Effects of a beta-blocker on the cardiovascular response to MDMA (Ecstasy).
MDMA (3,4-methylenedioxymethamphetamine, 'Ecstasy') produces tachycardia and hypertension and is rarely associated with cardiovascular and cerebrovascular complications. In clinical practice, beta-blockers are often withheld in patients with stimulant intoxication because they may increase hypertension and coronary artery vasospasm due to loss of beta(2)-mediated vasodilation and unopposed alpha-receptor activation. However, it is unknown whether beta-blockers affect the cardiovascular response to MDMA. The effects of the non-selective beta-blocker pindolol (20 mg) on the cardiovascular effects of MDMA (1.6 mg/kg) were investigated in a double-blind placebo-controlled crossover study in 16 healthy subjects. Pindolol prevented MDMA-induced increases in heart rate. Peak values (mean+/-SD) for heart rate were 84+/-13 beats/min after MDMA vs 69+/-7 beats/min after pindolol-MDMA. In contrast, pindolol pretreatment had no effect on increases in mean arterial blood pressure (MAP) after MDMA. Peak MAP values were 115+/-11 mm Hg after MDMA vs 114+/-11 mm Hg after pindolol-MDMA. Pindolol did not change adverse effects of MDMA. The results of this study indicate that beta-blockers may prevent increases in heart rate but not hypertensive and adverse effects of MDMA.


Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug-induced liver injury.
The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.


Methyl tert-butyl ether causes alpha2u-globulin nephropathy and enhanced renal cell proliferation in male Fischer-344 rats.
Methyl tert-butyl ether (MTBE), a fuel additive blended into unleaded gasoline to decrease carbon monoxide emissions, induces renal tumors in male, but not female, rats exposed by inhalation to > or =3000 ppm MTBE. A number of chemicals that induce male rat-specific renal tumors also cause a syndrome unique to male rats referred to as alpha2u-globulin nephropathy (alpha2u-N). The objective of the present study was to determine if MTBE induces an alpha2u-N and renal cell proliferation in male F-344 rats. Male and female F-344 rats were exposed to MTBE vapors of 0, 413, 1516, or 3013 ppm for 6 hr/day for 10 consecutive days. Significant proximal tubule necrosis and protein droplet accumulation were observed in kidneys from male rats exposed to 1516 and 3013 ppm MTBE. Significantly greater labeling indices were observed in all groups of MTBE-exposed male rats. alpha2u-Globulin immunoreactivity was present in and confined to protein droplets in male rat kidney. A mild dose-related increase in alpha2u concentration in the kidney, as measured by an enzyme-linked immunosorbent assay, was observed in male rats exposed to MTBE, with a statistically significant increase in alpha2u concentration in male rats exposed to 3013 ppm MTBE. There was a strong positive correlation (r = 0.994) with exposure concentration between cell proliferation and alpha2u concentration in male rat kidney. No significant differences were observed in female rats for any of these responses. Further analysis of kidney cytosol failed to demonstrate the accumulation of any protein besides alpha2u in MTBE-exposed male rat kidney. These findings demonstrate that MTBE causes a mild induction of alpha2u-N and enhanced renal cell proliferation in male, but not female, F-344 rats, suggesting a role for alpha2u-N in renal tumorigenesis.


[Forms and factors of the variability of paranasal sinuses].
The form, structural variations, sex variations (connected with zygosityz), right and left positions of the sinuses were studied according to the data obtained while measuring the contours of the frontal, sphenoid and maxillary sinuses in the cranial roentgenograms made in the frontal and sagittal projections. By means of the twin method, relationship of the hereditary and environmental influences on the sinus formation was estimated. The data obtained in 111 Ukrainians (30--60 years of age), inhabitants of Vinnitsa region, mono- and dizygote twins of both sex were used. Greater dimensions in the male sinuses and a high variability of their size not connected with sex were stated. Among women the dizygote twin had larger dimensions than the monozygote ones. The sinus size is characterized by a predominant right-sided asymmetry. The hereditary effect is clearly seen in the sinus paranasales formation. A decreasing hereditary influence noted in the maxillary sinus is considered as a dependence of its dimensions on the state of the masticatory apparatus.


Propensity score-integrated composite likelihood approach for augmenting the control arm of a randomized controlled trial by incorporating real-world data.
In this paper, a propensity score-integrated composite likelihood (PSCL) approach is developed for cases in which the control arm of a two-arm randomized controlled trial (RCT) (treated vs control) is augmented with patients from real-world data (RWD) containing both clinical outcomes and covariates at the patient-level. RWD patients who were treated with the same therapy as the control arm of the RCT are considered for the augmentation. The PSCL approach first estimates the propensity score for every patient as the probability of the patient being in the RCT rather than the RWD, and then stratifies all patients into strata based on the estimated propensity scores. Within each propensity score stratum, a composite likelihood function is specified and utilized to down-weight the information contributed by the RWD source. Estimates of the stratum-specific parameters are obtained by maximizing the composite likelihood function. These stratum-specific estimates are then combined to obtain an overall population-level estimate of the parameter of interest. The performance of the proposed approach is evaluated via a simulation study. A hypothetical two-arm RCT and a hypothetical RWD source are used to illustrate the implementation of the proposed approach.


Cognitive Enhancement: Perceptions Among Parents of Children with Disabilities.
Cognitive enhancement is an increasingly discussed topic and policy suggestions have been put forward. We present here empirical data of views of parents of children with and without cognitive disabilities. Analysis of the interviews revealed six primary overarching themes: meanings of health and treatment; the role of medicine; harm; the 'good' parent; normality and self-perception; and ability. Interestingly none of the parents used the term ethics and only one parent used the term moral twice.


The impact of dose and route of estrogen administration on the somatotropic axis in normal women.
Oral estrogen therapy has reliably been found to reduce levels of serum IGF-I and increase mean 24-h GH levels in postmenopausal women as well as increase GH requirements in patients with GH deficiency. It is thought to act by inhibiting GH-stimulated IGF-I secretion, thus resulting in diminished feedback at the hypothalamic-pituitary axis and, hence, increased GH levels. In contrast, the administration of transdermal estrogen has variably been found to reduce, not change or increase, levels of serum IGF-I. We sought to clarify the effect of transdermal estrogen on the GH/IGF-I axis by using the IGF-I generation test, in which the acute response to a bolus dose of GH is examined. Nine healthy postmenopausal women received three different formulations of estrogen: oral estradiol (1 mg every 12 h), transdermal estradiol (50 micro g/d), and transdermal estradiol (200 micro g/d) for a 6-wk period in random order, separated by an 8-wk washout period. At the start of the study and in the last week of each estrogen formulation treatment, subjects underwent an IGF-I generation test. Oral estradiol reduced baseline (P < 0.05) and GH stimulated (P < 0.05) IGF-I levels, and GH stimulated IGF-binding protein-3 (IGFBP-3) levels (P < 0.05). High dose transdermal estrogen did not affect basal levels of IGF-I or IGFBP-3, but reduced the response of these GH-dependent peptides to GH stimulation (P < 0.05). Low dose transdermal estrogen did not alter either baseline or peak IGF-I levels, but reduced the peak IGFBP-3 response to GH stimulation (P < 0.05). Estradiol levels were lower during both transdermal estrogen preparations than during oral estrogen. It has been suggested that the effect of estrogen on responsiveness to GH is limited to that administered by the oral route. We have demonstrated that transdermal estrogen also has a significant impact on responsiveness to GH despite achieving levels of circulating estrogen lower than those achieved by oral estrogen replacement.


Combined beta-galactosidase and immunogold/silver staining for immunohistochemistry and DNA in situ hybridization.
A combination of beta-galactosidase enzyme and the immunogold/silver staining method was studied for evaluation of double-staining experiments. Applications are shown for immunohistochemical double staining using two monoclonal antibodies and for combined immunohistochemistry and DNA in situ hybridization in one tissue section. The following advantages for the present double-staining method were evaluated: superior sensitivity of the immunogold/silver staining method for at least one epitope, which also allows detection of biotinylated DNA probes. The structure of the indolyl precipitate after revelation of beta-galactosidase activity did not show a concealing effect during a sequential double-staining method, as compared with the visualization of peroxidase with diaminobenzidine. These factors, and the sharply contrasting colored reaction products of beta-galactosidase (blue-green) and the immunogold/silver staining method including silver enhancement (brown-black), allow clear distinction of mixed-stained cell constituents.


Circulating levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in patients with severe head injury.
There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury. We have measured the circulating level of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures. The serum level of IGF-1 was significantly lower in patients with both head injury and fracture and fracture only compared with that in healthy volunteers (p < 0.01 and p < 0.02, respectively). The level of IGFBP-3 was also significantly lower in patients with both head injury and fracture (p < 0.01). Our findings showed, however, that the level of IGF-1 and IGFBP-3 varied from week to week in both the patients and healthy control subjects. These results indicate that the levels of circulating IGF-1 and IGFBP-3 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury.


Pirfenidone may revert the epithelial-to-mesenchymal transition in human lung adenocarcinoma.
The epithelial-to-mesenchymal transition (EMT) in cancer is associated with invasion, metastasis and chemoresistance. Recent studies have revealed the increased expression of programmed death-ligand 1 (PD-L1) in cells undergoing EMT. The underlying mechanism of EMT involves transforming growth factor-β (TGF-β) and fibroblast growth factor-2 (FGF-2). Pirfenidone and the known EMT-suppressor nintedanib suppress pulmonary fibrosis partially through suppression of TGF-β. The present study aimed to determine whether pirfenidone has the potential to induce EMT-reversion, using nintedanib as a reference. The human lung adenocarcinoma cell lines A-549, HCC-827, and PC-9 were treated with TGF-β and FGF-2 to induce EMT. The EMT-induced cells were further treated with pirfenidone or nintedanib. Phenotypic alterations associated with EMT were assessed by examining the following: i) The expression levels of E-cadherin, vimentin, fibronectin and slug, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescent immunohistochemistry; ii) cell motility via wound-healing assays; and iii) the expression of PD-L1 using RT-qPCR. The combination of TGF-β and FGF-2 successfully induced EMT in all three cell lines, characterized by a significant reduction in E-cadherin expression in the A-549 and HCC-827 cells, increased expression levels of vimentin, fibronectin, slug and PD-L1, and increased cell motility in all three cell lines. Pirfenidone and nintedanib reverted all of these phenotypes, with the exception of unaltered E-cadherin expression in all three cell lines, and inconsistent expression of vimentin in the HCC-827 and PC-9 cells. Thus, pirfenidone and nintedanib have the ability to induce EMT-reversion in human lung adenocarcinoma.


Informal care and economic appraisal: a discussion of possible methodological approaches.
The role played by informal carers in the care of people with chronic disabilities is well known. Given its importance, it is essential to consider the evaluation methodology applied in economic appraisals of different care options. Few studies attempt any evaluation and those that do use varied, inconsistent and controversial methodologies. This paper aims to elicit the major issues and methodological problems related to economic appraisal of informal care. The main concern over the present methods utilized is the lack of explicit exploration of the benefits, as perceived by carers. Carers, through their decision to care it is argued, will consider both costs and benefits. Although concepts encompassed by benefits tend to be less tangible they may considerably outweigh any financial burdens. Various methods have been utilized in the past. Financial outlays are fairly straightforwardly costed, personal effort on the part of carers causes more problems. Methods applied include: the cost of substitute services; state benefits; and travel time values. The most useful is probably the latter, although it is not problem-free. Assessing benefits relating to concepts of direct and indirect utility and welfare is more complex and difficult to measure. Despite considerable literature on carers' attitudes, often these concepts are not applied (especially to residential care options) or if they are, negative aspects are emphasized (with domiciliary care). A useful application of economic appraisal would elicit optimal solutions to care dilemmas. Producing economic burden information about informal care may not be particularly constructive. Brief assessment of eight scenarios of care, considering cost differences for the public sector and the preferences of patient and carer gives insight to the problem. It emphasizes the complexity of the issue and the essential role likely to be placed on care managers in helping carers to maximize the net benefit of their efforts.


Contrast-Enhanced Magnetic Resonance Cholangiography: Practical Tips and Clinical Indications for Biliary Disease Management.
Since its introduction, MRCP has been improved over the years due to the introduction of several technical advances and innovations. It consists of a noninvasive method for biliary tree representation, based on heavily T2-weighted images. Conventionally, its protocol includes two-dimensional single-shot fast spin-echo images, acquired with thin sections or with multiple thick slabs. In recent years, three-dimensional T2-weighted fast-recovery fast spin-echo images have been added to the conventional protocol, increasing the possibility of biliary anatomy demonstration and leading to a significant benefit over conventional 2D imaging. A significant innovation has been reached with the introduction of hepatobiliary contrasts, represented by gadoxetic acid and gadobenate dimeglumine: they are excreted into the bile canaliculi, allowing the opacification of the biliary tree. Recently, 3D interpolated T1-weighted spoiled gradient echo images have been proposed for the evaluation of the biliary tree, obtaining images after hepatobiliary contrast agent administration. Thus, the acquisition of these excretory phases improves the diagnostic capability of conventional MRCP-based on T2 acquisitions. In this paper, technical features of contrast-enhanced magnetic resonance cholangiography are briefly discussed; main diagnostic tips of hepatobiliary phase are showed, emphasizing the benefit of enhanced cholangiography in comparison with conventional MRCP.


Modulation of embryonic development due to mating with immunised males.
The modification of pre- and postnatal development conferred by immunogenic stimulation of mothers provides a population-level adaptation mechanism for non-genetic transfer of maternal experiences to progeny. However little is known about the transmission of paternal immune experiences to offspring. Here, we show that immune priming of males 3-9 days before mating affects the growth and humoral environment of developing embryos of outbred (ICR) and inbred (C57BL and BALB/c) mice. Antigenic stimulation of fathers caused a significant increase in embryonic bodyweight as measured on Day 16 of pregnancy and altered other gestation parameters, such as feto-placental ratio. Pregnant females mated with immunised males were also characterised by changes in humoral conditions as shown by measurements of blood and amniotic progesterone, testosterone and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine concentrations. These results emphasise the role of paternal effects of immune priming on the in utero environment and fetal growth.


Regio- and Stereoselective Oxysulfonylation of Allenes.
A highly regio- and stereoselective oxysulfonylation of allenes was developed that provided direct access to 2-sulfonyl allylic alcohols in good yields. By means of dioxygen activation, selective difunctionlization of allenes could be successfully achieved under mild metal-free conditions. Preliminary mechanistic investigation disclosed that this transformation probably goes through a radical process.


Combining machine learning and quantum mechanics yields more chemically aware molecular descriptors for medicinal chemistry applications.
Molecular interaction fields (MIFs), describing molecules in terms of their ability to interact with any chemical entity, are one of the most established and versatile concepts in drug discovery. Improvement of this molecular description is highly desirable for in silico drug discovery and medicinal chemistry applications. In this work, we revised a well-established molecular mechanics' force field and applied a hybrid quantum mechanics and machine learning approach to parametrize the hydrogen-bonding (HB) potentials of small molecules, improving this aspect of the molecular description. Approximately 66,000 molecules were chosen from available drug databases and subjected to density functional theory calculations (DFT). For each atom, the molecular electrostatic potential (EP) was extracted and used to derive new HB energy contributions; this was subsequently combined with a fingerprint-based description of the structural environment via partial least squares modeling, enabling the new potentials to be used for molecules outside of the training set. We demonstrate that parameter prediction for molecules outside of the training set correlates with their DFT-derived EP, and that there is correlation of the new potentials with hydrogen-bond acidity and basicity scales. We show the newly derived MIFs vary in strength for various ring substitution in accordance with chemical intuition. Finally, we report that this derived parameter, when extended to non-HB atoms, can also be used to estimate sites of reaction.


Sex differences in outcomes of disease-modifying treatments for multiple sclerosis: A systematic review.
Multiple sclerosis (MS) is a chronic immune mediated demyelinating disease of the central nervous system that exhibits sexual dimorphism and may benefit from sex-specific treatment. To investigate a potential influence of sex on immunomodulatory therapeutic effects in patients with MS, we performed a comprehensive analysis of published studies examining sex differences in the effects of disease-modifying treatments (DMTs) for MS. PubMed, Cochrane Library, and Web of Science databases were searched for clinical studies involving patients with MS who were undergoing DMTs. Studies were included if they investigated sex differences in DMT outcomes. Fourteen studies with 11,425 participants were included; 11 of these studies were randomized controlled trials, and 3 were cohort studies. Although the studies did occasionally show sex-specific differences for some clinical outcomes in patients with MS who received DMTs, the limitation of subgroup analysis design made it difficult to draw conclusions on the direction or the extent of the sex-based effect. No clear sex-based differences in response to DMTs have been documented to date. More studies will be needed to better elucidate the presence of sex differences on the DMT effects.


Detection of abnormal extracellular matrix in the interstitium of regenerating renal tubules.
Stem/progenitor cells are promising candidates for the regeneration of parenchyma in acute and chronic renal failure. However, recent data exhibit that survival of stem/progenitor cells after implantation in diseased renal parenchyma is restricted. To elaborate basic parameters improving survival, cell seeding was simulated under advanced in vitro conditions. After isolation, renal stem/progenitor cells were mounted in a polyester interstitium for perfusion culture. During generation of tubules, chemically defined CO2 Independent Medium or Leibovitz's L-15 Medium was applied. Specimens were then fixed for transmission electron microscopy to analyze morphological features in generated tubules. Fixation in conventional glutaraldehyde (GA) solution shows development of tubules each exhibiting a polarized epithelium, an intact basal lamina and an inconspicuous interstitium. In contrast, special fixation of specimens in GA solution containing cupromeronic blue, ruthenium red or tannic acid unveils previously not visible extracellular matrix. Control experiments elucidate that a comparable extracellular matrix is not present in the interstitium of the matured kidney. Thus, generation of renal tubules in combination with advanced fixation of specimens for electron microscopy demonstrates that development of abnormal features in the newly developed interstitium has to be considered, when repair of renal parenchyma is performed by implantation of stem/progenitor cells.


Utility of lactate dehydrogenase vs radiographic severity in the differential diagnosis of Pneumocystis carinii pneumonia.
In patients with HIV infection, serum lactate dehydrogenase (LDH) level is commonly stated to be more elevated in Pneumocystis carinii pneumonia (PCP) than in non-PCP. We hypothesized that LDH level reflects radiographic extent and severity of pneumonia rather than P carinii infection specifically and therefore is not useful in the differential diagnosis of lung infections in AIDS. We compared radiographic features and LDH values in 93 sequential patients with HIV infection and a new hospital admission for pneumonia (53 PCP and 40 non-PCP) after excluding all patients with other potential causes for elevated LDH levels. The chest radiograph was graded using a quantitative scale (0 to 24) to assess radiographic extent and severity of pneumonia by two independent observers in blinded fashion. The relationship between radiographic score and hospital admission LDH level was analyzed by linear regression and Bayesian analysis was applied to different LDH ranges to calculate the clinical value of LDH measurements. Tertiary care teaching hospital and regional AIDS referral center. Mean LDH level was higher in the PCP group (1.217 +/- 88 U/L compared with 776 +/- 55 U/L; p < 0.001), as was mean radiographic score (12.4 +/- 0.6 for PCP compared with 6.3 +/- 0.5 for non-PCP; p < 0.001). For the whole sample of 93, LDH level was significantly related to chest radiographic score (r = 0.43, p < 0.0001). Significant overlap occurred between the two groups at all levels of LDH such that no cutoff level could be established that impacted significantly on posttest probability of PCP, whereas a radiographic score of > 12 yielded a 96% posttest probability of PCP. Serum LDH level reflects the degree of radiographic abnormality and is elevated in both PCP and non-PCP pneumonia to an extent that limits its utility in differentiating the two processes in hospitalized patients. The extent of radiographic involvement more clearly distinguishes the two conditions.


Development of variable pulse width mode-locked femtosecond laser by applying coherent coupling technology.
A novel femtosecond mode-locked variable-pulse-width laser system is developed based on coherent coupling technology. The laser system is composed of two fiber ring lasers that share an output coupler. Output longitudinal modes are emitted by the corresponding longitudinal modes of the laser modules. In this study, one longitudinal-mode spacing is changed arbitrarily by tuning the cavity length to control the output longitudinal modes. In the experiment, the laser system generates about 150 fs pulse width. The coupling result, which is the output pulse width, is changed by a length deviation of about 500 μm. As a result, the laser successful widens the pulse width to 1.5 ps at maximum and the tuning pulse width with 10 fs resolution at minimum.


Growth and Aggregation Regulate Clusters Structural Properties and Gel Time.
When particles undergo aggregation, very often they form structures that can be described with fractal geometry concepts. The spatial organization of the particles embedded in these aggregates, quantified by means of their fractal dimension, plays a key role in the clusters' diffusion and aggregation process. Fractal dimensions are typically known for some specific, ideal aggregation scenarios, such as for diluted diffusion limited cluster aggregation (DLCA) or reaction limited cluster aggregation (RLCA). The situation becomes significantly more complicated as soon as the initial particle concentration increases and fractal-dimension changing phenomena, such as particle growth, occur. In this frame, the aim of the present work is twofold: (i) to investigate the clusters' spatial organization in a scenario where growth and aggregation occur simultaneously and (ii) to assess the corresponding aggregation kinetics. To this end, an ad hoc Monte Carlo model has been developed. Both DLCA and RLCA regimes have been explored at several initial primary particle concentrations and for different growth rates. The results were discussed in terms of the characteristic times of growth (τG) and aggregation (τA), as well as the rate at which the structural properties change, vR. It was then possible to propose empirical correlations in the form dm = dm (vR) and tgel = tgel (τA, τG) to relate the evolution of the mass mobility exponent dm and the gel times to the simultaneously occurring processes of growth and aggregation.


Cardiac transplantation in giant cell myocarditis. A case report.
The present report describes a 15-year-old boy who underwent an urgent cardiac transplantation for giant cell myocarditis because of fulminant progressive heart failure, complicated by ventricular tachycardia, unresponsive to classical inotropic medical treatment. The physiopathology and the treatment are discussed.


PPARα-Target Gene Expression Requires TIS21/BTG2 Gene in Liver of the C57BL/6 Mice under Fasting Condition.
The TIS21/BTG2/PC3 gene belongs to the antiproliferative gene (APRO) family and exhibits tumor suppressive activity. However, here we report that TIS21 controls lipid metabolism, rather than cell proliferation, under fasting condition. Using microarray analysis, whole gene expression changes were investigated in liver of TIS21 knockout (TIS21-KO) mice after 20 h fasting and compared with wild type (WT). Peroxisome proliferator-activated receptor alpha (PPARα) target gene expression was almost absent in contrast to increased lipid synthesis in the TIS21-KO mice compared to WT mice. Immunohistochemistry with hematoxylin and eosin staining revealed that lipid deposition was focal in the TIS21-KO liver as opposed to the diffuse and homogeneous pattern in the WT liver after 24 h starvation. In addition, cathepsin E expression was over 10 times higher in the TIS21-KO liver than that in the WT, as opposed to the significant reduction of thioltransferase in both adult and fetal livers. At present, we cannot account for the role of cathepsin E. However, downregulation of glutaredoxin 2 thioltransferase expression might affect hypoxic damage in the TIS21-KO liver. We suggest that the TIS21/BTG2 gene might be essential to maintain energy metabolism and reducing power in the liver under fasting condition.


In vivo activity of HSR-903, a new fluoroquinolone, against respiratory pathogens.
The in vivo activity of HSR-903, a new fluoroquinolone, against major bacteria which cause respiratory tract infections was evaluated. HSR-903 was active against experimental respiratory tract infections in mice challenged with penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae and Haemophilus influenzae strains. Treatment with HSR-903 reduced the bacterial numbers in infected murine lungs. In accord with the pulmonary clearance results, the rates of survival for mice treated with HSR-903, sparfloxacin, levofloxacin, ciprofloxacin, and benzylpenicillin were 50, 30, 10, 0, and 0%, respectively, 14 days after being infected with penicillin-resistant S. pneumoniae. A pharmacokinetic study with pneumonic mice showed that the levels of HSR-903 in the lungs were seven to eight times higher than those in the plasma. These results indicate that clinical studies of HSR-903 against respiratory tract infections may be warranted.


Characterization of pyrazinamide resistance in consecutive multidrug-resistant mycobacterium tuberculosis isolates in sweden between 2003 and 2015.
The first line anti-tuberculosis drug pyrazinamide (PZA) is important when treating PZA susceptible multidrug-resistant tuberculosis (MDR-TB). Several drug resistance surveys have however reported PZA resistance among a significant proportion of multidrug-resistant (MDR) cases and this undoubtedly highlights the need for accurate and reliable detection of PZA resistance. Unfortunately, the testing of PZA susceptibility is associated with technical difficulties and even though the introduction of pncA sequencing has helped to address this issue, misclassification may still occur. In this study, we determined the prevalence and characteristics of PZA resistance in Swedish MDR-TB strains. 153 MDR-TB strains isolated in Sweden between 2003 and 2015 were analyzed for PZA resistance by considering both phenotypic and genotypic data. The phenotypic test showed that 58% of the multidrug-resistant isolates were PZA resistant and the correlation between phenotype and genotype was solid, although a small number of isolates deviate from the expected phenotypic-genotypic pattern. The results indicate that the prevalence of pyrazinamide resistance among Swedish MDR cases is increasing.


Acquisition of Clostridium difficile Colonization and Infection After Transfer From a Veterans Affairs Hospital to an Affiliated Long-Term Care Facility.
BACKGROUND Clostridium difficile infection (CDI) and asymptomatic carriage of toxigenic C. difficile are common in long-term care facilities (LTCFs). However, whether C. difficile is frequently acquired in the LTCF versus during acute-care admissions remains unknown. OBJECTIVE To test the hypothesis that LTCF residents often acquire C. difficile colonization and infection in the LTCF DESIGN This 5-month cohort study was conducted to determine the incidence of acquisition of C. difficile colonization and infection in asymptomatic patients transferred from a Veterans Affairs hospital to an affiliated LTCF. METHODS Rectal swabs were cultured for toxigenic C. difficile at the time of transfer to the LTCF and weekly for up to 6 weeks. We calculated the proportion of LTCF-onset CDI cases within 1 month of transfer that occurred in residents colonized on admission versus those with new acquisition in the LTCF. RESULTS Of 110 patients transferred to the LTCF, 12 (11%) were asymptomatically colonized with toxigenic C. difficile upon admission, and 4 of these 12 patients (33%) developed CDI within 1 month, including 3 recurrent and 1 initial CDI episode. Of 82 patients with negative cultures on transfer and at least 1 follow-up culture, 22 (27%) acquired toxigenic C. difficile colonization, and 4 developed CDI within 1 month, including 1 recurrent and 3 initial CDI episodes. CONCLUSION LTCF residents frequently acquired colonization with toxigenic C. difficile after transfer from the hospital, and 3 of 4 initial CDI cases with onset within 1 month of transfer occurred in residents who acquired colonization in the LTCF. Infect Control Hosp Epidemiol 2017;38:1070-1076.


The impact of polyol-containing chewing gums on dental caries: a systematic review of original randomized controlled trials and observational studies.
The authors conducted a systematic review of original studies that was designed to assess the impact of polyol-containing chewing gum on dental caries compared with the effect with no chewing gum. The authors searched MEDLINE, The Cochrane Library and Google Scholar up to May 2008 to identify peer-reviewed articles that compared polyol-containing chewing gum with no chewing gum. The authors extracted study characteristics, data on incremental dental caries and quality by consensus. Data on prevented fraction (PF) were pooled across studies. The results of 19 articles with data from 14 study populations showed that the use of xylitol, xylitol-sorbitol blend and sorbitol were associated with mean PF (95 percent confidence interval) of 58.66 percent (35.42-81.90), 52.82 percent (39.64-66.00) and 20.01 percent (12.74-27.27), respectively. For the sorbitol-mannitol blend, it was 10.71 percent (-20.50-41.93), which was not statistically significant. Sensitivity analyses confirmed the robustness of the findings. Although research gaps exist, particularly on optimal dosing and relative polyol efficacy, research evidence supports using polyol-containing chewing gum as part of normal oral hygiene to prevent dental caries.


Cortical surface area and cortical thickness in the precuneus of adult humans.
The precuneus has received considerable attention in the last decade, because of its cognitive functions, its role as a central node of the brain networks, and its involvement in neurodegenerative processes. Paleoneurological studies suggested that form changes in the deep parietal areas represent a major character associated with the origin of the modern human brain morphology. A recent neuroanatomical survey based on shape analysis suggests that the proportions of the precuneus are also a determinant source of overall brain geometrical differences among adult individuals, influencing the brain spatial organization. Here, we evaluate the variation of cortical thickness and cortical surface area of the precuneus in a sample of adult humans, and their relation with geometry and cognition. Precuneal thickness and surface area are not correlated. There is a marked individual variation. The right precuneus is thinner and larger than the left one, but there are relevant fluctuating asymmetries, with only a modest correlation between the hemispheres. Males have a thicker cortex but differences in cortical area are not significant between sexes. The surface area of the precuneus shows a positive allometry with the brain surface area, although the correlation is modest. The dilation/contraction of the precuneus, described as a major factor of variability within adult humans, is associated with absolute increase/decrease of its surface, but not with variation in thickness. Precuneal thickness, precuneal surface area and precuneal morphology are not correlated with psychological factors such as intelligence, working memory, attention control, and processing speed, stressing further possible roles of this area in supporting default mode functions. Beyond gross morphology, the processes underlying the large phenotypic variation of the precuneus must be further investigated through specific cellular analyses, aimed at considering differences in cellular size, density, composition, and structural covariance compared to other brain areas.


Effect of indomethacin on pulmonary vasomotor response in patients with mitral stenosis.
In 10 patients with mitral stenosis, ingestion of 125 mg indomethacin over a 24-h period had no effect on the elevated pressure in pulmonary artery. It did, however, in all patients, slightly potentiate a fall in pulmonary pressure induced by breathing of 100% oxygen. The results do not suggest that a prostaglandin mechanism is involved in chronic pulmonary vasoconstriction or that this mechanism is responsible for acute vasodilatation of the pulmonary bed induced by oxygen inhalation.


[Research on Anti-Camouflaged Target System Based on Spectral Detection and Image Recognition].
To be able to quickly and efficiently identify Enemy camouflaged maneuvering targets in the wild environment, target recognition system was designed based on spectral detection technology and video target recognition method. System was composed of the visible light image acquisition module and static interferometer module. The system used image recognition technology to obtain two dimensional video images of measurement region, and through spectrum detection technology to identify targets. Ultimately, measured target was rebuilt on the corresponding position in the image, so the visual target recognition was realized. After the theoretical derivation, identifiable target function formula of the system was obtained, and based on the functional relationship to complete the quantitative experiments for target recognition. In the experiments, maneuvering target in the battlefield environment was simulated by a car. At different distances, the background was respectively selected to detect a flat wasteland, bushes and abandoned buildings. Obvious target, coated camouflage target and covered disguises target was respectively spectrum detection. Experimental results show that spectrum detection technology can overcome the shortcomings of unrecognized the camouflaged target by traditional image target recognition method. Testing background had some influence on spectrum detection results, and the continuity of the background was conducive to target recognition. Covered disguises target was the hardest to identify in various camouflage mode. As the distance between the target and the system increases, signal to noise ratio of the system was reduced. In summary, the system can achieve effective recognition of camouflaged targets to meet the design requirements.


A novel calcium fluorinated alkoxyaluminate salt as a next step towards Ca metal anode rechargeable batteries.
Ca metal anode rechargeable batteries are seen as a sustainable high-energy density and high-voltage alternative to the current Li-ion battery technology due to the low redox potential of Ca metal and abundance of Ca. Electrolytes are key enablers on the path towards next-generation battery systems. Within this work, we synthesize a new calcium tetrakis(hexafluoroisopropyloxy) aluminate salt, Ca[Al(hfip)4]2, and benchmark it versus the state-of-the-art boron analogue Ca[B(hfip)4]2. The newly developed aluminate-based electrolyte exhibits improved performance in terms of conductivity, Ca plating/stripping efficiency, and oxidative stability as well as Ca battery cell performance. A marked improvement of 0.5 V higher oxidative stability can pave the path towards high-voltage Ca batteries. A critical issue of solvent quality during salt synthesis is identified as well as solvent decomposition at the Ca metal/electrolyte interface, which leads to passivation of the Ca metal anode. However, the new aluminate salt with preferable electrochemical properties over the existing boron analogue opens up a new area for future Ca battery research based on aluminium compounds.


Primary adenocarcinoma of the appendix presenting with fresh bleeding per rectum: A case report.
Primary adenocarcinoma of appendix is a rarely diagnosed malignancy accounting for less than 6% of appendiceal neoplastic lesions and less than 0.5% of all gastrointestinal malignancies. It is mostly diagnosed as an incidental finding after appendicectomy. An 81 year old male patient presented with bleeding per rectum in a background of previous rectal polyp, hypertension, diabetes and hypothyroidism. CECT of whole abdomen findings revealed thickening at the appendix and base of the caecum. Colonoscopy showed a sessile polypoid growth at appendicular orifice, at the base of the caecum. Laparoscopy confirmed the clinical suspicion of appendicular carcinoma and laparoscopy assisted radical right hemicolectomy was performed. Final histopathology revealed well differentiated adenocarcinoma of the appendix with no lymph node involvement (pT3N0M0). Patients with primary adenocarcinoma of the appendix present with features similar to acute appendicitis whereas anaemia or fresh bleeding per rectum is a rare presentation. Surgery is the mainstay of treatment, the extent of which will depend upon the stage. Tumours staged as T1 may be managed by appendicectomy alone provided the base is free and there are no lymphadenopathies. T2 or above require right hemicolectomy as chances of lymph node metastasis are high. Nodal involvement warrants the need for adjuvant chemotherapy. Distant metastasis to the peritoneum or liver and lungs is very rare. While investigating unexplained anaemia or bleeding per rectum, full colonoscopic examination up to the appendicular orifice is important and if required, should be combined with CT scan of abdomen, to clinch the rare but possible and potentially curable diagnosis of appendicular carcinoma.


The emerging importance of lymphatics in health and disease: an NIH workshop report.
The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled "Yet to be Charted: Lymphatic System in Health and Disease," held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field.


Waardenburg syndrome with familial unilateral renal agenesis: a new syndrome variant?
A 64-year-old man with Waardenburg syndrome presented with anuria and was subsequently discovered by renal ultrasound to have unilateral renal agenesis. The patient is one of three generations with incidental finding of renal agenesis also marked by the presence of Waardenburg syndrome. To our knowledge, there has been no mention elsewhere in the scientific literature of a variant of Waardenburg syndrome with associated renal agenesis.


Gold-Catalyzed One-Pot Synthesis of Polyfluoroalkylated Oxazoles from N-Propargylamides Under Visible-Light Irradiation.
A gold-catalyzed synthesis of polyfluoroalkylated oxazoles from N-propargylamides under visible-light irradiation has been developed. These reactions display excellent compatibility of radicals and gold catalysts under visible-light irradiation. Mechanistic experiments indicate that polyfluoroalkyl iodides play a dual role in enhanced compatibility of radicals and gold catalysts through assisted protodeauration of vinyl gold and reactivated the gold catalyst. In addition, PPh3 AuNTf2 not only activates N-propargylamide to generate vinyl gold intermediate, but also greatly promotes homolysis of polyfluoroalkyl iodides under blue light irradiation.


[Bacterial contamination of the inspiratory circuit of artificial ventilation apparatus: influence of the frequency of circuit renewal and the duration of ventilation].
In a study concerning contamination of artificial ventilators (Drager model UV1), the influence of 2 parameters was assessed: the frequency of changing the circuit (2 and 4 days) and the interval between admission of the patient into the intensive care unit and obtaining the sample. As a function of these variables, 4 groups of 15 patients each were constituted. The levels of contamination noted at 4 sites in the inspiratory phase tubing (cascade humidifier, condensate collector, tubing nearest to the patient and tubing nearest to the humidifier) and in the gas flow showed no significant difference between the groups, regardless of whether the circuit was changed after 2 or 4 days, or whether the patient had been recently admitted to the department or had been there for at least 6 days. Quantitative and qualitative study of bacteria showed that the one(s) contaminating the inspiratory phase tubing were the same as the one(s) colonizing the tracheal secretions of the patient, and that the most contaminated areas were those nearest to the patient (proximal tubing, collector), which confirms the retrograde contamination of the circuit.


Developmental abnormalities induced by X-irradiation in p53 deficient mice.
In order to assess the influence of p53 inactivation on radiation-induced developmental effects, male mice heterozygous for the wild-type p53 allele (mimicking the human Li-Fraumeni syndrome) were crossed with C57BL females, and their heterozygous p53+/- progeny were mated with each other to obtain p53+/-, p53-/- and p53+/+ embryos. Pregnant females were X-irradiated with 0.5 Gy on days 1 (pre-implantation period), 8 or 11 (organogenesis period) of gestation. Dissection of the pregnant females occurred on day 19 of gestation. The p53 genotype of the foetuses was determined by PCR from small pieces of soft tissues. Exencephaly was the only external malformation found in the control group. It affected essentially p53-/- female foetuses. A number of p53+/- and p53+/- control foetuses also showed dwarfism, or underdevelopment. In the group irradiated on day 1, the frequency of abnormal foetuses was, paradoxically, lower than that found in the control group. As in that group, exencephaly and dwarfism constituted the only anomalies that were found. Exencephaly affected only homozygous p53-/- females, while dwarfism concerned either p53-/- or p53+/- foetuses, with a majority of females. Irradiation on day 8 of gestation induced a significant increase in the frequency of abnormal foetuses, compared to the control group. Various malformations were observed in addition to exencephaly, including gastroschisis, polydactyly, cephalic oedema and cleft palate. All malformed foetuses were either homozygous p53-/- or heterozygous p53+/- while most affected foetuses were females, as was the case for dwarf individuals. Irradiation on day 11 did not cause an increase in the frequency of abnormal foetuses, in comparison with the controls. However, a large spectrum of external malformations was again noticed, as in the group irradiated on day 8. All affected foetuses were homozygous p53-/- and there were slightly more abnormal females than males (3 out of 5). No dwarfs were found in this group. Overall, these results confirm the importance of the p53 tumour-suppressor protein for normal embryonic development. They clearly show that homozygous p53-/- (or heterozygous p53+/- to a lesser extent) foetuses are more at risk for radiation-induction of external malformations during the organogenesis period, and that the risk of developing such malformations is much higher for females than for males. In contrast to results published very recently by others, we found that malformed foetuses resulting from an X-irradiation with a low-dose during the highly sensitive period of gastrulation are able to survive to birth.


Genetic Factors and the Risk of Periodontitis Development: Findings from a Systematic Review Composed of 13 Studies of Meta-Analysis with 71,531 Participants.
Purpose. This work aimed to synthesize the results of recent meta-analysis focusing on polymorphism in inflammatory mediators and its relation with the risk of periodontitis development. Materials and Methods. A systematic search was conducted using databases for publications prior to October 2016. Three examiners extracted data from articles with a clear association between polymorphisms in the inflammatory mediator gene and the development of periodontitis through meta-analysis using the fixed or randomized statistical models to calculate the Odds Ratio with values of P < 0.05 considered significant. Results. A total of 13 meta-analysis articles with 25 polymorphisms in seven interleukins (IL-1A, IL-1B, IL-4, IL-6, IL-8, IL-10, and IL-18), three cellular receptors (Fcγ receptors: FCGR2A, FCGR3A, and FCGR3B), and five inflammatory mediators (COX-2, MMP-2, MMP-3, MMP-8, and MMP-9), with a total of 71,531 participants, approaching different classifications of the disease. Conclusion. The study demonstrated that polymorphisms in the IL-1A, IL-1B, IL-6, IL-10, MMP-3 (chronic form), and MMP-9 (chronic form) polymorphisms were significantly associated with the risk of developing periodontitis, whereas other polymorphisms in the IL-4, IL-8, IL-18, Fcγ, COX-2, MMP-2, MMP-3 (aggressive), MMP-8, and MMP-9 (aggressive) polymorphisms had no significant association with risk of developing periodontitis.


Clinical aspects of juvenile and adult ankylosing spondylitis.
Ankylosing spondylitis (AS) is a heterogeneous and systemic rheumatic disorder that is characterized primarily by inflammation of the spine and sacroiliac joints. Consequently, back pain is a frequent presenting complaint although the disease can begin with peripheral arthritis as well as acute anterior uveitis. Unlike men, however, women appear to have milder or atypical AS that may go unrecognized for years. Moreover, the presentation in children rests on the recognition of two distinct subgroups that may be indistinguishable from juvenile chronic polyarthritis. The more frequent subgroup includes primarily teenage boys who present initially with an asymmetric peripheral pauciarthritis that most often affects lower-limb joints. Only some years later does sacroiliitis evolve, and, much later still, back complaints or other clinical and radiographic features typical of AS. A second subgroup includes mostly girls with a polyarticular onset that is subsequently characterized by cervical fusion, micrognathia, acute anterior uveitis, sacroiliitis, spondylitis, and rheumatoid-like hands that persist into adulthood.


Automated cytochemistry in the prediction of remission following chemotherapy of patients with de novo acute myeloblastic leukemia.
In seven patients with de novo acute myeloblastic leukemia, the concentration of large unstained cells (LUC) in peripheral blood and the ratio between this quantity and the concentration of lymphocytes (LUC/LYMPH) were measured at short intervals during each patient's clinical course. An automated differential analyzer (the Hemalog-D) was used. Both quantities were significantly higher 12 days after the institution of daunomycin and cytosine arabinoside chemotherapy (between first and second treatment series when all patients were pancytopenic) in three of the patients who did not achieve remission (mean LUC = 59 cells/microliter, mean LUC/LYMPH = 13.9), as compared with four of the patients who went into remission following two series of chemotherapy (mean LUC = 16 cells/microliter, mean LUC/LYMPH = 3.11).


Lymphatic drainage in the muscle and subcutis of the arm after breast cancer treatment.
Breast cancer-related lymphoedema of the arm (BCRL) results from impaired lymph drainage after axillary surgery. Little is known about lymphatic changes in the arm between surgery and oedema onset. We measured forearm muscle and subcutis lymph drainage in 36 women at 7 and 30 months after surgery by quantitative lymphoscintigraphy. None had BCRL initially but 19% had BCRL by 30 months. At 7 months muscle and subcutis drainage in both arms of BCRL-destined women exceeded that of non-BCRL women (P < 0.01). Muscle lymph drainage always exceeded subcutis drainage (P < 0.0001). Muscle lymph drainage in the ipsilateral arm was unimpaired relative to the contralateral arm. BCRL therefore developed in women with higher peripheral lymph flows. The major lymphatic load was generated by muscle; there was no pre-BCRL lymphatic impairment in the muscle of the ipsilateral arm. We propose that some women have a defined, constitutive predisposition to secondary lymphoedema. Specifically, women with higher filtration rates, and therefore higher lymph flows through the axilla that are closer to the maximum sustainable, are at greater risk of BCRL following axillary trauma, even following removal of 1-2 nodes.


[Complement and its role in immune response].
The complement system as a part of innate immunity is considered to provide rapid tough incomplete antimicrobial activity. However, besides providing a first-line defence, innate immunity plays additional important roles: it initiates and improves the slower, but more specific, acquired immune response. The recognition and destruction of noxious substances, as well as initiation of the acquired immune response, are accompanied by potentially hazardous inflammation. The inflammatory process has thus to be tightly regulated. In this overview, innate immunity and its interactions with acquired immunity are discussed with the main focus on the complement system. Our scientific interests are integrated into the discussion on complement.


The complete mitogenome of Achalarus lyciades (Lepidoptera: Hesperiidae).
We obtained a complete mitochondrial genome of a skipper butterfly Achalarus lyciades (Hesperiidae, Eudaminae) from next generation sequencing reads. The 15,612 bp mitogenome covers 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes (rRNAs), and an A+T rich region. Its gene order is typical for mitogenomes of Lepidoptera. Phylogenetic analysis placed A. lyciades as a sister to Lobocla bifasciatus, the only other Eudaminae with available mitogenome.


[Predictive value of procalcitonin in postoperative intra-abdominal infections after definitive operation of intestinal fistulae].
To investigate the predictive value of procalcitonin(PCT) in postoperative intra-abdominal infections (IAI) after definitive operation of intestinal fistulae(IF). With the exclusion of emergence operation, preoperative clinical infection, preoperative renal or hepatic dysfunction, and age less than 18 years, a total of 356 consecutive patients who underwent elective digestive tract reconstruction of intestinal fistulae from February 2012 to December 2015 at Intestinal Fistula Center of Jinling Hospital were prospectively enrolled in the study. All the patients were divided into IAI group (26 cases, 21 of anastomosis leakage and 5 of peritoneal abscess) and non-IAI group (330 cases) based on the existence of postoperative IAI. The non-IAI group was then divided into two subgroups of other infection (93 cases) and non-infection(237 cases) according to the presence of other infections. Plasma PCT level, serum CRP concentration and WBC count were assessed preoperatively and on postoperative days (PODs) 1, 3, 5, 7 by immunofluorescence, turbidimetry and automatic blood analyzer, respectively. The predictive value of each marker for IAI was calculated by receiver operating characteristic (ROC) curve. There was no significant difference in general clinical data between IAI and non-IAI group (all P>0.05). The proportions of multi-IF (53.8%, 14/26) and colectomy (61.5%, 16/26) in IAI group were higher than those of non-IAI group [20.0% (66/330), χ2=15.847, P=0.000 and 31.2%(103/330), χ2=9.961, P=0.002]. Differences of preoperative PCT, CRP and WBC levels among IAI, other infection and non-infection groups were not significant. These three markers all increased obviously and immediately after surgery. PCT and WBC values reached the peak point on POD 1, whereas CRP on POD 3. In IAI group, mean PCT values were (5.4±4.2) μg/L, (2.9±1.9) μg/L and (1.6±1.8) μg/L on POD 1, POD 3 and POD 5, respectively, which were higher than those of other infection group [(4.2±8.7) μg/L, (1.9±3.8) μg/L and (0.6±0.8) μg/L] and non-infection group [(2.7±5.8) μg/L, (1.1±1.7) μg/L and (0.5±0.7) μg/L, all P<0.05]. Mean CRP values in IAI group were 99.4 mg/L and 183.9 mg/L respectively on POD 1 and POD 3,and mean WBC values of IAI group on POD 1, POD 3 and POD 5 were 16.0×109/L, 10.8×109/L and 8.7×109/L, respectively, which were all significantly higher than those in the other 2 groups (all P<0.05). No significant differences were obtained between other infection group and non-infection group in all these three markers (all P>0.05). ROC curve demonstrated that PCT had the biggest area under the curve (AUC) of 0.86 and 0.84 on POD 3 and POD 5, with the cut-off value of 0.98 μg/L and 0.83 μg/L, 92.0% sensitivity and 74.0% specificity, 91.0% sensitivity and 73.0% specificity, respectively. The highest AUC was 0.72 on POD 3 for CRP and 0.71 on POD 3 for WBC, with 80.0% sensitivity and 54.0% specificity, 56.0% sensitivity and 73.0% specificity, respectively. The value of procalcitonin above 0.98 μg/L on POD 3 and 0.83 μg/L on POD 5 can predict the occurrence of IAI after definitive operations of intestinal fistulae.


Clinical Ethics Consultations in the Opinion of Polish Physicians.
Clinical Ethics Consultations (CEC) are an important tool for physicians in solving difficult cases. They are extremely common in North America and to a lesser extent also present in Europe. However, there is little data on this practice in Poland. We present results of a survey of 521 physicians practising in Poland concerning their opinion on CECs and related practices. We analysed the data looking at such issues as CECs' perceived availability, use of CECs, and perceived usefulness of such support. Physicians in our study generally encounter hard ethics cases, even-surprisingly-those who do not work in hospitals. Most physicians have no CEC access, and those that do still do not employ CECs. However, physicians perceive this form of support as useful-even more so among actual users of CECs. We compared these findings with similar studies from other European countries and the North America. We point out peculiarities of our results as compared to those in other countries, with some possible explanations. We hope the results may encourage regulatory debate on the need to formally introduce CECs into the Polish healthcare system.


HATH1 expression in mucinous cancers of the colorectum and related lesions.
Mucinous cancers and signet ring carcinomas are distinct classes of colon cancers characterized by their production of copious quantities of intestinal goblet cell mucin, MUC2. Deletion of transcription factor HATH1 ablates the biogenesis of goblet cells in developing mouse intestine, and forced expression of HATH1 results in elevated expression of MUC2 in colon cancer cells. The aim of this study was to assess the possible role of HATH1 in the development of mucinous cancers and signet ring carcinomas. Immunohistochemistry and confocal microscopy was used to examine HATH1 expression and subcellular distribution in normal colon and small intestine, mucinous cancers, signet ring carcinomas, and nonmucinous cancers and in precursor lesions, including hyperplastic polyps, serrated adenomas, tubular adenomas, and villous adenomas. We also analyzed the transactivation of MUC2 promoter/reporter constructs by a HATH1 expression vector. HATH1 expression transactivated MUC2 promoter/reporter constructs, an activity that was significantly inhibited by mutation of putative HATH1-binding sites. HATH1 was expressed in the nuclei of goblet cells and in the cytoplasm and nuclei of enteroendocrine cells of the colon. In the small intestine, only cytoplasmic expression of HATH1 in enteroendocrine cells was detected. HATH1 was found to be strongly expressed in the nuclei of hyperplastic polyps, serrated adenomas, villous adenomas, mucinous cancers, and signet ring carcinomas but repressed in nonmucinous cancers and tubular adenomas. This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas. In addition, the expression of HATH1 in hyperplastic polyps, serrated adenomas, and villous adenomas lends support to the hypothesis that these neoplasms are frequent precursors in mucinous cancer and signet ring carcinoma development.


Innovation technology opportunity identification of civil aircraft mechanical connections based on generative topographic mapping.
In order to advance civil aircraft manufacturing to higher levels, there is an urgent need to identify technological innovation opportunities to help new technology development. This paper first analyses the current state of the research field and determines the topic. It preprocesses papers and patents within the research topic to obtain a base database. Then, the database is analyzed using the LDA (Latent Dirichlet Analysis) cluster analysis method. The TF-IDF (Term Frequency-Inverse Document Frequency) algorithm processes the data to obtain critical technical words. The abstracts of patents and papers are processed to construct a binary-based vector of technical keywords. The papers and patents are visualized in a two-dimensional space technology map by generative topographic mapping (GTM) to create a technology map to identify technology blank dots. The combination of technologies characterized by each technology blank dot is obtained by GTM inverse mapping. Finally, technology opportunities with a high probability of development are identified to achieve innovation opportunity identification. It also provides countermeasures for the research institution, enterprise, sector, and industry. After research and analysis, the future in the mechanical connection technology of civil aircraft is necessary to strengthen basic technology development and improve the study of intelligence, integration, and flexibility. Technology such as sensors and lasers can improve the precision and efficiency of mechanical connections.


Identification of the patient at risk in the physician's office and drug management of dyslipoproteinemia.
The wealth of convincing evidence favouring the major role of lipids in atherosclerosis and the benefit of lipid lowering therapy for its prevention now sets the stage for more practical questions: "Whom to treat? When to treat? How to treat?". Although each patient must be considered individually, there are general rules and specific guidelines that should be underlined. An isolated finding of abnormal lipid levels should by no means be a systematic starting point for initiating treatment. In a step by step approach, guidelines for individual risk assessment, systematic search for specific clinical clues and pertinence of complementary investigative measures are given. In addition to ensuring a correct diagnosis, these recommendations will orient the physician's decision with respect to the necessity of initiating treatment and, if warranted, the choice of an optimal treatment algorithm. Therapeutic modalities are discussed both in general and specific terms, focusing mostly on pharmacologic agents. Clinical indications, mechanisms of action, adverse effects and expected efficacy are seen for each drug or family of drugs, including those with a promising future. In summary, 10 easy rules of thumb are provided to ensure adequate diagnosis and management of hyperlipidemia.


Predicting Current Glycated Hemoglobin Levels in Adults From Electronic Health Records: Validation of Multiple Logistic Regression Algorithm.
Electronic health record (EHR) systems generate large datasets that can significantly enrich the development of medical predictive models. Several attempts have been made to investigate the effect of glycated hemoglobin (HbA1c) elevation on the prediction of diabetes onset. However, there is still a need for validation of these models using EHR data collected from different populations. The aim of this study is to perform a replication study to validate, evaluate, and identify the strengths and weaknesses of replicating a predictive model that employed multiple logistic regression with EHR data to forecast the levels of HbA1c. The original study used data from a population in the United States and this differentiated replication used a population in Saudi Arabia. A total of 3 models were developed and compared with the model created in the original study. The models were trained and tested using a larger dataset from Saudi Arabia with 36,378 records. The 10-fold cross-validation approach was used for measuring the performance of the models. Applying the method employed in the original study achieved an accuracy of 74% to 75% when using the dataset collected from Saudi Arabia, compared with 77% obtained from using the population from the United States. The results also show a different ranking of importance for the predictors between the original study and the replication. The order of importance for the predictors with our population, from the most to the least importance, is age, random blood sugar, estimated glomerular filtration rate, total cholesterol, non-high-density lipoprotein, and body mass index. This replication study shows that direct use of the models (calculators) created using multiple logistic regression to predict the level of HbA1c may not be appropriate for all populations. This study reveals that the weighting of the predictors needs to be calibrated to the population used. However, the study does confirm that replicating the original study using a different population can help with predicting the levels of HbA1c by using the predictors that are routinely collected and stored in hospital EHR systems.


YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment.
CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.


Biomarkers in neuroendocrine neoplasms.
Neuroendocrine tumors are a heterogenous group of rare neoplasms with different morphological features, immunophenotype, molecular profile, and clinical presentation. They can derive from any neuroendocrine cell throughout the body, but the majority of NENs is developed in the gastrointestinal tract. They can be divided into two groups, based on hormone secretion, functioning and non-functioning NENs. The first group is characterised from the secretion of specific substances, defining the clinical manifestations. Functional NENs can be divided into carcinoid tumors, with serotonin overproduction, and functional GEP NEN's (mostly located in pancreas) that may secrete insulin, VIP, gastrin, glucagon or somatostatin. Non-functioning NENs, comprise approximately 85% of NEN's. As these tumors lack specific symptoms, they come to clinical attention later, when they have a large size or metastases. Apart from the specific biomarkers that functional NENs are producing, there are some general markers that are produced from all NENs and play a major role in the diagnosis, prognosis and follow up of these patients. These are chromogranin (CgA), neuron-specific enolase (NSE) and 5-hydroxyindolic acetic acid (5-HIAA).


ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress.
Endothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. The molecular mechanism for endothelial dysfunction in the heart is still not clearly understood. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury. ECs were treated with ischemic insults (lipopolysaccharide and 1% hypoxia) to determine the role of ALKBH5 in ECs angiogenesis. siRNA mediated ALKBH5 gene silencing was used for examining the loss of function. In this study, we report that ALKBH5 levels are upregulated following ischemia and are associated with maintaining ischemia-induced ECs angiogenesis. To decipher the mechanism of action, we found that ALKBH5 is required to maintain eNOS phosphorylation and SPHK1 protein levels. ALKBH5 silencing alone or with ischemic stress significantly increased SPHK1 m6A mRNA methylation. In contrast, METTL3 (RNA methyltransferase) overexpression resulted in the reduced expression of SPHK1. We reported that ALKBH5 helps in the maintenance of angiogenesis in endothelial cells following acute ischemic stress via reduced SPHK1 m6A methylation and downstream eNOS-AKT signaling.


Socio-Economic Position and Suicidal Ideation in Men.
People in low socio-economic positions are over-represented in suicide statistics and are at heightened risk for non-fatal suicidal thoughts and behaviours. Few studies have tried to tease out the relationship between individual-level and area-level socio-economic position, however. We used data from Ten to Men (the Australian Longitudinal Study on Male Health) to investigate the relationship between individual-level and area-level socio-economic position and suicidal thinking in 12,090 men. We used a measure of unemployment/employment and occupational skill level as our individual-level indicator of socio-economic position. We used the Index of Relative Socio-Economic Disadvantage (a composite multidimensional construct created by the Australian Bureau of Statistics that combines information from a range of area-level variables, including the prevalence of unemployment and employment in low skilled occupations) as our area-level indicator. We assessed suicidal thinking using the Patient Health Questionnaire (PHQ-9). We found that even after controlling for common predictors of suicidal thinking; low individual-level and area-level socio-economic position heightened risk. Individual-level socio-economic position appeared to exert the greater influence of the two; however. There is an onus on policy makers and planners from within and outside the mental health sector to take individual- and area-level socio-economic position into account when they are developing strategic initiatives.


Aquaporin 3 promotes prostate cancer cell motility and invasion via extracellular signal-regulated kinase 1/2-mediated matrix metalloproteinase-3 secretion.
Aquaporins (AQPs) are known to be important in cancer progression. The present study used a cDNA microarray to demonstrate that AQP3, a member of the AQP family, was overexpressed in prostate cancer cells. In order to determine the role of AQP3 in prostate cancer, AQP3 expression was silenced by transfection with small interfering RNA, following which wound healing and invasion assays were conducted in DU‑145 and PC‑3 cells. Notably, the results showed that silencing of AQP3 suppressed prostate cancer cell motility and invasion. The possible mechanisms underlying the AQP3‑enhanced motility and invasion of prostate cancer cells was also investigated. Knockdown of AQP3 expression was shown to reduce extracellular signal‑regulated kinase 1/2 (ERK1/2) activation in DU‑145 and PC‑3 cells. Blocking the ERK pathway inhibited AQP3‑mediated motility and invasion of these cells. Finally, the results demonstrated that AQP3 upregulated matrix metalloproteinase‑3 (MMP‑3) expression and secretion in prostate cancer cells via activation of the ERK pathway. In conclusion, the present study suggests that AQP3 induces ERK1/2 activation, thereby increasing MMP‑3 expression and secretion, which in turn promotes prostate cancer cell motility and invasion. Thus, AQP3 may be considered to be a potential therapeutic target for prostate cancer.


Roentgen findings in occipital pole tumors.
The arteriographic findings of occipital pole tumors consist of the following:1. Anterior displacement and elevation of the middle cerebral group.2. "Accordioning" of the anterior choroidal artery.3. Anterior displacement of the lateral branch of the posterior choroidal artery.4. Local stretching of vessels about the tumor.5. "Onion skinning" of the pial vessels.6. Anterior displacement of the vein of the occipital horn.7. Greater displacement of the internal cerebral vein than of the anterior cerebral artery. Air studies require precise radiographic technique lest the subtle displacements of the occipital horn and trigone area be missed.


Vesicular Delivery of the Antifungal Antibiotics of Lysobacter enzymogenes C3.
Lysobacter enzymogenes C3 is a predatory strain of Gram-negative gliding bacteria that produces antifungal antibiotics by the polyketide synthetic pathway. Outer membrane vesicles (OMV) are formed as a stress response and can deliver virulence factors to host cells. The production of OMV by C3 and their role in antifungal activity are reported here. Vesicles in the range of 130 to 150 nm in diameter were discovered in the cell-free supernatants of C3 cultures. These OMV contain molecules characteristic of bacterial outer membranes, such as lipopolysaccharide and phospholipids. In addition, they contain chitinase activity and essentially all of the heat-stable antifungal activity in cell supernatants. We show here that C3 OMV can directly inhibit growth of the yeast Saccharomyces cerevisiae as well as that of the filamentous fungus Fusarium subglutinans The activity is dependent on physical contact between OMV and the cells. Furthermore, fluorescent lipid labeling of C3 OMV demonstrated transfer of the membrane-associated probe to yeast cells, suggesting the existence of a mechanism of delivery for membrane-associated molecules. Mass spectrometric analysis of C3 OMV extracts indicates the presence of molecules with molecular weights identical to some of the previously identified antifungal products of C3. These data together suggest that OMV act as an important remote mobile component of predation by LysobacterIMPORTANCE The data presented here suggest a newly discovered function of outer membrane vesicles (OMV) that are produced from the outer membrane of the bacterial species Lysobacter enzymogenes strain C3. We show that these OMV can be released from the surface of the cells to deliver antibiotics to target fungal organisms as a mechanism of killing or growth inhibition. Understanding the role of OMV in antibiotic delivery can generally lead to improved strategies for dealing with antibiotic-resistant organisms. These results also add to the evidence that some bacterially produced antibiotics can be discovered and purified using methods designed for isolation of nanoscale vesicles. Information on these systems can lead to better identification of active molecules or design of delivery vehicles for these molecules.


[Voluminous hypothalamic hamartoma in a 5-month-old boy: Epilepsy and surgery].
The authors report the case of 5-month-old boy with a hypothalamic hamartoma and persistent gelastic seizures in spite of a wide combination of different antiepileptic drugs. It was decided to carry out only partial removal of the tumor for decompression and to decreasing the activity of the epileptogenic focus. Surgical therapy revealed as a valid option in the treatment of the uncontrollable gelastic seizures.


Immune Response And Anamnestic Immune Response In Children After A 3-Dose Primary Hepatitis B Vaccination.
Diseases caused by Hepatitis B virus (HBV) have a worldwide distribution. Pakistan adopted the recommendations of World Health Organization (WHO) for routine universal infant vaccination against hepatitis B in 2002, currently being administered at 6, 10, and 14 weeks of age in a combination vaccine. This study was conducted to determine the immune response & anamnestic immune response in children, 9 months-10 years of age, after a 3dose primary Hepatitis B vaccination. This cross sectional study was conducted in the Department of Paediatrics, King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from January to June, 2014. A total of 200 children of either sex between the ages of 9 months to 10 years, documented to have received 3 doses of hepatitis B vaccines according to Expanded Program of Immunization (6,10,14 weeks) schedule in infancy, were recruited by consecutive sampling. The level of serum antiHBsAb by ELIZA was measured. Children with antiHBs titers ≥10 mIU/mL were considered to be immune. Those with anti HBsAb levels <10 mIU/mL were offered a booster dose of infant recombinant hepatitis B vaccine. The second serum sample was obtained 21-28 days following the administration of the booster dose and the anamnestic immune response was measured. Data was analysed using SPSS 17 to determine the relation between time interval since last vaccination and antibody titer. Chi square test was applied. Of the 200 children, protective antibody response was found in 58%. Median serological response was 18.60 (range 2.82 - 65.15). Antibody levels were found to have a statistically significant ( pvalue 0.019) negative correlation with the time since last administration of vaccine. A booster dose of Hepatitis B vacci ne was administered to all nonresponders, with each registering a statistically significant (pvalue 0.00) anamnestic response. The vaccination schedule with short dosage interval was unable to provide protection to 42% of the study population. Introduction of birth dose of Hepatitis B vaccine to the existing schedule is recommended.


Trafficking of immature DeltaF508-CFTR to the plasma membrane and its detection by biotinylation.
Recent studies suggest that immature, core-glycosylated DeltaF508-CFTR [the predominant mutant form of the CFTR (cystic fibrosis transmembrane conductance regulator)] can reach the plasma membrane under some conditions. In the present study we investigated this possibility since it has implications for understanding how therapeutics rescue the trafficking of mutant CFTR and perhaps other misfolded proteins. Core-glycosylated CFTR was labelled and pulled down on streptavidin beads after exposure to sulfo-NHS-SS-biotin [biotin attached to a reactive NHS (N-hydroxysuccinimide) ester with a disulfide spacer; molecular mass=606.7 Da]; however, intracellular proteins were also detected in the precipitates. When the R domain of CFTR was expressed in the cytosol of BHK (baby-hamster kidney) cells as a soluble polypeptide it was also labelled after surface biotinylation and pulled down on streptavidin beads. Intracellular biotinylation was reduced when cells were treated with sulfo-NHS-LC-biotin (biotin attached to a reactive NHS ester with an aminocaproic acid spacer) or sulfo-NHS-PEO(12)-biotin [biotin attached to a reactive NHS ester with a poly(ethylene glycol) spacer], but the reduction could be explained by the lower reactivity of these reagents. The R domain was detected on Western blots after loading <0.25% of the pulldown sample ( approximately 0.01% of total lysate protein), a fraction that could be ascribed to cells that were permeable to ethidium homodimer-1 (molecular mass=856.8 Da) and propidium iodide (molecular mass=668.6 Da). When BHK cells were incubated at 29 degrees C to rescue DeltaF508-CFTR trafficking, and then biotinylated and sorted to remove permeable cells, labelling of core-glycosylated DeltaF508-CFTR was no longer detected although a weak signal was still observed using CFBE (cystic fibrosis bronchial epithelial) cells. These results suggest that there is weak surface expression of immature DeltaF508-CFTR on airway epithelial cells and demonstrate the need to remove permeable cells when studying CFTR glycoforms by surface biotinylation.


p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light.
The Japanese have a much lower incidence of nonmelanoma skin cancers (NMSCs) than Caucasians, presumably due in part to their skin type conferring relative protection from ultraviolet light radiation (UVR). To examine the contribution of environmental or endogenous mutagens other than UVR, which are expected to be relatively more important to the overall burden of NMSCs in the Japanese, we directly sequenced exons 5-8 of the p53 tumour suppressor gene in 29 Japanese patients with Bowen's disease, an in situ squamous-cell carcinoma of the skin. We found 9 mutations, including two CC:GG to TT:AA tandem transitions (presumably related to UVR), 3 transversions and 4 frameshift mutations. The mutational spectrum seen in our study contrasts with that we previously found in Bowen's disease from a Caucasian population, in keeping with a different aetiology for Bowen's disease in the respective populations. The unexpectedly high prevalence of frameshift mutations suggests that environmental mutagens other than UVR that preferentially induce deletion or insertion mutations may play an important role in the tumorigenesis of Japanese Bowen's disease, and warrants further investigation.


Comparative teratogenicity of selected glucocorticoids applied ocularly in mice.
Three glucocorticoids (dexamethasone, hydrocortisone, and prednisolone), were ocularly applied to pregnant CD-1 mice on days 10-13 of gestation. The drug concentrations were various multiples of the common therapeutic dose levels and were applied to both eyes in 1 microliter drops five times a day. Eighteen-day fetuses were examined for malformations. A significant increase in the incidence of cleft palate was observed in fetuses treated with each of these glucocorticoids. There appeared to be a dose related effect on cleft palate width among fetuses from both dexamethasone and prednisolone treated dams. The incidence of sex organ anomalies, although lower than the incidence of cleft palate, also showed a positive dose relationship. Analysis of variance was used to compare the teratogenic effects of these glucocorticoids ocularly applied in equipotent anti-inflammatory concentrations. Our results indicate that dexamethasone produces a higher incidence of cleft palate, than either of the other two drugs when given in equipotent concentrations. It appears that the teratogenic potency of these ocularly applied glucocorticoids cannot be predicted on the basis of anti-inflammatory potency.


A simple and highly reproducible method for the detection of erythrocyte membrane ZIP metal transporters by immunoblotting.
Manganese is one of the essential trace elements found in erythrocytes. Metal transporters situated on the plasma membrane generally facilitate the movement of manganese into and out of cells. This study aims at determining whether two recently discovered manganese importers, ZIP8 and ZIP14, are located in the erythrocyte membrane. We outline a simple, effective and repeatable method for the isolation of erythrocyte membrane from a minimum of 50 µL mouse blood, followed by the identification of ZIP metal transporters using immunoblotting. Our results revealed that ZIP8 is expressed within the erythrocyte membrane, in contrast to ZIP14 which is not identified using immunoblotting approach. A direct measurement of the ZIP8 protein expression in erythrocyte membranes could provide valuable information for further analyzing its biological function.


Ghrelin did not change coronary angiogenesis in diet-induced obese mice.
Ghrelin is a 28 amino acids peptide that initially was recognized as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Recently, a number of studies demonstrated that ghrelin is a cardiovascular hormone with a series cardiovascular effect. The main objective of this study was to investigate the effect of systemic ghrelin administration on angiogenesis in the heart and its correlation with serum leptin levels in normal and diet-induced obese mice. 24 male C57BL/6 mice were randomly divided into four groups: normal diet (ND) or control, ND+ghrelin, high-fat-diet (HFD) or obese and HFD+ghrelin (n=6/group). Obese and control groups received HFD or ND, respectively, for 14 weeks. Then, the ghrelin was injected subcutaneously 100µg/kg twice daily. After 10 days, the animals were sacrificed, blood samples were taken and the hearts were removed. The angiogenic response in the heart was assessed by immunohisochemical staining. HFD significantly increased angiogenesis in the heart expressed as the number of CD31 positive cells than standard diet. Ghrelin did not alter angiogenesis in the heart in both obese and control groups, however, it reduced serum nitric oxide (NO) and leptin levels in obese mice. There was a strong positive correlation between the number of CD31 positive cells and serum leptin concentration (r=0.74). Leptin as an angiogenic factor has a positive correlation with angiogenesis in the heart. Although systemic administration of ghrelin reduced serum leptin and NO levels in obese mice, however, it could not alter coronary angiogenesis.


Influence of Rock Mineralogy on Reactive Fracture Evolution in Carbonate-Rich Caprocks.
Fractures present environmental risks for subsurface engineering activities, such as geologic storage of greenhouse gases, because of the possibility of unwanted upward fluid migration. The risks of fluid leakage may be exacerbated if fractures are subjected to physical and chemical perturbations that alter their geometry. This study investigated this by constructing a 2D fracture model to numerically simulate fluid flow, acid-driven reactions, and mechanical deformation. Three rock mineralogies were simulated: a limestone with 100% calcite, a limestone with 68% calcite, and a banded shale with 34% calcite. One might expect transmissivity to increase fastest for rocks with more calcite due to its high solubility and fast reaction rate. Yet, results show that initially transmissivity increases fastest for rocks with less calcite because of their ability to deliver unbuffered-acid downstream faster. Moreover, less reactive minerals become persistent asperities that sustain mechanical support within the fracture. However, later in the simulations, the spatial pattern of less reactive mineral, not abundance, controls transmissivity evolution. Results show that a banded mineral pattern creates persistent bottlenecks, prevents channelization, and stabilizes transmissivity. For sites for geologic storage of CO2 that have carbonate caprocks, banded mineral variation may limit reactive evolution of fracture transmissivity and increase storage reliability.


The microbial sulfur cycle at extremely haloalkaline conditions of soda lakes.
Soda lakes represent a unique ecosystem with extremely high pH (up to 11) and salinity (up to saturation) due to the presence of high concentrations of sodium carbonate in brines. Despite these double extreme conditions, most of the lakes are highly productive and contain a fully functional microbial system. The microbial sulfur cycle is among the most active in soda lakes. One of the explanations for that is high-energy efficiency of dissimilatory conversions of inorganic sulfur compounds, both oxidative and reductive, sufficient to cope with costly life at double extreme conditions. The oxidative part of the sulfur cycle is driven by chemolithoautotrophic haloalkaliphilic sulfur-oxidizing bacteria (SOB), which are unique for soda lakes. The haloalkaliphilic SOB are present in the surface sediment layer of various soda lakes at high numbers of up to 10(6) viable cells/cm(3). The culturable forms are so far represented by four novel genera within the Gammaproteobacteria, including the genera Thioalkalivibrio, Thioalkalimicrobium, Thioalkalispira, and Thioalkalibacter. The latter two were only found occasionally and each includes a single species, while the former two are widely distributed in various soda lakes over the world. The genus Thioalkalivibrio is the most physiologically diverse and covers the whole spectrum of salt/pH conditions present in soda lakes. Most importantly, the dominant subgroup of this genus is able to grow in saturated soda brines containing 4 M total Na(+) - a so far unique property for any known aerobic chemolithoautotroph. Furthermore, some species can use thiocyanate as a sole energy source and three out of nine species can grow anaerobically with nitrogen oxides as electron acceptor. The reductive part of the sulfur cycle is active in the anoxic layers of the sediments of soda lakes. The in situ measurements of sulfate reduction rates and laboratory experiments with sediment slurries using sulfate, thiosulfate, or elemental sulfur as electron acceptors demonstrated relatively high sulfate reduction rates only hampered by salt-saturated conditions. However, the highest rates of sulfidogenesis were observed not with sulfate, but with elemental sulfur followed by thiosulfate. Formate, but not hydrogen, was the most efficient electron donor with all three sulfur electron acceptors, while acetate was only utilized as an electron donor under sulfur-reducing conditions. The native sulfidogenic populations of soda lakes showed a typical obligately alkaliphilic pH response, which corresponded well to the in situ pH conditions. Microbiological analysis indicated a domination of three groups of haloalkaliphilic autotrophic sulfate-reducing bacteria belonging to the order Desulfovibrionales (genera Desulfonatronovibrio, Desulfonatronum, and Desulfonatronospira) with a clear tendency to grow by thiosulfate disproportionation in the absence of external electron donor even at salt-saturating conditions. Few novel representatives of the order Desulfobacterales capable of heterotrophic growth with volatile fatty acids and alcohols at high pH and moderate salinity have also been found, while acetate oxidation was a function of a specialized group of haloalkaliphilic sulfur-reducing bacteria, which belong to the phylum Chrysiogenetes.


Ag2Hg2(TeO4)3.
Red single crystals of disilver(I) dimercury(II) tris[tetraoxotellurate(VI)], Ag2Hg2(TeO4)3, were obtained under hydrothermal conditions at 523 K. The structure is built up of infinity1[(TeO2/1O4/2)({TeO2/1O2/2}2O4/2)] chains, with an overall composition [TeO4]2-, that run parallel to the crystallographic a axis. Distorted AgO6 and HgO6 polyhedra (the latter with two short and nearly collinear Hg-O bonds) link the tellurate chains into a three-dimensional network. Except for one Te atom situated on an inversion center, all atoms occupy general positions.


Design and Characterization of Phosphatidylcholine-Based Solid Dispersions of Aprepitant for Enhanced Solubility and Dissolution.
This study aimed to improve the solubility and dissolution of aprepitant, a drug with poor aqueous solubility, using a phosphatidylcholine (PC)-based solid dispersion system. When fabricating the PC-based solid dispersion, we employed mesoporous microparticles, as an adsorbent, and disintegrants to improve the sticky nature of PC and dissolution of aprepitant, respectively. The solid dispersions were prepared by a solvent evaporation technique and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry, and X-ray powder diffraction. The FTIR results showed that aprepitant interacted with the PC carrier by both hydrogen bonds and van der Waals forces that can also be observed in the interaction between aprepitant and polymer carriers. The solid dispersions fabricated with only PC were not sufficient to convert the crystallinity of aprepitant to an amorphous state, whereas the formulations that included adsorbent and disintegrant successfully changed that of aprepitant to an amorphous state. Both the solubility and dissolution of aprepitant were considerably enhanced in the PC-based solid dispersions containing adsorbent and disintegrant compared with those of pure aprepitant and polymer-based solid dispersions. Therefore, these results suggest that our PC-based solid dispersion system is a promising alternative to conventional formulations for poorly water-soluble drugs, such as aprepitant.


Eye pathology and low vision aids.
The primary cause of impaired vision was retinal pathology for 414 (83%) patients, optic nerve pathology (including glaucoma) for 33 patients (7%), other pathology for 53 (11%) patients. The following optical aids were prescribed: 35 distant spectacle corrections, 159 high-add bifocals, five high-add trifocals, 52 full-size magnifying spectacles, 102 half-eye magnifying spectacles, four stand magnifiers, and 44 paperweight type magnifiers. Of 193 patients evaluated, 122 (63%) were considered to have success with the aid prescribed.


Natural History of Invasive Papillary Breast Carcinoma Followed for 10 Years: A Case Report and Literature Review.
Diachronic research on untreated breast cancer completely depends on past medical records when no more recent, advanced methods are available. Herein, we report a case of invasive papillary breast carcinoma followed for 10 years in a 59-year-old woman who refused any treatment. The diagnosis was based on core needle biopsies. At the patient's first visit in July 2006, the tumor measured 10.4 × 7.2 × 3.5 cm. It was staged as IIIB (T4bN1). In May 2016, the tumor was staged as IIIC (T4bN3a). In the past 10 years, the tumor has increased to 12.1 × 9.0 × 4.2 cm. However, a whole-body bone scan and 18F-FDG PET/CT showed no evidence of distant metastasis. Immunohistochemistry results, corresponding to biopsies taken at subsequent examinations, have remained unaltered since 2006. The tumor was estrogen/progesterone receptor-positive and C-erbB2 expression was not detected. The Ki-67 labeling index was around 10%.


Reframing anorexia nervosa as a metabo-psychiatric disorder.
Anorexia nervosa (AN) is a serious and often fatal illness. Despite decades of research, investigators have failed to adequately advance our understanding of the biological aspects of AN that could inform the development of effective interventions. Genome-wide association studies are revealing the important role of metabolic factors in AN, and studies of the gastrointestinal tract are shedding light on disruptions in enteric microbial communities and anomalies in gut morphology. In this opinion piece, we review the state of the science through the lens of the clinical presentation of illness. We project how the integration of rigorous science in genomics and microbiology, in collaboration with experienced clinicians, has the potential to markedly enhance treatment outcome via precision interventions.