The IVF-generated human embryonic microenvironment reverses progestin resistance in endometrial cancer cells by inducing cancer stem cell differentiation.
Progestin resistance is a critical factor that prevents patients with endometrial cancer (EC) from receiving conservative therapy. However, the etiology remains elusive. Cancer stem cells (CSCs) may be a contributing factor to progestin resistance in EC. These cells share similar stemness properties with embryonic stem cells that have a multipotent but differential naïve phenotype. Embryonic stem cells are programed to self-renew, to differentiate and to show plasticity toward a normal cellular phenotype in their defined microenvironment. However, whether this microenvironment may promote CSC differentiation toward a better responsive phenotype and reverse progestin resistance has not yet been clarified. In the current study, we found that progestin resistance of endometrial CSCs can be improved or reversed by using in vitro fertilization (IVF)-generated embryonic sac-derived fluid containing the embryonic microenvironment. Furthermore, suppression or reversal of progestin resistance was mediated by placental alkaline phosphatase (ALPP), a factor secreted into the embryonic microenvironment by IVF-generated blastocysts. ALPP significantly reversed progestin resistance by facilitating endometrial CSC differentiation through downregulating the stemness genes NANOG, OCT4 and SOX2. We further showed that the downregulation of NANOG, OCT4 and SOX2 by ALPP was carried out by TET1/2-mediated epigenetic modulation of the promoter regions of these genes. Such changes at the molecular level initiated endometrial CSC differentiation and promoted a better responsive endometrial cancer phenotype. In fact, their response to progestin treatment was similar to that of well-differentiated endometrioid carcinoma cells without CSCs. ALPP could be a novel target in the process to overcome progestin resistance, and such findings may provide a new approach for the conservative treatment of endometrial cancer.


Eosinophilic airway inflammation and airway hyperresponsiveness according to aeroallergen sensitization pattern in patients with lower airway symptoms.
Sensitization to specific allergens may be important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). We evaluated the effect of specific aeroallergen sensitization on eosinophilic airway inflammation and AHR. We reviewed retrospectively the clinical data of subjects who underwent skin prick tests to aeroallergens, induced sputum analysis, and methacholine bronchial provocation tests to evaluate lower airway symptoms as well as analyzed the associations between the pattern of aeroallergen sensitization and sputum eosinophilia or AHR. Of the 1,202 subjects be enrolled, 534 (44.4%) were sensitized to at least one aeroallergen in skin tests. AHR was demonstrated in 23.5% and sputum eosinophilia in 38.8%. Sputum eosinophilia was significantly associated with sensitization to perennial allergens (OR, 1.9; 95% CI, 1.4-2.5), house dust mite (OR, 1.7; 95% CI, 1.3-2.3), dog (OR, 1.9; 95% CI, 1.1-3.3), and cat (OR, 2.1; 95% CI, 1.4-3.4). AHR was associated with sensitization to perennial allergens (OR, 2.7; 95% CI, 2.0-3.7), house dust mite (OR, 2.2; 95% CI, 1.6 3.2), Alternaria (OR, 2.3; 95% CI, 1.2-4.7), and cat (OR, 2.7; 95% CI, 1.7-4.3). Sensitization to more perennial allergens increased the risk for sputum eosinophilia and AHR. There was no relationship with individual seasonal allergens. The development of airway eosinophilic inflammation and AHR in an adult Korean population was associated with sensitization to perennial allergens rather than seasonal allergens.


Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis.
The IL-7/IL-7R-dependent signaling pathway plays a crucial role in regulating the immune response in intestinal mucosa. Here we demonstrate the pivotal role of this pathway in the development and treatment of chronic colitis. T cells expressing high levels of IL-7R were substantially infiltrated in the chronic inflamed mucosa of TCR alpha-chain knockout mice and IL-7 transgenic mice. Transfer of mucosal T cells expressing high levels of IL-7R, but not T cells expressing low levels of IL-7R, from these mice into recombinase-activating gene-2(-/-) mice induced chronic colitis. Selective elimination of T cells expressing high levels of IL-7R by administrating small amounts of toxin-conjugated anti-IL-7R Ab completely ameliorated established, ongoing colitis. These findings provide evidence that therapeutic approaches targeting mucosal T cells expressing high levels of IL-7R are effective in the treatment of chronic intestinal inflammation and may be feasible for use in the therapy of human inflammatory bowel disease.


Electrophysiology of basolateral bicarbonate transport in the rabbit proximal tubule.
Conventional microelectrodes were used to examine the electrogenic pathways for bicarbonate transport across the basolateral membranes of proximal convoluted (PCT) and straight (PST) tubule segments of the rabbit kidney perfused in vitro. When bath bicarbonate concentration was reduced from 22 to 6.6 mM at a constant pH, transient depolarizations lasting several seconds with a peak value of approximately 15 mV were seen in both tubule segments. Acetazolamide (0.1 mM) in the lumen and bath solutions reduced the magnitude and increased the duration fo this response. The final pH of the bathing solution influenced both the peak height and steady-state values of the intracellular potential when bicarbonate concentration was reduced either with constant CO2 or with an increase in CO2. Reducing bath sodium concentration by replacement with either tetramethylammonium or N-methyl-D-glucamine resulted in a sustained depolarization of both PCT and PST cells. This response was inhibited by the addition of 10(-4) M 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS) in the bathing solution. By analogy with bicarbonate transport in rat and amphibian proximal tubules, these data suggest that bicarbonate exit across the basolateral membrane of the rabbit proximal tubule is electrogenic and coupled to sodium and that basolateral bicarbonate exit can be inhibited by both acetazolamide and SITS in the bathing solution.


Screening for Distress in Young People After Treatment for Sarcoma: A Feasibility Study.
Few validated tools are available in childhood cancers settings to assess distress and worry. Twenty-one young people (mean age = 14 years), with an average 4 years since diagnosis, attended a sarcoma follow-up clinic and were asked to complete questionnaires assessing general mood and behavior, quality of life, and distress. All young people completed the Distress Thermometer. However, as the age range was quite wide (9-18 years), different questionnaires were also used with different age groups to assess feasibility and acceptance. In addition, young people were asked for their views about the questionnaires they had completed, asked about previous psychological support, and were asked to rate how useful they had found the medical appointment. Finally, they were asked whether or not they would like a member of the psychology team to contact them to discuss any issues that had been raised by the questionnaires. Patients reported impaired health status and worry about lifestyle, daily activities, and emotional well-being. A health-related quality of life measure (EQ-5D) and an adapted version of the Distress Thermometer were more sensitive than traditional measures and may serve as useful tools to screen for psychological concerns in busy clinical settings.


Intermediate filaments of the lung.
Intermediate filaments (IF), a subfamily of the cytoskeletal filaments, provide structural support to cells. Human diseases related to mutations in IF proteins in which their tissue-specific expression is reflected have been found in a broad range of patients. The properties of identified IF mutants are well-studied in vitro in cultured cells and in vivo using transgenic mice expressing IF mutants. However, the association of IF proteins with diseases of the lung is not fully studied yet. Epithelial cells in normal lung express vimentin and various keratins, and the patterns of their expression are altered depending on the progression of the lung diseases. A growing number of studies performed in alveolar epithelial cells demonstrated IF involvement in disease-related aspects including their usefulness as tumor marker, in epithelial-mesenchymal transition and cell migration. However, the lung disease-associated IF functions in animal models are poorly understood, and IF mutations associated with lung diseases in humans have not been reported. In this review, we summarize recent studies that show the significance of IF proteins in lung epithelial cells. Understanding these aspects is an important prerequisite for further investigations on the role of lung IF in animal models and human lung diseases.


Risk Gambling and Personality: Results from a Representative Swedish Sample.
The association between personality and gambling has been explored previously. However, few studies are based on representative populations. This study aimed at examining the association between risk gambling and personality in a representative Swedish population. A random Swedish sample (N = 19,530) was screened for risk gambling using the Lie/Bet questionnaire. The study sample (N = 257) consisted of those screening positive on Lie/Bet and completing a postal questionnaire about gambling and personality (measured with the NODS-PERC and the HP5i respectively). Risk gambling was positively correlated with Negative Affectivity (a facet of Neuroticism) and Impulsivity (an inversely related facet of Conscientiousness), but all associations were weak. When taking age and gender into account, there were no differences in personality across game preference groups, though preferred game correlated with level of risk gambling. Risk gamblers scored lower than the population norm data with respect to Negative Affectivity, but risk gambling men scored higher on Impulsivity. The association between risk gambling and personality found in previous studies was corroborated in this study using a representative sample. We conclude that risk and problem gamblers should not be treated as a homogeneous group, and prevention and treatment interventions should be adapted according to differences in personality, preferred type of game and the risk potential of the games.


Family and carer smoking control programmes for reducing children's exposure to environmental tobacco smoke.
Exposure to other people's cigarette smoke (environmental tobacco smoke, or ETS) is an important child health issue. To determine the effectiveness of interventions aiming to reduce exposure of children to ETS. The Tobacco Addiction Group register of studies was searched. MEDLINE, EMBASE and four other health and psychology databases were searched electronically, bibliographies of retrieved primary studies were checked and specialists in the area consulted. Controlled trials with or without random allocation were included in this review if they addressed participants (parents and other family members, child care workers and teachers) involved with the care and education of infants and young children (aged 0-12 years). All mechanisms for reduction of children's environmental tobacco smoke exposure, and smoking prevention, cessation, and control programmes targeting these participants are included. These include smoke free policies and legislation, health promotion, social-behavioural therapies, technology, education and clinical interventions. Two reviewers independently assessed studies and extracted data. Due to heterogeneity of methodologies and outcomes, no summary measures were possible and results were synthesised using narrative summaries. Nineteen studies met the inclusion criteria, one of which was subsequently excluded. Three interventions were targeted at populations or community settings, seven studies were conducted in the well child health care setting and eight in the ill child health care setting. Twelve of these studies are from North America. In 12 of the 18 studies there was reduction of ETS exposure for children in both intervention and comparison groups. In only four of the 18 studies was there a statistically significant intervention effect. Three of these successful studies employed intensive counselling interventions targeted to smoking parents. There is little difference between the well infant, child respiratory illness and other child illness settings as contexts for parental smoking cessation interventions. The fourth successful intervention was in the school setting targeting the ETS exposure of children from smoking fathers. Brief counselling interventions, successful in the adult health setting when coming from physicians, cannot be extrapolated to adults in the setting of child health. There is limited support for more intensive counselling interventions. There is no clear evidence for differences between the respiratory, non-respiratory ill child, well child and peripartum settings as contexts for reduction of children's ETS exposure.


Field-induced slow magnetic relaxation in low-spin S = 1/2 mononuclear osmium(v) complexes.
Photochemical reactions of (PPh4)[OsVI(N)(L)(CN)3] (NO2-OsN) with piperidine and pyrrolidine afforded two osmium(v) hydrazido compounds, (PPh4)[OsV(L)(CN)3(NNC5H10)] ([PPh4]1) and (PPh4)[OsV(L)(CN)3(NNC4H8)] ([PPh4]2), respectively. Their structures consist of isolated, mononuclear distorted octahedral osmium anions that are well-separated from each other by PPh4+. Their low spin S = 1/2 and L = 1 ground state was confirmed by magnetometry and DFT calculations. Interestingly, both compounds exhibit slow magnetic relaxation under a bias dc-field. These osmium(v) complexes are potentially useful building-blocks for the construction of molecule-based architectures with interesting magnetic properties. In contrast, the structurally related (PPh4)[OsIII(L)(CN)3(NH3)] ([PPh4]3), which also has a low-spin S = 1/2 ground state but with a different electronic configuration (5d5), does not exhibit slow magnetic relaxation, due to the absence of any orbital moment (L = 0). Furthermore, the structurally different osmium(v) hydrazido compound reported by Meyer, [OsV(tpy)(Cl)2(NNC5H10)](PF6) (4[PF6]), also does not exhibit slow magnetic relaxation due possibly to a change in magnetic anisotropy from axial for [PPh4]1 and [PPh4]2 to planar.


Neurosarcoidosis without systemic sarcoidosis--case report.
A 20-year-old male presented with symptoms of isolated neurosarcoidosis including epilepsy. Magnetic resonance imaging disclosed multiple enhanced right temporal and frontal lesions. Cerebrospinal fluid examination identified mild lymphocytic pleocytosis, and histological examination of a stereotactic brain biopsy specimen demonstrated noncaseating granulomas, so fungal or other inflammatory or granulomatous diseases were excluded. The diagnosis was cerebral sarcoidosis, despite the absence of systemic manifestations. Corticosteroid therapy improved his neurological state and radiological findings. Neurosarcoidosis is a well-recognized occurrence in systemic sarcoidosis, but diagnosis may be difficult in the absence of extracerebral manifestations.


Immunomodulation of Antibody Glycosylation through the Placental Transfer.
Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.


Assessing the efficiency of supercritical fluid extraction for the decontamination of archaeological bones prior to radiocarbon dating.
Bone is one of the main sample types used for building chronologies in archaeology. It is also used in other research areas such as palaeodiet and palaeoenvironmental studies. However, for results to be accurate, samples must be free of exogenous carbon. Contamination can originate from a wide range of sources in the post-depositional environment but may also occur during excavation and post excavation activities (i.e. with the application of conservation materials) or during laboratory handling. Efficient procedures to remove contamination are therefore crucial prior to radiocarbon or stable isotope measurements. This work describes the development of an innovative sample pretreatment for bones, based on using supercritical CO2, which shows unique solvation properties. The effectiveness of supercritical fluid extraction (SFE) to remove conservation materials was compared with that obtained when applying a routine extraction based on the use of organic solvents (methanol, acetone and chloroform). The chemical composition of the bone samples before and after the two pre-treatments was then investigated using analytical pyrolysis-based techniques: EGA-MS (Evolved Gas Analysis-Mass Spectrometry) and Py-GC/MS (Pyrolysis-Gas Chromatography coupled with Mass Spectrometry). Collagen samples extracted from the same bones, prepared with the two cleaning protocols, were also radiocarbon dated by Accelerator Mass Spectrometry (AMS). The results of this study show that SFE is an efficient alternative method because it was as effective as the established treatment protocol. It removes contaminants such as conservation materials from bone samples with a minimum of handling and can be used routinely in radiocarbon dating laboratories. This work also demonstrates that analytical pyrolysis is not only a very efficient method to identify contaminants in bones but also to assess the effectiveness of the pretreatment prior to the radiocarbon measurement of the samples.


Expression and activation of the nonreceptor tyrosine kinase Tec in human B cells.
The tyrosine kinase Tec belongs to a new group of structurally related nonreceptor tyrosine kinases that also includes Btk and Itk. Previous studies have suggested that these kinases have lineage-specific roles, with Tec being involved mainly in the regulation of cytokine-mediated myeloid cell growth and differentiation. In this study, we investigated expression and activation of Tec in human B-lymphoid cell lines representing different stages of B-cell maturation, including pro-B (RS4;11, 380, REH), pre-B (NALM6), and mature B (Ramos, and one Epstein-Barr virus [EBV]-transformed lymphoblastoid line) cells. Like Btk, Tec protein was expressed in all B-cell lines tested. Tec was also highly expressed in two EBV-transformed lymphoblastoid lines derived from patients with X-linked agammaglobulinemia (XLA) lacking Btk expression, as well as in tonsillar lymphoid cells. In surface immunoglobulin-positive B cells (Ramos), ligation of the B-cell antigen receptor (BCR) with anti-IgM antibodies caused marked tyrosine phosphorylation of Tec and increased Tec tyrosine kinase activity. Likewise, cross-linking of CD19 with a monoclonal antibody in BCR-negative pro-B (RS4;11, 380) and pre-B (NALM6) cells induced Tec tyrosine phosphorylation and increased Tec autophosphorylation, as well as Btk activation. Tyrosine phosphorylation of Tec, but not of Btk, was detectable in RS4;11 cells after CD38 ligation, suggesting that these kinases are regulated differently. We conclude that Tec is expressed and can be stimulated throughout human B-cell differentiation, implying that this tyrosine kinase plays a role in B-cell development and activation.


Least concern to endangered: Applying climate change projections profoundly influences the extinction risk assessment for wild Arabica coffee.
Arabica coffee (Coffea arabica) is a key crop in many tropical countries and globally provides an export value of over US$13 billion per year. Wild Arabica coffee is of fundamental importance for the global coffee sector and of direct importance within Ethiopia, as a source of harvestable income and planting stock. Published studies show that climate change is projected to have a substantial negative influence on the current suitable growing areas for indigenous Arabica in Ethiopia and South Sudan. Here we use all available future projections for the species based on multiple general circulation models (GCMs), emission scenarios, and migration scenarios, to predict changes in Extent of Occurrence (EOO), Area of Occupancy (AOO), and population numbers for wild Arabica coffee. Under climate change our results show that population numbers could reduce by 50% or more (with a few models showing over 80%) by 2088. EOO and AOO are projected to decline by around 30% in many cases. Furthermore, present-day models compared to the near future (2038), show a reduction for EOO of over 40% (with a few cases over 50%), although EOO should be treated with caution due to its sensitivity to outlying occurrences. When applying these metrics to extinction risk, we show that the determination of generation length is critical. When applying the International Union for Conservation of Nature's Red list of Threatened Species (IUCN Red List) criteria, even with a very conservative generation length of 21 years, wild Arabica coffee is assessed as Threatened with extinction (placed in the Endangered category) under a broad range of climate change projections, if no interventions are made. Importantly, if we do not include climate change in our assessment, Arabica coffee is assessed as Least Concern (not threatened) when applying the IUCN Red List criteria.


Assessment of the Antibiotic Resistance Profile, Genetic Heterogeneity and Biofilm Production of Methicillin-Resistant Staphylococcus aureus (MRSA) Isolated from The Italian Swine Production Chain.
The main aim of the present study was to evaluate the level of antibiotic resistance, prevalence and virulence features of methicillin-resistant Staphylococcus aureus (MRSA) isolated from heavy swine at abattoir level and farming environments in Lombardy (Northern Italy). With this scope, 88 different heavy swine farms were surveyed, obtaining a total of n = 440 animal swabs and n = 150 environmental swabs. A total of n = 87 MRSA isolates were obtained, with an overall MRSA incidence of 17.50% (n = 77) among animal samples and a 6.67% (n = 10) among environmental. Molecular characterisation using multilocus sequence typing (MLST) plus spa-typing showed that sequence type ST398/t899 and ST398/t011 were the most commonly isolated genotypes, although other relevant sequence types such as ST1 or ST97 were also found. A lack of susceptibility to penicillins, tetracycline and ceftiofur was detected in >91.95, 85.05 and 48.28% of the isolates, respectively. Resistance to doxycycline (32.18%), enrofloxacin (27.59%) and gentamicin (25.29%) was also observed. Additionally, a remarkable level of antibiotic multiresistance (AMR) was observed representing a 77.01% (n = 67) of the obtained isolates. Genetic analysis revealed that 97.70% and 77.01% of the isolates harboured at least one antibiotic resistance or enterotoxin gene, respectively, pointing out a high isolate virulence potential. Lastly, 55.17% (n = 48) were able to produce measurable amounts of biofilm after 24 h. In spite of the current programmes for antibiotic reduction in intensively farming, a still on-going high level of AMR and virulence potential in MRSA was demonstrated, making this pathogen a serious risk in swine production chain, highlighting once more the need to develop efficient, pathogen-specific control strategies.


GABA receptors in the olfactory epithelium of the gilthead seabream (Sparus aurata).
Exposure to high PCO2/low pH seawater induces behavioural alterations in fish; a possible explanation for this is a reversal of Cl-/HCO3- currents through GABAA receptors (the GABAA receptor theory). However, the main evidence for this is that gabazine, a GABAA receptor antagonist, reverses these effects when applied to the water, assuming that exposure to systems other than the CNS would be without effect. Here, we show the expression of both metabotropic and ionotropic GABA receptors, and the presence of GABAA receptor protein, in the olfactory epithelium of gilthead seabream. Furthermore, exposure of the olfactory epithelium to muscimol (a specific GABAA receptor agonist) increases or decreases the apparent olfactory sensitivity to some odorants. Thus, although the exact function of GABAA receptors in the olfactory epithelium is not yet clear, this may complicate the interpretation of studies wherein water-borne gabazine is used to reverse the effects of high CO2 levels on olfactory-driven behaviour in fish.


Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory.
The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.


[Inherited relationship of levels of serum lipid and lipoprotein in nuclear families in patients with arteriosclerotic stroke].
This report presents the study on inherited relationship of levels of lipids and lipoprotein in 20 nuclear families of patients with arteriosclerotic stroke through application of analysis of correlation and regression. The results showed that the levels of serum lipids between spouses had little or nearly no correlation; and that between mid-parent and their children had positive or significant positive correlation, and so did that between siblings. It seems that the genetic factor have an important influence on levels of serum lipids in members of nuclear families of patients with arteriosclerotic stroke.


Making surrogate β-cells from mesenchymal stromal cells: perspectives and future endeavors.
Generation of surrogate β-cells is the need of the day to compensate the short supply of islets for transplantation to diabetic patients requiring daily shots of insulin. Over the years several sources of stem cells have been claimed to cater to the need of insulin producing cells. These include human embryonic stem cells, induced pluripotent stem cells, human perinatal tissues such as amnion, placenta, umbilical cord and postnatal tissues involving adipose tissue, bone marrow, blood monocytes, cord blood, dental pulp, endometrium, liver, labia minora dermis-derived fibroblasts and pancreas. Despite the availability of such heterogonous sources, there is no substantial breakthrough in selecting and implementing an ideal source for generating large number of stable insulin producing cells. Although the progress in derivation of β-cell like cells from embryonic stem cells has taken a greater leap, their application is limited due to controversy surrounding the destruction of human embryo and immune rejection. Since multipotent mesenchymal stromal cells are free of ethical and immunological complications, they could provide unprecedented opportunity as starting material to derive insulin secreting cells. The main focus of this review is to discuss the merits and demerits of MSCs obtained from human peri- and post-natal tissue sources to yield abundant glucose responsive insulin producing cells as ideal candidates for prospective stem cell therapy to treat diabetes.


The impact of personality, morphotype and shore height on temperature-mediated behavioural responses in the beadlet anemone Actinia equina.
Between-individual variation in behavioural phenotype, termed personality, is an important determinant of how populations cope with acute environmental fluctuation related to climate change. Personality in the beadlet sea anemone Actinia equina is linked to genetically distinct morphotypes, which are associated with different heights on the shore. In the intertidal zone, high-shore environments experience more environmental fluctuation due to longer periods of exposure, and animals adapted to live in these environments are predicted to deal more effectively with environmental perturbation than their low-shore counterparts. We collected beadlet anemones of two different morphotypes from three different shore heights. We investigated variation in two behaviours at three different temperatures and in a temporal control treatment where the temperature was not changed: startle response time, the time it took an anemone to re-extend its tentacles after a threatening stimulus, and immersion response time, the time to re-extend tentacles after simulated tidal immersion. These behaviours reflect risk-taking and allow individuals to be categorized as bold, shy or intermediate based upon response times. Both behaviours showed significant changes as the temperature increased. For immersion response, the morphotype associated with the low-shore-lengthened response times at high temperatures. For startle response, all animals lengthened their response times at high temperatures but animals collected from the low-shore lengthened theirs to the greatest degree. At the individual level, although control individuals exhibited temporal changes in their response times, a clear effect of temperature was present in both behaviours. Shy and bold individuals became more intermediate at higher temperatures in immersion response (this effect was present to a lesser degree in control individuals), while intermediate individuals raised their response times at higher temperatures for startle response. Given that prolonged tentacle retraction reduces foraging opportunities and can negatively impact respiratory efficiency, our data suggest that some individuals within a single population of A. equina, particularly those associated with the lower shore, may exhibit less effective behavioural responses to temperature shifts than others. These findings demonstrate that acute temperature changes influence risk-taking, and could have profound short and long-term implications for survival in the face of climate change.


Neural stem cells persist to generate new neurons in the hippocampus of adult and aged human brain - Fiction or accurate?
Adult neurogenesis, comprising the generation, differentiation and integration of new neurons in the mature brain, has emerged as a dynamic area of research over decades. The discovery of adult neurogenesis was a paradigm shift to comprehend mechanisms underlying brain plasticity, cognitive function, and neurological disorders. This review deliberates significant findings from articles published over four decades on adult neurogenesis, highlighting key milestones, methodological advances, and controversies that have shaped our comprehension of the phenomenon of adult neurogenesis. Early skepticism gave way to a rich body of evidence via various reliable approaches. Studies on neurogenic niches, microenvironmental factors, molecular regulators, and functional implications have uncovered the involvement of adult neurogenesis in learning, memory, mood, and even neurological and neurodegenerative conditions. Despite significant progress, several questions still need to be answered, including the exact contributions of new neurons to brain function, their integration into existing circuits, and the impact of enhancing adult neurogenesis in the human hippocampus. While the existence of robust neurogenesis in the adult and aged human hippocampus is yet to be confirmed, this review highlights evidence from a significant number of studies supporting the persistence of hippocampal neurogenesis during adulthood and aging in humans, including in some neurological conditions, such as epilepsy and Alzheimer's disease. Nonetheless, additional large-scale studies using single cell-RNA-seq, single nucleus-RNA-seq, and spatial transcriptomics are critical to validate the presence and contribution of hippocampal neurogenesis in the pathophysiology of various neurological and neurodegenerative conditions at different stages of the disease. There is also a need to develop standardized protocols for analyzing postmortem hippocampal tissues for cellular and molecular analyses.


The Nucleation Rate of Single O2 Nanobubbles at Pt Nanoelectrodes.
Nanobubble nucleation is a problem that affects efficiency in electrocatalytic reactions since those bubbles can block the surface of the catalytic sites. In this article, we focus on the nucleation rate of O2 nanobubbles resulting from the electrooxidation of H2O2 at Pt disk nanoelectrodes. Bubbles form almost instantaneously when a critical peak current, inbp, is applied, but for lower currents, bubble nucleation is a stochastic process in which the nucleation (induction) time, tind, dramatically decreases as the applied current approaches inbp, a consequence of the local supersaturation level, ζ, increasing at high currents. Here, by applying different currents below inbp, nanobubbles take some time to nucleate and block the surface of the Pt electrode at which the reaction occurs, providing a means to measure the stochastic tind. We study in detail the different conditions in which nanobubbles appear, concluding that the electrode surface needs to be preconditioned to achieve reproducible results. We also measure the activation energy for bubble nucleation, Ea, which varies in the range from (6 to 30) kT, and assuming a spherically cap-shaped nanobubble nucleus, we determine the footprint diameter L = 8-15 nm, the contact angle to the electrode surface θ = 135-155°, and the number of O2 molecules contained in the nucleus (50 to 900 molecules).


Visual-size molecular recognition based on gels.
Since their discovery, stimuli-responsive organogels have garnered considerable and increasing attention from a broad range of research fields. In consideration of an one-dimensional ordered relay in anisotropic phase, the assembled gel networks can amplify various properties of the functional moieties possessed by the gelator molecules. Recently, substantial efforts have been focused on the development of facile, straightforward, and low-cost molecular recognition approaches by using nanostructured gel matrices as visual sensing platforms. In this research news, the recent progresses in macroscopic or visual-size molecular recognition for a number of homologues, isomers, and anions, as well as extremely challenging chiral enantiomers, using polymer and molecular gels are reviewed. Several strategies--including guest molecular competition, hydrogen-bonding blocking, and metal-coordination--for visual discrimination are included. Finally, the future trends and potential application in facile visual-size molecular recognition based on organogel matrices are highlighted.


Coal fly ash and bottom ash low-cost feedstocks for CO2 reduction using the adsorption and catalysis processes.
Combustion of fossil fuels, industry and agriculture sectors are considered as the largest emitters of carbon dioxide. In fact, the emission of CO2 greenhouse gas has been considerably intensified during the last two decades, resulting in global warming and inducing variety of adverse health effects on human and environment. Calling for effective and green feedstocks to remove CO2, low-cost materials such as coal ashes "wastes-to-materials", have been considered among the interesting candidates of CO2 capture technologies. On the other hand, several techniques employing coal ashes as inorganic supports (e.g., catalytic reduction, photocatalysis, gas conversion, ceramic filter, gas scrubbing, adsorption, etc.) have been widely applied to reduce CO2. These processes are among the most efficient solutions utilized by industrialists and scientists to produce clean energy from CO2 and limit its continuous emission into the atmosphere. Herein, we review the recent trends and advancements in the applications of coal ashes including coal fly ash and bottom ash as low-cost wastes to reduce CO2 concentration through adsorption and catalysis processes. The chemical routes of structural modification and characterization of coal ash-based feedstocks are discussed in details. The adsorption and catalytic performance of the coal ashes derivatives towards CO2 selective reduction to CH4 are also described. The main objective of this review is to highlight the excellent capacity of coal fly ash and bottom ash to capture and selective conversion of CO2 to methane, with the aim of minimizing coal ashes disposal and their storage costs. From a practical view of point, the needs of developing new advanced technologies and recycling strategies might be urgent in the near future to efficient make use of coal ashes as new cleaner materials for CO2 remediation purposes, which favourably affects the rate of global warming.


Chronic inhibition of nitric oxide ameliorates splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension.
Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (approximately 25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P < 0.001) without modulating portal pressure (P > 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P < 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P < 0.05). Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity.


[Pseudarthroses with low osteogenetic activity].
An experience with treatment of 176 patients having false joints with low osteogenic activity is presented. An investigation of peripheral blood supply by the method of angiography and rheovasography has shown considerable alterations of the arterial blood flow. The internal osteosynthesis with retained ++inter-fragment tissues was used, as well as the interosseous fixation with repeated alternations of distraction and compression. Union was diagnosed in 162 patients (92%).


Measurement of bacterial ingestion and killing by macrophages.
This unit presents assays that allow accurate measurement of phagocytosis and killing of bacteria by macrophages. The first basic protocol describes how to measure the ability of macrophages to ingest bacteria. Importantly, because macrophage phagocytosis entails separate binding and internalization steps, assays are described here that will also determine the extent to which bacteria bound to the macrophage are in fact internalized. Two effective methods to do this are described in alternate protocols. Both of these alternate protocols rely on enumeration of differentially labeled bacteria by fluorescence microscopy to distinguish intracellular from extracellular bacteria. The unit also presents two protocols to measure the ability of a macrophage to kill bacteria it has internalized. The second basic is a straightforward assay in which bacterial colonies are enumerated before and after a killing period. Bactericidal activity is evidenced by reduced CFU bacteria on agar plates. Because it is critical to remove residual extracellular organisms, the protocol presents two alternative steps to accomplish this: a washing procedure and a more stringent method in which cells are sedimented through sucrose. An alternate protocol describes a way to measure bacterial viability based on bacterial metabolism, in which the ability of bacterial dehydrogenases to mediate the reduction of a tetrazolium salt to purple formazan is monitored by measuring absorbance spectrophotometrically.


Developing and gaining acceptance for patient care protocols.
The purpose of developing protocols and guidelines is greater than reducing variation in practice. The process also creates new paradigms and changes the culture in which health care is delivered. The protocol itself is designed to be transient. The new environment and perceptions of how to improve health care in the future, along with new relationships and processes to accomplish this, are the real power of learning to develop and implement protocols and guidelines. Framing the process of protocol development, therefore, is more important than the resulting document. In developing protocols, attention to changing the thinking and practice of the front-line practitioners, establishing new relationships, and devising new methods of delivering and improving care is key. The process of developing protocols should include all practitioners. They should remain in control of patient care using new methods that allow: a) the monitoring of process and outcomes, b) identification of problems, and c) the evaluation and validation of the effectiveness of implemented change. Evidence from the literature of strategies for protocol development and implementation which are effective in creating change are reviewed, and an example of a known effective method which improves practice is given.


Revision of unicompartmental arthroplasty to total knee arthroplasty: not always a slam dunk!
As the number of UKA performed in the world continues to increase, so will the number of failures. A better understanding of the outcomes after revision UKAto TKA is warranted. The objective of this study is to report the outcomes of modern UKA revised to TKA in three US centers. A total of 175 revisions of medial UKA in 168 patients (81 males, 87 females; average age of 66 years) performed from 1995 to 2009 in three institutions and with a minimum of 2-year clinical follow-up were reviewed. Individual joint registries and chart reviews were performed to collect data regarding reasons for revision, type of implants used, and re-revision rates. The average time from UKA to revision TKA was 71.5 months (range 2 months to 262 months). The four most common reasons for failure of the UKA were femoral or tibial loosening (55%), progressive arthritis of the lateral or patellofemoral joints (34%), polyethylene failure (4%) and infection (3%). The average follow-up after revision was 75 months. Nine of 175 knees (4.5%) were subsequently revised at an average of 48 months (range 6 months to 123 months.) The rate of revision was 1.23 revisions per 100 observed component years. The average Knee Society pain and function score increased to 75 and 66, respectively. In the present series, the re-revision rate after revision TKA from UKA was 4.5 % at an average of 75 months or 1.2 revisions per 100 observed component years. Compared to published individual institution and national registry data, re-revision of a failed UKA is equivalent to revision rates of primary TKA and substantially better than re-revision rates of revision TKA. These data should be used to counsel patients undergoing revision UKA to TKA.


Identifying muscle regulatory elements and genes in the nematode Caenorhabditis elegans.
We report the identification of several putative muscle-specific regulatory elements, and genes which are expressed preferentially in the muscle of the nematode Caenorhabditis elegans. We used computational pattern finding methods to identify cis-regulatory motifs from promoter regions of a set of genes known to express preferentially in muscle; each motif describes the potential binding sites for an unknown regulatory factor. The significance and specificity of the identified motifs were evaluated using several different control sequence sets. Using the motifs, we searched the entire C. elegans genome for genes whose promoter regions have a high probability of being bound by the putative regulatory factors. Genes that met this criterion and were not included in our initial set were predicted to be good candidates for muscle expression. Some of these candidates are additional, known muscle expressed genes and several others are shown here to be preferentially expressed in muscle cells by using GFP (green fluorescent protein) constructs. The methods described here can be used to predict the spatial expression pattern of many uncharacterized genes.


Absolute strength and loss of strength as predictors of mobility decline in older adults: the InCHIANTI study.
Theoretical definitions of sarcopenia traditionally emphasize age-related loss of muscle strength; however, most analyses of the association between strength and mobility examine strength at a single time point. This study sought to identify sex-specific cutpoints for muscle strength and power (at one time point) and 3-year changes in strength and power that would maximize prediction of 3-year mobility decline. Longitudinal analysis of 934 adults aged ≥65 years enrolled in the Invecchiare in Chianti study was conducted. Grip strength, knee extension strength, and lower extremity power were measured at baseline and 3 years postenrollment. Mobility function (gait speed and self-reported mobility disability) was measured at 3 and 6 years postenrollment. Classification and regression tree analysis was used to predict mobility decline from Years 3 to 6. Men with knee extension strength <19.2 kg and grip strength <39.0 kg had clinically meaningful declines in gait speed of .24 m/s. Furthermore, men with power <105 W were nearly nine times more likely to develop incident mobility disability (likelihood ratio = 8.68; 95% confidence interval = 3.91, 19.44). Among women, knee extension strength <18.0 kg was associated with a minimal gait speed decline of 0.06 m/s, and women with leg power <64 W were three times more likely to develop incident mobility disability (likelihood ratio = 3.01; 95% confidence interval = 1.79, 5.08). Three-year changes in strength and power did not predict mobility decline in either sex. Findings suggest that strength and power measured at one time point are more predictive of mobility decline than 3-year changes and that low strength and power are particularly powerful risk factors in men.


Antigenic phenotyping of lymphoid cells and B cell gene rearrangement in type B gastritis and in gastritis not associated with Helicobacter pylori colonization.
Marginal-zone B cells of the mucosa-associated lymphoid tissue (MALT) are the normal counterpart of the neoplastic cells in MALT lymphoma. In both cases these lymphocytes express surface immunoglobulins, but are negative when stained for B cell associated antigens like CD10 and CD23. Furthermore, the B cell gene rearrangement has been found in Helicobacter pylori associated chronic gastritis and in extranodal type of marginal-zone lymphoma. The aim of this study was to quantify the number of IgM-, CD10-, and CD23-positive lymphocytes in patients with type B gastritis and to compare the results with the antigen profile of mononuclear cells in patients with gastritis not associated with H. pylori. Additionally, the immunoglobulin heavy-chain (IgH) gene rearrangement in H. pylori positive and H. pylori negative gastritis was studied. From 23 patients with a positive urease test and/or histologically proven H. pylori infection and chronic gastritis and from 22 patients with H. pylori negative chronic gastritis mucosa biopsy specimens were taken. Single-cell suspensions were obtained following enzymatic digestion. For immunocytochemistry, an alkaline phosphatase-antialkaline phosphatase method was applied. IgH gene rearrangement in formalin-fixed, paraffin-embedded specimens was determined by polymerase chain reaction in 11 patients with chronic gastritis. An increase in mu-positive plasma cells and B lymphocytes was detected in patients with H. pylori positive gastritis as compared with patients with H. pylori negative gastritis (10.0 vs. 3.9%, p < 0.001, and 4.3 vs. 1.6%, p < 0.01, respectively). In both groups, the proportion of CD10- and CD23-positive lymphocytes was <1%. IgH gene rearrangement was not restricted to type B gastritis; single bands were also present in 3 of 7 patients with H. pylori negative chronic gastritis. Our finding of IgH gene rearrangement in some of the patients with H. pylori negative chronic gastritis indicates that additional factors may be critical for these genotypical changes and for the pathogenesis of gastric MALT lymphoma.


Effect of indomethacin and salt depletion on renal proton MR imaging. An experimental study in the rat.
Blockade of the synthesis of vasodilating prostaglandins with non-steroidal anti-inflammatory drugs (NSAID) renders the renal medulla susceptible to hypoxic injury with reduced renal function, especially in clinical conditions characterized by volume depletion. Alterations in renal hemodynamics and urine production may affect renal MR imaging under these circumstances. We injected salt-depleted and control rats undergoing proton MR imaging with indomethacin 10 mg/kg. Indomethacin abolished the cortico-medullary T2-gradient and markedly diminished the overall renal signal in salt-depleted rats only. These changes, which progressed over a period of 40 min after indomethacin was injected, probably result from renal oligemia and decreased urine production, with an associated decrease in T2-values. We suggest that a history of consumption of non-steroidal anti-inflammatory drugs should be obtained and taken into account in the evaluation of renal proton MR imaging, especially in the presence of salt and volume depletion.


Identifying effective moderators of cognitive behavioural trauma treatment with caregiver involvement for youth with PTSD: a meta-analysis.
Children can develop post-traumatic stress disorder (PTSD) and mental health symptoms after traumatic events. This meta-analysis evaluated the influence of moderators of cognitive behavioural trauma treatment (CBTT) with caregiver involvement in traumatized children. A total of 28 studies were included, with 23 independent samples and 332 effect sizes, representing the data of 1931 children (M age = 11.10 years, SD = 2.36). Results showed a significant medium overall effect (d = 0.55, t = 2.478, p = 0.014), indicating CBTT with caregiver involvement was effective in treating PTSD (d = 0.70), with somewhat smaller effect sizes for internalizing, externalizing, social, cognitive and total problems (0.35 < d > 0.48). The positive treatment effect was robust; we found somewhat smaller effect sizes at follow-up (d = 0.49) compared to post-test (d = 0.57) assessments. Furthermore, several sample (i.e. child's age, gender, and trauma event), programme (i.e. the duration of treatment, number of sessions), study (i.e. control condition, type of instrument, informant, type of sample), and publication (i.e. publication year and impact factor) characteristics moderated the treatment outcomes of the child. In sum, the results of our meta-analysis might help to improve the effectiveness of cognitive behavioural trauma treatment for youth with PTSD, and guide the development of innovative trauma interventions that involve caregivers. Implications for theory and practice are discussed.


Morphometric study of histological changes in sublabial salivary glands due to aging process.
The sublabial salivary glands were studied by morphometric methods in 68 healthy volunteers to establish possible changes related to age in those tissue components that are affected in Sjögren's syndrome and connective tissue diseases (and which might stimulate Sjögren's syndrome). There was an increase in the amount of connective tissue and intralobular ducts with age and a corresponding decrease in acinar tissue. During the aging process changes in the intralobular ducts occurred: the outer and inner diameters of these ducts and the thickness of the epithelium decreased, but the ratio of the outer and inner diameters of the ducts remained constant. The amount of diffuse lymphoplasmacytic infiltrate and the vascularity of the tissue remains constant with age. In 15 of the subjects, however, discrete lymphocytic foci were seen and in six of these more than one focus/4 mm2 of salivary tissue was found, which has been described as suggestive of Sjögren's syndrome. The volume percentage of lymphocytic foci is constant during the aging process. The histological features commonly used to diagnose Sjögren's syndrome may occur in normal people, and false positive diagnoses will occur if these criteria are rigidly adhered to. Morphometry may provide more reliable criteria for distinguishing changes induced by inflammation and related to age which occur in salivary tissue.


Thermoregulation: A journey from physiology to computational models and the intensive care unit.
Thermoregulation plays a vital role in homeostasis. Many species of animals as well as humans have evolved various physiological mechanisms for body temperature control, which are characteristically flexible and enable a fine-tuned spatial and temporal regulation of body temperature in different environmental conditions and circumstances. Human beings normally maintain a core body temperature at around 37°C, and maintenance of this relatively high temperature is critical for survival. Therefore, principles of thermoregulatory control have also important clinical implications. Infections can cause the body temperature to rise internally and several diseases can cause a dysfunction of thermoregulatory mechanisms. Moreover, the utilization of thermotherapies in treating various diseases has been known for thousands of years with a recent resurgence of interest. An increasing amount of research suggests that targeted temperature management is of paramount importance to patient outcomes in certain clinical scenarios. We provide a concise summary of the basic concepts of thermoregulation. Emphasis is given to the principles of thermoregulation in humans in basic pathological states and to targeted temperature management strategies in the clinical environment, with special attention on therapeutic hypothermia in postcardiac arrest patients. Finally, the discussion is focused on the potential offered by computational thermophysiological models for predicting thermal responses of patients in various clinical circumstances, for proposing new perspectives in the design of novel thermal therapies, and to optimize targeted temperature management strategies. This article is categorized under: Cardiovascular Diseases > Cardiovascular Diseases>Computational Models Cardiovascular Diseases > Cardiovascular Diseases>Environmental Factors Cardiovascular Diseases > Cardiovascular Diseases>Biomedical Engineering.


Recent advances in applications and performance of inorganic hollow spheres in devices.
Inorganic hollow spheres have wide, important applications due to their unique structure, controllable morphology, and composition. Recent developments in the application and performance of inorganic hollow spheres in solar cells, UV photodectors, gas sensors, and supercapacitors are discussed. For each inorganic hollow sphere based device, a critical comment is given based on knowledge and related research experience. Some perspectives on the future research and development of these inorganic-hollow-sphere devices are given.


Highly selective fluorescent sensing of proteins based on a fluorescent molecularly imprinted nanosensor.
A fluorescent molecularly imprinted nanosensor was obtained by grafting imprinted polymer onto the surface of multi-wall carbon nanotubes and post-imprinting treatment with fluorescein isothiocyanate (FITC). The fluorescence of lysozyme-imprinted polymer (Lys-MIP) was quenched more strongly by Lys than that of nonimprinted polymer (NIP), which indicated that the Lys-MIP could recognize Lys. The resulted imprinted material has the ability to selectively sense a target protein, and an imprinting factor of 3.34 was achieved. The Lys-MIP also showed selective detection for Lys among other proteins such as cytochrome C (Cyt C), hemoglobin (HB) and bovine serum albumin (BSA) due to the imprinted sites in the Lys-MIP. This approach combines the high selectivity of surface molecular imprinting technology and fluorescence, and converts binding events into detectable signals by monitoring fluorescence spectra. Therefore, it will have further applications for Lys sensing.


Surface functionalization of zirconium phosphate nanoplatelets for the design of polymer fillers.
Inorganic-organic hybrid materials were synthesized by covalent attachment of epoxides to the surface of zirconium phosphate (ZrP) nanoplatelets. X-ray powder diffraction, FTIR, and TGA were utilized to confirm the presence of the modifiers and exclusive functionalization of the ZrP surface. NMR experiments were conducted to confirm the formation of P-O-C bonds between surface phosphate groups and epoxide rings. The applicability of the organically modified products was demonstrated by their use as fillers in a polymer matrix. Subsequently, a two step intercalation and surface modification procedure was utilized to prepare polymer nanocomposites that were imparted with functionality through the encapsulation of molecules within the interlayer of surface modified ZrP.


Understanding Anaplasmataceae pathogenesis using "Omics" approaches.
This paper examines how "Omics" approaches improve our understanding of Anaplasmataceae pathogenesis, through a global and integrative strategy to identify genes and proteins involved in biochemical pathways key for pathogen-host-vector interactions. The Anaplasmataceae family comprises obligate intracellular bacteria mainly transmitted by arthropods. These bacteria are responsible for major human and animal endemic and emerging infectious diseases with important economic and public health impacts. In order to improve disease control strategies, it is essential to better understand their pathogenesis. Our work focused on four Anaplasmataceae, which cause important animal, human and zoonotic diseases: Anaplasma marginale, A. phagocytophilum, Ehrlichia chaffeensis, and E. ruminantium. Wolbachia spp. an endosymbiont of arthropods was also included in this review as a model of a non-pathogenic Anaplasmataceae. A gap analysis on "Omics" approaches on Anaplasmataceae was performed, which highlighted a lack of studies on the genes and proteins involved in the infection of hosts and vectors. Furthermore, most of the studies have been done on the pathogen itself, mainly on infectious free-living forms and rarely on intracellular forms. In order to perform a transcriptomic analysis of the intracellular stage of development, researchers developed methods to enrich bacterial transcripts from infected cells. These methods are described in this paper. Bacterial genes encoding outer membrane proteins, post-translational modifications, eukaryotic repeated motif proteins, proteins involved in osmotic and oxidative stress and hypothetical proteins have been identified to play a key role in Anaplasmataceae pathogenesis. Further investigations on the function of these outer membrane proteins and hypothetical proteins will be essential to confirm their role in the pathogenesis. Our work underlines the need for further studies in this domain and on host and vector responses to infection.


Effects of high-intensity interval training on retinal vessel diameters and oxygen saturation in patients with hypertension: A cross-sectional and randomized controlled trial.
Arterial hypertension is a global healthcare burden that affects macrovascular and microvascular structure and function and can promote vascular end-organ damage. This study aimed 1) to evaluate differences in microvascular health between normotensive individuals and patients with arterial hypertension and 2) to assess the effects of short-term high-intensity interval training (HIIT) on microvascular health in the subgroup with arterial hypertension as add-on treatment to antihypertensive medication. In the cross-sectional part, central retinal arteriolar (CRAE) and venular diameter equivalent (CRVE), arteriolar-to-venular diameter ratio (AVR), and retinal oxygen saturation (O2-saturation) were investigated in 19 normotensive healthy controls (mean age 56 ± 7 years) and 41 patients with arterial hypertension (mean age 59 ± 7 years). In the subsequent randomized controlled trial (RCT), patients with arterial hypertension were randomized to an intervention group (HIIT 3×/week) or a control group that received standard physical activity recommendations after baseline assessment. Assessments of retinal vessel biomarkers and patients` characteristics were repeated after the intervention period of 8 weeks. In the cross-sectional part, individuals with normal blood pressure (BP) showed lower body mass index (BMI), body fat, 24 h systolic and diastolic BP, higher peak oxygen uptake, wider CRAE (174 ± 17 μm vs. 161 ± 17 μm, p = 0.009), and higher AVR (0.84 ± 0.05 vs. 0.79 ± 0.05, p = 0.003) compared to patients with hypertension. In the RCT, patients with arterial hypertension showed reduced BMI and fasting glucose levels after HIIT and control condition. In addition, the intervention group reduced body fat percentage (27.0 ± 5.5 vs. 25.8 ± 6.1, p = 0.023) and increased peak oxygen uptake (33.3 ± 5.7 vs. 36.7 ± 5.1, p < 0.001). No changes in BP were found in either group. The intervention group showed narrower CRVE (β -4.8 [95 % CI, -8.85, -0.81] p = 0.020) and higher AVR (0.03 [0.01, 0.04] p < 0.001) after eight weeks of HIIT compared to the control group. No statistically significant changes in retinal O2-saturation were found in either group. Short-term HIIT proved to be an effective treatment to ameliorate hypertension-induced retinal microvascular abnormalities in patients with hypertension. Retinal vessel diameters may prove to be a sensitive biomarker to quantify treatment efficacy at the microvascular level, at the earliest possible stage in patients with hypertension.


History of unintended pregnancy and patterns of contraceptive use among racial and ethnic minority women veterans.
Nearly half of all pregnancies in the United States each year are unintended, with the highest rates observed among non-Hispanic black and Hispanic women. Little is known about whether variations in unintended pregnancy and contraceptive use across racial and ethnic groups persist among women veteran Veterans Affairs users who have more universal access than other populations to health care and contraceptive services. The objectives of this study were to identify a history of unintended pregnancy and describe patterns of contraceptive use across racial and ethnic groups among women veterans accessing Veterans Affairs primary care. Cross-sectional data from a national random sample of women veterans (n = 2302) aged 18-44 years who had accessed Veterans Affairs primary care in the previous 12 month were used to assess a history of unintended pregnancy (pregnancies reported as either unwanted or having occurred too soon). Any contraceptive use at last sex (both prescription and nonprescription methods) and prescription contraceptive use at last sex were assessed in the subset of women (n = 1341) identified as being at risk for unintended pregnancy. Prescription contraceptive methods include long-acting reversible contraceptive methods (intrauterine devices and subdermal implants), hormonal methods (pill, patch, ring, and injection), and female or male sterilization; nonprescription methods include barrier methods (eg, condoms, diaphragm), fertility-awareness methods, and withdrawal. Multivariable logistic regression models were used to examine the relationship between race/ethnicity with unintended pregnancy and contraceptive use at last sex. Overall, 94.4% of women veterans at risk of unintended pregnancy used any method of contraception at last sex. Intrauterine devices (18.9%), female surgical sterilization (16.9%), and birth control pills (15.9%) were the 3 most frequently used methods across the sample. Intrauterine devices were the most frequently used method for Hispanic, non-Hispanic white, and other non-Hispanic women, while female surgical sterilization was the most frequently used method among non-Hispanic black women. In adjusted models, Hispanic women (adjusted odds ratio, 1.60, 95% confidence interval, 1.15-2.21) and non-Hispanic black women (adjusted odds ratio, 1.84, 95% confidence interval, 1.44-2.36) were significantly more likely than non-Hispanic white women to report any history of unintended pregnancy. In the subcohort of 1341 women at risk of unintended pregnancy, there were no significant racial/ethnic differences in use of any contraception at last sex. However, significant differences were observed in the use of prescription methods at last sex. Hispanic women (adjusted odds ratio, 0.51, 95% confidence interval, 0.35-0.75) and non-Hispanic black women (adjusted odds ratio, 0.69, 95% confidence interval, 0.51-0.95) were significantly less likely than non-Hispanic white women to have used prescription contraception at last sex. Significant racial and ethnic differences exist in unintended pregnancy and contraceptive use among women veterans using Veterans Affairs care, suggesting the need for interventions to address potential disparities. Improving access to and delivery of patient-centered reproductive goals assessment and contraceptive counseling that can address knowledge gaps while respectfully considering individual patient preferences is needed to support women veterans' decision making and ensure equitable reproductive health services across Veterans Affairs.


Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders.
The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.


Tanshinone IIA ameliorates bleomycin-induced pulmonary fibrosis and inhibits transforming growth factor-beta-β-dependent epithelial to mesenchymal transition.
Epithelial to mesenchymal transition (EMT) of alveolar epithelial cells occurs in lung fibrotic diseases. Tanshinone IIA (Tan IIA) has been reported to exert anti-inflammatory effects in pulmonary fibrosis. Nonetheless, whether Tan IIA affects lung fibrosis-related EMT remains unknown and requires for further investigations. A single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg body weight) was performed to induce pulmonary fibrosis in Sprague-Dawley rats. Rats receiving an instillation of equivoluminal normal saline served as controls. Then, these rats were given a daily intraperitoneal administration of Tan IIA (15 mg/kg body weight) for 28 d before sacrifice. In vitro, recombinant transforming growth factor-beta 1 (TGF-β1; 10 ng/mL) was used to treat human alveolar epithelial A549 cells for 48 h. Tan IIA (10 μM) or control DMSO was used to pretreat cells for 2 h before TGF-β1 stimulation. Rat lung tissue samples and A549 cells were then subjected to further assessments. Tan IIA was noted to alleviate BLM-induced pulmonary collagen deposition and macrophage infiltration in rats. Epithelial-cadherin expression was decreased after BLM stimulation, whereas α-smooth muscle actin, fibronectin, and vimentin were increased. These expression alterations were partially reversed by Tan IIA. Moreover, Tan IIA suppressed BLM-induced increases in TGF-β1, phosphorylated Smad-2, and -3 in rats. Additionally, pretreatment of Tan IIA inhibited TGF-β1-triggered EMT, reduced collagen Ⅰ production, and blocked TGF-β signal transduction in A549 cells. Our research suggests that Tan IIA mitigates BLM-induced pulmonary fibrosis and suppresses TGF-β-dependent EMT of lung alveolar epithelial cells.


Nardostachys jatamansi extract protects against cytokine-induced beta-cell damage and streptozotocin-induced diabetes.
To investigate the anti-diabetogenic mechanism of Nardostachys jatamansi extract (NJE). Mice were injected with streptozotocin via a tail vein to induce diabetes. Rat insulinoma RINm5F cells and isolated rat islets were treated with interleukin-1beta and interferon-gamma to induce cytotoxicity. Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was confirmed by immunohistochemical staining of the islets. The diabetogenic effects of streptozotocin were completely abolished when mice were pretreated with NJE. Inhibition of streptozotocin-induced hyperglycemia by NJE was mediated by suppression of nuclear factor (NF)-kappaB activation. In addition, NJE protected against cytokine-mediated cytotoxicity. Incubation of RINm5F cells and islets with NJE resulted in a significant reduction in cytokine-induced NF-kappaB activation and downstream events, inducible nitric oxide synthase expression and nitric oxide production. The protective effect of NJE was further demonstrated by the normal insulin secretion of cytokine-treated islets in response to glucose. NJE provided resistance to pancreatic beta-cell damage from cytokine or streptozotocin treatment. The beta-cell protective effect of NJE is mediated by suppressing NF-kappaB activation.


The Trunk Control Measurement Scale: reliability and discriminative validity in children and young people with neuromotor disorders.
This study investigated the intra- and interrater reliability of the Trunk Control Measurement Scale (TCMS) German version, with its subscores, in children with neuromotor disorders. Further, the discriminative validity of the TCMS was assessed by comparing the TCMS scores with the Functional Independence Measure for children. Bland-Altman analyses and intraclass correlation coefficients were applied to investigate reliability. The discriminative ability of the TCMS was evaluated with receiver operating characteristics. Ninety children (mean age 11y 5mo; range 5y-18y 11mo) participated for the reliability, and 50 for the discriminative validity study. The reliability proved to be excellent (intrarater: bias=0.57 points, 95% confidence interval [CI] -3.71 to 4.85; interrater: bias=-0.31 points, 95% CI -5.77 to 5.10). A change in the TCMS total score of six points (10%) can be considered a true change. The TCMS subscores appeared to be clinically relevant because children with less than around 80% of the static balance score, less than 55% of the dynamic reaching score, or less than around 35% of the selective movement control score needed support for daily life activities. The TCMS is a reliable and clinically relevant assessment for children aged 5 years and older with different neurological impairments.


Percutaneous stenting of an latrogenic superior mesenteric artery dissection complicating suprarenal aortic aneurysm repair.
To report endovascular repair of an iatrogenic superior mesenteric artery (SMA) dissection caused by a balloon occlusion catheter. A 68-year-old man with a suprarenal aortic aneurysm underwent conventional prosthetic replacement, during which visceral artery back bleeding was controlled with balloon occlusion catheters. Six hours postoperatively, the patient experienced an episode of bloody diarrhea with abdominal pain and tenderness and mild metabolic acidosis. Colonoscopy revealed colitis (grade I) without necrosis of the right and left colon. An emergent abdominal computed tomographic scan showed signs of mesenteric ischemia with bowel dilatation and SMA wall hematoma; angiography identified a dissection 1 cm distal to the SMA origin. An Easy Wallstent was deployed percutaneously, successfully reestablishing SMA patency. The postoperative course was uneventful, and the patient remains asymptomatic with a patent SMA stent and aortic graft at 1 year. latrogenic SMA dissection should be suspected after suprarenal aortic aneurysm repair if signs of mesenteric ischemia arise. Prompt and thorough imaging studies are necessary to confirm the diagnosis and assess the potential for an endoluminal treatment.


Self-Sorting and Coassembly of Fluorinated, Hydrogenated, and Hybrid Janus Dendrimers into Dendrimersomes.
The modular synthesis of a library containing seven self-assembling amphiphilic Janus dendrimers is reported. Three of these molecules contain environmentally friendly chiral-racemic fluorinated dendrons in their hydrophobic part (RF), one contains achiral hydrogenated dendrons (RH), while one denoted hybrid Janus dendrimer, contains a combination of chiral-racemic fluorinated and achiral hydrogenated dendrons (RHF) in its hydrophobic part. Two Janus dendrimers contain either chiral-racemic fluorinated dendrons and a green fluorescent dye conjugated to its hydrophilic part (RF-NBD) or achiral hydrogenated and a red fluorescent dye in its hydrophilic part (RH-RhB). These RF, RH, and RHF Janus dendrimers self-assembled into unilamellar or onion-like soft vesicular dendrimersomes (DSs), with similar thicknesses to biological membranes by simple injection from ethanol solution into water or buffer. Since RF and RH dendrons are not miscible, RF-NBD and RH-RhB were employed to investigate by fluorescence microscopy the self-sorting and coassembly of RF and RH as well as of phospholipids into hybrid DSs mediated by the hybrid hydrogenated-fluorinated RHF Janus dendrimer. The hybrid RHF Janus dendrimer coassembled with both RF and RH. Three-component hybrid DSs containing RH, RF, and RHF were formed when the proportion of RHF was higher than 40%. With low concentration of RHF and in its absence, RH and RF self-sorted into individual RH or RF DSs. Phospholipids were also coassembled with hybrid RHF Janus dendrimers. The simple synthesis and self-assembly of DSs and hybrid DSs, their similar thickness with biological membranes and their imaging by fluorescence and (19)F-MRI make them important tools for synthetic biology.


Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson's disease-associated protein.
The 15-20 kDa synuclein (SYN) phosphoproteins are abundantly expressed in nervous tissue. Members of the family include alpha- and beta-SYN, and the more distantly related gamma-SYN and synoretin. SYN genes have been identified in Torpedo, canary, and several mammalian species, indicating an evolutionary conserved role. Expression of alpha-SYN was found to be modulated in situations of neuronal remodeling, namely, songbird learning and after target ablation of dopaminergic striatonigral neurons in the rat. The presynaptic localization of alpha-SYN is further supportive of a direct physiological role in neuronal plasticity. The extensive synaptic co-localization of alpha- and beta-SYN might indicate functional redundancy of these highly homologous synucleins. However, alpha-SYN was the only family member identified in Lewy bodies and cytoplasmic inclusions characteristic for multiple system atrophy. Moreover, alpha-SYN was genetically linked to familial Parkinson's disease. The two Parkinson's disease-associated mutations accelerated the intrinsic aggregation property of alpha-SYN in vitro. Post-translational modifications, such as phosphorylation and proteolysis, and/or interaction with other proteins, might regulate alpha-SYN fibril formation in vivo. Cytoskeletal elements and signal transduction intermediates have been recently identified as binding partners for alpha-SYN. Preliminary data available from transgenic mice suggest that (over)expressed human alpha-SYN proteins are less efficiently cleared from the neuronal cytosol. Thus, Parkinson's disease-associated mutations might perturb axonal transport, leading to somal accumulation of alpha-SYN and eventually Lewy body formation.


Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance.
Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development.


RENA Study: Cross-Sectional Study to Evaluate CKD Prevalence in Portugal.
Chronic kidney disease (CKD) is a major global public health problem associated with increased risk of cardiovascular morbidity, premature mortality, and decreased quality of life. In Portugal, the PREVADIAB study showed a prevalence of CKD stages 3-5 of 6.1%. To overcome the limitations of the PREVADIAB study, the RENA study aimed to provide an estimate of the prevalence of CKD at a national level and to characterize CKD patients. This was a cross-sectional study including users of Primary Health Care Units aged 18 or more. After obtaining written informed consent, sociodemographic and clinical data were recorded through a structured questionnaire, anthropometric measurements were taken, and blood and urine samples were collected. All participants initially meeting the criteria for CKD were contacted at least 3 months after the initial assessment for confirmation of the analytical results. A total of 3,135 individuals were included, 65.4% were female, and the mean age was 56.7 ± 15.9 years. The prevalence of hypertension, dyslipidemia, and diabetes was 38, 32, and 16%, respectively, and 31% were obese. After data adjustment by gender, age group, and geographical region, the global prevalence of CKD was 20.9% (95% CI: 6.5-35.3%), with no differences between genders and a significant increase with the advance of the age groups. Our study showed a CKD prevalence above the worldwide and Europe average. Despite the study limitations, it has become clear that it is urgent to identify CKD patients earlier and to develop awareness and educational programs to prevent CKD and its associated diseases.


Medial Patellofemoral Ligament Reconstruction Using the Hamstring Tendon for Patellofemoral Joint Instability in an 81-Year-Old Female.
Chronic patellofemoral instability occurs mainly in adolescent females and can also be induced by medial patellofemoral ligament (MPFL) injury. There are no case reports of MPFL reconstruction for chronic patellofemoral instability due to MPFL injury in aged populations. 81-year-old female presented with left knee pain, giving way, and patellar instability while climbing stairs, which continued for 18 months. Patellar apprehension test was positive, and roentgenogram showed lateral patellar subluxation. Conservative therapy was not successful; hence, we performed a lateral release and MPFL reconstruction surgery. After arthroscopic lateral release, the hamstring tendon was harvested, and a graft composite made of doubled hamstring tendon and polyester tape with a suspensory fixation device was prepared. Then, a femoral bone tunnel was constructed in a socket shape at the anatomical footprint of the MPFL. The graft was passed through the femoral tunnel, and free ends of the graft composite were sutured to the periosteum of the patella, using two suture anchors at 60° of knee flexion with patellar reduction. Physiotherapy was gradually started using a patella-stabilizing orthosis on the first postoperative day. Her Kujala score improved from 66 to 97 points, and Barthel index score improved from 70 to 100 points at 1 year after surgery. She neither developed patellofemoral joint OA nor had any recurrence of symptoms at the 5-year postoperative follow up. MPFL reconstruction using the hamstring tendon is an effective procedure for patients with chronic patellofemoral instability even after the age of 80 years.


Propagating density spikes in light-powered motility-ratchets.
Combining experiments and computer simulations, we use a spatially periodic and flashing light-field to direct the motion of phototactic active colloids. Here, the colloids self-organize into a density spike pattern, which resembles a shock wave and propagates over long distances, almost without dispersing. The underlying mechanism involves a synchronization of the colloids with the light-field, so that particles see the same intensity gradient each time the light-pattern is switched on, but no gradient in between (for example). This creates pulsating transport whose strength and direction can be controlled via the flashing protocol and the self-propulsion speed of the colloids. Our results might be useful for drug delivery applications and can be used to segregate active colloids by their speed.


Structural and thermodynamic analysis of the packing of two alpha-helices in bacteriophage T4 lysozyme.
Packing interactions in bacteriophage T4 lysozyme were explored by determining the structural and thermodynamic effects of substitutions for Ala98 and neighboring residues. Ala98 is buried in the core of T4 lysozyme in the interface between two alpha-helices. The Ala98 to Val (A98V) replacement is a temperature-sensitive lesion that lowers the denaturation temperature of the protein by 15 degrees C (pH 3.0, delta delta G = -4.9 kcal/mol) and causes atoms within the two helices to move apart by up to 0.7 A. Additional structural shifts also occur throughout the C-terminal domain. In an attempt to compensate for the A98V replacement, substitutions were made for Val149 and Thr152, which make contact with residue 98. Site-directed mutagenesis was used to construct the multiple mutants A98V/T152S, A98V/V149C/T152S and the control mutants T152S, V149C and A98V/V149I/T152S. These proteins were crystallized, and their high-resolution X-ray crystal structures were determined. None of the second-site substitutions completely alleviates the destabilization or the structural changes caused by A98V. The changes in stability caused by the different mutations are not additive, reflecting both direct interactions between the sites and structural differences among the mutants. As an example, when Thr152 in wild-type lysozyme is replaced with serine, the protein is destabilized by 2.6 kcal/mol. Except for a small movement of Val94 toward the cavity created by removal of the methyl group, the structure of the T152S mutant is very similar to wild-type T4 lysozyme. In contrast, the same Thr152 to Ser replacement in the A98V background causes almost no change in stability. Although the structure of A98V/T152S remains similar to A98V, the combination of T152S with A98V allows relaxation of some of the strain introduced by the Ala98 to Val replacement. These studies show that removal of methyl groups by mutation can be stabilizing (Val98----Ala), neutral (Thr152----Ser in A98V) or destabilizing (Val149----Cys, Thr152----Ser). Such diverse thermodynamic effects are not accounted for by changes in buried surface area or free energies of transfer of wild-type and mutant side-chains. In general, the changes in protein stability caused by a mutation depend not only on changes in the free energy of transfer associated with the substitution, but also on the structural context within which the mutation occurs and on the ability of the surrounding structure to relax in response to the substitution.(ABSTRACT TRUNCATED AT 400 WORDS)


Childhood Maltreatment and Violent Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies.
The risk of violence following childhood maltreatment is uncertain. This meta-analytic review identified prospective studies that have examined this association. We systematically searched three electronic databases (PsycINFO, EMBASE, and MEDLINE) and completed a targeted search on Google Scholar. These were supplemented with scanning reference lists and correspondence with authors. We considered non-English-language and unpublished studies. Studies were included if childhood maltreatment was measured before age 18 years and occurred before violent outcomes. We identified 18 eligible studies with data on 39,271 participants. We conducted meta-analysis to calculate odds ratios (ORs) using random-effects models. Heterogeneity was explored through subgroup analyses and meta-regression. The overall OR of violent outcomes in childhood maltreatment was 1.8 (95% confidence interval [1.4, 2.3]) with substantial heterogeneity (I2 = 92%). Meta-regression suggested that risk of violence following childhood maltreatment was more elevated in samples with higher percentage of females, in higher quality investigations, in studies with case-linkage methods compared to that followed-up participants over time using a prospective cohort design, when general population or matched controls were used rather than selected population controls, and when violent outcomes were ascertained in older individuals. In conclusion, the risk of later violence perpetration was modestly increased in individuals with a history of childhood maltreatment. Preventative strategies and interventions for childhood maltreatment may have an important role in violence reduction. Methodological issues and recommendations for future research are discussed.


Melanocytic Matricoma With Consumption of the Epidermis: An Atypical Histologic Attribute or a Malignant Variant?
Melanocytic matricoma is a recently described cutaneous adnexal tumor composed of matrical and supramatrical cells admixed with pigmented dendritic melanocytes, thought to recapitulate the anagen bulb of the hair follicle. We report a case of a 75-year-old white man, which demonstrates consumption of the epidermis that is defined as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of the normal rete architecture in areas of direct contact with neoplastic cells. It has been associated with aggressive histologic features in melanoma and likely represents an early phase of ulceration due to attenuation. Epidermal consumption has not been previously reported in nonmelanocytic tumors and it is uncertain whether this atypical histologic feature represents a sign of malignant behavior in this rare tumor.


Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC). Our purpose is to describe three extended HNPCC families, each of which manifests novel germline mutations in Uruguay, a small country that is a study model for cancer investigation given its high cancer incidence and mortality rate. This is a study of three extended HNPCC families in which extensive genealogic information, medical history, and pathology findings are critically reviewed. DNA testing was performed for evidence of HNPCC mutations. The findings reveal three novel germline mutations, namely MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) in one of the families; in the second family, MSH2 exon 1, codon 61 at nucleotide 181, which results in immediate stop of translation; and in the third family, a mutation in MSH2 at exon 3: the amino acid at nucleotide 530, codon 117, causing a frameshift and a premature stop codon eight base pairs later. We conclude that it is important to study HNPCC mismatch repair genes because of emerging evidence for genotypic and phenotypic heterogeneity, which will harbor the potential to eventually translate this knowledge into specific screening and management protocols. Future projections for such mutations could even contribute to the emergence of molecular-based designer drugs developed through advances in genomics, proteomics, high-throughput screening, and bioinformatics, which would be effective therapeutically for these high-cancer risk patients.


Independent measures of insulin secretion and insulin sensitivity during the same test: the glucagon-insulin tolerance test.
To validate a test for independent assessment of insulin secretion and insulin sensitivity during the same occasion for metabolic studies in clinical practice, i.e. combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). We measured C-peptide response to 0.5 mg of intravenous glucagon followed 30 min later by administration of 0.05 U kg(-1) insulin (insulin tolerance test, ITT). Ten subjects with normal glucose tolerance participated on different days in an ITT, glucagon-C-peptide test, ITT followed by glucagon-C-peptide test and glucagon-C-peptide test followed by ITT to establish whether and how the tests could be combined. The test was then repeated in nine patients with type 2 diabetes to investigate its reproducibility. In 20 subjects with varying degrees of glucose tolerance, the test was compared with the Botnia clamp (an intravenous glucose tolerance test combined with a euglycaemic hyperinsulinemic clamp). When ITT preceded the glucagon test, C-peptide response was blunted. Therefore, we first administered glucagon and then insulin (GITT). The K(ITT) from the GITT was reproducible (CV = 13 %) and correlated strongly with the glucose disposal rate from the Botnia clamp (r = 0.87, r(2) = 0.75, P < 0.001). The C-peptide response to glucagon was reproducible (CV = 13 %). The disposition index, providing a measure of beta-cell function adjusted for insulin sensitivity, calculated from the GITT showed good discrimination between individuals with varying degrees of glucose tolerance. The GITT provides simple, reproducible and independent estimates of insulin sensitivity and secretion on the same occasion for metabolic studies in individuals with normal and abnormal glucose tolerance.


A Second Mortuary Hiatus on Lake Baikal in Siberia and the Arrival of Small-Scale Pastoralism.
The spread of pastoralism in Asia is poorly understood, including how such processes affected northern forager populations. Lake Baikal's western shore has a rich Holocene archaeological record that tracks these processes. The Early Bronze Age here is evidenced by numerous forager burials. The Early Iron Age (EIA) is thought to mark the arrival of pastoralists, but archaeological remains from this period have received little analysis. New radiocarbon dates for EIA human remains from 23 cemeteries indicate that no burials were created along this shore for ~900 years. This period, from ~3670 to 2760 cal. BP, spans from the end of the Early Bronze Age to the advent of the EIA. The burial gap may mark disruption of local foraging populations through incursions by non-local pastoralists. Radiocarbon dates on faunal remains indicate that domestic herd animals first appear around 3275 cal. BP, just prior to the first EIA human burials. Stable carbon and nitrogen isotope analysis of human remains and zooarchaeological data indicate that domestic fauna were minor dietary components for EIA people. Like preceding foragers, the EIA groups relied extensively on Baikal's aquatic food sources, indicating that the scale of pastoralism during this period was relatively limited.


The Blood-Brain Barrier Breakdown During Acute Phase of the Pilocarpine Model of Epilepsy Is Dynamic and Time-Dependent.
The maintenance of blood-brain barrier (BBB) integrity is essential for providing a suitable environment for nervous tissue function. BBB disruption is involved in many central nervous system diseases, including epilepsy. Evidence demonstrates that BBB breakdown may induce epileptic seizures, and conversely, seizure-induced BBB disruption may cause further epileptic episodes. This study was conducted based on the premise that the impairment of brain tissue during the triggering event may determine the organization and functioning of the brain during epileptogenesis, and that BBB may have a key role in this process. Our purpose was to investigate in rats the relationship between pilocarpine-induced status epilepticus (SE), and BBB integrity by determining the time course of the BBB opening and its subsequent recovery during the acute phase of the pilocarpine model. BBB integrity was assessed by quantitative and morphological methods, using sodium fluorescein and Evans blue (EB) dyes as markers of the increased permeability to micromolecules and macromolecules, respectively. Different time-points of the pilocarpine model were analyzed: 30 min after pilocarpine injection and then 1, 5, and 24 h after the SE onset. Our results show that BBB breakdown is a dynamic phenomenon and time-dependent, i.e., it happens at specific time-points of the acute phase of pilocarpine model of epilepsy, recovering in part its integrity afterwards. Pilocarpine-induced changes on brain tissue initially increases the BBB permeability to micromolecules, and subsequently, around 5 h after SE, the BBB breakdown to macromolecules occurs. After BBB breakdown, EB dye is captured by damaged cells, especially neurons, astrocytes, and oligodendrocytes. Although the BBB permeability to macromolecules is restored 24 h after the start of SE, the leakage of micromolecules persists and the consequences of BBB degradation are widely disseminated in the brain. Our findings reveal the existence of a temporal window of BBB dysfunction in the acute phase of the pilocarpine model that is important for the development of therapeutic strategies that could prevent the epileptogenesis.