[Clinical evaluation of high dose rate intra-cavitary irradiation in the treatment of uterine cervical cancer, combined with pepleomycin suppository in uterine cavity].
By means of re-irradiation using pepleomycin suppository in uterine cavity, we attained local control for one patient who had local recurrence in uterine cavity and suffered from uterine fluor in which viable cancer cells were confirmed. We were enlightened by this therapeutic experience, so we attempted combination therapy using pepleomycin suppositories to supplement intra-cavitary irradiation, for the 11 selected patients who were suffering from uterine fluor. We investigated the treatment results in 7 patients of stage III out of 11 patients (of all stages), in comparison with 13 patients of stage III who were treated by irradiation alone. Consequently, these treatment results were approximately equivalent, and the incidence of sigmoid complications could be decreased. Side effects which were followed by the combination therapy were not serious, and so we believe that pepleomycin suppository is a simple method and valuable to supplement radiation therapy of uterine cervical cancer.


Immunogenetic Determinants of Parkinson's Disease Etiology.
Parkinson's disease (PD) is increasingly recognised as a systemic disorder in which inflammation might play a causative role rather than being a consequence or an epiphenomenon of the neurodegenerative process. Although growing genetic evidence links the central and peripheral immune system with both monogenic and sporadic PD, our understanding on how the immune system contributes to PD pathogenesis remains a daunting challenge. In this review, we discuss recent literature aimed at exploring the role of known genes and susceptibility loci to PD pathogenesis through immune system related mechanisms. Furthermore, we outline shared genetic etiologies and interrelations between PD and autoimmune diseases and underlining challenges and limitations faced in the translation of relevant allelic and regulatory risk loci to immune-pathological mechanisms. Lastly, with the field of immunogenetics expanding rapidly, we place these insights into a future context highlighting the prospect of immune modulation as a promising disease-modifying strategy.


[Ultrasonographic evaluation of gallbladder and gastric emptying after ingestion of water with various saline compositions].
Evaluation of gallbladder and gastric emptying after ingestion of a saline enriched water ("Acqua Santa" di Chianciano) in comparison with a commercial oligomineral water. A 40-minute blind prospective study. The study was performed at the Terme of Chianciano (Siena) for subjects of group A and at the Institute of Clinica Medica Generale and Terapia Medica of the University of Bologna for subjects of group B. Two groups of healthy subjects were studied. Each group consisted of 12 subjects without gallbladder disease. Fasting subjects of group A ingested alternatively, for two consecutive mornings, 400 ml of the saline enriched water at the natural temperature of 33 degrees C or 400 ml of oligomineral water warmed to the same temperature. Subjects of group B ingested the same waters at 18 degrees C. Gastric and gallbladder emptying were evaluated, after ingestion of the different waters, by means of ultrasonography. In both groups gallbladder emptying was significantly higher after ingestion of the saline enriched water. On the other hand gastric emptying was similar with both waters. This study demonstrated that saline enriched water determines a greater emptying of the gallbladder in comparison with an oligomineral water. This effects is not related to gastric emptying but rather it is due to a higher concentration of saline components and thus to their possible effect on gallbladder motility.


Radiocontrast-induced DNA fragmentation of renal tubular cells in vitro: role of hypertonicity.
Radiocontrast-induced nephropathy is a clinically important complication of invasive cardiological procedures. It has been associated with DNA fragmentation of renal tubular cells, which is a hallmark feature of programmed cell death (apoptosis). We investigated the mechanism of this DNA fragmentation in an in vitro model of radiocontrast cytotoxicity on renal epithelial cells. Madin Darby canine kidney (MDCK) cell monolayers were incubated (for 2-8 h) with isoiodine doses (37-111 mg iodine/ml) of the highly hyperosmolal, ionic radiocontrast agent diatrizoate or of the less hyperosmolal, non-ionic substance iopamidol. Mannitol, urea, and NaCl control media of corresponding hyperosmolality were used to evaluate the contribution of hypertonicity, hyperosmolality and/or ionic strength to radiocontrast toxicity. DNA fragmentation was assessed using fluorescence-activated cell sorting (FACS), agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated deoxyuridine nick end labelling (TUNEL), cell morphology was analysed in Giemsa-stained cytospins. Diatrizoate induced concentration- and time-dependent DNA fragmentation of MDCK cells which was associated with morphological signs of apoptosis. Cycloheximide (1 microg/ml) did not prevent diatrizoate-induced DNA fragmentation, indicating that it is not dependent on protein synthesis. Diatrizoate-mediated cell death was associated with cell detachment from the tissue culture matrix. However, the DNA fragmentation is not a consequence of cell detachment since the prevention of cell attachment on agarose-coated dishes induced significantly less DNA fragmentation than diatrizoate. Iopamidol caused no detectable DNA breakdown. In contrast, hypertonic mannitol and sodium chloride, but not hyperosmolal urea, induced DNA fragmentation in MDCK cells, albeit less than diatrizoate. The DNA fragmentation of MDCK cells induced by diatrizoate is related to its hypertonicity in this in vitro model of radiocontrast cytotoxicity. Nuclear disintegration with subsequent cell death may contribute to the pathophysiology of radiocontrast-induced nephropathy, particularly in the hypertonic/hypoxic environment of the renal medulla. The present results underscore the importance of avoiding hyperosmolal urine states in patients at high risk of radiocontrast-induced nephropathy.


Impact of sludge retention time on the fine composition of the microbial community and extracellular polymeric substances in a membrane bioreactor.
Membrane bioreactors (MBRs) are an advanced technology for wastewater treatment whose wide application has been hindered by rapid fouling of the membranes. MBRs can be operated with long sludge retention time (SRT), a crucial parameter impacting microbial selection in the reactor. This also affects filtration performance, since a major fouling agent are the extracellular polymeric substances (EPS). In this study, the impact of the SRT on the ecophysiology of the MBRs and, consequently, on membrane fouling was evaluated. A MBR was operated under a SRT of 60 days followed by a SRT of 20 days. A comprehensive analysis of the microbial community structure and EPS proteins and polysaccharide profiles of the mixed liquor and cake layer was carried out throughout both operation periods. The results of this study showed that the imposition of a shorter SRT led to a shift in the dominant bacterial populations. The mixed liquor and cake layer communities were very different, with Actinomycetales order standing out in the cake layer at SRT of 20 days. Overall, higher EPS concentrations (particularly proteins) were found at this SRT. Furthermore, EPS profiles were clearly affected by the SRT: it was possible to correlate a group of soluble EPS proteins with the SRT of 60 days, and a lower sludge age led to a lower diversity of polysaccharide sugar monomers, with an increase of glucose and galactose in the cake layer. This study improves our knowledge regarding the molecular reasons for fouling, which may contribute to improve MBR design and operation.


A decade of atrial fibrillation ablation : Shifts in patient characteristics and procedural outcomes.
Over the past decade, radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) has evolved into a frequently performed procedure. The aim of this study was to monitor changes in patient characteristics, procedural characteristics, outcomes and complications over the past 10 years. All consecutive patients who underwent primary RFCA treatment of AF in the University Medical Center Utrecht from 2005-2015 were included. In all patients, the primary ablation strategy was pulmonary vein (PV) antrum isolation without additional substrate modification. Baseline patient and procedure characteristics, and 1‑year follow-up data of 975 patients were prospectively collected. In 2005, 73.4% of patients suffered from paroxysmal AF, which decreased to 45.3% in 2014. Mean age increased from 54 ± 9 to 61 ± 10 years and CHA2DS2-VASc score ≥2 from 18 to 40.6%. History of AF decreased significantly from 7 to 4 years. Mean procedure duration was 237 ± 53 min in 2005 and 163 ± 41 min in 2014. Fluoroscopy time significantly decreased from 41 ± 17 to 19 ± 8 min and total radiation exposure from 465 (263-687) to 210 (118-376) mGy. One-year success remained similar (2005: 55.6%, 2014: 54.8%), as did the amount of PV reconnection observed during redo procedures. Due to a marked reduction in vascular complications and moderate PV stenosis, the total complication rate decreased significantly. Over the past decade, AF ablation has increasingly been performed in older patients with persistent AF and more comorbidity. Moreover, it has been performed earlier after AF diagnosis. Although several performance parameters, such as procedure duration and complication rate, improved, 1‑year single procedure success remained unchanged.


Tracking a century of changes in microbial eukaryotic diversity in lakes driven by nutrient enrichment and climate warming.
High-throughput sequencing of sedimentary DNA (sed-DNA) was utilized to reconstruct the temporal dynamics of microbial eukaryotic communities (MECs) at a centennial scale in two re-oligotrophicated lakes that were exposed to different levels of phosphorus enrichment. The temporal changes within the MECs were expressed in terms of richness, composition and community structure to investigate their relationships with two key forcing factors (i.e., nutrient enrichment and climate warming). Various groups, including Apicomplexa, Cercozoa, Chrysophyceae, Ciliophora, Chlorophyceae and Dinophyceae, responded to phosphorus enrichment levels with either positive or negative impacts on their richness and relative abundance. For both lakes, statistical modelling demonstrated that phosphorus concentration ([P]) was a dominant contributor to MECs modifications before the 1980s; after the mid-80s, the contribution of air temperature changes increased and potentially surpassed the contribution of [P]. Co-occurrence network analysis revealed that some clusters of taxa (i.e., modules) composed mainly of Dinophyceae and unclassified Alveolata were strongly correlated to air temperature in both lakes. Overall, our data showed that sed-DNA constitutes a precious archive of information on past biodiversity changes, allowing the study of the dynamics of numerous eukaryotic groups that were not traditionally considered in paleo-reconstructions.


What's up with witch rings?
'Witch rings' are well-known novelty rings that show a size-change illusion when rotated. We have replicated the illusion of expansion of the reflections in the rings in a variety of contexts with animations, though not as yet so successfully imitated the sense that the whole ring expands and contracts.


Microbial Transglutaminase Used in Bread Preparation at Standard Bakery Concentrations Does Not Increase Immunodetectable Amounts of Deamidated Gliadin.
The effect of standard bakery concentrations of microbial transglutaminase (MTG) in wheat bread preparation on the immunoreactivity of sera of celiac disease (CD) patients was investigated. Immunoblotting using monoclonal antibodies specific to unmodified and/or deamidated gliadin showed no differences between control bread and MTG bread. Deamidation of gliadin could not be detected at standard MTG concentrations. Sera of CD patients were characterized using anti-gliadin and anti-deamidated gliadin peptide (DGP) enzyme-linked immunosorbent assay and grouped into DGP high- and low-titer pools. The recognition pattern obtained after using both CD sera pools for immunoblotting did not reveal differences between control and MTG-treated bread protein extracts. Our results indicate that MTG treatment of wheat bread prepared with typical MTG concentrations used in standard bakery processes does not lead to immunodetectable amounts of CD immunotoxic deamidated gliadins.


Iron(II) spin crossover complexes with diaminonaphthalene-based Schiff base-like ligands: mononuclear complexes.
The synthesis of new Schiff base-like ligands with extended π-system and their iron complexes is described. Some of the iron(ii) complexes with N-heterocycles as axial ligands show spin crossover behaviour. The influence of the extended aromatic system on cooperative interactions is investigated by single crystal X-ray structure analysis, X-ray powder diffraction, and magnetic measurements. A combination of C-Hπ and C-HO interactions is made responsible for up to 10 K wide thermal hysteresis loops.


Model-independent estimation of lag times with first-order absorption and disposition.
The effectiveness of five model-independent procedures for the estimation of lag times (Tlag) was evaluated. Two new methods utilize early concentrations which are weighted by a term exponential in time. They estimate Tlag by weighted linear regression. One of these approaches evaluates also the time when maximum concentration is reached (Tmax). In addition, three older, empirically used procedures are considered. Two methods apply either the first two or three quantifiable concentrations and estimate the lag time by linear regression. Finally, the last unquantifiable concentration is often used as a measure of lag time. Simulations demonstrated that this procedure had large bias and generally high standard deviation. In contrast, the new methods showed small variation and negligible bias. The procedures applying linear regression had intermediate characteristics. Lag times were evaluated effectively by an average of two observations between Tlag and Tmax.


Matrix metalloproteinase-1 takes advantage of the induced fit mechanism to cleave the triple-helical type I collagen molecule.
The collagenases are members of the matrix metalloproteinase family (MMP) that degrade native triple-helical type I collagen. To understand the mechanism by which these enzymes recognize and cleave this substrate, we studied the substrate specificity of a modified form of MMP-1 (FC) in which its active site region (amino acids 212-254) had been replaced with that of MMP-9 (amino acids 395-437). Although this substitution increased the activity of the enzyme toward gelatin and the peptide substrate Mca-PLGL(Dpa)AR-NH2 by approximately 3- and approximately 11-fold, respectively, it decreased the type I collagenolytic activity of the enzyme to 0.13%. The replacement of Gly233, the only amino acid in this region of FC that is conserved in all collagenase family members, with the corresponding Glu residue in MMP-9 resulted in a substantial decrease in the type I collagenolytic activity of the enzyme without affecting its general proteolytic activities. The kinetic parameters of the FC/G233E mutant for the collagen substrate were similar to those of the chimeric enzyme. In addition, substituting Gly233 for Glu in the chimera increased the collagenolytic activity of the enzyme by 12-fold. Interestingly, replacing Glu415 in MMP-9 with Gly, its corresponding residue in FC, endowed the enzyme with type I collagenolytic activity. The catalytic activity of the MMP-9 mutant toward triple-helical type I collagen was 2-fold higher than that of the collagenase chimera. These data in conjunction with the X-ray crystal structure of FC indicate that Gly233 provides the flexibility necessary for the enzyme active site to change conformation upon substrate binding. The flexibility provided by the Gly residue is essential for type I collagenolytic activity.


[Mediastinal pancreas pseudocyst].
We report on the diagnosis and treatment of a pancreatic pseudocyst of the mediastinum. The patterns of signs and symptoms, diagnosis and treatment of this rare disease are discussed on the basis of literature.


Rapid screening for specific glycosylation and pathogen interactions on a 78 species avian egg white glycoprotein microarray.
There is an urgent need for discovery of novel antimicrobials and carbohydrate-based anti-adhesive strategies are desirable as they may not promote resistance. Discovery of novel anti-adhesive molecules from natural product libraries will require the use of a high throughput screening platform. Avian egg white (EW) provides nutrition for the embryo and protects against infection, with glycosylation responsible for binding certain pathogens. In this study, a microarray platform of 78 species of avian EWs was developed and profiled for glycosylation using a lectin panel with a wide range of carbohydrate specificities. The dominating linkages of sialic acid in EWs were determined for the first time using the lectins MAA and SNA-I. EW glycosylation similarity among the different orders of birds did not strictly depend on phylogenetic relationship. The interactions of five strains of bacterial pathogens, including Escherichia coli, Staphylococcus aureus and Vibrio cholera, identified a number of EWs as potential anti-adhesives, with some as strain- or species-specific. Of the two bacterial toxins examined, shiga-like toxin 1 subunit B bound to ten EWs with similar glycosylation more intensely than pigeon EW. This study provides a unique platform for high throughput screening of natural products for specific glycosylation and pathogen interactions. This platform may provide a useful platform in the future for discovery of anti-adhesives targeted for strain and species specificity.


Subconjunctival haemorrhages in neonatal thoroughbred foals.
A survey of 169 neonatal thoroughbred foals revealed that 8.3 per cent had subconjunctival haemorrhages, but there was no indication of a relationship between retinal and subconjunctival haemorrhages. The haemorrhages were not related to any abnormality of the foals and there was no sex or eye predisposition. In most cases the haemorrhages were fresh and red, occurred mainly dorsally or dorsonasally and extended up to the limbus; they resolved completely within four to 10 days, depending on their initial severity and extent. They had no effect on the foals' vision in the short or long term. The incidence of subconjunctival haemorrhages was associated with foaling category, multiparity and country of birth.


The rearing environment persistently modulates mouse phenotypes from the molecular to the behavioural level.
The phenotype of an organism results from its genotype and the influence of the environment throughout development. Even when using animals of the same genotype, independent studies may test animals of different phenotypes, resulting in poor replicability due to genotype-by-environment interactions. Thus, genetically defined strains of mice may respond differently to experimental treatments depending on their rearing environment. However, the extent of such phenotypic plasticity and its implications for the replicability of research findings have remained unknown. Here, we examined the extent to which common environmental differences between animal facilities modulate the phenotype of genetically homogeneous (inbred) mice. We conducted a comprehensive multicentre study, whereby inbred C57BL/6J mice from a single breeding cohort were allocated to and reared in 5 different animal facilities throughout early life and adolescence, before being transported to a single test laboratory. We found persistent effects of the rearing facility on the composition and heterogeneity of the gut microbial community. These effects were paralleled by persistent differences in body weight and in the behavioural phenotype of the mice. Furthermore, we show that environmental variation among animal facilities is strong enough to influence epigenetic patterns in neurons at the level of chromatin organisation. We detected changes in chromatin organisation in the regulatory regions of genes involved in nucleosome assembly, neuronal differentiation, synaptic plasticity, and regulation of behaviour. Our findings demonstrate that common environmental differences between animal facilities may produce facility-specific phenotypes, from the molecular to the behavioural level. Furthermore, they highlight an important limitation of inferences from single-laboratory studies and thus argue that study designs should take environmental background into account to increase the robustness and replicability of findings.


Impact of Gag sequence variability on level, phenotype, and function of anti-HIV Gag-specific CD8(+) cytotoxic T lymphocytes in untreated chronically HIV-infected patients.
The role of cytotoxic T lymphocyte responses in controlling viral replication during chronic HIV infection remains controversial. Viral escape mutations driven by immune pressure have been postulated to be an important mechanism contributing to the evasion of CD8(+) T cell responses. To explore this issue in more detail, HIV-1 p17 sequence variability was examined in chronically HIV-infected patients, in parallel with the level, phenotype, and function of HIV-SL9-specific CD8(+) T cell. Thirty-one HLA-A*0201(+) (A2(+)) and 10 HLAA* 02() (A2()) patients were included. The phenotype of SL9-specific CD8(+) T cell and their ability to produce IFN-gamma were analyzed by multiparameter flow cytometry. The HIV Gag p17 was sequenced and the mean variability score for each residue within SL9 and the two epitope flanking regions were calculated using Shannon entropy. The mean variability of SL9 and the proportion of patients with amino acid changes within SL9 were similar in A2(+) and A2() patients. Patients without Tet(+) cells had a significantly higher prevalence of aminoacid changes in SL9 than patients with Tet(+) cells. Interestingly, in patients with Tet(+) cells, the Y79F mutation within SL9 tended to be associated with lower levels of Tet(+) cells. We did not find any association between amino acid changes within SL9 and the differentiation stage of Tet(+) cells, or with IFN-gamma production. A similar analysis within the epitope flanking sequences did not reveal differences in the variability of these regions. These results suggest that viral mutations driven by immune selection pressure may play an important role in evading the immunological response in chronically HIV-infected individuals.


Associations of Physical Activity, Sedentary Time, and Screen Time With Cardiovascular Fitness in United States Adolescents: Results From the NHANES National Youth Fitness Survey.
Most US adolescents do not meet guidelines of at least 60 daily minutes of moderate- to vigorous-intensity physical activity. In addition, sedentary behaviors among this age group are of increasing concern. This study examined the association of movement behaviors with cardiovascular fitness among US adolescents. Data from the 2012 NHANES National Youth Fitness Survey were used to assess the association of movement behaviors (physical activity, sedentary time, screen time) with cardiovascular fitness among adolescent males and females. Multiple logistic regressions were used to test the independent and interactive effects of movement behaviors on cardiovascular fitness. Among females, physical activity was directly associated with cardiovascular fitness; no significant association was observed between sedentary behaviors and CVF. Among males, sedentary time moderated the relationship between physical activity and cardiovascular fitness, such that a significant, direct association was only observed among those with high sedentary time (OR: 5.01; 95% CI: 1.60, 15.70). Results from this cross-sectional analysis suggest that among female US adolescents, physical activity, but not sedentary behavior, is associated with cardiovascular fitness. Among males, the interaction between physical activity and sedentary time seems to be important for cardiovascular fitness. Longitudinal studies are warranted to confirm these findings.


Myristic acid-modified thymopentin for enhanced plasma stability and immune-modulating activity.
Natural albumin ligand (fatty acids)-conjugated peptides can rapidly bind to circulating albumin and form complexes to control the release of peptides. The purpose of this study was to prolong the half-life and immune-modulating effects of thymopentin (TP5) by using the albumin binding strategy. We synthesized myristic acid-modified TP5 (TP5-MA) by conjugating a myristic acid-acylated lysine to a permissive site of TP5, which improved the albumin binding affinity of TP5-MA and dramatically enhanced its stability in human plasma. We observed well-preserved bioactivities of TP5-MA in RAW264.7 macrophages using a tumor necrosis factor (TNF)-α stimulation assay. Moreover, the prolonged immune-modulating effect of TP5-MA was confirmed by the normalized CD4+/CD8+ ratio in immune-depressed rat models, which resulted in a reduced administration frequency (twice per week). In general, the enhanced pharmacokinetic and pharmacodynamic properties of TP5-MA make it a promising product for the treatment of immunodeficiency diseases.


Extended pancreatectomy as defined by the ISGPS: useful in selected cases of pancreatic cancer but invaluable in other complex pancreatic tumors.
Extended pancreatectomy aimed at R0 resection of pancreatic tumors with adjacent vessel and organ involvement may be the only option for cure. This study was done with an objective to analyze the short- and long-term outcomes of extended pancreatic resections. All pancreatectomies performed between 2006 and 2015 were included. The pancreatectomies were classified as standard or extended, as per the International Study Group for Pancreatic Surgery. All surgical complications and terminologies were according to Clavien-Dindo classification and International Study Group for Pancreatic Surgery guidelines. Morbidity and mortality were primary outcomes and disease-free survival was a secondary outcome. Sixty-three extended and 620 standard pancreatectomies were performed. Major morbidity (Clavien grades III, IV and V) (37 vs. 29%, p = 0.21) and mortality (6 vs. 4%, p = 0.3) for extended pancreatectomies were comparable to those for standard pancreatectomies. Blood loss > 855 ml, need for blood transfusion, and tumor size were independent risk factors for morbidity, and the latter two for mortality. Standard pancreatectomies were associated with better 3-year disease-free survival than extended pancreatectomies (67 vs. 41%, p < 0.001). Extended pancreatectomies resulted in a significantly better median disease-free survival for non-pancreatic adenocarcinoma vs. pancreatic adenocarcinoma (33.3 vs. 9.5 months, p = 0.01). Extended pancreatectomies resulted in similar peri-operative morbidity and mortality compared to standard pancreatectomies. Although the survival of patients undergoing these complex procedures is inferior to standard pancreatectomies, they should be undertaken not only in selected cases of pancreatic cancer but even more so in other complex pancreatic tumors.


Sexual arousal and orgasm in subjects who experience forced or non-consensual sexual stimulation -- a review.
The review examines whether unsolicited or non-consensual sexual stimulation of either females or males can lead to unwanted sexual arousal or even to orgasm. The conclusion is that such scenarios can occur and that the induction of arousal and orgasm does not indicate that the subjects consented to the stimulation. A perpetrator's defence simply built upon the fact that evidence of genital arousal or orgasm proves consent has no intrinsic validity and should be disregarded.


Comparison of the efficacy and patients' tolerability of Nepafenac and Ketorolac in the treatment of ocular inflammation following cataract surgery: A meta-analysis of randomized controlled trials.
As a new ophthalmic non-steroidal anti-inflammatory drug (NSAID) with prodrug structure, Nepafenac was supposed to have a better efficacy than conventional NSAIDs both in patients' tolerability and ocular inflammation associated with cataract surgery. However, many current studies reached contradictory conclusions on the superiority of Nepafenac over Ketorolac. The objective of our study is to evaluate the efficacy and patients' tolerability of Nepafenac and Ketorolac following cataract surgery. To clarify this, we conducted a meta-analysis of randomized controlled trials. Eleven articles were included in this study. The dataset consisted of 1165 patients, including 1175 cataract surgeries. Among them, 574 patients were in the Nepafenac group and 591 in the Ketorolac group. Our analysis indicated that these two drugs were equally effective in controlling post cataract surgery ocular inflammation, reducing macular edema, achieving a better visual ability and maintaining intraoperative mydriasis during cataract surgery. However, Nepafenac was more effective than Ketorolac in reducing the incidence of postoperative conjunctival hyperemia and ocular discomfort. This meta-analysis indicated that topical Nepafenac is superior to Ketorolac in patients' tolerability following cataract surgery. However, these two drugs are equally desirable in the management of anterior chamber inflammation, visual rehabilitation and intraoperative mydriasis. Given the limitations in our study, more researches with larger sample sizes and focused on more specific indicators such as peak aqueous concentrations of drugs or PEG2 levels are required to reach a firmer conclusion.


Effects of leisure activities and general health on the survival of older people: a cohort study in China.
This study aimed to examine the influence of physical and cognitive leisure activities on the survival of older adults in China, while also exploring the potential mediating and moderating effects of general health. This study utilized the China Longitudinal Healthy Longevity Survey (CLHLS) datasets spanning from 2008 to 2018, and 10,347 eligible participants were included. The primary study outcome was all-cause mortality, and independent variables included physical leisure activities (PLA), cognitive leisure activities (CLA), and self-rated general health. Three sets of covariates were adjusted, including socio-demographic characteristics, health behaviors, and health status. The longest survival time was the older people participating in PLA & CLA (mean = 50.31 months), while those participating in neither exhibited the lowest (mean = 29.60 months). Significant differences in survival status were observed in different types of leisure activities participation (Log-rank test, Chi-square = 576.80, p < 0.001). Cox regression indicated that PLA (HR = 0.705, 95% CI: 0.651-0.764), CLA (HR = 0.872, 95% CI: 0.816-0.933), and the both PLA & CLA (HR = 0.700, 95% CI: 0.656-0.747) were protective factors for the survival. Additionally, general health significantly moderated the relationship between PLA and reduced mortality risk (Coefficient = -0.089, p = 0.042). While CLA indirectly influenced the survival through general health (Coefficient = -0.023, p < 0.001). For the older people participating in PLA and CLA, general health played mediating (Coefficient = -0.031, p < 0.001) and moderating (Coefficient = -0.026, p = 0.013) role in the relationship between leisure activities and survival. Leisure activities and self-rated general health were important predictors of survival of the older adults, and general health exhibited a mediator and moderator in the relationship between leisure activities and survival status.


DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons.
Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state.


Specific translocation of protein kinase Calpha to the plasma membrane requires both Ca2+ and PIP2 recognition by its C2 domain.
The C2 domain of protein kinase Calpha (PKCalpha) controls the translocation of this kinase from the cytoplasm to the plasma membrane during cytoplasmic Ca2+ signals. The present study uses intracellular coimaging of fluorescent fusion proteins and an in vitro FRET membrane-binding assay to further investigate the nature of this translocation. We find that Ca2+-activated PKCalpha and its isolated C2 domain localize exclusively to the plasma membrane in vivo and that a plasma membrane lipid, phosphatidylinositol-4,5-bisphosphate (PIP2), dramatically enhances the Ca2+-triggered binding of the C2 domain to membranes in vitro. Similarly, a hybrid construct substituting the PKCalpha Ca2+-binding loops (CBLs) and PIP2 binding site (beta-strands 3-4) into a different C2 domain exhibits native Ca2+-triggered targeting to plasma membrane and recognizes PIP2. Conversely, a hybrid containing the CBLs but lacking the PIP2 site translocates primarily to trans-Golgi network (TGN) and fails to recognize PIP2. Similarly, PKCalpha C2 domains possessing mutations in the PIP2 site target primarily to TGN and fail to recognize PIP2. Overall, these findings demonstrate that the CBLs are essential for Ca2+-triggered membrane binding but are not sufficient for specific plasma membrane targeting. Instead, targeting specificity is provided by basic residues on beta-strands 3-4, which bind to plasma membrane PIP2.


Using Strand Displacing Polymerase To Program Chemical Reaction Networks.
Chemical reaction networks (CRNs) provide a powerful abstraction to formally represent complex biochemical processes. DNA provides a promising substrate to implement the abstract representation (or programming language) of CRNs due to its programmable nature. Prior works that used DNA to implement CRNs either used DNA-only systems or multienzyme DNA circuits. Architectures with DNA-only components had the rationale of being biologically simple systems. Multienzyme systems, on the other hand, aimed at using natural enzymes to improve circuit performance, although, at the cost of increased complexity. In this work, we explore an alternative architecture that lies along the spectrum in between DNA-only systems and multienzyme DNA systems. Our architecture relies on only a strand displacing polymerase enzyme and DNA hybridization reactions for implementing CRNs. First, we briefly introduce the theory and DNA design of simple CRNs and then explore the fundamental properties of polymerase-based strand displacement systems. Finally, we engineer a catalytic amplifier in vitro as a use-case of our framework since such amplifiers require the intricate design of DNA sequences and reaction conditions.


Linear Parameter Varying Identification of Dynamic Joint Stiffness during Time-Varying Voluntary Contractions.
Dynamic joint stiffness is a dynamic, nonlinear relationship between the position of a joint and the torque acting about it, which can be used to describe the biomechanics of the joint and associated limb(s). This paper models and quantifies changes in ankle dynamic stiffness and its individual elements, intrinsic and reflex stiffness, in healthy human subjects during isometric, time-varying (TV) contractions of the ankle plantarflexor muscles. A subspace, linear parameter varying, parallel-cascade (LPV-PC) algorithm was used to identify the model from measured input position perturbations and output torque data using voluntary torque as the LPV scheduling variable (SV). Monte-Carlo simulations demonstrated that the algorithm is accurate, precise, and robust to colored measurement noise. The algorithm was then used to examine stiffness changes associated with TV isometric contractions. The SV was estimated from the Soleus EMG using a Hammerstein model of EMG-torque dynamics identified from unperturbed trials. The LPV-PC algorithm identified (i) a non-parametric LPV impulse response function (LPV IRF) for intrinsic stiffness and (ii) a LPV-Hammerstein model for reflex stiffness consisting of a LPV static nonlinearity followed by a time-invariant state-space model of reflex dynamics. The results demonstrated that: (a) intrinsic stiffness, in particular ankle elasticity, increased significantly and monotonically with activation level; (b) the gain of the reflex pathway increased from rest to around 10-20% of subject's MVC and then declined; and (c) the reflex dynamics were second order. These findings suggest that in healthy human ankle, reflex stiffness contributes most at low muscle contraction levels, whereas, intrinsic contributions monotonically increase with activation level.


Prostate Cancer Stem Cell Markers Drive Progression, Therapeutic Resistance, and Bone Metastasis.
Metastatic or recurrent tumors are the primary cause of cancer-related death. For prostate cancer, patients diagnosed with local disease have a 99% 5-year survival rate; however, this 5-year survival rate drops to 28% in patients with metastatic disease. This dramatic decline in survival has driven interest in discovering new markers able to identify tumors likely to recur and in developing new methods to prevent metastases from occurring. Biomarker discovery for aggressive tumor cells includes attempts to identify cancer stem cells (CSCs). CSCs are defined as tumor cells capable of self-renewal and regenerating the entire tumor heterogeneity. Thus, it is hypothesized that CSCs may drive primary tumor aggressiveness, metastatic colonization, and therapeutic relapse. The ability to identify these cells in the primary tumor or circulation would provide prognostic information capable of driving prostate cancer treatment decisions. Further, the ability to target these CSCs could prevent tumor metastasis and relapse after therapy allowing for prostate cancer to finally be cured. Here, we will review potential CSC markers and highlight evidence that describes how cells expressing each marker may drive prostate cancer progression, metastatic colonization and growth, tumor recurrence, and resistance to treatment.


The pH-dependent conformational states of kyotorphin: a constant-pH molecular dynamics study.
An extensive conformational study of the analgesic dipeptide kyotorphin (L-Tyr-L-Arg) at different pH values was performed using a constant-pH molecular dynamics method. This dipeptide showed a remarkable pH-dependent conformational variety. The protonation of the N-terminal amine was identified as a key element in the transition between the more extended and the more packed conformational states, as monitored by the dihedral angle defined by the atoms 1Cbeta-1Calpha-2Calpha-2Cbeta. The principal-component analysis of kyotorphin identified two major conformational populations (the extended trans and the packed cis) together with conformations that occur exclusively at extreme pH values. Other, less stable conformations were also identified, which help us to understand the transitions between the predominant populations. The fitting of kyotorphin's conformational space to the structure of morphine resulted in a set of conformers that were able to fulfill most of the constraints for the mu-receptor. These results suggest that there may be strong similarities between the kyotorphin receptor and the structural family of opioid receptors.


Physical mapping of a rice lesion mimic gene, Spl1 , to a 70-kb segment of rice chromosome 12.
The rice lesion mimic mutant spotted leaf 1 ( spl1) was first identified in the rice ( Oryza sativa) cultivar Asahi in 1965. This mutant displayed spontaneous disease-like lesions in the absence of any pathogen, and was found to confer resistance to multiple isolates of rice blast. We employed a map-based cloning strategy to localize the Spl1 gene. A total of ten cleaved amplified polymorphic sequence (CAPS) markers linked to the Spl1 gene were identified and mapped to an 8.5-cM region on chromosome 12. A high-resolution genetic map was developed using these ten CAPS markers and a segregating population consisting of 3202 individuals. A BAC contig containing four BAC clones was constructed, and Spl1 was localized to a 423-kb region. Seven spl1 mutants were obtained from the IR64 deletion mutant collection, and molecular analysis using these mutants delimited the Spl1 gene to a 70-kb interval, covered by two BAC clones. These results provide the basis for cloning this gene, which is involved in cell death and disease resistance in rice.


Developmental expression of VGF mRNA in the prenatal and postnatal rat.
VGF is a developmentally regulated, secretory peptide precursor that is expressed by neurons and neuroendocrine cells and that has its transcription and secretion induced rapidly by neurotrophins and by depolarization. To gain insight into the possible functions and regulation of VGF in vivo, we have characterized the distribution of VGF mRNA in the developing rat nervous system. VGF expression was first detectable at embryonic day 11.5 in the primordia of cranial, sympathetic, and dorsal root ganglia, and its distribution expanded throughout development to include significant expression throughout the brain, spinal cord, and retina of the adult rat. The earliest expression of VGF, therefore, appeared in the peripheral nervous system as developing neurons settled in their designated ganglia. In many regions of the brain, VGF mRNA levels were found to be highest during periods when axonal outgrowth and synaptogenesis predominate. Areas of the central nervous system that contain predominantly dividing cells never displayed any VGF mRNA expression, nor did the vast majority of nonneural tissues.


Bioinspired amphiphilic phosphate block copolymers as non-fluoride materials to prevent dental erosion.
Inspired by the fact that certain natural proteins, e.g. casein phosphopeptide or amelogenin, are able to prevent tooth erosion (mineral loss) and to enhance tooth remineralization, a synthetic amphiphilic diblock copolymer, containing a hydrophilic methacryloyloxyethyl phosphate block (MOEP) and a hydrophobic methyl methacrylate block (MMA), was designed as a novel non-fluoride agent to prevent tooth erosion under acidic conditions. The structure of the polymer, synthesized by reversible addition-fragment transfer (RAFT) polymerization, was confirmed by gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). While the hydrophilic PMOEP block within the amphiphilic block copolymer strongly binds to the enamel surface, the PMMA block forms a hydrophobic shell to prevent acid attack on tooth enamel, thus preventing/reducing acid erosion. The polymer treatment not only effectively decreased the mineral loss of hydroxyapatite (HAP) by 36-46% compared to the untreated control, but also protected the surface morphology of the enamel specimen following exposure to acid. Additionally, experimental results confirmed that low pH values and high polymer concentrations facilitate polymer binding. Thus, the preliminary data suggests that this new amphiphilic diblock copolymer has the potential to be used as a non-fluoride ingredient for mouth-rinse or toothpaste to prevent/reduce tooth erosion.


Dopamine-induced stress signaling in COS-7 cells transfected with selectively vulnerable muscarinic receptor subtypes is partially mediated via the i3 loop and antagonized by blueberry extract.
Muscarinic receptors (MAChRs) are intimately involved in various aspects of both neuronal and vascular functioning, and there is selective oxidative stress sensitivity (OSS) among MAChR subtypes, with M1, M2, and M4 showing>OSS. OSS was assessed by determining the loss of ability of the cell to extrude or sequester Ca2+ following oxotremorine-induced depolarization following exposure to dopamine (DA) subtypes in transfected COS-7 cells. This OSS can be prevented by pretreatment with blueberry (BB) extract. Present studies were carried out to determine BB treatment of the cells transfected with wild type, truncated or chimeric [where the i3 loop of one receptor was switched with the i3 loop of the other; i.e., M1(M3i3) and M3(M1i3)] receptors would alter DA-induced changes in calcium buffering and would confer protection through alterations in pMAPK, pCREB or PKC signaling. These findings also suggest that BB may antagonize OS effects by lowering activation of pCREB and possibly PKCgamma induced by DA. In the truncated and chimeric receptors, results indicated that BB reduced OSS in response to DA in M1-transfected cells. However, BBs were also effective in preventing these Ca2+ buffering deficits in cells transfected with M1 receptors in which the i3 loop had been removed, but only partially enhanced the protective effects of the M3 i3 loop in the M1(M3i3) chimerics. A similar partial effect of BBs was seen in the M3(M1i3) chimerics which showed increased OSS in response to DA. It appears that antioxidants found in BBs might be targeting additional sites on these chimerics to decrease OSS.


Equine Calming Products: A Short Survey Into Their Use, Effect, and Knowledge Using a Small Sample of Horse Owners in the North of Scotland, UK.
Equine calming products (ECPs) are often used by horse owners to alter or mitigate unwanted or dangerous behaviors in various situations. Little scientific research to date examines horse owners' knowledge surrounding these products. The objective of this pilot survey was to determine horse owners' use and perceptions of ECPs. For convenience, a survey was distributed to riding club members, livery yards, and riding instructors in the North of Scotland, UK, to ascertain the following information; the number of horse owners and caretakers who use an ECP, whether the product was considered to be effective, reasons for use and identification of the effective ingredient. Total response rate was 63% (n = 58); correctly completed questionnaires were received. Of the total respondents, 69% (n = 40) confirmed the use of an ECP and 82% would use them again, and 45% reporting regular use. Over half (59%) thought the calming effect was induced by magnesium, 9% thought the calming effect was induced by herbs, valerian, or tryptophan, and 32% did not know what ingredient had a possible calming effect. Of those using or having used an ECP, 40% felt that there was some positive effect, 30% were unsure as to whether there was any difference or not, 25% felt there was no difference, and 5% felt there was a negative effect on horse's behavior. A variety of reasons were given for using an ECP. The results suggest that horse owners are willing to use ECPs without underpinning knowledge of ingredients or scientific evidence of efficacy.


Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02).
Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients. Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR). From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%). In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2. NCT00303771.


Oncological diagnosis using positron coincidence gamma camera with fluorodeoxyglucose in comparison with dedicated PET.
The purpose of this study was to compare the utility of a dual-head positron coincidence detection gamma camera (PCD) with that of dedicated positron emission tomography (PET) in the imaging of various malignancies using (18)F-fluorodeoxyglucose (FDG). 25 patients with known or suspected malignancies at various sites underwent imaging with both methods, and diagnostic performance on a lesion basis was compared. Tumour lesions were analyzed visually and semi-quantitatively using the ratio of tumour-to-background counts (T/B ratio). FDG PCD and FDG PET visually detected 34 (72.3%) lesions and 37 (78.7%) lesions, respectively. The mean T/B ratio and standard deviation (SD) of FDG PCD was 3.5+/-3.3, significantly lower than that of FDG PET (8.4+/-7.1, p<0.001). When tumour lesions were less than 2.0 cm in diameter, the sensitivity of FDG PCD was 37.5%, significantly inferior to that of FDG PET (50.0%, p<0.01). Sensitivity between FDG PCD and FDG PET in lesions of more than 2.0 cm diameter showed no statistically significant difference. This study indicates that FDG imaging with a dual-head coincidence detection gamma camera can provide suitable diagnostic performance for lesions greater than 2.0 cm diameter, but performed significantly worse than dedicated PET for lesions smaller than this.


Papaya CpbHLH1/2 regulate carotenoid biosynthesis-related genes during papaya fruit ripening.
The ripening of papaya is a physiological and metabolic process associated with accumulation of carotenoids, alternation of flesh color and flavor, which depending on genotype and external factors such as light and hormone. Transcription factors regulating carotenoid biosynthesis have not been analyzed during papaya fruit ripening. RNA-Seq experiments were implemented using different ripening stages of papaya fruit from two papaya varieties. Cis-elements in lycopene β-cyclase genes (CpCYC-B and CpLCY-B) were identified, and followed by genome-wide analysis to identify transcription factors binding to these cis-elements, resulting in the identification of CpbHLH1 and CpbHLH2, two bHLH genes. The expressions of CpbHLH1/2 were changed during fruit development, coupled with transcript increase of carotenoid biosynthesis-related genes including CpCYC-B, CpLCY-B, CpPDS2, CpZDS, CpLCY-E, and CpCHY-B. Yeast one-hybrid (Y1H) and transient expression assay revealed that CpbHLH1/2 could bind to the promoters of CpCYC-B and CpLCY-B, and regulate their transcriptions. In response to strong light, the results of elevated expression of carotenoid biosynthesis-related genes and the changed expression of CpbHLH1/2 indicated that CpbHLH1/2 were involved in light-mediated mechanisms of regulating critical genes in the carotenoid biosynthesis pathway. Collectively, our findings demonstrated several TF family members participating in the regulation of carotenoid genes and proved that CpbHLH1 and CpbHLH2 individually regulated the transcription of lycopene β-cyclase genes (CpCYC-B and CpLCY-B). This study yielded novel findings on regulatory mechanism of carotenoid biosynthesis during papaya fruit ripening.


Use of the Learning Curve-Cumulative Summation Test for Leopold Maneuvers Assessment in a Simulator: A Pilot Study.
Simulation enables medical students to practice clinical skills in a safe environment. Graduates in medicine must be able to correctly perform an examination on a pregnant woman using Leopold maneuvers. Learning curves-cumulative summation (LC-CUSUM) may help determine when the student has achieved a specific skill. Our objective was to perform the LC-CUSUM test regarding the ability of students to correctly carry out Leopold maneuvers; a pregnancy simulator was used, transferring the results to a clinical setting. Five medical students were trained to carry out Leopold maneuvers using the simulator. Each student performed maneuvers for 50 cases of different fetus positions; a LC-CUSUM was plotted for each student. Afterward, the students performed the Leopold maneuvers on 5 pregnant women. Of the 5 students, 3 achieved a level of proficiency; the attempts needed for reaching this level were 13, 13, and 37, respectively. The other 2 students did not reach proficiency level. Of the students who became successfully proficient with the simulator, one of them attained a 100% success rate in pregnant patients, whereas the other two had success rates of 80%. The students who did not achieve a level of competency with the simulator had only a 60% success rate with patients. Because of the differences observed between students in the number of attempts needed for achieving proficiency in Leopold maneuvers, we believe that each student should build his/her own learning curve. Achieving competency in carrying out Leopold maneuvers using the simulator could be transferable to patients.


Influence of launch-beam distribution on bandwidth in step-index plastic optical fibers.
The power-flow equation is employed to calculate bandwidth of step-index plastic optical fibers (POFs) for different launch conditions. The outcome specifies bandwidth as a function of the mean input angle and width of the launch-beam distribution. For small distribution widths, bandwidth is shown to decrease with increasing mean input angle of the launch-beam distribution. For large distribution widths, bandwidth becomes independent of the launch angle. Launch-beam distribution, mode-dependent attenuation, and mode dispersion and coupling in POFs strongly influence the bandwidth of data transmission systems.


Genomic profiling in CEPH cell lines distinguishes between the camptothecins and indenoisoquinolines.
We have attempted to use a familial genetics strategy to study mechanisms of topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds and interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of 15 families of Centre d'Etude Polymorphisme Humain (CEPH) cell lines (n = 142) to 9 camptothecin analogues. Linkage analysis revealed a pattern of 7 quantitative trait loci (QTL) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining 3 QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, 8 QTLs were identified, which were unique to the indenoisoquinolines.


Metabolic evaluation in stone disease metabolic differences between the pediatric and adult patients with stone disease.
To determine the metabolic risk factors in children and adults with stone disease and any differences between the metabolic risk factors of children and adult patients with stone disease. Between 1999 and 2007, 285 adults with recurrent stone disease and 71 children with primary or recurrent urinary stone disease underwent metabolic evaluation in our clinic. The evaluation included blood chemistry studies and 24-hour urine collection in the pediatric and adult groups. The mean age of the children was 9.35 years (range: 1-14) and 42.1 years (range: 14-71) in the adult patients. Metabolic risk factors were demonstrated in 90.53% (n = 258) of the adult and 88.73% (n = 63) of the pediatric patients. Although hypercalciuria (50.5%, n = 144) was the most common metabolic risk factor in the adult group, hypocitraturia was the most common metabolic risk factor in the pediatric group (57.74%, n = 41). Furthermore, in the adult group, 136 patients had more than 1 risk factor, and in the pediatric group, 24 patients had more than 1 risk factor. Although hypocitraturia is the most common risk factor in pediatric urolithiasis patients and hypercalciuria is the most common risk factor in adult patients, all patients with stone formation should be given a limited metabolic evaluation because such patients may also have a metabolic abnormality.


The Associated Factors of Low Birthweight Among Term Singletons in Japan: A Pregnancy Birth Registry Analysis.
Progress in reducing the global low birthweight (LBW) has been insufficient. Although the focus has been on preventing preterm birth, evidence regarding LBW in term births is limited. Despite its low preterm birth prevalence, Japan has a higher LBW proportion than other developed countries. This study aimed to examine the prevalence of LBW in term singleton births and its associated factors using a national database. We retrospectively analyzed the data of neonates registered in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System who were born 2013-2017. Exclusion criteria included stillbirths, delivery after 42 gestational weeks, and missing data. Logistic regression analyses were performed to investigate the maternal and perinatal factors associated with LBW in term singletons using the data of 715,414 singleton neonates. The overall prevalence of LBW was 18.3%, and 35.7% of LBWs originated from singleton term pregnancies. Multiple logistic regression analyses indicated that both modifiable and non-modifiable factors were independently associated with LBW in term neonates. The modifiable maternal factors included pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, while the non-modifiable factors included younger maternal age, nulliparity, hypertensive disorders of pregnancy, cesarean section delivery, female offspring, and congenital anomalies. Using the Japanese pregnancy birth registry data, more than one-third of LBWs were found to originate from singleton term pregnancies. Both modifiable and non-modifiable factors were independently associated with LBW in term neonates. Prevention strategies on modifiable risk factor control will be effective in reducing LBW worldwide.


Feasibility of nephrinuria as a screening tool for the risk of pre-eclampsia: prospective observational study.
To investigate the possibility of nephrinuria as a screening tool for the risk of pre-eclampsia (PE). Prospective observational study. A single university hospital. Changes in urinary nephrin:creatinine ratio (NCR, ng/mg) and protein:creatinine ratio (PCR, mg/mg) in pregnancy were determined. Significant proteinuria in pregnancy (SPIP) was defined as PCR>0.27. PE was diagnosed in women with both SPIP and hypertension. 89 pregnant women in whom neither hypertension nor SPIP was present at enrolment, providing 31, 125 and 93 random urine samples during first, second and third trimesters, respectively. PE developed in 14 of the 89 women. NCR increased with increasing PCR in 14 women with PE (correlation coefficient, 0.862; p<0.0001). In contrast, NCR did not change significantly despite significant increases in PCR in 75 women with normotensive pregnancies defined as neither SPIP nor hypertension, indicating that there was little increase in nephrinuria over the physiological range of proteinuria in pregnancy. Relative risk of later development of PE among asymptomatic second and third trimester women with NCR (ng/mg) >122 (95th centile value for 75 women with normotensive pregnancies) was 5.93 (95% CI 2.59 to 13.6; 60% (6/10) vs 10% (8/79)) and 13.5 (95% CI 3.31 to 55.0; 75% (6/8) vs 5.5% (2/36)), respectively, compared with women with NCR≤122 at that time. Nephrinuria was unlikely to increase in normal pregnancy. A certain NCR cut-off may efficiently differentiate women at higher risk of PE.


Gamma-interferon production capacity and T lymphocyte subpopulation after allogeneic bone marrow transplantation.
T cell phenotypes after bone marrow transplantation (BMT) were investigated using monoclonal antibodies (moAbs) reactive to lymphocyte cell surface antigens. Patients' T cells showed decreased percentages of OKT4, 4A and 9.3-positive T cells, and increased percentages of OKT8, human Ia, and Leu-7-positive T cells. These changes in T cell phenotype persisted for a long period after BMT and had no correlation with the occurrence of graft-versus-host disease (GVHD). No lymphocyte activation antigens such as TIA (Tac) or transferrin receptor (5E9) were detected after BMT. The capacity of the patients' lymphocytes to produce gamma-interferon (IFN-gamma) was measured after incubation of lymphocytes with mitogen. Patients' lymphocytes produced significantly lower levels of IFN-gamma than the normal controls. This failure of IFN-gamma production showed no correlation with stimulation index of mitogen blastogenesis or changes of T cell population. Thus, not only T cell phenotype but also measurement of IFN-gamma production of lymphocyte may be useful in detecting immunological abnormalities in patients who receive BMT.


The apelinergic system: a promising therapeutic target.
Apelin is a bioactive peptide known as the ligand of the G-protein-coupled receptor APJ. In recent years, there has been a growing body of evidence regarding the importance of apelin and APJ in the pathophysiology of cardiovascular, metabolic and gastrointestinal diseases, brain signalling, HIV infection and tumor angiogenesis. Therefore, the apelinergic system is involved in the pathogenesis of several diseases that represent a major burden to our society. The goal of this paper is to give an up-to-date review of existing information on apelin/APJ since the discovery of apelin in 1998, with particular focus on their involvement in the regulation of human body systems and potential therapeutic applications. An overview of the most important physiological functions of the apelinergic system and the diseases that may benefit in the future from its modulation as a therapeutic target. Today, the established biological effects of apelin involve major cardiovascular actions, neoangiogenesis, immunologic modulation and insulinemia control as well as body fluid and glucose homeostasis. However, the physiological and pathophysiological role of endogenous apelin is still unsettled and a better and profound knowledge of this system in humans is necessary for the development of novel apelinergic-based therapeutic targets.


Early Microcirculatory Hemodynamic Changes Are Correlated With Functional Outcomes at Discharge in Patients With Aneurysmal SAH.
The technique of color-coding blood flow analysis was used to explore the correlation between the microcirculatory hemodynamic changes on digital subtraction angiography (DSA) images in patients with aneurysmal subarachnoid hemorrhage (SAH) at the early stage and functional outcomes at discharge. Data of 119 patients who underwent DSA examination due to SAH were retrospectively analyzed. The following hemodynamic parameters of the four region of interests (ROIs) [an ophthalmic segment of the internal carotid artery (ICA), frontal and parietal lobe, and superior sagittal sinus] were analyzed: the time-to-peak (TTP), the area under the curve (AUC), the full width at half maximum (FWHM), mean transit time (MTT), and circulation time. Multifactor regression analysis was performed to explore the correlation between the hemodynamic parameters and functional outcomes in patients at discharge. Of 119 patients with SAH, good and poor outcomes were found in 83 (69.7%) and 36 (30.3%) patients, respectively. The hemodynamic parameters including the FWHM, relative TTP (rTTP), and circulation time were significantly correlated with the Hunt-Hess grade (p < 0.005, p = 0.03, and p < 0.005) and the World Federation of Neurological Societies Scale grade (p < 0.005, p = 0.02, and p = 0.01). The FWHM was significantly prolonged with the increase of modified Fisher grade (p = 0.02). The multifactor analysis showed that the FWHM [odds ratio (OR) 17.56, 95% CI: 1.13-272.03, p = 0.04] was an independent risk factor predicting the functional outcomes in patients at discharge. The technique of color-coding blood flow analysis could be suitable for the qualified evaluation of disease conditions at an early stage of SAH as well as the prediction of outcomes.


Tamoxifen and the endometrium: review of 102 cases and comparison with HRT-related and non-HRT-related endometrial pathology.
Tamoxifen, a synthetic anti-estrogen that paradoxically acts as a partial estrogen agonist on the endometrium, is associated with an increased frequency of proliferative endometrial lesions, including hyperplasias, neoplasms, and polyps. Tamoxifen-related polyps are characteristically multiple and fibrotic. A variety of metaplasias and periglandular stromal condensation may be seen. Relatively few articles have focused on the descriptive morphology of the full range of tamoxifen-associated lesions. The present study further defines the histologic features in both endometrial polyps and nonpolyp endometrium. One hundred and two specimens (including 50 polyps) were reviewed using hormone replacement therapy-related endometrial specimens and conventional polyps as the control groups. The most characteristic findings of tamoxifen-associated lesions included polarized glands along the long axis of polyps (40%), a cambium layer (72%), frequent and diverse metaplasias, staghorn glands (36%), myxoid degeneration (12%), and small glands (36%). Similar morphologic features were identified in the hormone replacement therapy and control groups but to a variable, lesser extent. Overall, the tamoxifen group consisted of 18 cases of hyperplasia (11 complex, 7 simple) and one case each of adenofibroma, adenosarcoma, endometrial stromal sarcoma, and leiomyosarcoma. Although none of the features is diagnostic, the presence of diverse metaplasias, polarized glands, staghorn glands, and a cambium layer strongly suggest tamoxifen exposure especially if a number of these features are present concurrently within the same material.


A new genus of huntsman spiders (Araneae, Sparassidae, Sparianthinae) from the Neotropical region.
Uaiuara gen. nov. is described to include Sparianthis amazonica Simon from Brazil, Sparianthis barroana Chamberlin from Panama, and five new species, namely: Uaiuara quyguaba sp. nov. from the states of Amazonas, Pará and Amapá; Uaiuara ope sp. nov. from Acre and Uaiuara jirau sp. nov. from Rondônia, all in northern Brazil, Uaiuara palenque sp. nov. from Ecuador and Uaiuara dianae sp. nov. from Peru. The genus is easily distinguished from the remaining Neotropical Sparianthinae by the very recurved anterior eye row, the large number of ventral spines on tibiae of legs I-II, the retrolateral grove on the male palpal cymbium and the convoluted duct system of the female vulva. In addition, the female of S. barroana and the male of S. amazonica are described for the first time. The latter species is newly recorded from Colombia, Suriname, Ecuador and Bolivia.


Recent advances in the pathology and classification of ovarian germ cell tumors.
In recent years, our knowledge of ovarian germ cell tumors has increased, and their classification has evolved. The introduction of cisplatin-based chemotherapy and the discovery of tumor markers, including alpha-fetoprotein and human chorionic gonadotropin, have dramatically changed the clinical outlook for most of these patients. In this review, recent advances in the classification and pathology of ovarian germ cell tumors are discussed. Where appropriate, comparisons are made with testicular germ cell tumors. The last section of the article discusses the pathogenesis of germ cell tumors. This review will emphasize the articles written in the last 10 years and those that have significantly advanced our knowledge of germ cell tumors in past decades.


Dietary association of iron deficiency anemia and related pregnancy outcomes.
Iron deficiency anemia (IDA) is a common public health occurrence of pregnancy which is particularly prevalent in developing countries like Pakistan. During this critical period, the deficiency of iron is very common as the iron requirements are greatly enhanced. IDA during pregnancy is associated with intrauterine growth retardation, premature birth, low birthweight, increased labor time, higher risk of infection, elevated maternal and prenatal mortality, muscle dysfunction, and low physical capacity. The present study was aimed to check the prevalence, effect of diet on IDA and its association with the pregnancy outcome, that is, birthweight. Five different public sector hospitals of Rawalpindi and Islamabad were analyzed. A sample size of 500 pregnant females of third trimester was observed which were then followed after delivery from September 2020 to January 2021. A well-designed questionnaire was developed where different demographic factors, dietary recalls, biomarkers, and other determinants were obtained. The data from the questionnaires were later coded for the purpose of analysis in the statistical package (SPSS) using chi-square test. Our study indicated that IDA is a moderate public health problem among pregnant women in twin cities and more than half of study subjects have depleted iron stores. Approximately 63% of the subjects were having iron deficiency and 24.8% were facing severe iron deficiency anemia. Only 12% of the subjects were considered as normal. The high prevalence of anemia in our subjects was probably due to low iron intake and poor dietary habits. The results of the study may not be generalizable due to time constraints and other factors. Maternal anemia still remains a major public health concern that requires more attention especially in developing and underdeveloping countries.


The idiopathic nephrotic syndrome.
The nephrotic syndrome is defined by edema, hypoalbuminemia, proteinuria, and hyperlipemia with elevated cholesterol and triglyceride concentrations in serum or plasma. It may be primary or secondary to systemic disorders. Because of its incidence--between 2.0 and 7.0 cases per 100,000 children per year--this disorder is not uncommon in a busy pediatric practice, and it forms the basis of the referrals evaluated by a pediatric nephrology service. Over the 2 years since this subject was reviewed, several articles have appeared that have provided insights into the clinical features, etiology, pathology, pathogenesis, complications, and therapy of the idiopathic primary nephrotic syndrome. Nevertheless, a remarkable feature of this condition remains that the fundamental cause and pathogenesis of the most common form of primary nephrotic syndrome, minimal lesion nephrotic syndrome of childhood, is largely unknown. Hence, a huge challenge remains for researchers in the area of pediatric nephrology.


Causation as Strategy: Interpreting Humours among Tibetan Refugees.
The article focuses on the incidence of humoural wind ( rlung ) disorders among Tibetan exiles in India. It investigates the reasons behind the emergence of rlung as a significant problem among Tibetan exiles, and seeks to unpack some of the local meanings of this 'epidemic'. Previous studies have generally described rlung disorders as symptomatic of political and moral concerns, highlighting the connections that Tibetans make between physical, moral and psychological states in the context of Buddhist practice and everyday life. This paper aims to further nuance these findings by showing that, while Tibetan exiles include complex causes linked to morality and psychosocial wellbeing in their explanations of rlung disorders, they also 'cut' into this explanatory network in strategic ways, sometimes bypassing religious or psychosocial interpretations of illness altogether. Drawing on this analysis, the article warns researchers against literal readings of general religious precepts when analysing people's everyday negotiations of illness and wellbeing: the attribution of causation is always strategic, and religious observance should never be assumed to be uniform, or taken as a given.


Salutary effects of prostaglandin E1 in perfused rat lungs injured with hydrogen peroxide.
Studies were conducted in isolated, buffer-perfused rat lungs to determine if prostaglandin (PG) E1 attenuated pulmonary edema provoked by hydrogen peroxide (H2O2). When lungs were challenged by 60 min of perfusion with H2O2 (generated by the reaction between glucose and glucose oxidase) the wet weight-to-dry weight ratio increased from control by 54%, indicating development of pulmonary edema. In contrast, lungs treated simultaneously with H2O2 plus PGE1 (1 microgram/min) failed to exhibit an elevated wet-to-dry weight ratio. H2O2-injured lungs demonstrated a modest 2 torr increase in pulmonary arterial perfusion pressure that was not influenced by simultaneous treatment with PGE1. Both radioimmunoassay (RIA) and high-performance liquid chromatographic (HPLC) analysis detected increased amounts of (5S)-5-hydroxy-6,8,11,14 eicosatetraenoic acid in the perfusion medium of H2O2-injured lungs (RIA, 48.0 +/- 14.7; HPLC, 54.8 +/- 13.5) relative to controls (RIA, 6.6 +/- 1.6; HPLC, 6.8 +/- 1.9), and simultaneous treatment with PGE1 tended to blunt this increase (RIA, 29.2 +/- 8.3; HPLC, 29.8 +/- 7.6). PGE1 abolished the increase in wet weight-to-dry weight ratio induced by exogenous leukotriene C4. Production of H2O2 by the glucose-glucose oxidase reaction was not influenced by PGE1. Taken together, these observations indicate that PGE1 attenuates H2O2-induced pulmonary edema formation in buffer-perfused rat lungs by mechanisms that may relate to inhibition of lung 5'-lipoxygenase activation and/or to inhibition of the injurious effects of endogenously produced lipoxygenase products.


[Pyogenic sacroiliac arthritis in children. Apropos of 6 cases].
Pyogenic arthritis of the sacro-iliac joint is uncommon in children; 6 cases were observed over 4 years. The diagnosis may be difficult and should include specific examination of the sacro-iliac joint. Posterior pain with a febrile illness needs radiological examination and a skeletal scintigraphy, which has always been positive in our experience. All the patients had a very good functional recovery after antibiotherapy and rest (bed or plaster).


Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain.
Cannabinoids have been used for pain relief for centuries and recent studies have investigated their analgesic and anti-inflammatory mechanisms, as well as clinical efficacy, in treating chronic pain. We report an open-label study addressed to evaluate the effect and adverse events of orally administered Delta-9-tetrahydrocannabinol (Delta-9-THC) in 13 patients with chronic nonmalignant pain (CNMP) unresponsive to conventional pharmacotherapy. The effect of the treatment was assessed on an eight-item HRQoL questionnaire. Five out of 13 patients reported adequate response to the treatment while eight patients reported inadequate or no response. Seven patients did not experience any adverse events (AEs), six patients reported AEs, two of which discontinued the treatment. We conclude that oral THC may be a valuable therapeutic option for selected patients with CNMP that are unresponsive to previous treatments, though further research is warranted to characterize those patients.


Management of metastatic HER2-positive breast cancer progression after adjuvant trastuzumab therapy - current evidence and future trends.
Trastuzumab is now considered the standard of care for the adjuvant treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients, yet a sizable number of HER2-positive patients do not benefit from this treatment. For patients who progress on or after completion of adjuvant trastuzumab therapy, the standard of care is uncertain. Newer tyrosine kinase inhibitors and monoclonal antibodies are being evaluated in clinical trials for optimisation of treatment in this group. The interplay of HER2 and hormonal signalling pathways is being manipulated to see if response rates can be bettered. In this reveiw we explain the present role of the new molecules with a case scenario. The new anti-HER2 drugs have the potential to change clinical practise of targeting HER2 in the future. Better understanding of HER2 functions and interactions of different signalling pathways will be essential for optimal targetted therapies.


Serum ferritin in patients with various haemolytic disorders.
174 serum ferritin assays in 121 patients with various haemolytic disorders have been performed. The mean serum ferritin levels were significantly increased in all these disorders in contrast to healthy controls. The highest serum ferritin levels were found in pyruvate kinase (PK) deficiency, moderate increase was observed in hereditary sphaerocytosis (HS) and in autoimmune haemolytic anaemia (AIHA) with massive haemolysis and in glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Mild elevation of serum ferritin levels was depicted in paroxysmal nocturnal haemoglobinuria (PNH), in beta thalassaemia minor and in other types of haemoglobinopathies. The range of values was associated with a degree of haemolysis and its relation to duration of the disease was not apparent in most cases. Highly significant differences between serum ferritin levels in splenectomized and non-splenectomized patients with HS and between serum ferritin levels in patients with AIHA with massive haemolysis or in remission were found. As compared to normal controls, significant increase of serum ferritin levels was observed even in patients with AIHA in remission or in splenectomized patients with HS. In two patients with PK deficiency the levels exceeding 2,000 micrograms/l indicated manifest iron overload. A reliability of serum ferritin assay as an index of iron stores in haemolytic disorders has been discussed.


Pharmacist and physician evaluation of drug information sources.
A survey was conducted to compare how pharmacists and physicians in Tennessee rated six sources of drug information (journals, textbooks, physicians, pharmacists, the Physicians' Desk Reference and detail men) in nine different categories. A one-page questionnaire was mailed to a 10% random sample of pharmacists and physicians. The physicians rated professional journals and the PDR consistently good and rated the pharmacist poor as a source of drug information. Pharmacists rated textbooks good and rated physicians poor for some categories of information. Both groups found the available information in certain categories to be inadequate.


Spontaneous emergence of ordered phases in crumpled sheets.
X-ray tomography is performed to acquire 3D images of crumpled aluminum foils. We develop an algorithm to trace out the labyrinthian paths in the three perpendicular cross sections of the data matrices. The tangent-tangent correlation function along each path is found to decay exponentially with an effective persistence length that shortens as the crumpled ball becomes more compact. In the meantime, we observed ordered domains near the crust, similar to the lamellae phase mixed by the amorphous portion in lyotropic liquid crystals. The size and density of these domains grow with further compaction, and their orientation favors either perpendicular or parallel to the radial direction. Ordering is also identified near the core with an arbitrary orientation, exemplary of the spontaneous symmetry breaking.


Health risk assessment of heavy metals via dietary intake of wheat grown in Tianjin sewage irrigation area.
The possible health risks from heavy metal (Zn, Cu, Cr, Ni, Pb, and Cd) contamination to the local population through the food chain were evaluated in Tianjin, China, a city with a long history of sewage irrigation. Results showed that the continuous application of wastewater has led to an accumulation of heavy metals in the soil, and 54.5 and 18.25% soil samples accumulated Cd and Zn in concentrations exceeding the permissible limits in China. Concentrations of heavy metals in wheat grain decreased in the order of Zn > Cu > Cr > Ni > Pb > Cd, and transfer factors for the six heavy metals showed the trend as Zn > Cd > Cu > Pb > Cr > Ni. The risk assessment for the six heavy metals through wheat consumption suggests that concentrations of Cr and Cd in some wheat samples exceed their reference oral dose for adults and children. In general, no target hazard quotient value of any individual element was greater than one, which means they are within the safe interval. However, 36.4 and 63.6% hazard index values for adults and children were greater than one, respectively. The health risk due to the added effects of heavy metals was significant for children and adults, and more attention should be paid tothe potential added threat fromheavy metals to the health of children via dietary intake of wheat in Tianjin.


Emerging technologies for identification of disinfection byproducts: GC/FT-ICR MS characterization of solvent artifacts.
Water samples from a local water treatment plant were analyzed, using gas chromatography Fourier transform ion cyclotron resonance mass spectrometry (GC/FT-ICR MS), to identify potential disinfection byproducts (DBPs). Both liquid-liquid extraction (LLE) and solid-phase microextraction (SPME) techniques were used for sample preparation prior to GC/MS analyses. Based on the averaged mass measurement accuracy (MMA) of better than five parts-per-million (<5 ppm), multiple solvent artifacts were identified. It is shown that solventless SPME can be utilized to reduce potential interferences from solvent stabilizers. Six DBPs were detected and their molecular compositions were assigned at a high level of confidence. At the ppb concentration ranges and in the broadband mass spectral detection mode, internally calibrated mass spectra provided concurrent high resolution (resolving power M/deltaM50% > 30,000 at m/z values -110) and MMA of better than one part-per-million (MMA < 1 ppm). The use of thermochemical data, such as proton affinities, as a complementary tool to enhance analytical resolution is also demonstrated.


Ablation of Survivin in T Cells Attenuates Acute Allograft Rejection after Murine Heterotopic Heart Transplantation by Inducing Apoptosis.
Although studies in oncology have well explored the pharmacological effects of Birc5, little is known about its role in allogeneic T-cell responses. Therefore, the present study used a mouse model of acute heart allograft rejection to investigate the protective effect and mechanism of conditional knockout of Birc5 in T cells. Survivin (encoded by Birc5) was up-regulated in T cells activated in vivo and in vitro. Deletion of Birc5 in T cells attenuated acute heart allograft rejection by reducing the ratio of effector to naive T cells and Th1 to Tregs. In addition, deletion of Birc5 had no noticeable effect on proliferation but on apoptosis and the secretion of IFN-γ. The results revealed a significant increase in the percentage of Annexin V positive CD4+ T cells in the Birc5-/- group, compared to the WT. Moreover, there was significant increase in early apoptotic alloreactive T cells in Birc5-/- mice and this was partly mediated by caspase-3. Furthermore, treatment with YM155 inhibited acute heart allograft rejection in vivo and increased T-cell apoptosis in healthy human PBMCs in vitro. The results highlight a potential therapeutic target for the prevention and treatment of acute transplant rejection.


Use of low-dose thrombolytics for treatment of intracardiac thrombus and massive pulmonary embolus after aborted liver transplant leads to recovery of right ventricular function and redo liver transplantation.
This is a 61-year-old man with end-stage liver disease who experienced cardiac arrest secondary to a massive pulmonary embolus and intracardiac thrombus during cannulation for veno-venous extracorporeal membrane oxygenation (ECMO) in preparation for orthotopic liver transplantation (OLT). Surgery was aborted and the patient was taken back to the intensive care unit in cardiogenic shock on multiple vasopressors. The patient was unresponsive to heparin bolus and too high risk for systemic thrombolytics or embolectomy. He was ultimately treated with 12 mg total of alteplase through his pulmonary artery catheter over 3 hours. He had subsequent resolution of his cardiogenic shock and proceeded with successful liver transplantation 5 days after his initial event without any bleeding complications. Low-dose thrombolytic therapy in the setting of absolute contraindications to thrombolysis allowed for recovery of cardiac function and, ultimately redo OLT in a patient with otherwise little hope of survival.


A Luminacin D Analog HL142 Inhibits Ovarian Tumor Growth and Metastasis by Reversing EMT and Attenuating the TGFβ and FAK Pathways.
Epithelial to mesenchymal transition (EMT) is known to contribute to tumor metastasis and chemoresistance. Reversing EMT using small molecule inhibitors to target EMT associated gene expression represents an effective strategy for cancer treatment. The purpose of this study is to test whether a new luminacin D analog HL142 reverses EMT in ovarian cancer (OC) and has the therapeutic potential for OC. We chemically synthesized HL142 and tested its functions in OC cells in vitro and its efficacy in inhibiting ovarian tumor growth and metastasis in vivo using orthotopic OC mouse models. We first demonstrate that ASAP1 is co-amplified and interacts with the focal adhesion kinase (FAK) protein in serous ovarian carcinoma. HL142 inhibits ASAP1 and its interaction protein FAK in highly invasive OVCAR8 and moderately invasive OVCAR3 cells. HL142 inhibits EMT phenotypic switch, accompanied by upregulating epithelial marker E-cadherin and cytokeratin-7 and downregulating mesenchymal markers vimentin, β-catenin, and snail2 in both cell lines. Functionally, HL142 inhibits proliferation, colony formation, migration, and invasion. HL142 also sensitizes cell responses to chemotherapy drug paclitaxel treatment and inhibits ovarian tumor growth and metastasis in orthotopic OC mouse models. We further show that HL142 attenuates the TGFβ and FAK pathways in vitro using OC cells and in vivo using orthotopic mouse models.


Psychiatric Disorders after Switching to Dolutegravir: A Case Report of a 59-Year-Old Virosuppressed HIV-1 Positive Woman.
We report a case of a woman who experienced psychiatric disorders after switching her antiretroviral therapy (c-ART) to dolutegravir (DTG). She is a 59-year-old HIV-1 positive woman with a recent story of cardiovascular disorders treated with beta-blockers, clopidogrel, and rosuvastatin. She underwent a c-ART switch from darunavir/cobicistat and maraviroc to emtricitabine/tenofovir alafenamide fumarate in association with dolutegravir due to drug-drug interactions. One week later, she started to show psychiatric symptoms that required admission to the psychiatric unit. These disorders resolved within a couple of days after DTG discontinuation to allow a regular discharge. With this case-report, we would like to analyse the possible correlation between integrase inhibitor and severe psychiatric disorders in order to confirm the evidences already published in literature.


Effect of exercise at three exercise intensities on salivary cortisol.
Changes in cortisol concentration in response to exercise at 3 different intensities were quantified. Ten apparently healthy, recreationally active males participated. On 4 separate occasions, subjects were assigned a random order of 1-hour cycle ergometer bouts of exercise at 44.5 +/- 5.5%, 62.3 +/- 3.8%, and 76.0 +/- 6.0% (mean +/- SD) of VO2peak and a resting control session. Saliva samples were collected before exercise at 10, 20, 40, and 59 minutes of exercise and at 20 minutes of recovery. Differences in cortisol concentration were assessed via multivariate analysis of variance (alpha = 0.05) Tukey post hoc analysis when indicated. During the highest-intensity exercise session, cortisol was significantly higher at 59 minutes of exercise (p = 0.004) and at 20 minutes of recovery (p = 0.016) than at those same time points during the resting control session. No significant differences in cortisol concentration were noted among resting, low-, and moderate-intensity exercise. Exercise <40 minutes in duration elicited no significant differences at any intensity. These data indicate that only exercise of high intensity and long duration results in significant elevations of salivary cortisol.


Metabolism cage for carbon dioxide trapping studies.
This report describes the design and construction of a metabolism cage that allows for separation of urine and feces and for trapping expired CO2. Such a cage could find use in pharmacokinetic studies of drug excretion rates where potential metabolism to CO2 should be considered. To demonstrate the separation qualities of this cage design, the radioactivity appearing in the urine, feces, and exhaust gases was determined daily for 14 days after the single oral administration of 26-[14C]cholesterol. Less than 1% of the administered radioactivity appeared in the urine, whereas 61% appeared in the feces and 19% in the expired CO2.


Feasibility analysis of in-plant control for water minimization and wastewater reuse in a wool finishing textile mill.
This study evaluates the feasibility of water minimization and wastewater reuse for a wool finishing textile mill. The evaluation process is based upon a detailed analysis on water use, process profile and wastewater characterization, indicating a potential for 34% reduction in water consumption and for 23% of wastewater recovery for reuse. Wastewater reuse requires treatment and results in a remaining wastewater stream with stronger character and consequently more costly to treat. The feasibility includes technical considerations for appropriate treatment alternatives and related cost factors for water consumption, treatment for reuse and for discharge either to sewer or to receiving media.


Low-grade papillary adenocarcinoma of palatal salivary gland origin.
The clinicopathologic features of five low-grade papillary adenocarcinomas of palatal salivary gland origin are presented and seven well-documented cases from the literature are reviewed. Patients in our series ranged in age from 30 to 77 years (median 48). Symptoms were nonspecific and related to a mass present for a long duration. Histologically, these were complex cystic, papillary, focally solid tumors that were partially encapsulated. Cytologically, they were composed of bland, predominantly cuboidal cells with eosinophilic or clear cytoplasm. Four tumors were initially considered to be benign mixed tumors, but long-term follow-up indicates that these are slowly growing, malignant neoplasms. Three patients developed solitary cervical lymph node metastases from 2 to 21 years after initial presentation. One tumor underwent an anaplastic transformation to solid adenocarcinoma, and this was from the only patient in our series who died with tumor. Low-grade papillary adenocarcinoma is a clinicopathologically distinctive salivary gland neoplasm, with histologic features unlike those of other papillary salivary gland tumors.


Immune Escape Mechanism is Impaired in the Microenvironment of Thyroid Lymph Node Metastasis.
We previously identified the infiltration of CD8+ lymphocytes and COX2 expression as an independent factor of risk for recurrence in papillary thyroid carcinoma (PTC) patients. However, the presence of lymph node (LN) metastasis at diagnosis lost its significance in a multivariate model analysis. These results encouraged us to compare the immune cells arrangement in the microenvironment of the LN metastasis and the primary tumor. We studied 104 consecutive PTC patients. Tissue specimens of both primary tumor and LN metastasis at the time of diagnosis were available in 19 out of them. These 19 patients were followed up for 32 to 81 months (64.7 ± 47.5 months). Immune cell markers were investigated using immunohistochemistry and included tumor infiltrating lymphocytes subsets such as CD3, CD4, CD8, CD16, CD20, CD45RO, GRANZYME B, CD69, and CD25. We also investigated the expression of COX2 in tumor cells. Paired t test showed an increase of GRANZYME-B+ lymphocytes density in LN metastasis compared to the corresponding primary tumor, suggesting that LN metastasis is enriched with activated immune cells. In addition, we observed a decrease in COX2 expression levels in LN metastasis compared to the corresponding primary tumors, reinforcing the idea that the immune escape mechanism is impaired in the microenvironment of thyroid LN metastasis. In conclusion, our data demonstrated that the microenvironment of PTC LN metastasis present features that favor an anti-tumor immune response. This may help to explain why the presence of LN metastasis at diagnosis is not a good predictor of PTC patients' survival or disease progression.


Self-medication practices in two California Mexican communities.
Although social scientists have taken up the study of medication use in both developing and developed nations, the medication practices of immigrants remain largely unstudied. In this study, qualitative research was employed in order to describe and compare self-medication practices in two California Mexican immigrant groups: families living along the border near Tijuana, Mexico, and migrant farm worker families residing in illegal encampments and substandard housing in San Diego's North County. Medication and health seeking practices were found to vary according to the specific political-economic, sociocultural, and geographic contexts in which different subpopulations of California Mexicans live. The California-Mexico border area was examined as an important context for considering self-medication behaviors, since it permits border-crossing into Tijuana for the purpose of buying Mexican pharmaceuticals at low cost without a prescription. The popularity of injections among California Mexicans and the cross-border purchasing of injectable antibiotics and vitamins are discussed as issues of particular relevance for immigrants living along the border.


Free "kite" flap: a new flap for reconstruction of small hand defects.
Small, thin, and pliable flaps are frequently required in hand surgery to reconstruct defects in functionally important areas such as the pulp or the "contact zones" of the digits. The innervated first metacarpal artery flap ("kite" flap) is a reliable procedure to restore sensibility in the thumb and the digits. Four microsurgical (free) kite flaps to the hand were performed between February, 1993 and August, 1999 in male patients. Follow-up examinations were performed in three patients. The static two-point discrimination in the kite flaps ranged from 8 to 15 mm and did not show any difference compared to flaps from the foot described in the literature. Semmes-Weinstein testing results ranged from normal to protective sensation with a normal sharp vs. dull discrimination. A free kite flap provides a valuable, safe alternative to venous flaps or other free flaps for reconstruction of small defects in the hand