Assessment of the prevalence of intestinal parasitosis and associated risk factors among primary school children in Chencha town, Southern Ethiopia.
Parasitic infection is the most prevalent among rural communities in warm and humid regions and where water, hygiene and sanitation facilities are inadequate. Such infection occurs in rural areas where water supplies are not enough to drink and use, and in the absence of environmental sanitation, when the rubbish and other wastes increased, and sewage and waste water are not properly treated. Hence the aim of the study was to assess the prevalence of intestinal parasitosis and associated risk factors. This cross sectional study was conducted on children of the selected primary schools in Chencha town from March to May, 2012. Children were selected within age group 5-15 years. The socio-demographic, environmental and behavioral variables data were collected using structured questionnaire from the guardians of children and school teachers to assess the risk factors. Prevalence of intestinal parasitosis was determined using direct method and formol-ether concentration method. Participants' data were analyzed using SPSS version 16.0. Of 422 selected school children, 400 participated in the study with full information for analysis. The overall prevalence of intestinal parasitosis was high (81.0%). Soil-transmitted helminths (STHs) infections (63.0%) were more prevalent than protozoa infections (23.5%). The predominant parasites were A. lumbricoides (60.5%), E. histolytica/dispar (16.25%), Giardia lamblia (11.7%) and T. trichuria (9.7%). The presence of Intestinal Parasitic Infections (IPIs) have statistically significant association with the educational status of the household heads, absence of washing facility, home cleanness condition and type of latrine used with (p < 0.05). The prevalence of intestinal parasitic infections, especially soil-transmitted helminths (STHs) is very high in the school children. The high prevalence of parasitic infections in these children indicates that the protozoa and helminths concerned are very common in the environment of these villages and the results of the risk factors analysis suggests that the transmission is from several routes. Therefore, multiple intervention strategies should be implemented for the school children, households and the environment to reduce the disease burden.


Hexon-only binding of VP26 reflects differences between the hexon and penton conformations of VP5, the major capsid protein of herpes simplex virus.
VP26 is a 12-kDa capsid protein of herpes simplex virus 1. Although VP26 is dispensable for assembly, the native capsid (a T=16 icosahedron) contains 900 copies: six on each of the 150 hexons of VP5 (149 kDa) but none on the 12 VP5 pentons at its vertices. We have investigated this interaction by expressing VP26 in Escherichia coli and studying the properties of the purified protein in solution and its binding to capsids. Circular dichroism spectroscopy reveals that the conformation of purified VP26 consists mainly of beta-sheets (approximately 80%), with a small alpha-helical component (approximately 15%). Its state of association was determined by analytical ultracentrifugation to be a reversible monomer-dimer equilibrium, with a dissociation constant of approximately 2 x 10(-5) M. Bacterially expressed VP26 binds to capsids in the normal amount, as determined by quantitative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cryoelectron microscopy shows that the protein occupies its usual sites on hexons but does not bind to pentons, even when available in 100-fold molar excess. Quasi-equivalence requires that penton VP5 must differ in conformation from hexon VP5: our data show that in mature capsids, this difference is sufficiently pronounced to abrogate its ability to bind VP26.


Intestinal graft versus native liver cytokine expression in a rat model of intestinal transplantation with and without donor-specific cell augmentation.
Immunomodulatory strategies such as donor-specific bone marrow or blood transfusions have been used to promote engraftment after intestinal transplants. We previously showed that delivery of donor antigen via the portal vein can effectively reduce the rate of intestinal graft rejection. The purpose of our current study was to investigate the impact of donor-specific cell augmentation (blood versus bone marrow) via the portal vein on cytokine expression in intestinal grafts versus native livers. We performed heterotopic small intestinal transplants between male Brown-Norway (donor) and female Lewis (recipient) rats. We studied 10 groups according to the type of donor-specific cell augmentation and the use and dose of immunosuppressive therapy. For cell augmentation, donor-specific blood or bone marrow was transfused via the donor portal vein immediately before graft implantation. For immunosuppression, tacrolimus was used post-transplant at a high or low dose. Control rats received neither immunosuppression nor cell augmentation. Tissue samples for histological assessment were obtained at designated time points. RNA was extracted from intestinal graft and native liver biopsies for cytokine measurements (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta). Chimerism levels were determined using Q-PCR analysis. Without concurrent immunosuppression, neither portal donor-specific blood nor bone marrow transfusion reduced the rate of rejection. With immunosuppression, outcome was significantly better after portal donor-specific blood (versus bone marrow) transfusion. Irrespective of the type of donor-specific cell augmentation, severe rejection caused strong cytokine expression in the grafts of IL-1 alpha, IL-1 beta, IFN-gamma, and TNF-alpha; in the native livers, mainly of TNF-alpha (with IFN-gamma showing hardly any increase). In general, rejection caused stronger cytokine expression in the grafts than in the native livers. Mild rejection correlated well with strong intragraft expression of IL-6, TNF-alpha, and TNF-beta (early rejection markers); severe rejection with IL-1 alpha, IL-1 beta, IFN-gamma, and TNF-alpha (late rejection markers). In addition to cell augmentation per se, the type of cell augmentation also had an impact on cytokine expression in both grafts and native livers. Cell-augmented (versus tacrolimus-treated) rats showed hardly any differences in intragraft cytokine expression, but the expression of almost all cytokines was significantly stronger in the native livers. With immunosuppression, bone marrow infusion increased intragraft cytokine expression of IL-1 alpha, IL-1 beta, IFN-gamma, and TNF alpha, as well as liver cytokine expression of IL-1 beta, compared to blood transfusion. This finding reflected the more advanced rejection stages in the bone marrow infused group; different types of donor-specific cell augmentation had similar effects on liver cytokine expression. In the absence of myoablative therapy, chimerism levels were low, in both cell-augmented and non-cell-augmented groups. Rejection and donor-specific cell augmentation independently causes differences in intragraft versus native liver cytokine expression after intestinal transplants. Portal donor-specific blood transfusion, as compared with donor-specific bone marrow infusion, lowered the incidence of rejection and diminished intragraft cytokine up-regulation.


Clostridium perfringens type C and Clostridium difficile co-infection in foals.
Clostridium perfringens type C is one of the most important agents of enteric disease in newborn foals. Clostridium difficile is now recognized as an important cause of enterocolitis in horses of all ages. While infections by C. perfringens type C or C. difficile are frequently seen, we are not aware of any report describing combined infection by these two microorganisms in foals. We present here five cases of foal enterocolitis associated with C. difficile and C. perfringens type C infection. Five foals between one and seven days of age were submitted for necropsy examination to the California Animal Health and Food Safety Laboratory. The five animals had a clinical history of acute hemorrhagic diarrhea followed by death and none had received antimicrobials or been hospitalized. Postmortem examination revealed hemorrhagic and necrotizing entero-typhlo-colitis. Histologically, the mucosa of the small intestine and colon presented diffuse necrosis and hemorrhage and it was often covered by a pseudomembrane. Thrombosis was observed in submucosal and/or mucosal vessels. Immunohistochemistry of intestinal sections of all foals showed that many large bacilli in the sections were C. perfringens. C. perfringens beta toxin was detected by ELISA in intestinal content of all animals and C. difficile toxin A/B was detected in intestinal content of three animals. C. perfringens (identified as type C by PCR) was isolated from the intestinal content of three foals. C. difficile (typed as A(+)/B(+) by PCR) was isolated from the intestinal content in 3 out of the 5 cases. This report suggests a possible synergism of C. perfringens type C and C. difficile in foal enterocolitis. Because none of the foals had received antibiotic therapy, the predisposing factor, if any, for the C. difficile infection remains undetermined; it is possible that the C. perfringens infection acted as a predisposing factor for C. difficile and/or vice versa. This report also stresses the need to perform a complete diagnostic workup in all cases of foal digestive disease.


[6]-Gingerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophages and prevents peroxynitrite-induced oxidation and nitration reactions.
Reactive nitrogen species (RNS), such as nitric oxide (NO) and its derivatives, e.g. peroxynitrite (ONOO-), have been proposed as being able to influence signal transduction and cause DNA damage, contributing to carcinogenic processes. In this study, the effect of [6]-gingerol, a pungent phenolic compound present in ginger (Zingiber officinale Roscoe), on NO synthesis in lipopolysaccharide (LPS)-activated J774.1 macrophages was tested, and the protective ability of this compound against peroxynitrite-mediated oxidation and nitration reactions were evaluated. [6]-Gingerol exhibited dose-dependent inhibition of NO production and significant reduction of inducible NO synthase (iNOS) in LPS-stimulated J774.1 cells. Moreover, [6]-gingerol effectively suppressed peroxynitrite-induced oxidation of dichlorodihydrofluorescein, oxidative single strand breaks in supercoiled pTZ 18U plasmid DNA, and formation of 3-nitrotyrosine in bovine serum albumin (BSA) and J774.1 cells. Our results indicate that [6]-gingerol is a potent inhibitor of NO synthesis and also an effective protector against peroxynitrite-mediated damage.


Comparative biodynamic response of two primate species to the same vibrational environment.
Four Rhesus monkeys and three baboons, all young adult males of nearly the same size (8-17 kg), were implanted with an accelerometer on the upper thoracic and lower lumbar spinous process, respectively. Each animal was exposed to sinusoidal vibrations from 4 to 50 Hz at +/- 0.177 and 0.283 rms GZ acceleration levels, respectively, for approximately 30 s/frequency and to the whole vibration spectrum for about 1h X d-1 up to 4 consecutive days. The impedance magnitude, impedance phase and transmissibility between the seat and two spinal accelerometers were compared at the two acceleration levels. The resonant frequency, other impedance characteristics, and the linearity of the response were compared between the two primate species. Modeling parameters, including the damping and elastic coefficients and spring mass, were calculated from impedance data using an established two-mass model. The majority of each species showed a tendency to be less rigid at 0.283 rms Gz than the lower G level, suggesting more decoupling from the seat with higher acceleration. Over most of the frequency range tested, all the animals vibrated out of phase rather than rigidly with the seat. When the impedance and transmissibility results of the two species were plotted and compared, it raised the question of the phylogenicity and the appropriateness of selecting as a biodynamic model the baboon over the Rhesus monkey in the interspecies scaling efforts up to man.


Ethanol modulation of the hormonal and nutritional regulation of glucose 6-phosphate dehydrogenase activity in primary cultures of rat hepatocytes.
The hormonal and nutritional regulation of glucose 6-phosphate dehydrogenase (G6PDH; EC 188.8.131.52) was studied in primary cultures of rat hepatocytes maintained in a chemically defined medium. Inoculation of hepatocytes from starved rats into primary cultures resulted in a 4-5-fold increase in G6PDH activity in 48 h in the absence of hormones. Parallel cultures treated simultaneously with glucocorticoids and insulin exhibited a 12-15-fold increase during the same time. Glucocorticoids by themselves did not elevate G6PDH activity, whereas insulin alone significantly stimulated enzyme activity. Thus the glucocorticoids acted in a 'permissive' role to amplify the insulin stimulation of G6PDH. Elevated concentrations of glucose in the culture medium increased enzyme activity in both the control cultures and those treated with hormones. Ethanol was found to potentiate G6PDH activity in cultures treated with glucocorticoids and insulin. The effect of ethanol was time- and dose-dependent. These results establish that insulin, glucocorticoids, glucose and ethanol interact in some undefined manner to regulate hepatic G6PDH activity.


Amygdala Response to Emotional Stimuli without Awareness: Facts and Interpretations.
Over the past two decades, evidence has accumulated that the human amygdala exerts some of its functions also when the observer is not aware of the content, or even presence, of the triggering emotional stimulus. Nevertheless, there is as of yet no consensus on the limits and conditions that affect the extent of amygdala's response without focused attention or awareness. Here we review past and recent studies on this subject, examining neuroimaging literature on healthy participants as well as brain-damaged patients, and we comment on their strengths and limits. We propose a theoretical distinction between processes involved in attentional unawareness, wherein the stimulus is potentially accessible to enter visual awareness but fails to do so because attention is diverted, and in sensory unawareness, wherein the stimulus fails to enter awareness because its normal processing in the visual cortex is suppressed. We argue this distinction, along with data sampling amygdala responses with high temporal resolution, helps to appreciate the multiplicity of functional and anatomical mechanisms centered on the amygdala and supporting its role in non-conscious emotion processing. Separate, but interacting, networks relay visual information to the amygdala exploiting different computational properties of subcortical and cortical routes, thereby supporting amygdala functions at different stages of emotion processing. This view reconciles some apparent contradictions in the literature, as well as seemingly contrasting proposals, such as the dual stage and the dual route model. We conclude that evidence in favor of the amygdala response without awareness is solid, albeit this response originates from different functional mechanisms and is driven by more complex neural networks than commonly assumed. Acknowledging the complexity of such mechanisms can foster new insights on the varieties of amygdala functions without awareness and their impact on human behavior.


Ca2+ channel ligand activities in uterine smooth muscle: influence of hormonal status.
The effects of estrogen and progesterone domination, achieved by administering estrogen (E) and estrogen plus progesterone (E + P), on rat uterine reactivity to Ca2+ and to Ca2+ channel ligands (antagonist and activator) were compared. The inhibitory activities of nifedipine, diltiazem, and D 600 against K+ depolarization-induced responses were not significantly different between E- and E + P-dominated states in longitudinal or circular muscle preparations. Tonic responses were significantly more sensitive than phasic responses, but the rank orders of activity for a series of 14 antagonists were identical, suggesting the existence of a common structure-activity relationship which paralleled that seen previously in other smooth muscles. E + P-dominated uteri were slightly more sensitive to Ca2+ responses in K+ depolarizing media, but pA2 values for nifedipine, diltiazem, and D 600 inhibition were not significantly different in tissues from animals in either hormone-dominated state. Binding of [3H]nitrendipine did not differ between hormonal states. Responses to Bay K 8644 were larger in E + P-dominated uteri but the binding density was twofold greater in the E-dominated uterus. This study suggests that pathways of Ca2+ mobilization through potential-dependent Ca2+ channels in rat uterus are not significantly altered between E- and E + P-dominated environments.


The impact of real and illusory perturbations on the early trajectory adjustments of goal-directed movements.
Examinations of goal-directed movements reveal a process of control that operates to make adjustments on the basis of the expected visual afference associated with the limb's movement. This experiment examined the impact of perturbations to the perceived and actual velocity of aiming movements when each was presented alone or in tandem with the other. Perturbations to perceived velocity were achieved by translating the background over which aiming movements were performed. An aiming stylus that discharged air either in the direction of the movement or in the direction opposite the movement generated the actual velocity perturbations. Kinematic analyses of the aiming movements revealed that only the actual perturbation influenced the control of early movement trajectories. The results are discussed with respect to the influence that visual information has on the control exerted against physical perturbations. Speculations are raised regarding how potential for perturbations influences the strategies adopted for minimizing their impact.


Jo1-antisynthetase syndrome and severe interstitial lung disease with organising pneumonia on histopathology with favourable outcome on early combined treatment with corticosteroids, mycophenolate mofetil and rituximab.
Antisynthetase syndrome is a rare autoimmune disease and represents a distinct entity within the idiopathic inflammatory myopathies. Its variable systemic manifestations are composed of myositis, interstitial lung disease, non-erosive arthritis, fever, Raynaud's phenomenon, hyperkeratotic skin changes and the presence of antibodies against aminoacyl-transfer-RNA-synthetases. Interstitial lung disease is the major determinant of morbidity and mortality. The role of lung biopsy remains controversial but it might be considered on an individual basis and may provide information regarding prognosis and treatment response. An integrated clinical, radiological and pathological approach to interstitial lung disease has to be emphasised. Due to the rarity of the disease, no standardised treatment guidelines for antisynthetase syndrome exist. We discuss a patient with anti-Jo1-autoantibody antisynthetase syndrome with proximal myositis and severe, rapid onset, interstitial lung disease with a histopathological pattern of organising pneumonia on surgical lung biopsy and good response to early combined immunosuppressive treatment with corticosteroids, mycophenolate mofetil and rituximab.


The stellate cells phenotypic transformation in the CCl4- injured liver fibrosis of ICR mice: their desmin immunoreactivity and vitamin A storage.
To elucidate the process of phenotypic transformation of stellate cells which were responsible in the production of collagen fibers, ICR mice were injected subcutaneously with CCl4 twice weekly for 5 weeks and the livers were examined by light and electron microscopy every week. Stellate cells were detected by desmin immunoreaction and vitamin A-autofluorescence. In the first week, following cell necrosis in the pericentral areas, granulomas were formed. Two distinct stellate cell phenotypes were developed i.e. desmin-negative cells in the granuloma and a row of intense desmin-positive cells in its boundaries. Both phenotypes seemed to be derived mostly from perisinusoidal stellate cells and involved in collagen synthesis as evidenced by the presence of reticulin meshwork within the granulomas. The meshwork formation was the initial stage of a new septum formation since in the second week the intense desmin-positive cell rows were closer to the central vein concomitant with the growth of several protrusions to form thin layer septa towards neighboring central or portal veins. The myofibroblast-like cells in the septa with features interposed between stellate cells and myofibroblasts were likely derived from the stellate cells phenotypes. During the transformation of stellate cells, the decline of vitamin A storage was accompanied by the formation of connective tissue septa. The desmin immunoreactivity and vitamin A storage in the stellate cell phenotypes during liver fibrogenesis described in this study may reveal their phenotypic transformation in association with the collagen synthesis.


Risk factors for recurrences in patients with hepatitis C virus after achieving a sustained virological response: a multicentre study from Turkey.
In this study, we aimed to determine the late relapse rate in hepatitis C patients with sustained virological response after interferon-based regimens, and evaluated the predictors of late relapse while comparing the real-life data of our country with that of others. A multicenter retrospective study was performed to investigate the data of patients infected with HCV who obtained sustained virological response after classical or pegylated interferon alpha (PegIFNα) and ribavirin (RBV) for 48 weeks. Sustained virological response was based on negative HCV RNA level by PCR at the end of six months after the therapy. The information of patients enrolled in the study was retrieved from the hospital computer operating system and outpatient follow-up archives. We evaluated the age, gender, HCV RNA levels, HCV genotype, six-month and further follow-up of patients with sustained virologic response, presence of cirrhosis, steatosis and relapse. In all, 606 out of 629 chronic hepatitis C patients (mean age was 53±12 years; 57.6% of them were female) with sustained virological response were evaluated. We excluded 23 patients who relapsed within six months after the end of treatment (EOT). The mean follow-up period of the patients was 71 months (range: 6-136) after therapy. Late relapse rate was 1.8% (n=11) in all patients. Univariate Cox proportional hazard regression models identified that cirrhosis and steatosis were associated with the late relapse [(p = 0.027; Hazard Ratio (HR) 2.328; 95% confidence interval (CI): 1.309-80.418), (p = 0.021; HR 1.446; 95% CI: 1.243-14.510, respectively]. In multivariable Cox regression analysis, steatosis was the only independent risk factor for late relapse (p = 0.03; HR 3.953; 95% CI: 1.146-13.635). Although the late relapse rate was approximately 2% in our study, clinicians should consider that pretreatment steatosis may be an important risk factor for late relapse.


Compartmentalizing and sculpting nanovesicles by phase-separated aqueous nanodroplets.
Phase-separated liquid droplets inside giant vesicles have been intensely studied as biomimetic model systems to understand cellular microcompartmentation and molecular crowding and sorting. On the nanoscale, however, how aqueous nanodroplets interact with and shape nanovesicles is poorly understood. We perform coarse-grained molecular simulations to explore the architecture of compartmentalized nanovesicles by phase-separated aqueous nanodroplets, and their morphological evolution under osmotic deflation. We show that phase separation of a biphasic liquid mixture can form both stable two-compartment and meta-stable multi-compartment nanovesicles. We identify morphological transitions of stable two-compartment nanovesicles between tube, sheet and cup morphologies, characterized by membrane asymmetry and phase-separation propensity between the aqueous phases. We demonstrate that the formation of local sheets and in turn cup-shaped nanovesicles is promoted by negative line tensions resulting from large separation propensities, an exclusive nanoscale phenomenon which is not expected for larger vesicles where energetic contributions of the line tensions are dominated by those of the membrane tensions. Despite their instability, we observe long-lived multi-compartment nanovesicles, such as nanotubules and branched tubules, whose prolonged lifetime is attributed to interfacial tensions and membrane asymmetry. Aqueous nanodroplets can thus form novel membrane nanostructures, crucial for cellular processes and forming cellular organelles on the nanoscale.


Yb-doped large mode area fiber for beam quality improvement using local adiabatic tapers with reduced dopant diffusion.
A newly designed all-solid step-index Yb-doped aluminosilicate large mode area fiber for achieving high peak power at near diffraction limited beam quality with local adiabatic tapering is presented. The 45µm diameter fiber core and pump cladding consist of active/passively doped aluminosilicate glass produced by powder sinter technology (REPUSIL). A deliberate combination of innovative cladding and core materials was aspired to achieve low processing temperature reducing dopant diffusion during fiber fabrication, tapering and splicing. By developing a short adiabatic taper, robust seed coupling is achieved by using this Yb-doped LMA fiber as final stage of a nanosecond fiber Master Oscillator Power Amplifier (MOPA) system while maintaining near diffraction limited beam quality by preferential excitation of the fundamental mode. After application of a fiber-based endcap, the peak power could be scaled up to 375 kW with high beam quality and a measured M2 value of 1.3~1.7.


Serologic survey for Leptospira spp. in captive neotropical felids in Foz do Iguaçu, Paraná, Brazil.
Leptospirosis is a bacterial zoonosis of worldwide distribution and is endemic in tropical countries, where rodents and other wild mammals are abundant and may act as reservoirs. Leptospirosis has become a concern in captive wild animals, due mostly to their exposure to contaminated urine or environment. Although domestic cats (Felis catus) have been reported refractory to leptospirosis, serology and disease in captive wild felids is still unclear. In this study 57 adult, clinically healthy felids, including 1 Geoffroy's cat (Leopardus geoffroyi), 3 jaguarundis (Puma yagouaroundi), 17 margays (Leopardus wiedii), 22 little spotted cats (Leopardus tigrinus), and 14 ocelots (Leopardus pardalis) kept in captivity at the Sanctuary at the Itaipu Binacional hydroelectric power plant (Bela Vista Biological Sanctuary), Foz do Iguacu City, Paraná State, Brazil, were serologically surveyed for the presence of antibodies against 28 serovars of Leptospira spp. by microagglutination test (MAT). Two animals (3.5%) were seropositive: one male ocelot to the serovar Cynopteri (titer 100) and one female margay to Autumnalis (100) and Butembo (200). The captive-born, 5-yr-old ocelot had been solitary housed in an individual cage. The approximately 21-yr-old wild-caught margay was also kept individually. None of the tested animals showed signs ofleptospirosis. During a study conducted 4 yr previously in the same facility, this particular margay also tested positive for the same two serovars, among others. The present study indicates that the felids tested for Leptospira spp. by MAT were exposed to serovars, but did not demonstrate clinical signs of disease. Comparison with a previous study suggests that serovar titers may vary over time and that leptospirosis dynamics remains unclear in wild felids.


[Acute anaemia in a Vietnamese patient with alpha-thalassaemia and a parvovirus infection].
A 14-year-old girl of Vietnamese descent with an unremarkable medical history presented with haemodynamic shock due to severe anaemia. This was caused by an aplastic crisis resulting from the combined effects of a Parvovirus infection and HbH disease. The HbH disease was a result of compound heterozygosity for the South East Asia (SEA) deletion and the Constant Spring mutation in the genes coding for alpha-globin chains (HbH/Hb Bart's). The girl had multiple blood transfusions and recovered. Family investigation revealed that, in addition to these 2 mutations in the alpha-globin gene, some family members also carried the 3.7-kb deletion of the alpha-globin gene, a mutation in the beta-globin gene resulting in HbE, and a novel mutation of unknown clinical significance in the beta-globin gene. This case demonstrates that essentially asymptomatic carriership of thalassaemia can have serious consequences when coupled with a concurrent infection.


Women's Health at High Altitude: An Introduction to a 7-Part Series by the International Climbing and Mountaineering Federation Medical Commission.
Horakova, Lenka, Peter Paal, Jacqueline Pichler Hefti, Marija Andjelkovic, Beth A. Beidleman, Mia Derstine, David Hillebrandt, Dominique Jean, Kastė Mateikaitė-Pipirienė, Alison J. Rosier, Susi Kriemler, and Linda E. Keyes. Women's health at high altitude: An introduction to a 7-part series by the International Climbing and Mountaineering Federation Medical Commission. High Alt Med Biol. 00:000-000, 2023. Background: Women have been traveling to high altitude since the inception of modern mountaineering. Although there are distinct female-specific features such as menstruation and menopause relevant to adaptation to and performance at high altitude, very little data exist on women's high-altitude health. To summarize what is known to date, the Medical Commission of the International Climbing and Mountaineering Federation (UIAA) has created a series of articles on women's health, high altitude illness, and performance at high altitude. Methods: Assembling an international author team, two types of manuscripts were developed: (1) reviews on female-specific topics such as pregnancy; (2) reviews on sex differences in high-altitude related illnesses, nutrition, cold injuries, and mortality. Results: The literature search yielded 7,165 articles, with 482 studies meeting the inclusion criteria for full-text review. The authors of individual chapters reviewed these articles and performed additional hand searches. Conclusions: Some important questions on women sojourning and exercising at high altitude have been studied, but many are still awaiting a qualified and evidence-based response. Our seven reviews, to be published in future issues of this journal, summarize what is known about lowland women sojourning at high altitude, provide recommendations, and highlight knowledge gaps in high altitude women's medicine.


Comparative metabolomic analysis of wild type and mads3 mutant rice anthers.
Rice (Oryza sativa L.) MADS3 transcription factor regulates the homeostasis of reactive oxygen species (ROS) during late anther development, and one MADS3 mutant, mads3-4, has defective anther walls, aborted microspores and complete male sterility. Here, we report the untargeted metabolomic analysis of both wild type and mads3-4 mature anthers. Mutation of MADS3 led to an unbalanced redox status and caused oxidative stress that damages lipid, protein, and DNA. To cope with oxidative stress in mads3-4 anthers, soluble sugars were mobilized and carbohydrate metabolism was shifted to amino acid and nucleic acid metabolism to provide substrates for the biosynthesis of antioxidant proteins and the repair of DNA. Mutation of MADS3 also affected other aspects of rice anther development such as secondary metabolites associated with cuticle, cell wall, and auxin metabolism. Many of the discovered metabolic changes in mads3-4 anthers were corroborated with changes of expression levels of corresponding metabolic pathway genes. Altogether, this comparative metabolomic analysis indicated that MADS3 gene affects rice anther development far beyond the ROS homeostasis regulation.


Glutamine supplementation alleviates vasculopathy and corrects metabolic profile in an in vivo model of endothelial cell dysfunction.
Endothelial Cell Dysfunction (ECD) is a recognized harbinger of a host of chronic cardiovascular diseases. Using a mouse model of ECD triggered by treatment with L-Nω-methylarginine (L-NMMA), we previously demonstrated that renal microvasculature displays a perturbed protein profile, including diminished expression of two key enzymes of the Krebs cycle associated with a Warburg-type suppression of mitochondrial metabolism. We hypothesized that supplementation with L-glutamine (GLN), that can enter the Krebs cycle downstream this enzymatic bottleneck, would normalize vascular function and alleviate mitochondrial dysfunction. To test this hypothesis, mice with chronic L-NMMA-induced ECD were co-treated with GLN at different concentrations for 2 months. Results confirmed that L-NMMA led to a defect in acetylcholine-induced relaxation of aortic rings that was dose-dependently prevented by GLN. In caveolin-1 transgenic mice characterized by eNOS inactivation, L-NMMA further impaired vasorelaxation which was partially rescued by GLN co-treatment. Pro-inflammatory profile induced by L-NMMA was blunted in mice co-treated with GLN. Using an LC/MS platform for metabolite profiling, we sought to identify metabolic perturbations associated with ECD and offset by GLN supplementation. 3453 plasma molecules could be detected with 100% frequency in mice from at least one treatment group. Among these, 37 were found to be differentially expressed in a 4-way comparison of control vs. LNMMA both with and without GLN. One of such molecules, hippuric acid, an "uremic toxin" was found to be elevated in our non-uremic mice receiving L-NMMA, but normalized by treatment with GLN. Ex vivo analysis of hippuric acid effects on vasomotion demonstrated that it significantly reduced acetylcholine-induced vasorelaxation of vascular rings. In conclusion, functional and metabolic profiling of animals with early ECD revealed macrovasculopathy and that supplementation GLN is capable of improving vascular function. Metabolomic analyses reveal elevation of hippuric acid, which may further exacerbate vasculopathy even before the development of uremia.


DNA-Damaging Anticancer Drugs - A Perspective for DNA Repair- Oriented Therapy.
DNA-damaging drugs in cancer present two main problems: therapeutic resistance and side effects and both can associate with DNA repair, which can be targeted in cancer therapy. Bleomycin (BLM) induces complex DNA damages, including strand breaks, base loss and 3'-phosphoglycolate (3'PG) residues repaired by several pathways, but 3'PGs must be processed to the 3'-OH ends, usually by tyrosyl-DNA phosphodiesterase 1 (Tdp1). Therefore, targeting Tdp1 can improve anticancer therapy with BLM. Mitomycin C (MMC) produces a variety of adducts with DNA, including inter-strand cross-links (ICLs) and Xeroderma pigmentosum (XP) proteins, including XPG, XPE and XPF can be crucial for the initial stage of ICL repair, so they can be targeted by inhibitors to increase toxicity of MMC in cancer cells. Although these proteins are essential for nucleotide excision repair (NER), their decreased activity may not be fatal in normal cells as almost all NER substrates can be repaired by other pathways. Four-stranded DNA, resulted mainly from guanine quadruplexes (G-4s), are highly overexpressed at the end of telomeres, where they can inhibit telomerase, hence stabilization G-4s at the telomeres ends can hamper proliferation of cancer cells. Quadruplexes are also found in the promoters of genes important for cancer and are resolved by DNA helicases, which can be targeted in cancer along with stabilization of quadruplexes. As cancer cells often have defects in DNA repair pathway(s), they can be subjected by synthetic lethality, with the most promising results with poly(ADP-ribose) polymerase 1 (PARP-1) and DNA-dependent protein kinase, catalytic subunit (DNA-PKCS).


Pharyngo-tonsillar involvement of Mpox in a cohort of men who have sex with men (MSM): A serious risk of missing diagnosis.
During the 2022-outbreak, peculiar clinical presentations of Mpox have been described, some of which can make the diagnosis of the disease extremely challenging. Here we report a case series of fourteen patients with Mpox pharynogotonsillar involvement (PTI) seen at National Institute for Infectious Diseases, "Lazzaro Spallanzani", in Rome, Italy from May to September 2022. All included patients were men who have sex with men (median age 38 years) reporting unprotected sex within three weeks from symptoms onset. Seven out of fourteen patients needed hospitalization due to uncontrolled pain, reduced airspace and difficulty swallowing, of whom five were effectively treated with tecovirimat or cidofovir. The remaining two patients were treated with symptomatic drugs. The typical Mpox muco-cutaneous manifestations were not observed simultaneously with PTI in three patients, two of whom developed the lesions after several days, while one never manifested them. Polymerase Chain Reaction (PCR) for Mpox virus was positive in oropharyngeal swab, saliva and serum. Although PTI occurs in only a small percentage of Mpox cases, its diagnosis is of utmost importance. In fact, this localization, if not identified, could lead to serious complications in the absence of early antiviral treatment and to missed diagnosis with an increased risk of disease transmission.


The in vitro effects of Newcastle disease virus on the metabolic and antibacterial functions of human neutrophils.
Live Newcastle disease virus (NDV) was used to investigate the in vitro effects of a viral infection on phagocytosis, chemiluminescence generation, superoxide production, oxygen consumption, NADPH-oxidase activity, and intracellular killing of bacteria by Ficoll-Hypaque separated human neutrophils. Phagocytosis of oil red O particles by NDV-treated PMN was inhibited by 50%. Chemiluminescence by PMN was inhibited 79% after zymosan stimulation and 86% after tetradeconyl phorbol acetate stimulation. Superoxide generation was inhibited by 68%. Oxygen consumption was inhibited in the presence of NDV by 37% after stimulation with phorbol myristate acetate, while membrane-associated NADPH-enzyme activity was decreased by 19%. The percent of surviving intracellular S. aureus was significantly elevated in NDV-treated PMN after 60 and 120 min of incubation. Purified bacterial neuraminidase markedly suppressed chemiluminescence, while neuraminic acid blocked the effects of the virus. These observations suggest that infections with myxoviruses may suppress a number of vital neutrophil functions. It appears that the effects may be partly mediated by the interaction of viral neuraminidase with the external neutrophil membrane.


High resolution image formation from low resolution frames using Delaunay triangulation.
An algorithm based on spatial tessellation and approximation of each triangle patch in the Delaunay (1934) triangulation (with smoothness constraints) by a bivariate polynomial is advanced to construct a high resolution (HR) high quality image from a set of low resolution (LR) frames. The high resolution algorithm is accompanied by a site-insertion algorithm for update of the initial HR image with the availability of more LR frames till the desired image quality is attained. This algorithm, followed by post filtering, is suitable for real-time image sequence processing because of the fast expected (average) time construction of Delaunay triangulation and the local update feature.


In Vitro, In Silico, and In Vivo Assessments of Pharmacokinetic Properties of ZM241385.
Parkinson's disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut.


SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline.
Barely 10-20% of patients with metastatic colorectal cancer (mCRC) receive a clinical benefit from the use of anti-EGFR monoclonal antibodies (mAbs). We hypothesized that this could depends on their efficiency to reduce Store Operated Calcium Entry (SOCE) that are known to enhance cancer cells. In the present study, we demonstrate that SOCE promotes migration of colon cancer cell following the formation of a lipid raft ion channel complex composed of TRPC1/Orai1 and SK3 channels. Formation of this complex is stimulated by the phosphorylation of the reticular protein STIM1 by EGF and activation of the Akt pathway. Our data show that, in a positive feedback loop SOCE activates both Akt pathway and SK3 channel activity which lead to SOCE amplification. This amplification occurs through the activation of Rac1/Calpain mediated by Akt. We also show that Anti-EGFR mAbs can modulate SOCE and cancer cell migration through the Akt pathway. Interestingly, the alkyl-lipid Ohmline, which we previously showed to be an inhibitor of SK3 channel, can dissociated the lipid raft ion channel complex through decreased phosphorylation of Akt and modulation of mAbs action. This study demonstrates that the inhibition of the SOCE-dependent colon cancer cell migration trough SK3/TRPC1/Orai1 channel complex by the alkyl-lipid Ohmline may be a novel strategy to modulate Anti-EGFR mAb action in mCRC.


Orchidectomy and immune response.
The effects of orchidectomy on the structure and function of lymphoid tissues in mice have been studied. Both pre- and postpuberal orchidectomy caused relative hypertrophy of the thymus. There was also an increase in size of peripheral lymph nodes to reach a sustained maximum (6 weeks). Sychronous thymectomy and orchidectomy prevented the lymph node enlargement that follows orchidectomy alone. Enlargement of the thymus was due to increased numbers of thymocytes, and it could be abrogated by administration of androgens. Orchidectomy was associated with an acceleration of rejection of skin allografts which was prevented by androgen administration and abrogated by antilymphocyte serum. The reactivity of orchidectomized mice to sheep red blood cells and the early response to oxazolone, which is limited by thymus-processed cells, was increased, whereas production of antibodies to oxazolone, skin allografts, and pneumococcal polysaccharide was unchanged. It is suggested that orchidectomy increases cell-mediated immune responses but has no direct effect upon responses that are mainly dependent on B cells. Orchidectomy prolongs the interval between the subcutaneous injection of methylcholanthrene and the appearance of subcutaneous sarcomas. In tumour transplantation experiments orchidectomy casued protection against the Meth A tumour grown in ascitic or subcutaneous form. This protection was counteracted by antilymphocyte serum and partially countered by adult thymectomy combined with orchidectomy. In contrast, the appearance in AKR mice of spontaneous leukaemia, a tumour known to be thymus dependent, was increased after orchidectomy. The results of experiments with hypopituitary mice suggested that the effects of orchidectomy on immune response result from androgen withdrawal rather than interference with the hormonal milieu.


["Fiction and Truth": Goethe's anatomical research at the University of Jena].
Johann Wolfgang von Goethe was one of the most renowned German poets of the late Age of Enlightenment. However, his engagement went far beyond literature especially relating to politics and natural science. Goethe, primarily trained as a lawyer, developed his own theory of colors and even challenged the concepts of Isaac Newton. His discovery of the human intermaxilary bone questioned all the dogmas of the religious-minded world of the 18th century. Together with the anatomy professor Justus Christian Loder, Goethe performed comparative anatomy and proved the conceptual uniformity of humans and animals on 27 March 1784. Even though, Félix Vicq d'Azyr described the intermaxilary bone simultaneously in Catholic France, Goethe's findings were politically accepted due to the liberal Protestantism of the Duchy of Weimar. Nevertheless, leading anatomists of the century (Johann Friedrich Blumenbach, Petrus Camper and Samuel Thomas v. Soemmerring) mainly rejected Goethe's postulates which led to a delayed publication in 1820; almost 36 years after writing his original manuscript. Today, Goethe's discovery is known to be a fundamental basis for the development of Charles Darwin's theory of phylogenetic evolution. Nowadays, the Department of Anatomy contains the Museum Anatomicum Jenense which was founded by the Duke of Weimar, Carl August and Goethe and entails Goethe's premaxillary bones as its main attraction. The University values the cultural heritage of Goethe's contribution to Medicine and provides access to the collection to the public and generations of medical students. Still today Goethe's legacy is noticeable in the halls of the Alma Mater Jenensis.


Assessment of deoxyhypusine hydroxylase as a putative, novel drug target.
Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.


Accuracy of buffered-force QM/MM simulations of silica.
We report comparisons between energy-based quantum mechanics/molecular mechanics (QM/MM) and buffered force-based QM/MM simulations in silica. Local quantities-such as density of states, charges, forces, and geometries-calculated with both QM/MM approaches are compared to the results of full QM simulations. We find the length scale over which forces computed using a finite QM region converge to reference values obtained in full quantum-mechanical calculations is ∼10 Å rather than the ∼5 Å previously reported for covalent materials such as silicon. Electrostatic embedding of the QM region in the surrounding classical point charges gives only a minor contribution to the force convergence. While the energy-based approach provides accurate results in geometry optimizations of point defects, we find that the removal of large force errors at the QM/MM boundary provided by the buffered force-based scheme is necessary for accurate constrained geometry optimizations where Si-O bonds are elongated and for finite-temperature molecular dynamics simulations of crack propagation. Moreover, the buffered approach allows for more flexibility, since special-purpose QM/MM coupling terms that link QM and MM atoms are not required and the region that is treated at the QM level can be adaptively redefined during the course of a dynamical simulation.


Dopamine D2/3 receptor availability and amphetamine-induced dopamine release in obesity.
The neurotransmitter dopamine is important in the regulation of food intake. It is hypothesised that obese people experience less reward from food due to lower striatal dopamine release, which consequently leads to overeating. This study is the first to assess whether obese subjects have blunted striatal dopamine release. We measured striatal dopamine D2/3 receptor (DRD2/3) availability and amphetamine-induced striatal dopamine release in 15 obese and 15 age-matched, normal-weight women using [(123)I]iodobenzamide single photon emission computed tomography (SPECT) imaging. In addition, correlations with food craving were examined. Baseline striatal DRD2/3 availability was lower in obese subjects (0.91 ± 0.16) compared to controls (1.09 ± 0.16; p = 0.006). Amphetamine-induced dopamine release was significant in controls (7.5% ± 9.2; p = 0.007) and not in obese subjects (1.2% ± 17.7; p = 0.802), although the difference in release between groups (d=0.45) was not significant. Dopamine release positively correlated with the trait food craving in obese subjects. This study replicates previous findings of lower striatal DRD2/3 availability in obesity and provides preliminary data that obesity is associated with blunted dopamine release. The positive correlation between dopamine release and food craving in obesity may seem contradictory with the latter finding but is presumably related to heterogeneity within the obese subjects.


Phylogeny of the core Malvales: evidence from ndhF sequence data.
The monophyly of the group comprising the core malvalean families, Bombacaceae, Malvaceae, Sterculiaceae, and Tiliaceae, was recently confirmed by molecular studies, but the internal structure of this clade is poorly understood. In this study, we examined sequences of the chloroplast ndhF gene (aligned length 2226 bp) from 70 exemplars representing 35 of the 39 putative tribes of core Malvales. The monophyly of one traditional family, the Malvaceae, was supported in the trees resulting from these data, but the other three families, as traditionally circumscribed, are nonmonophyletic. In addition, the following relationships were well supported: (1) a clade, /Malvatheca, consisting of traditional Malvaceae and Bombacaceae (except some members of tribe Durioneae), plus Fremontodendron and Chiranthodendron, which are usually treated as Sterculiaceae; (2) a clade, /Malvadendrina, supported by a unique 21-bp (base pair) deletion and consisting of /Malvatheca, plus five additional subclades, including representatives of Sterculiaceae and Tiliaceae, and Durionieae; (3) a clade, /Byttneriina, with genera traditionally assigned to several tribes of Tiliaceae, plus exemplars of tribes Byttnerieae, Hermannieae, and Lasiopetaleae of Sterculiaceae. The most striking departures from traditional classifications are the following: Durio and relatives appear to be more closely related to Helicteres and Reevesia (Sterculiaceae) than to Bombacaceae; several genera traditionally considered as Bombacaceae (Camptostemon, Matisia, Phragmotheca, and Quararibea) or Sterculiaceae (Chiranthodendron and Fremontodendron) appear as sister lineages to the traditional Malvaceae; the traditional tribe Helictereae (Sterculiaceae) is polyphyletic; and Sterculiaceae and Tiliaceae, as traditionally circumscribed, represent polyphyletic groups that cannot sensibly be maintained with their traditional limits for purposes of classification. We discuss morphological characters and conclude that there has been extensive homoplasy in characters previously used to delineate major taxonomic groups in core Malvales. The topologies here also suggest that /Malvatheca do not have as a synapormophy monothecate anthers, as has been previously supposed but, instead, may be united by dithecate, transversely septate (polysporangiate) anthers, as found in basal members of both /Bombacoideae and /Malvoideae. Thus, "monothecate" anthers may have been derived at least twice, independently, within the /Bombacoideae (core Bombacaceae) and /Malvoideae (traditional Malvaceae).


Changes in community composition of ammonia-oxidizing betaproteobacteria from stands of Black mangrove (Avicennia germinans) in response to ammonia enrichment and more oxic conditions.
In flooded and non-flooded impounded forests of Black mangrove (Avicennia germinans), the community structure of the ammonia-oxidizing betaproteobacteria (β-AOB) differed among distinct mangrove vegetation cover types and hydrological regimes. This had been explained by a differential response of lineages of β-AOB to the prevailing soil conditions that included increased levels of moisture and ammonium. To test this hypothesis, slurries of soils collected from a flooded and a non-flooded impoundment were subjected to enhanced levels of ammonium in the absence and presence of additional shaking. After a period of 6 days, the community composition of the β-AOB based on the 16S rRNA gene was determined and compared with the original community structures. Regardless of the incubation conditions and the origin of the samples, sequences belonging to the Nitrosomonas aestuarii lineage became increasingly dominant, whereas the number of sequences of the lineages of Nitrosospira (i.e., Cluster 1) and Nitrosomonas sp. Nm143 declined. Changes in community structure were related to changes in community sizes determined by quantitative PCR based on the amoA gene. The amoA gene copy numbers of β-AOB were compared to those of the ammonia-oxidizing archaea (AOA). Gene copy numbers of the bacteria increased irrespective of incubation conditions, but the numbers of archaea declined in the continuously shaken cultures. This observation is discussed in relation to the distribution of the β-AOB lineages in the impounded Black mangrove forests.


Transanal minimally invasive surgery for total mesorectal excision (ETM) through transanal approach (TaETM) with robotic and Transanal Endoscopic Operations (TEO) combined access: step by step surgery.
In the treatment of colorectal cancer, from 1982 Heald proposed standardization of the total mesorectal excision, with a significant reduction in the recurrence rate. But the treatment of lower rectal lesions is still a challenge. To describe the association of robotic low anterior resection- TATA (Transanal Abdominal Transanal Resection), with transanal access using Transanal Endoscopic Operations - TEO in the treatment of lower rectal cancer. The TATA performs robotic abdominal approach and the TEO performs the perineal approach, developing total mesorectal excision (TME) transanally (TaETM). The TaETM technique was applied in a woman with rectal adenocarcinoma 5 cm from the anal verge that had been submitted to chemoradiation. The procedure was performed with satisfatory operative time and favorable oncological outcome (grade 3 mesorectal excision). This is a promising minimally invasive procedure in the armamentarium of rectal cancer treatment, specially in challenging scenarios such as narrow pelvis, obesity and very low rectal tumors.


Unexpected square symmetry seen by atomic force microscopy in bilayer films of disk-like molecules.
Thin films of disk-shaped molecules are expected to display anisotropic optical and transport properties, leading to applications in optical display or sensor technologies. Bilayer Langmuir-Blodgett films of monomeric triphenylene mesogens have been studied by atomic force microscopy. The triphenylene cores of the constituent molecules tend to promote the formation of columnar structures in the plane of the substrate and along the direction of deposition of the film. Atomic force microscopy images of bilayer Langmuir-Blodgett films revealed two types of structure, one corresponding to an aligned columnar structure and the other to an unusual square lattice, which may result from the superposition of columnar structures in adjacent layers that intersect at near right angles. Annealing such bilayers near the melting point of the bulk compound improved the structural ordering by reducing the angular spread of orientations associated with the well-developed columnar structure in some areas and by producing a more distinct square lattice in other areas of the sample.


Correction: Internet of Things (IoT) for Smart Agriculture: Assembling and assessment of a low-cost IoT system for polytunnels.
[This corrects the article DOI: 10.1371/journal.pone.0278440.].


Developmental changes in AT1 and AT2 receptor-protein expression in rats.
It has long been known that angiotensin type-1 receptors (AT1R) play a critical role in sympathetic regulation, cardiovascular activity, and hormone secretion under physiological and pathological states. On the other hand, the functional significance of angiotensin type-2 receptors (AT2R) is poorly understood. In a recent study we demonstrated that, in rats with chronic heart failure, AT1R protein expression was increased but AT2R expression was decreased in the rostral ventrolateral medulla (RVLM). This imbalance of angiotensin receptors contributed to sympatho-excitation in the heart failure state. In the current experiment, we measured AT1R and AT2R protein expressions in the brainstem, kidney and liver from male foetuses (3 days before birth), male neonates (3 days after birth), male and female adults (8 weeks) and male aged (28 months) rats by Western blot analysis. In the brainstem, we found that the foetuses and neonates exhibited a significantly lower AT2R protein expression compared with adult rats (foetus 0.08 ± 0.01, neonate 0.12 ± 0.01, male adult 0.25 ± 0.01, female adult 0.22 ± 0.02; n = 4 per group, p < 0.001 foetus and neonate compared with male or female adults). In contrast, the foetuses and neonates expressed significantly higher AT1R protein than that of the adults (foetus 0.64 ± 0.09, neonate 0.56 ± 0.01, male adult 0.13 ± 0.02, female adult 0.08 ± 0.02; n = 4 each group, p < 0.001 foetus and neonate compared with male and female adults). In the liver, the AT2R protein was also higher in foetus and neonate, than in adult rats. Interestingly, the foetal liver expressed higher AT1R protein compared with that of the neonate. In the kidney, AT2R expression was significantly increased with age (foetus 0.08 ± 0.01, neonate 0.19 ± 0.02, male adult 0.49 ± 0.04, female adult 0.90 ± 0.10; n = 4 per group, p < 0.01-0.001). AT1R expression, on the other hand, was higher in the foetuses than that in both neonate and male adults. This study provides data contrary to existing dogma that AT2R expression is higher in foetal life and low in adults, suggesting an involvement of a potentially important functional role for AT2R in adult animals and AT1R in foetal development and/or physiology.


Failure to detect binding of LcrH to the V antigen of Yersinia pestis.
V antigen of Yersinia pestis has been reported to bind the chaperone LcrH. We were unable to demonstrate this interaction. Despite methodological differences between our study and an earlier study, we believe that the previous findings were artifactual. One likely confounding element was the tendency of LcrH to adhere on its own to metal chelation chromatographic resin.


Improved model for the refractive index: application to potential components of ambient aerosol.
Understanding the impact of atmospheric aerosols on the global radiative balance requires knowing the refractive index (RI) of their components. Currently available methods to estimate this property from molecular structure are mostly empirical and exhibit significant errors (>10%). This work reports a more physically sound model leading to predictions within ±5% from experiment. The root mean square relative error is <1% for general organic compounds, and <2% for oxygen-rich compounds of special interest in aerosol chemistry. In this approach, the RI is obtained from the Lorentz-Lorenz equation. The molar volume and polarizability required as input are obtained from the addition of a so-called geometrical fragment (GF) associated with every non-hydrogen atom in the molecule. The value of this GF method to the study of ambient aerosol is demonstrated through extensive validation and application to compounds that may be present in aerosol droplets. In so doing, insight is provided into the origin of significant errors previously noted using earlier methods. Moreover, it is demonstrated that reference values of the refractive index reported in widely used compilations should be considered with caution. Finally, a Python script is provided as supplementary information for easy use of the present model to estimate molar volume and refractive index for any molecule.


How, when, and where new inhibitory neurons release neurotransmitters in the adult olfactory bulb.
Adult-born neurons continuously incorporate into the olfactory bulb where they rapidly establish contacts with a variety of synaptic inputs. Little is known, however, about the functional properties of their output. Characterization of synaptic outputs from new neurons is essential to assess the functional impact of adult neurogenesis on mature circuits. Here, we used optogenetics to control neurotransmitter release from new neurons. We found that light-induced synaptic GABA release from adult-born neurons leads to profound modifications of postsynaptic target firing patterns. We revealed that functional output synapses form just after new cells acquire the faculty to spike, but most synapses were made a month later. Despite discrepancies in the timing of new synapse recruitment, the properties of postsynaptic signals remain constant. Remarkably, we found that all major cell types of the olfactory bulb circuit, including output neurons and several distinct subtypes of local interneurons, were contacted by adult-born neurons. Thus, this study provides new insights into how new neurons integrate into the adult neural network and may influence the sense of smell.


Nurses' knowledge of evidence-based guidelines for prevention of ventilator-associated pneumonia in critical care areas: a pre and post test design.
Ventilator associated pneumonia (VAP) is a common hospital acquired pneumonia in ventilated patients. VAP is associated with increased morbidity, mortality duration of hospitalization and cost of treatment. Critical care nurses are usually unaware of evidence based preventive guidelines for VAP, resulting in negative impact on all aspects of patient care. This study investigated the impact of a 5-hour teaching module on nurses' knowledge to practice evidence based guidelines for the prevention of VAP. This study was conducted at a private tertiary care teaching hospital in Karachi, Pakistan. Single group pre-test design was used. Forty nurses were included in the study. The knowledge of nurses was assessed before, immediately after and 4 weeks after the intervention. The final sample (n=40) was selected on the basis of the set inclusion criteria. The demographic data sheet was used to collect relevant information about the participants. Knowledge was assessed through a self-developed validated tool, consisting of multiple choice questions. The difference in knowledge was analysed through repeated measures of analysis of variance. The mean scores at 3 time points were compared using the Tukey's multiple comparison procedure. Knowledge scores of participants increased significantly after the educational intervention in the first post-test; however, there was a decline in the score in post-test 2. the 5-hour teaching module significantly enhanced nurses' knowledge towards evidence based guidelines for the prevention of VAP. Further research is needed to assess the impact of training on nursing practice and to explore factors affecting attitudinal change.


RNAi depletion of deoxycytidine and deoxyguanosine kinase in human leukemic CEM cells.
Resistance toward nucleoside analogues is often due to decreased activities of the activating enzymes deoxycytidine kinase (dCK) and/or deoxyguanosine kinase (dGK). With small interfering RNA (siRNA), dCK and dGK were downregulated by approximately 70% in CEM cells and tested against six nucleoside analogues using the methyl thiazol tetrazolium assay. SiRNA-transfected cells reduced in dCK activity were 3- to 6-fold less sensitive to CdA, AraC, and CAFdA. The sensitivity to AraG and FaraA was unchanged, while the sensitivity toward gemcitabine was significantly increased. dGK depletion in cells resulted in lower sensitivity to FaraA, dFdC, CAFdA, and AraG, but slightly higher sensitivity to CdA and AraC.


Pelvic reconstruction with a structural pelvic allograft after resection of a malignant bone tumor.
Reconstruction of the pelvic arch after resection of a malignant pelvic tumor remains a major surgical challenge because of the high rate of associated complications. The purpose of this investigation was to assess the functional outcome and complication rate following treatment with a bone allograft to reconstruct the pelvis. Twenty-four consecutive patients underwent excision of a malignant pelvic bone tumor and reconstruction with a pelvic bone allograft. The living patients were followed for a minimum of twenty-four months. There were nineteen primary malignant bone tumors, sixteen of which were high-grade sarcomas, and there were five isolated metastases. Patients were examined clinically and radiographically and were assessed functionally with the Musculoskeletal Tumor Society score. The mean age of the patients at the time of the index surgery was thirty-four years, and the mean duration of follow-up was forty-one months. Eighteen of the twenty-four resections involved the periacetabular area and were followed by reconstruction either with a hip prosthesis (thirteen) or with an osteochondral allograft alone (five). The six other resections involved the iliac bone. All patients received a massive bone allograft that had been sterilely procured without secondary irradiation. At the time of our last evaluation, eight patients were alive and free of disease. Seven patients had a local recurrence. Neurological deficits were present in six patients, and three had a deep infection. Nonunion of three of the sixteen allografts that could be evaluated was observed. Neither graft fracture nor lysis was observed. Eleven patients underwent surgical revision, with nine of these revisions related to the reconstruction. The average Musculoskeletal Tumor Society score at the time of the latest follow-up was 73% of the maximal possible score. The average score was 82% for the eleven patients with an age of less than twenty years at the time of the index procedure and 65% for the thirteen older patients. Ten patients walked without any assistive device, and five of them had normal function with no or only a slight limp. Pelvic reconstruction after a limb-sparing resection is associated with a high risk of surgical complications and usually should be reserved for patients with a primary bone sarcoma. A pelvic allograft can restore the anatomy and provide good functional results, especially in young patients. Nonunion was the most common allograft-related complication.


The influence of health knowledge in shaping political priorities: examining HIV/AIDS knowledge and public opinion about global health and domestic policies.
Public opinion polls have historically indicated that the US public favours domestic over global priorities. It is not known what influence health knowledge has in shaping public opinion about domestic and global health policy. This study examines how knowledge of HIV/AIDS is related to the rated importance of domestic and global health issues. Participants were recruited to participate in an electronic survey (N = 995) and were predominantly White (86.3%), married (61.9%) and female (71.8%). HIV/AIDS knowledge was significantly associated with both domestic (β = 0.12, p < 0.05) and global health (β = 0.14, p < 0.01) priorities after controlling for sociodemographic variables. In addition, global health was found to act as a mediator between HIV/AIDS knowledge and perceived importance of domestic issues. Study findings suggest that those with greater HIV/AIDS knowledge rate global health issues higher, which in turn affects ratings of more domestic issues. This research has implications for ways to gain support for implementation of public health policy through increasing health knowledge.


Sensing trehalose biosynthesis in plants.
A most unexpected finding in research on plant carbohydrate metabolism is the recent discovery that angiosperms encode genes whose products are involved in trehalose metabolism. The presence and functionality of such genes has been elegantly shown by expressing Arabidopsis-derived trehalose phosphate synthase and trehalose phosphate phosphatase genes in yeast mutants lacking these enzymatic activities. Homologue sequences have now been cloned from a number of different plant species suggesting that the capacity to synthesise trehalose is ubiquitous in angiosperms. Except for Myrothamnus flabellifolius, trehalose biosynthesis has never been observed in tissues of higher plants, probably due to the presence of high levels of trehalase activity. The function of trehalose metabolism in plants is still a mystery. One of the postulated functions of trehalose metabolism in yeast is in the control of glucose repression and a similar function in sugar sensing can be proposed for plants as well.


GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation.
Patients with inflammatory autoimmune diseases are routinely treated with synthetic glucocorticoids to suppress immunopathology. A crucial outcome of glucocorticoid exposure is induction of glucocorticoid-induced leucine zipper (GILZ), a protein with multiple functions that include inhibition of key immune cell signalling pathways. Here we report that GILZ maintains a threshold for activation of Th17 responses and IL-17-dependent pathology. GILZ expression was deficient in lesional skin of psoriasis patients and was negatively correlated with the pro-inflammatory cytokines IL-23, IL-17A and IL-22, and with STAT3 expression. Deficiency of GILZ in mice resulted in excessive inflammation and pro-inflammatory cytokine expression in the imiquimod model of psoriasis, and dendritic cells lacking GILZ produced greater IL-1, IL-23 and IL-6 in response to imiquimod stimulation in vitro. These cytokines stimulate Th17 cell differentiation, and we found unchallenged GILZ-deficient mice to have spontaneous production of IL-17A and IL-22 in vivo. We also identified a T cell-intrinsic role for GILZ in limiting Th17 cell formation in vitro in response to Th17-promoting cytokines IL-1β and IL-23. Addition of IL-6 under these conditions suppressed GILZ, allowing T cell proliferation and expression of Th17 genes, whereas exogenous delivery of GILZ using a cell-permeable fusion protein restored regulation of Th17 cell proliferation. Thus, GILZ has a non-redundant function to constrain pathogenic Th17 responses, with clinical implications for psoriasis.


Association of methylmercury intake from seafood consumption and blood mercury level among the Asian and Non-Asian populations in the United States.
MeHg is a well-established neurotoxicant for fetal brain growth and development and has been shown to increase the risk of cardiovascular disease in aging populations. In the U.S., Asian populations are of particular concern because of their seafood consumption behaviors. Our objective was to calculate the average daily MeHg intake (ADMI) from seafood and to assess the relationship between ADMI with blood methylmercury (BMeHg) concentrations, specifically among women of reproductive age (WORA) and adults ≥ 50 years of age. We estimated ADMI from seafood using the 30-day fish consumption data from the NHANES 2011-2014 datasets. Using multivariable linear regression, we estimated the proportional change in mean BMeHg associated with a doubling of the ADMI. Further, correlations between ADMI and BMeHg were compared between Asians and other racial/ethnic groups. Our analysis found both Asian WORA and Asian adults age ≥ 50 years old had significantly higher BMeHg levels and ADMI than their Non-Asian counterparts. Correlations between ADMI from seafood and blood Hg levels were stronger among Asian WORA than among Non-Asian WORA. Key fish species that influenced the dietary MeHg intake for Asians were mackerel, tuna, and "other known/unknown fish species". We confirmed that Asian populations have higher MeHg intake than the Non-Asian population in the U.S. and seafood intake is a key predictor of blood Hg concentration, especially among Asian women of reproductive age. Future studies should incorporate information on other known and unknown fish species that are frequently consumed by Asian populations and different parts and fish organs eaten to better understand determinants of MeHg exposure.


Promoter hypomethylation of NY-ESO-1, association with clinicopathological features and PD-L1 expression in non-small cell lung cancer.
Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2'-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2'-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.


Tissue and cellular expression patterns of porcine CFTR: similarities to and differences from human CFTR.
Emerging porcine models of cystic fibrosis (CF) are expected to mimic the human disease more closely than current mouse models do. However, little is known of the tissue and cellular expression patterns of the porcine CF transmembrane conductance regulator (pCFTR) and possible differences from human CFTR (hCFTR). Here, the expression pattern of pCFTR was systematically established on the mRNA and protein levels. Using specific anti-pCFTR antibodies, the majority of the protein was immunohistochemically detected on paraffin-embedded sections and on cryostate sections in the apical cytosol of intestinal crypt epithelial cells, nasal, tracheal, and bronchial epithelial cells, and other select, mostly glandular epithelial cells. Confocal laser scanning microscopy with co-localization of the Golgi marker 58K localized the protein in the cytosol between the Golgi apparatus and the apical cell membrane with occasional punctate or diffuse staining of the apical membrane. The tissue and cellular distribution patterns were confirmed by RT-PCR from whole tissue lysates or select cells after laser capture microdissection. Thus, expression of pCFTR was found to largely resemble that of hCFTR except for the kidney, brain, and cutaneous glands, which lack expression in pigs. Species-specific differences between pCFTR and hCFTR may become relevant for future interpretations of the CF phenotype in pig models.


[Characteristics of the expressive and impressive aspects of emotions in drug dependence].
The data on verbal and nonverbal expression of emotions and their perception in patients suffering from drug dependence+ are related. Three experimental psychological methods were employed to examine 30 patients with opium dependence, 30 patients suffering from ephedrone dependence (mean age 30 years, the mean period of narcotic use 7 years, 50% of the test subjects were men, and 50% were women), and 60 test subjects of the control group. The majority of the drug dependence+ patients manifested the impairment of the impressive aspect: reduction of the ability to recognize emotions according to the mimicry, gestures and postures. The emotional expression was relatively preserved, its disorders were of secondary nature. It has been demonstrated that the derangement of the impressive aspect of emotions is a stable individual and typological characteristics which may be of premorbid nature in patients suffering from narcotic dependence.


Fatal asthma in a young patient with severe bronchial hyperresponsiveness but stable peak flow records.
We report the sudden death of a 16 yr old boy with asthma. At presentation, the patient had symptoms of active asthma, mild bronchoconstriction, severe airway hyperresponsiveness to methacholine, and increased variability of peak expiratory flow records. After the patient was placed on inhaled beclomethasone (1 mg b.i.d preceded by inhaled fenoterol 0.4 mg b.i.d) he rapidly felt better, lung function improved, but airway responsiveness remained severe. Four months later, on the day he died, he was well until a fatal attack of asthma occurred around midnight without identifiable precipitating factors. Taken to hospital, he was dead on arrival. Necroscopy and microscopy showed the characteristic features of asthma death. This case report suggests that; a) asthma death may occur suddenly and unexpectedly; b) asthma death may not be prevented by long-term treatment with high-dose inhaled beclomethasone; c) severe bronchial hyperresponsiveness, even in the presence of stable peak flow records, may identify asthmatic patients at risk of sudden death.


The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor.
Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF). 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10-13) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients.


Neovascularization directed by CAVIN1/CCBE1/VEGFC confers TMZ-resistance in glioblastoma.
Acquisition of resistance to temozolomide (TMZ) poses a significant challenge in glioblastoma (GBM) therapy. Neovascularization, a pivotal process in tumorigenesis and development, remains poorly understood in its contribution to chemoresistance in GBMs. This study unveils aberrant vascular networks within TMZ-resistant (TMZ-R) GBM tissues and identifies the extracellular matrix (ECM) protein CCBE1 as a potential mediator. Through in vivo and in vitro experiments involving gain and loss of function assessments, we demonstrate that high expression of CCBE1 promotes hyper-angiogenesis and orchestrates partial endothelial-to-mesenchymal transition (EndMT) in human microvascular endothelial cells (HCMEC/d3) within GBM. This is likely driven by VEGFC/Rho signaling. Intriguingly, CCBE1 overexpression substantially fails to promote tumor growth, but endows resistance to GBM cells in a vascular endothelial cell-dependent manner. Mechanically, the constitutive phosphorylation of SP1 at Ser101 drives the upregulation of CCBE1 transcription in TMZ resistant tumors, and the excretion of CCBE1 depends on caveolae associated protein 1 (CAVIN1) binding and assembling. Tumor cells derived CCBE1 promotes VEGFC maturation, activates VEGFR2/VEGFR3/Rho signaling in vascular endothelial cells, and ultimately results in hyper-angiogenesis in TMZ-R tumors. Collectively, the current study uncovers the cellular and molecular basis of abnormal angiogenesis in a chemo resistant microenvironment, implying that curbing CCBE1 is key to reversing TMZ resistance.


Emergency contraception: can we benefit from lessons learned?
The aim of the paper was to evaluate current emergency contraception (EC) methods and policies in order to implement lessons learned and maximize potential population impact while introducing dedicated EC pills in Croatia. Literature search for potential reasons for EC failing to show positive population impact and detecting actionable points to be implemented in national guidelines. Six potential reasons for ECs failure to show population impact were evaluated and four actionable points were detected: low use of EC compared to the numbers of risk events, low awareness on EC in general population, differences in efficacy of EC methods and EC vailability. In order to ensure EC's population impact in Croatia it is of a critical relevance to establish continuous education programs for population of women at risk. When recommending an EC method, superior efficacy must be a key decision-making criteria therefore cooper IUD and ulipristal acetate should be our primary options. Counseling is a critical step to ensure maximal efficacy of the EC method, but also to encourage future use of regular contraceptives. Finally, national ECP dispension protocol is needed to close the loop from effective women screening, prompt yet appropriate ECP administration/dispensing towards structured follow up after EC pills intake.


Achieving high-quality comprehensive dentistry with i.v. sedation.
This comprehensive approach requires a high-tech/touch staff environment and a dedication to excellence in all areas of patient care. Its rewards are financial and personal because it creates a highly satisfied and appreciative patient.


Posterior thoracic segmental pedicle screw instrumentation: evolving methods of safe and effective placement.
The use of pedicle screw instrumentation in the spine has evolved over the last two decades. The initial use of pedicle screws began in the lumbar spine. As surgeons have become more comfortable with the complex anatomy required for accurate screw placement, the use of pedicle instrumentation has evolved to include their use in the thoracolumbar and thoracic spine. The impetus behind their increased use is a result of the many advantages that pedicle screw anchorage offers over traditional hook and rod constructs. Improved deformity correction and overall construct rigidity are two important advantages of pedicle screw instrumentation due its three-column control over the spinal elements. First, pedicle screw instrumentation obviates the need to place instrumentation within the spinal canal with its inherent risk of neurologic injury. Second, the placement of pedicle screws is independent of facet or laminar integrity and thus has been extremely useful in traumatic, neoplastic, and degenerative conditions. The benefits of pedicle screws in the thoracic spine has been tempered by the potential for catastrophic neurological or soft tissue injuries due to the close proximity of these structures. The narrow and inconsistent shape of the thoracic pedicles, especially in spinal deformity, makes their placement technically challenging. As a result, surgeons have employed a number of techniques to ensure the safe and efficacious placement of thoracic pedicle screws. Detailed anatomic landmarks used to determine pedicle location, intraoperative imaging including navigation, and neurophysiological monitoring are some of the techniques currently used by surgeons. The implementation of these techniques and a thorough understanding of the complex three-dimensional anatomy have allowed surgeons to successfully place thoracic and thoracolumbar pedicle screws.


Simultaneous recovery of benzene-rich oil and metals by steam pyrolysis of metal-poly(ethylene terephthalate) composite waste.
The possibility of simultaneous recovery of benzene and metals from the hydrolysis of poly(ethylene terephthalate) (PET)-based materials such as X-ray films, magnetic tape, and prepaid cards under a steam atmosphere at a temperature of 450 °C was evaluated. The hydrolysis resulted in metal-containing carbonaceous residue and volatile terephthalic acid (TPA). The effects of metals and additives on the recovery process were also investigated. All metals were quantitatively recovered, and silver, maghemite (γ-Fe2O3), and anatase (TiO2) were recovered without any changes in their crystal structures or compositions. In a second step, TPA was decarboxylized in the presence of calcium oxide (CaO) at 700 °C, producing benzene with an average yield of 34% and purity of 76%. Maghemite (γ-Fe2O3) incorporated in magnetic tape and prepaid cards could decarboxylate TPA. Aluminum present in the prepaid cards produced hydrogen by the reaction with steam. However, the presence of metals had no adverse influence on the recovery of benzene-rich oil in the presence of CaO. Therefore, this method can be applied to PET-based materials containing inorganic substances, which cannot be recycled effectively otherwise.


Associations of a Prenatal Serum Per- and Polyfluoroalkyl Substance Mixture with the Cord Serum Metabolome in the HOME Study.
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent chemicals associated with multiple adverse health outcomes; however, the biological pathways affected by these chemicals are unknown. To address this knowledge gap, we used data from 264 mother-infant dyads in the Health Outcomes and Measures of the Environment (HOME) Study and employed quantile-based g-computation to estimate covariate-adjusted associations between a prenatal (∼16 weeks' gestation) serum PFAS mixture [perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] and 14,402 features measured in cord serum. The PFAS mixture was associated with four features: PFOS, PFHxS, a putatively identified metabolite (3-monoiodo-l-thyronine 4-O-sulfate), and an unidentified feature (590.0020 m/z and 441.4 s retention time; false discovery rate <0.20). Using pathway enrichment analysis coupled with quantile-based g-computation, the PFAS mixture was associated with 49 metabolic pathways, most notably amino acid, carbohydrate, lipid and cofactor and vitamin metabolism, as well as glycan biosynthesis and metabolism (P(Gamma) <0.05). Future studies should assess if these pathways mediate associations of prenatal PFAS exposure with infant or child health outcomes, such as birthweight or vaccine response.


Sevoflurane. A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia.
Sevoflurane is an ether inhalation general anaesthetic agent with lower solubility in blood than isoflurane or halothane but not desflurane. The low solubility and the absence of pungency facilitate rapid mask induction; the low blood solubility also expedites "wash-out' and therefore recovery from anaesthesia. Sevoflurane produces dose-dependent CNS, cardiovascular and respiratory depressant effects that generally parallel those of isoflurane. Sevoflurane is degraded by carbon dioxide absorbents to nephrontoxic (in rats) haloalkenes, although renal toxicity has not been observed in humans. Compared with other inhalation anaesthetics, negligible quantities of carbon monoxide are generated from degradation of sevoflurane by carbon dioxide absorbents. Sevoflurane has negligible airway irritant effects, which facilitates a "smooth' induction, even in comparison with halothane in paediatric patients, and makes sevoflurane especially amenable to rapid induction of anaesthesia in adults and children. Emergence, orientation an postoperative cognitive and psychomotor function recovery of paediatric outpatients is singnificantly more rapid from sevoflurane than from halothane anaesthesia. In adult inpatients and outpatients, emergence and orientation are significantly faster after sevoflurane than after isoflurane but not desflurane anaesthesia. Other recovery parameters (e.g. times to sitting, ambulation) occur at similar times after either sevoflurane or desflurane anaesthesia. Recovery of psychomotor function occurs at generally similar times after sevoflurane, isoflurane or desflurane. Compared with propofol, sevoflurane facilitates more predictable extubation times and significantly better postoperative modified Aldrete scores in outpatients, although cognitive and psychomotor recovery occurs at similar times for both agents. As a supplement to opioid anaesthesia during coronary bypass graft surgery or in those at risk for myocardial ischaemia, sevoflurane is comparable to isoflurane. Limited data suggest that it is also as useful as isoflurane for the maintenance of anaesthesia during neurosurgical or obstetric procedures. Sevoflurane is well tolerated by adult and paediatric patients during induction of anaesthesia, with a low incidence of mild airway complications (breath-holding, coughing, excitement and laryngospasm). During rapid induction, it is particularly better tolerated than isoflurane or halothane. Sevoflurane has a lower potential for hepatic injury than halothane. Unlike methoxyflurane, sevoflurane undergoes minimal intrarenal defluorination, which may account for the lack of fluoride ion-induced nephrotoxicity in humans, despite elevated plasma fluoride levels after its use. In summary, sevoflurane provides for a rapid and smooth induction of, and recovery from, anaesthesia. These features combined with its favourable cardiovascular profile should make sevoflurane the agent of choice for inhalation induction in adult and paediatric anaesthesia. Although further clinical evaluation will define the role of this agent relative to that of propofol and desflurane, sevoflurane should also prove to be a valuable alternative anaesthetic agent for adults in both outpatient and inpatient surgery.


Evolution of the casein multigene family: conserved sequences in the 5' flanking and exon regions.
The rat alpha- and bovine alpha s1-casein genes have been isolated and their 5' sequences determined. The rat alpha-, beta-, gamma- and bovine alpha s1-casein genes contain similar 5' exon arrangements in which the 5' noncoding, signal peptide and casein kinase phosphorylation sequences are each encoded by separate exons. These findings support the hypothesis that during evolution, the family of casein genes arose by a process involving exon recruitment followed by intragenic and intergenic duplication of a primordial gene. Several highly conserved regions in the first 200 base pairs of the 5' flanking DNA have been identified. Additional sequence homology extending up to 550 base pairs upstream of the CAP site has been found between the rat alpha- and bovine alpha s1-casein sequences. Unexpectedly, the 5' flanking promoter regions are conserved to a greater extent than both the entire mature coding and intron regions of these genes. These conserved 5' flanking sequences may contain potential cis regulatory elements which are responsible for the coordinate expression of the functionally-related casein genes during mammary gland development.


Folate conjugation to polymeric micelles via boronic acid ester to deliver platinum drugs to ovarian cancer cell lines.
In this study, a novel technique was used for the reversible attachment of folic acid on the surface of polymeric micelles for a tumor-specific drug delivery system. The reversible conjugation is based on the interaction between phenylboronic acid (PBA) and dopamine to form a borate ester. The conjugation is fast and efficient and in vitro experiments via confocal fluorescent microscopy show that the linker is stable in for several hours. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize two various sized water-soluble block copolymer of oligoethylene glycol methylether methacylate and methyl acrylic acid (POEGMEMA(35)-b-PMAA(200) and POEGMEMA(26)-b-PMAA(90)). The platinum drug, oxoplatin, was then subsequently attached to the polymer via ester formation leading to platinum loading of 12 wt % as determined by TGA. The platinum-induced amphiphilic block copolymers that consequently led to the formation of micelles of sizes 150 and 20 nm in an aqueous environment with the longer PMAA block forming larger micelles. The small micelles were in addition cross-linked using 1,8-diaminooctane to further stabilize their structure. The targeting ability of folate conjugated polymeric micelles was investigated against two types of tumor cell lines: A549 (-FR) and OVCAR-3 (+FR). The cell line growth inhibitory efficacy of material synthesized was evaluated by using SRB method. The results revealed that folate conjugated micelles showed higher activity in FR + OVCAR-3 cells but not in FR - A549 cells. Similar results were obtained for both small and large micelles without the conjugation of folate. Comparing large and small micelles it can be observed that larger micelles are more efficient, which has been attributed to the lower stability of the smaller micelles. Micelle stabilization via cross-linking could indeed increase the toxicity of the drug carrier.


Cooperation of ferrous ions and hydrated ferric oxide for advanced phosphate removal over a wide pH range: Mechanism and kinetics.
Excessive phosphate loading leads to eutrophication problems in rivers or lakes and causes serious environmental and economic damages, urging new technologies to reduce effluent phosphate at ultra-low levels. As a promising candidate, adsorption over metal oxides is restricted by the released hydroxide anions (OH-) through ligand exchange, which elevates pH and suppresses further adsorption. In this contribution, we found ferrous ions (Fe2+) significantly enhance phosphate removal over hydrated ferric oxide (HFO) in a wide pH range via a cooperation of adsorption and precipitation, and clarified the synergistic mechanism by a series of characterizations and the modified models of adsorption isotherms and pseudo second-order kinetics. The combination of Fe2+and HFO removed up to 51.7 mg/g of phosphate at pH 4.0, with 43.6 and 8.1 mg/g attributing to adsorption and precipitation, respectively. In comparison to HFO alone, HFO/Fe2+ system achieved 2.2-fold increase in phosphate removal, 1.9-fold increase in phosphate adsorption capacity, and 3.4-fold increase in phosphate removal rate. The enhancement is understood by that hydroxide anions released from ligand exchange over HFO are neutralized by protons produced from the oxidative precipitation of ferrous ions. The HFO/Fe2+ combining system is promising to realize advanced removal of low concentration phosphate containing wastewater, and these findings bring new insights for the development of novel phosphate removal technologies through a rational design of a combination process.