These findings elucidate previous misconceptions regarding pupillary effects and tolerance to opioids.


Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model.
Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the 'blood tumor barrier' (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg(-1). This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823 ± 600, 1817 ± 732 and 2432 ± 448 ng g(-1)) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222 ± 784, 3687 ± 796 and 5658 ± 821 ng g(-1)) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.


Changes in daily occupations and the meaning of work for three women caring for relatives post-stroke.
This qualitative study explored how some working Austrians experienced and coped with changes in their daily occupations after becoming informal carers of persons who had had a stroke. The study provides insights into the working carers' occupational experiences and strategies during a period of pronounced life changes. Three participants, who were employed in full- or part-time work, as well as being informal carers of persons who had had a stroke, were interviewed on two occasions. The data from these interviews were analysed using Interpretative Phenomenological Analyses. Carers found themselves in an ongoing process, ranging from the disruption of daily occupations to their eventual restructure. First, the stroke led to involuntary changes in the carers' daily life, which resulted in challenges in their own, and in shared, occupations. Second, carers actively changed their values and performance of occupations, which appeared to be a strategy to shape their well-being. Paid work was found to be a stabilizing and balancing occupation, which contributed to coping and the well-being of carers. The authors' findings demonstrate the benefits of paid work and engagement in meaningful occupation for the carers' well-being. These results should encourage occupational therapists to be sensitive to the complexity of the lives of working informal carers.


Bacteria fauna from the house fly, Musca domestica (L.).
The house fly, Musca domestica has long been considered a potential agent for disease transmission ever since its existence. The general truth of this assertion remains undisputed till the present day in spite of increasing awareness toward an improved sanitation and better hygiene. The habitual movement of house fly from filthy substrata such as human faeces, animal excreta, carcasses, garbage, etc. makes them ideal candidates for disease transmission such as cholera, shigellosis, salmonellosis and others when settling on food. Fly as a potential mechanical vector of pathogenic bacteria was elucidated in this study by examining flies from various breeding sites such as food courts, dumping ground, food processing areas and poultry farm in Peninsular Malaysia. The flies were baited with 10% sugar solution on a glass slide in the field. All materials used for collection of samples were sterile. Bacteria from fly sample were isolated using the normal isolation technique. Bacillus sp., Coccobacillus sp., Staphylococcus sp., Microccus sp., Streptococcus sp., Acinetobacter sp., Enterobacter sp., Proteus sp., Escherichia sp., Klebsiella sp. and yeast cells were isolated from feaces, vomitus, external surfaces and internal organs of house fly. Newly emerged house fly did not harbour any bacteria.


MR imaging of metallic implants and materials: a compilation of the literature.
Ferromagnetic metallic implants and materials are regarded as contraindications for MR imaging because of the potential risks associated with their movement or displacement. To date, 14 published articles have evaluated the ferromagnetic qualities of 127 different metallic implants and other materials, including aneurysm and hemostatic clips (32); dental implants and materials (five); intravascular coils, filters, and stents (13); ear implants (14); prosthetic heart valves (29); orthopedic implants and materials (eight); penile implants (nine); and miscellaneous metallic implants and materials (17). All of these materials were evaluated by measuring the deflection forces induced by static magnetic fields at strengths ranging from 0.147 to 4.7 T. This article is a compilation of the results of these studies; it lists all 127 of the materials tested, indicates whether they were found to be deflected by the static magnetic fields, and gives the highest static magnetic field strength at which they were evaluated. Of the metallic implants tested, 66 were nonferromagnetic, and 29 exhibited only minimal deflection relative to their in vivo applications (i.e., the deflection forces were thought to be insufficient to move or dislodge the implant or material in situ). The authors of these studies concluded that patients with these particular metallic implants or materials (95/127, 75%) can be examined safely by MR imaging with scanners having static magnetic field strengths up to and including those used for the specific evaluations. Patients with other ferromagnetic materials or implants may also undergo MR imaging safely; however, both careful consideration of the factors that influence the deflection of metallic implants and prudent clinical judgment are required before patients who have these objects are examined via MR imaging.


The use of waterworks sludge for the treatment of dye wastes.
Water treatment works using coagulation/flocculation in the process stream will generate a waste sludge. The works in Adana, Turkey uses ferric chloride. The potential for using this sludge for the treatment of reactive, direct, disperse, acidic, and basic dyestuffs by coagulation and sorption has been investigated. The sludge acted as a coagulant and removed colour with excellent removal efficiencies being obtained for basic, disperse and direct dyes. The optimum conditions were a pH value of 5 and a sludge dose of 2000 mg l(-1). Mediocre results were obtained for acidic and reactive dyes. The efficiency of the sludge was also compared with alum and ferric chloride for the same group of dyes. The sludge was also used as a coagulant to treat the wastewater from a textile factory. At doses of 2000-4000 mg l(-1), the sludge was as effective as ferric chloride and alum at removing COD. Sorption tests showed that the disperse and reactive dyes did not bind to the sludge. Langmuir and Freundlich constants were determined for the other three types of dye. Rate constants for the adsorption were determined using the Lagergren equation.


Surgical treatment of the acute cholecystitis in the laparoscopic age. A comparative study: laparoscopy against laparatomy.
The aim of this study was to assess the complications and results of the laparoscopic opposite to open treatment of the acute cholecystitis. A retrospective randomized study with two groups of 30 patients each one. The parameters tested were age, sex, risk factors, surgical time, hospital stay, cholecystitis type, and early or late complications. In the two groups there were no significant differences in age, sex, risk factors, type of cholecystitis and surgical time. The average of hospital stay was significantly longer for open cholecystectomy (9.5) than for laparoscopic technique (2.30) (p < 0.001). The complication rate was higher (7.30%) in open cholecystectomy. The laparoscopic cholecystectomy should be the standard procedure for the treatment of the acute cholecystitis.


Comparison of transcatheter arterial chemoembolization and microsphere embolization for treatment of unresectable hepatocellular carcinoma: a meta-analysis.
Survival of patients with surgically unresectable hepatocellular carcinoma (HCC) is very poor due to the limited effective treatments available. Transhepatic arterial chemoembolization (TACE) and microsphere embolization may offer hope for such patients; however, to date, their efficacy has not been evaluated. This study was designed to compare the effectiveness of these two treatments for patients with unresectable HCC. This meta-analysis searched literature using various databases and revealed 13 studies on surgically unresectable HCC patients treated with TACE or microsphere embolization. Response rate, 1-year survival, overall survival, and time to progression were then analyzed and compared. These thirteen studies included 597 and 1,233 patients with unresectable HCC for microsphere embolization and chemoembolization treatments, respectively. The data showed that microsphere embolization therapy was significantly better for longer overall survival, 1-year survival, longer time to progression, and complete or partial response rate than that of chemoembolization treatment. These data demonstrated that microsphere embolization treatment of patients with surgically unresectable HCC provided much better survival and treatment response than that of TACE.


Case of Bartter syndrome presenting with hypokalemic periodic paralysis.
Hypokalemic periodic paralysis can occur secondarily to excessive potassium loss. Thyrotoxicosis, diuretic ingestions, hyperaldosteronism, barium poisoning, Gitelman syndrome, and Bartter syndrome are among the disorders causing secondary hypokalemic periodic paralysis. Clinical presentation of Bartter syndrome with hypokalemic periodic paralysis is rare. A 12-year-old boy was admitted to our hospital because of transient paralysis. He had been suffering from transient weakness attacks for 2 years and had had a total of 10 attacks, lasting 1 to 3 days. He had growth retardation, polyuria, and polydipsia. Laboratory examinations revealed hypokalemic alkalosis, normomagnesemia, hypercalciuria, and hyperaldosteronism. The clinical and laboratory findings were in accordance with Bartter syndrome. He has been followed up for 6 months and has suffered no further paralytic attacks under indomethacin therapy. This case highlights the importance of blood pH measurement in patients with hypokalemic periodic paralysis; it might prevent misdiagnosis and mismanagement in such diseases.


Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2.
Thrombosis results in heparin-induced thrombocytopenia (HIT) from cellular activation involving Fc receptors. In this study, the FcγRIIA 131RR genotype was found to increase the risk of thrombosis in HIT patients (odds ratio: 5.9; 95% confidence interval: 1.7-20). When platelet aggregation tests (PATs) were performed with platelet-rich plasma (PRP), a shorter lag time was measured in 131RR donors compared to individuals with the HR and HH genotypes in response to HIT plasma or 5B9, a recently developed humanized monoclonal antibody to PF4/heparin. Importantly, this difference was no longer detectable when PATs were performed with washed platelets or immunoglobulin (Ig)G-depleted PRP. Moreover, polyclonal IgG or monoclonal IgG1 added to IgG-depleted PRP increased the lag time in response to 5B9. HH platelets were also sensitive to IgG2, which in contrast, failed to inhibit the response of 131RR platelets to 5B9. Finally, higher tissue factor messenger RNA levels were measured in the whole blood of 131RR donors after activation by HIT antibodies, with increased phospholipid procoagulant activity. These results demonstrate that HIT patients homozygous for the FcγRIIA 131R allele have a higher risk of thrombosis, probably due to increased cell activation by antibodies to PF4/heparin, with a lower inhibitory effect of endogenous IgG, especially from the IgG2 subclass.


Glyphosate-based herbicide enhances the uterine sensitivity to estradiol in rats.
In a previous work, we detected that postnatal exposure to a glyphosate-based herbicide (GBH) alters uterine development in prepubertal rats causing endometrial hyperplasia and increasing cell proliferation. Our goal was to determine whether exposure to low-dose of a GBH during postnatal development might enhance the sensitivity of the uterus to an estrogenic treatment. Female Wistar pups were subcutaneously injected with saline solution (control) or GBH using the reference dose (2 mg/kg/day, EPA) on postnatal days (PND) 1, 3, 5, and 7. At weaning (PND21), female rats were bilaterally ovariectomized and treated with silastic capsules containing 17β-estradiol (E2, 1mg/ml) until they were two months of age. On PND60, uterine samples were removed and processed for histology, immunohistochemistry and mRNA extraction to evaluate: i) uterine morphology, ii) uterine cell proliferation by the detection of Ki67, iii) the expression of the estrogen receptors alpha (ESR1) and beta (ESR2), and iv) the expression of WNT7A and β-catenin. GBH-exposed animals showed increased luminal epithelial height and stromal nuclei density. The luminal and glandular epithelium were markedly hyperplastic in 43% of GBH-exposed animals. GBH exposure caused an increase in E2-induced cell proliferation in association with an induction of both ESR1 and ESR2. GBH treatment decreased membranous and cytoplasmic expression of β-catenin in luminal and glandular epithelial cells and increased WNT7A expression in the luminal epithelium. These results suggest that early postnatal exposure to a GBH enhances the sensitivity of the rat uterus to estradiol, and induces histomorphological and molecular changes associated with uterine hyperplasia.


Per- and polyfluoroalkyl substances and kidney function: Follow-up results from the Diabetes Prevention Program trial.
Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in populations worldwide and may hinder kidney function. The objective of the study was to determine longitudinal associations of plasma PFAS concentrations with estimated glomerular filtration rate (eGFR) and evaluate whether a lifestyle intervention modify the associations. We studied 875 participants initially randomized to the lifestyle or placebo arms in the Diabetes Prevention Program (DPP, 1996-2002) trial and Outcomes Study (DPPOS, 2002-2014). We ran generalized linear mixed models accounting a priori covariates to evaluate the associations between baseline PFAS concentrations and repeated measures of eGFR, separately, for six PFAS (PFOS, PFOA, PFHxS, EtFOSAA, MeFOSAA, PFNA); then used quantile-based g-computation to evaluate the effects of the six PFAS chemicals as a mixture. The cohort was 64.9% female; 73.4% 40-64 years-old; 29.4% with hypertension; 50.5% randomized to lifestyle intervention and 49.5% to placebo and had similar plasma PFAS concentrations as the general U.S. population in 1999-2000. Most participants had normal kidney function (eGFR > 90 mL/min/1.73 m2) over the approximately 14 years of follow-up. We found that plasma PFAS concentrations during DPP were inversely associated with eGFR during DPPOS follow-up. Each quartile increase in baseline plasma concentration of the 6 PFAS as a mixture was associated with 2.26 mL/min/1.73 m2 lower eGFR (95% CI: -4.12, -0.39) at DPPOS Year 5, approximately 9 years since DPP randomization and PFAS measurements. The lifestyle intervention did not modify associations, but inverse associations were stronger among participants with hypertension at baseline. Among prediabetic adults, we found inverse associations between baseline plasma PFAS concentrations and measures of eGFR throughout 14 years of follow-up. The lifestyle intervention of diet, exercise and behavioral changes did not modify the associations, but persons with hypertension may have heightened susceptibility.


MDM2 promoter SNP55 (rs2870820) affects risk of colon cancer but not breast-, lung-, or prostate cancer.
Two functional SNPs (SNP285G > C; rs117039649 and SNP309T > G; rs2279744) have previously been reported to modulate Sp1 transcription factor binding to the promoter of the proto-oncogene MDM2, and to influence cancer risk. Recently, a third SNP (SNP55C > T; rs2870820) was also reported to affect Sp1 binding and MDM2 transcription. In this large population based case-control study, we genotyped MDM2 SNP55 in 10,779 Caucasian individuals, previously genotyped for SNP309 and SNP285, including cases of colon (n = 1,524), lung (n = 1,323), breast (n = 1,709) and prostate cancer (n = 2,488) and 3,735 non-cancer controls, as well as 299 healthy African-Americans. Applying the dominant model, we found an elevated risk of colon cancer among individuals harbouring SNP55TT/CT genotypes compared to the SNP55CC genotype (OR = 1.15; 95% CI = 1.01-1.30). The risk was found to be highest for left-sided colon cancer (OR = 1.21; 95% CI = 1.00-1.45) and among females (OR = 1.32; 95% CI = 1.01-1.74). Assessing combined genotypes, we found the highest risk of colon cancer among individuals harbouring the SNP55TT or CT together with the SNP309TG genotype (OR = 1.21; 95% CI = 1.00-1.46). Supporting the conclusions from the risk estimates, we found colon cancer cases carrying the SNP55TT/CT genotypes to be diagnosed at younger age as compared to SNP55CC (p = 0.053), in particular among patients carrying the SNP309TG/TT genotypes (p = 0.009).


Polymeric vesicles: from drug carriers to nanoreactors and artificial organelles.
One strategy in modern medicine is the development of new platforms that combine multifunctional compounds with stable, safe carriers in patient-oriented therapeutic strategies. The simultaneous detection and treatment of pathological events through interactions manipulated at the molecular level offer treatment strategies that can decrease side effects resulting from conventional therapeutic approaches. Several types of nanocarriers have been proposed for biomedical purposes, including inorganic nanoparticles, lipid aggregates, including liposomes, and synthetic polymeric systems, such as vesicles, micelles, or nanotubes. Polymeric vesicles--structures similar to lipid vesicles but created using synthetic block copolymers--represent an excellent candidate for new nanocarriers for medical applications. These structures are more stable than liposomes but retain their low immunogenicity. Significant efforts have been made to improve the size, membrane flexibility, and permeability of polymeric vesicles and to enhance their target specificity. The optimization of these properties will allow researchers to design smart compartments that can co-encapsulate sensitive molecules, such as RNA, enzymes, and proteins, and their membranes allow insertion of membrane proteins rather than simply serving as passive carriers. In this Account, we illustrate the advances that are shifting these molecular systems from simple polymeric carriers to smart-complex protein-polymer assemblies, such as nanoreactors or synthetic organelles. Polymeric vesicles generated by the self-assembly of amphiphilic copolymers (polymersomes) offer the advantage of simultaneous encapsulation of hydrophilic compounds in their aqueous cavities and the insertion of fragile, hydrophobic compounds in their membranes. This strategy has permitted us and others to design and develop new systems such as nanoreactors and artificial organelles in which active compounds are simultaneously protected and allowed to act in situ. In recent years, we have created a variety of multifunctional, proteinpolymersomes combinations for biomedical applications. The insertion of membrane proteins or biopores into the polymer membrane supported the activity of co-encapsulated enzymes that act in tandem inside the cavity or of combinations of drugs and imaging agents. Surface functionalization of these nanocarriers permitted specific targeting of the desired biological compartments. Polymeric vesicles alone are relatively easy to prepare and functionalize. Those features, along with their stability and multifunctionality, promote their use in the development of new theranostic strategies. The combination of polymer vesicles and biological entities will serve as tools to improve the observation and treatment of pathological events and the overall condition of the patient.


Abobotulinum - a toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor - only injections.
To evaluate if the injections of abobotulinum-A toxin in trigone and bladder neck/prostatic urethra in addition to detrusor provides better symptoms relief and urodynamic findings in patients with idiopathic detrusor overactivity (IDO) refractory to medical treatment. A total of 74 patients with IDO refractory to anticholinergics received injections in detrusor, trigone and bladder neck/prostatic urethra (Group A, N=36) versus detrusor only injections (Group B, N=38) of abobotulinum-A toxin. All patients were evaluated by a standard overactive bladder symptom score (OABSS) questionnaire and cystometrography before and 6 weeks after the operation. OABSS questionnaire was also completed 20 weeks after the operation. The magnitude of OABSS reduction from baseline to 6 weeks after operation in groups A and B patients was 13.4±2.2 versus 11.7±2.1 (p=0.001). Cystometry results were similar in both groups except for higher volume at urgent desire to void in Group B patients (p <0.001). The mean±SD change in residual volume in Group A at 6 weeks after the operation was -4.8±28.6mL (p=0.33) compared to 21.3±16.9mL in Group B patients (p <0.001). In patients with IDO, adding trigone, and bladder neck/prostatic urethra as sites of abobotulinum- A toxin injection produces greater reductions in OABSS score and less residual urine volume but a lower volume at urgent desire to void in comparison with detrusor only injections.