Accurate Physical Property Predictions via Deep Learning.
Neural networks and deep learning have been successfully applied to tackle problems in drug discovery with increasing accuracy over time. There are still many challenges and opportunities to improve molecular property predictions with satisfactory accuracy even further. Here, we proposed a deep-learning architecture model, namely Bidirectional long short-term memory with Channel and Spatial Attention network (BCSA), of which the training process is fully data-driven and end to end. It is based on data augmentation and SMILES tokenization technology without relying on auxiliary knowledge, such as complex spatial structure. In addition, our model takes the advantages of the long- and short-term memory network (LSTM) in sequence processing. The embedded channel and spatial attention modules in turn specifically identify the prime factors in the SMILES sequence for predicting properties. The model was further improved by Bayesian optimization. In this work, we demonstrate that the trained BSCA model is capable of predicting aqueous solubility. Furthermore, our proposed method shows noticeable superiorities and competitiveness in predicting oil-water partition coefficient, when compared with state-of-the-art graphs models, including graph convoluted network (GCN), message-passing neural network (MPNN), and AttentiveFP.


Linking Soil Microbial Diversity to Modern Agriculture Practices: A Review.
Agriculture is a multifarious interface between plants and associated microorganisms. In contemporary agriculture, emphasis is being given to environmentally friendly approaches, particularly in developing countries, to enhance sustainability of the system with the least negative effects on produce quality and quantity. Modern agricultural practices such as extensive tillage, the use of harmful agrochemicals, mono-cropping, etc. have been found to influence soil microbial community structure and soil sustainability. On the other hand, the question of feeding the ever-growing global population while ensuring system sustainability largely remains unanswered. Agriculturally important microorganisms are envisaged to play important roles in various measures to raise a healthy and remunerative crop, including integrated nutrient management, as well as disease and pest management to cut down agrochemicals without compromising the agricultural production. These beneficial microorganisms seem to have every potential to provide an alternative opportunity to overcome the ill effects of various components of traditional agriculture being practiced by and large. Despite an increased awareness of the importance of organically produced food, farmers in developing countries still tend to apply inorganic chemical fertilizers and toxic chemical pesticides beyond the recommended doses. Nutrient uptake enhancement, biocontrol of pests and diseases using microbial inoculants may replace/reduce agrochemicals in agricultural production system. The present review aims to examine and discuss the shift in microbial population structure due to current agricultural practices and focuses on the development of a sustainable agricultural system employing the tremendous untapped potential of the microbial world.


Aqueous phase adsorption of different sized molecules on activated carbon fibers: Effect of textural properties.
The effect that the textural properties of rayon-based activated carbon fibers (ACFs), such as the BET surface area and pore size distribution (PSD), have on the adsorption of differently sized molecules, namely, brilliant yellow (BY), methyl orange (MO) and phenol (PH), was investigated in the aqueous phase. ACF samples with different BET areas and PSDs were produced by steam-activating carbonized fibers for different activation times (0.25, 0.5, and 1 h). The samples activated for 0.25 h were predominantly microporous, whereas those activated for relatively longer times contained hierarchical micro-mesopores. The adsorption capacities of the ACFs for the adsorbate increased with increasing BET surface area and pore volume, and ranged from 51 to 1306 mg/g depending on the textural properties of the ACFs and adsorbate size. The adsorption capacities of the hierarchical ACF samples followed the order BY > MO > PH. Interestingly, the number of molecules adsorbed by the ACFs followed the reverse order: PH > MO > BY. This anomaly was attributed to the increasing molecular weight of the PH, MO and BY molecules. The equilibrium adsorption data were described using the Langmuir isotherm. This study shows that suitable textural modifications to ACFs are required for the efficient aqueous phase removal of an adsorbate.


Calculating molecular Rydberg states using the one-particle Green's function: application to HCO and C(NH2)3.
A simple but accurate and computationally efficient method for routine ab initio calculations of molecular Rydberg states is described. The method, which can be applied to Rydberg states associated with a nondegenerate ion core, consists in the self-consistent solution of an effective one-electron problem. First, the restricted Hartree-Fock problem of the ion core is solved. The orbital energies and certain two-electron Coulomb matrix elements with respect to the molecular orbital basis are then used to construct an energy-dependent many-body correction to the Hartree-Fock mean field. This correction is derived from the Dyson equation satisfied by the one-particle Green's function. The method is applied to calculate Rydberg potential-energy curves of HCO. The presented data confirm and extend recent large-scale multireference configuration-interaction calculations and help develop a detailed theoretical description of the astrophysically important dissociative recombination of a low-energy electron with HCO(+). As further illustration of the utility of the method, the first ab initio calculations of the excited states of an electron bound to the guanidinium cation [C(NH(2))(3)](+) are reported.


Better governance starts with better words: why responsible human tissue research demands a change of language.
The rise of precision medicine has led to an unprecedented focus on human biological material in biomedical research. In addition, rapid advances in stem cell technology, regenerative medicine and synthetic biology are leading to more complex human tissue structures and new applications with tremendous potential for medicine. While promising, these developments also raise several ethical and practical challenges which have been the subject of extensive academic debate. These debates have led to increasing calls for longitudinal governance arrangements between tissue providers and biobanks that go beyond the initial moment of obtaining consent, such as closer involvement of tissue providers in what happens to their tissue, and more active participatory approaches to the governance of biobanks. However, in spite of these calls, such measures are being adopted slowly in practice, and there remains a strong tendency to focus on the consent procedure as the tool for addressing the ethical challenges of contemporary biobanking. In this paper, we argue that one of the barriers to this transition is the dominant language pervading the field of human tissue research, in which the provision of tissue is phrased as a 'donation' or 'gift', and tissue providers are referred to as 'donors'. Because of the performative qualities of language, the effect of using 'donation' and 'donor' shapes a professional culture in which biobank participants are perceived as passive providers of tissue free from further considerations or entitlements. This hampers the kind of participatory approaches to governance that are deemed necessary to adequately address the ethical challenges currently faced in human tissue research. Rather than reinforcing this idea through language, we need to pave the way for the kind of participatory approaches to governance that are being extensively argued for by starting with the appropriate terminology.


[Esthetic breast surgery].
A well developed breast is an important feature of femininity and for self-confidence. Augmentation mammaplasty is done by using alloplastic-implants. The silicon problem is briefly discussed. Evaluation, principal surgical techniques, possible complications are described.


Brain synthesis and cerebrovascular action of epoxygenase metabolites of arachidonic acid.
The purpose of this study was to determine if whole brain makes epoxygenase metabolites of arachidonic acid and, if so, whether they are vasoactive on the cerebral microcirculation. Blood-free mouse brain slices were incubated with exogenous radiolabeled arachidonic acid, and the extracted metabolites were resolved by HPLC. Metabolite structures were confirmed by gas chromatography/mass spectrometry. In addition to prostaglandins, leukotriene B4, and hydroxyeicosatetraenoic acids, mouse brain metabolized arachidonic acid into several other compounds. Among them, we identified 5,6- and 14,15-epoxyeicosatrienoic acid. Next, we tested the effect of topical application of brain-synthesized 5,6-epoxyeicosatrienoic acid and synthetic epoxyeicosatrienoic acids on in vivo rabbit cerebral arteriolar diameter using the cranial window technique and in vivo microscopy. Brain-synthesized 5,6-epoxyeicosatrienoic acid caused a transient 28% arteriolar dilation, similar to that produced by 5 micrograms/ml of synthetic 5,6-epoxyeicosatrienoic acid. A concentration of synthetic 14,15- and 11,12-epoxyeicosatrienoic acid of 5 micrograms/ml CSF had little or no effect on diameter, whereas 8,9-epoxyeicosatrienoic acid caused a maximum dilation of 8%. These studies suggest that brain-synthesized 5,6-epoxyeicosatrienoic acid may play a role in the normal or pathophysiological regulation of the cerebral microcirculation.


Conditions influencing the synthesis of acid protease by Mucor pusillus Lindt.
Protease synthesis by Mucor pusillus Lindt, in a wheat bran medium under submerged conditions, was influenced by substrate concentration, initial pH of the medium, and temperature of incubation. A 4% wheat bran (dry weight) concentration was satisfactory for enzyme production. The initial pH of the medium had a substantial effect on enzyme synthesis; adjustment of the enzyme production medium to pH 5.0 prior to sterilization was desirable. Incubation at 35 C resulted in the best enzyme yields. Under optimal conditions of enzyme production, maximal activity was detected after 5 days of incubation. The enrichment of the medium with glucose increased the yield of mycelia but lowered the amount of enzyme produced.


Simultaneous Doppler measurement of portal venous peak velocity, hepatic arterial peak velocity, and splenic arterial pulsatility index for assessment of hepatic circulation.
Quantitative Doppler assessment of hepatic circulation is widely performed in patients with cirrhosis. Since few studies have attempted to evaluate the various parameters simultaneously, we sought to examine the applicability and possible advantages of such simultaneous measurement for assessment of hepatic function. In 64 patients (21 with cirrhosis, 17 with chronic hepatitis, and 26 with no liver disorder) we prospectively performed Doppler measurement of right portal venous peak velocity (PVPV), right hepatic arterial peak systolic velocity (HAPSV) and splenic arterial pulsatility index (SAPI) and calculated a novel parameter, the hepatic circulatory index (HCI). The HCI was calculated using the formula: HCI (cm2/s2) = PVPV (cm/s) x HAPSV (cm/s)/SAPI. Not every Doppler parameter was useful in itself for quantitative assessment of liver function. On the other hand, hepatic circulatory index was significantly higher in controls (1275.1 +/- 297.5) than in patients with hepatitis (931.7 +/- 270.5, P = 0.0003), or cirrhosis (586.4 +/- 264.9, P < 0.0001) and was highly correlated with the plasma clearance rate of indocyanine green (KICG; r = 0.848, P < 0.0001). Hepatic circulatory index was correlated with KICG, which reflects hepatic circulation. The hepatic circulatory index is a novel parameter of hepatic circulation that can be measured easily at bedside, accurately reflecting hepatic circulatory status.


Cultivating Clinical Judgment in Pharmacological Decision-Making Through Reflection on Practice.
Competent clinical judgment about pharmacological therapies by nurses is essential for safe medication outcomes. This study examined the impact of postclinical pharmacology-focused reflective debriefing sessions on clinical judgment in prelicensure senior nursing students. A nonrandomized repeated measures design was used to compare clinical judgment of students who participated in an additional learning activity with students who did not. Data were collected using Lasater's Clinical Judgment Rubric. Within-groups analysis of variance demonstrated statistically significant increases in clinical judgment scores at mid- and late-semester timepoints for the entire cohort of participants (n = 128). However, analysis of covariance showed no statistically significant differences in the clinical judgment scores for the intervention (n = 62) and control (n = 66) groups. Clinical experiences provide opportunities for prelicensure students to develop clinical judgment about pharmacological therapies. Nurse educators must implement and evaluate strategies to foster this process. [J Nurs Educ. 2022;61(3):143-146.].


PU.1 Regulates Cathepsin S Expression in Large Yellow Croaker (Larimichthys crocea) Macrophages.
Different morphologies have been detected in teleost macrophages. In this study, two macrophage cell lines were sub-cloned from a large yellow croaker head kidney cell line, LYCK. One type of sub-cloned cells was fusiform but the other was round, named LYC-FM and LYC-RM cells respectively, based on their morphologies. Both types showed the characteristics of macrophages, including expression of macrophage-specific marker genes, possession of phagocytic and bactericidal activities, and production of reactive oxygen species (ROS) and nitric oxide (NO). The transcription factor PU.1, crucial for the development of macrophages in mammals, was found to exist in two transcripts, PU.1a and PU.1b, in large yellow croaker, and constitutively expressed in LYC-FM and LYC-RM cells. The expression levels of PU.1a and PU.1b could be upregulated by recombinant large yellow croaker IFN-γ protein (rLcIFN-γ). Further studies showed that both PU.1a and PU.1b increased the expression of cathepsin S (CTSS) by binding to different E26-transformation-specific (Ets) motifs of the CTSS promoter. Additionally, we demonstrated that all three domains of PU.1a and PU.1b were essential for initiating CTSS expression by truncated mutation experiments. Our results therefore provide the first evidence that teleost PU.1 has a role in regulating the expression of CTSS.


Flow-mediated dilatation to relieve puncture-induced radial artery spasm: A pilot study.
Puncture-induced radial artery spasm (RAS) may extend the duration of coronary an-giography (CAG) or cause transradial access failure. Flow-mediated dilatation (FMD), a widely-used noninvasive approach for assessing endothelial function, was reported to remove the entrapped radial sheath after percutaneous coronary intervention. Herein, the efficacy and safety of FMD in treating puncture-induced RAS before transradial CAG was investigated. Ninety patients with puncture-induced RAS were randomized in a 1:1:1 ratio into three groups: FMD group was immediately treated with blockage of brachial artery blood for 5 min using a sphygmomanometric cuff and then rapid relief; nitroglycerin (NTG) group was administered with 0.5 mg sublingual NTG instantly; and the no-therapy group was treated with a wait-and-watch strategy. The time of radial pulse recovery, and regional and systemic complications were recorded. The rate of radial pulse recovery within 30 min in FMD group was significantly higher than that in no-therapy group (97% vs. 73%, p = 0.026). The median time to return of radial pulse in FMD group and NTG group was significantly shorter than that in no-therapy group (7 [6.5-9] min vs. 15 [12-18] min, 8 [7-9] min vs. 15 [12-18] min, respectively; both p < 0.001). Headache and decreased blood pressure were more prevalent in NTG group than those in FMD and no-therapy groups. FMD is a feasible, noninvasive and nonpharmacological approach to relieve RAS and facilitate radial artery cannulation after an initial failed attempt. (Cardiol J 2018; 25, 1: 1-6).


[Hilar cholangiocarcinoma (Klatskin's tumor): up-to-date radiologic diagnosis, intervention and treatment possibilities].
A 53-year-old man with jaundice was referred with suspected cholangiocarcinoma of the porta hepatis. He was found to be in a reduced general and nutritional condition. Cholinesterase was decreased, total bilirubin, GOT, GPT and alkaline phosphatase were increased. Abdominal contrast-enhanced computed tomography revealed a centrally located and contrast-enhancing mass at the proximal common hepatic duct. Metastases were not detectable. Endoscopic retrograde cholangiography showed a stenosis of the proximal common hepatic duct. An additional magnetic resonance tomography with cholangio-pancreatography confirmed the centrally located tumor as well as the stenosis of the common hepatic duct. The diagnostic tests were suggestive of a stage IV cholangiocarcinoma of the porta hepatis (Klatskin's tumor). The origin was subsequently proven histologically. There was no evidence of intra- or extrahepatic metastases. An interventional embolization of the right portal vein was performed preoperatively to stimulate the growth of the left hepatic lobe. But before surgery could take place a percutaneous transhepatic cholangiography and biliary drainage had to be done followed by an extended right-sided hemihepatectomy. During a 12 month follow-up no recurrence was observed. Klatskin's tumor is rare and requires interdisciplinary collaboration. Recent developments in diagnostic, interventional and surgical methods result in a better prognosis.


Non-pharmacological methods reduce drug use in the treatment of hypertension. A two-year trial in general practice.
In a primary-care based study, 122 patients who were taking antihypertensive drugs took part in a two-year trial that aimed at establishing the feasibility of non-pharmacological methods in the treatment of hypertension in general practice. The patients could choose from among 14 non-pharmacological methods of blood pressure reduction. Increased physical exercise; weight reduction, low-sodium and low-fat diet, relaxation training, and home-monitoring of blood pressure were the most popular methods. The use of anti-hypertensive drugs was reduced by 55% in the participants, with the defined daily dose (DDD) being lowered from 1.18 to 0.55 (P less than 0.001). At the end of the study, 46% of the participants were free from anti-hypertensive drugs. Significant reductions occurred in body mass index (27.1 to 26.4 kg/m2, P = 0.001) and serum cholesterol (6.89 to 6.48 mmol/l, P less than 0.001). According to some measures used, the study group's experience of "quality of life" was not reduced.


Teaching interventional cytopathology.
Interventional cytopathology is a unique area of pathology, where cytopathologists play a primary role in obtaining fine needle aspiration biopsies and/or making determinations through rapid on-site evaluations to guide sample procurement in real-time. Unsurprisingly, experience and skill are directly related to success in these endeavors, and both can be fostered with formal instruction. There is a wealth of resources available to aid in teaching interventional cytopathology, including instructional videos, courses, and model phantoms which can help to build familiarity and confidence. These tools can provide a basic framework upon which skills can be developed through in-person guidance, real-time feedback and practice. This article reviews the tools available to enhance training, details the authors' institutional experience in teaching interventional cytopathology at a tertiary care center, and provides recommendations and pearls for success in this endeavor.


Parish nurse practice with client aggregates.
The purpose of this study was to describe 1 aspect of parish nurses' practice: working with client aggregates. Nineteen parish nurses practicing in 22 faith communities collected data using 2 standardized nursing classification systems--North American Nurses Diagnosis Association Taxonomy and Nursing Intervention Classification. Nurses recorded 77 group encounters for services provided over a 5-month period. The most frequent nursing diagnoses and nursing interventions are reported and emphasize health promotion and illness prevention. The parish nurse roles of educator, counselor, referral agent, and advocate-facilitator described in the literature were consistent with the findings of this study. In addition, the parish nurse as a member of the ministerial team is discussed. A focus group of the parish nurses provided validation of the results of aggregate practice.


Analytic and heuristic processing influences on adolescent reasoning and decision-making.
The normative/descriptive gap is the discrepancy between actual reasoning and traditional standards for reasoning. The relationship between age and the normative/descriptive gap was examined by presenting adolescents with a battery of reasoning and decision-making tasks. Middle adolescents (N = 76) performed closer to normative ideals than early adolescents (N = 66), although the normative/descriptive gap was large for both groups. Correlational analyses revealed that (1) normative responses correlated positively with each other, (2) nonnormative responses were positively interrelated, and (3) normative and nonnormative responses were largely independent. Factor analyses suggested that performance was based on two processing systems. The "analytic" system operates on "decontextualized" task representations and underlies conscious, computational reasoning. The "heuristic" system operates on "contextualized," content-laden representations and produces "cognitively cheap" responses that sometimes conflict with traditional norms. Analytic processing was more clearly linked to age and to intelligence than heuristic processing. Implications for cognitive development, the competence/performance issue, and rationality are discussed.


Effect of the addition of montelukast to inhaled fluticasone propionate on airway inflammation.
The aim of the study was to investigate the effect of addition of montelukast to inhaled fluticasone propionate (FP) therapy, compared with FP therapy alone (100 microg twice a day) on airway immunopathology in individuals with mild asthma. Twenty-eight subjects received FP (100 microg twice a day) or FP (100 microg twice a day) plus montelukast (10 mg at night) for 8 weeks and were then crossed over to the alternate treatment for a further 8 weeks. Physiological measurements and bronchial biopsies were obtained at +/- 2 days before treatment and +/- 2 days at the end of each treatment period. A two-period crossover analysis was performed and the mean and SE were calculated. There was no significant difference in percent predicted FEV1 (p = 0.51) or PC20 mg/ml (p = 0.81) between the two treatment regimes after 8 weeks of therapy. There was no difference in the efficacy of either treatment in decreasing T cell (p = 0.97), CD45RO+ (p = 0.37), mast cell (p = 0.37), or activated eosinophils (p = 0.55) numbers in bronchial biopsies. There was no significant difference in the percentage area stained for IFN-gamma (p = 0.76) or interleukin-4 (p = 0.61) between treatments. Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP plus montelukast was not significantly different from the reduction observed with FP alone in individuals with mild asthma.


Surgery Trauma Severity but not Anesthesia Length Contributes to Postoperative Cognitive Dysfunction in Mice.
Perioperative, modifiable factors contributing to perioperative neurocognitive disorders (PND) have not been clearly defined. To determine the contribution of anesthesia lengths and the degrees of surgical trauma to PND and neuroinflammation, a critical process for PND. Three-month-old C57BL/6J mice were subjected to 2 h or 6 h isoflurane anesthesia plus a 5 min or 15 min left common carotid artery exposure (surgery) in a factorial design (two factors: anesthesia with two levels and surgery with three levels). Their learning and memory were tested by Barnes maze and novel object recognition paradigms. Blood, spleen, and hippocampus were harvested for measuring interleukin (IL)-6 and IL-1β. Eighteen-month-old C57BL/6J mice (old mice) were subjected to 6 h isoflurane anesthesia or 2 h isoflurane anesthesia plus 15 min surgery and then had learning and memory tested. Three-month-old mice with 15 min surgery (long surgery) under 2 h or 6 h anesthesia performed poorly in the learning and memory tests compared with controls. Anesthesia alone or anesthesia plus 5 min surgery did not affect mouse performance in these tests. Similarly, only mice with long surgery but not mice with other experimental conditions had increased IL-6 and IL-1β in the blood, spleen, and hippocampus and decreased spleen weights. Splenocytes were found in the hippocampus after surgery. Similarly, old mice with long surgery but not the mice with isoflurane anesthesia alone had poor performance in the Barnes maze and novel object recognition tests. Surgical trauma, but not anesthesia, contributes to the development of PND and neuroinflammation. Splenocytes may modulate these processes.


Morphostereometry of heterotopic ossicles in the rat.
The objective of this study was to describe induced heterotopic bone formation in the rat using stereologic methods and to optimize the sampling for toxicologic studies. Bone formation was induced by implants of demineralized bone powder in 24 male Wistar rats. The ossicles formed were removed after 14, 16, 17, 18, and 20 days. From each ossicle, six sections were sampled equidistantly, and seven microscopic fields were analyzed in each section. Ossicle volume and weight decreased from Day 16 to Day 20. Bone volume density increased during the experimental period because of the reduction in ossicle volume, whereas the total bone volume did not change. Bone thickness increased from Day 14 to Day 20. No changes were observed in the surface density and total area of formative surfaces. The major part of the total variation was due to true variation between animals. The described histomorphometric methods may prove useful in quantitative toxicologic studies, e.g., of fluoride effects on cartilage and bone formation.


Application of a transmission model to estimate performance objectives for Salmonella in the broiler supply chain.
The aim of the present study was to demonstrate how Performance Objectives (POs) for Salmonella at various points in the broiler supply chain can be estimated, starting from pre-set levels of the PO in finished products. The estimations were performed using an analytical transmission model, based on prevalence data collected throughout the chain in The Netherlands. In the baseline (current) situation, the end PO was set at 2.5% of the finished products (at end of processing) being contaminated with Salmonella. Scenario analyses were performed by reducing this baseline end PO to 1.5% and 0.5%. The results showed the end PO could be reduced by spreading the POs over the various stages of the broiler supply chain. Sensitivity analyses were performed by changing the values of the model parameters. Results indicated that, in general, decreasing Salmonella contamination between points in the chain is more effective in reducing the baseline PO than increasing the reduction of the pathogen, implying contamination should be prevented rather than treated. Application of both approaches at the same time showed to be most effective in reducing the end PO, especially at the abattoir and during processing. The modelling approach of this study proved to be useful to estimate the implications for preceding stages of the chain by setting a PO at the end of the chain as well as to evaluate the effectiveness of potential interventions in reducing the end PO. The model estimations may support policy-makers in their decision-making process with regard to microbiological food safety.


[Determination of the cytotoxic activity of Vibrio cholerae].
Cytotoxic activities of broth culture supernatants of 39 V. cholerae strains 01 and non 01 were studied in L-929 cell cultures. The examined strains differed by the cytotoxic factor production, which factors were identified (with the use of anti-cytolysin serum) as cytolysin. The strains capable of choleric enterotoxin secretion did not produce cytolysin.


Characterisation of thickness changes in the peripapillary retinal nerve fibre layer in patients with Leber's hereditary optic neuropathy.
Limited studies have identified the changes in peripapillary retinal nerve fibre layer (pRNFL) thickness in patients with chronic Leber's hereditary optic neuropathy (LHON) at different stages of the disease. We aimed to characterise the pRNFL thickness changes in patients with LHON having m.11778G>A (MT-ND4) mutation. This retrospective cross-sectional study included 221 eyes from patients with LHON (n=145)-classified into seven groups according to disease duration-and 52 eyes from healthy controls (n=26). All subjects underwent pRNFL examinations. pRNFL thickness of the superior, nasal and inferior, and temporal quadrants, and the 360° average were measured. Within 3 months of onset, the temporal pRNFL thickness decreased significantly, whereas the remaining quadrants and the average pRNFL thickness initially increased. The temporal quadrant (p<0.01) and average pRNFL thickness (p=0.02) significantly decreased at 3-6 months. Excluding that in the nasal quadrant (p=0.93), pRNFL thickness significantly decreased in all other quadrants at 6-9 months. At 9-12 months, the average and individual quadrant pRNFL thicknesses continued to decrease. Compared with 12-24 months, the pRNFL thickness was thinner at 24-60 months and >60 months. The papillomacular bundle was affected first and preferentially in LHON. pRNFL thickness initially increased and then decreased, corresponding to the retinal ganglion cell swelling and apoptosis. pRNFL thinning first occurred in the temporal quadrant, followed by the inferior and superior quadrants, and finally, the nasal quadrant. pRNFL continued to thin slowly in some quadrants even after 60 months.


Cerebral venous sinus system and stenting in pseudotumor cerebri.
The pathogenesis and treatment paradigm for idiopathic intracranial hypertension (IIH) is controversial. The goal of this article is to review the current literature addressing a relatively new and controversial therapeutic approach for a subset of IIH patients: dural venous sinus stenting. The debate continues as to whether transverse sinus stenosis is a primary or secondary process relative to raised intracranial pressure (ICP). Transverse sinus stenosis is seen in the majority of patients with IIH and appears to play some role in the disease process. Recent case reports and case series that looked at patients treated with venous sinus stents show encouraging results in decreasing ICP and its related signs and symptoms. Venous sinus stenting could be a treatment option for many patients with IIH. Exactly where in the treatment paradigm endovascular venous sinus stenting falls is unknown. Additional work, preferably controlled prospective studies, needs to be performed to prove its safety and efficacy. Finally, venous sinus stenting should be compared in head-to-head trials with optic nerve sheath fenestration and cerebrospinal fluid diversion surgeries to address its superiority or inferiority relative to these more traditional surgical options.


Comparison of HIV-1 envelope-specific CD4+ T cell lines simultaneously established from peripheral blood mononuclear cells and lymph node biopsy in HIV-1-infected individuals.
HIV-1 envelope-specific CD4+ T cell lines were established simultaneously from PBMC and lymph node mononuclear cells of two HIV-1-infected patients. Three recombinant envelope proteins were used to establish the CD4+ T cell lines: gp160NL4-3, gp120IIIB, and gp120MN. Six T cell lines were established from the first patient, one for each Ag from each compartment, and four T cell lines, two per compartment, were established from the second patient. Each line was challenged with a panel of overlapping peptides spanning the entire gp120 sequence to define its T cell epitope specificity. The pattern of recognition for all the lines from any given patient was similar between compartments. Each patient had a different pattern of peptide recognition. TCR analysis showed a heterogeneous usage of Vbeta between lines with same peptide specificity and established from different compartments. These data suggest that the cellular immune response does not phenotypically vary between the peripheral blood and lymph node compartments, but demonstrates genotypic heterogeneity, showing possible redundancy of the immune response to HIV-1 gp160.


Analysis of spatial niche structure in coexisting tidepool fishes: null models based on multi-scale experiments.
1. Fundamental and realized spatial niches were investigated through a combination of laboratory and mesocosm experiments, field observations and null model analysis in three intertidal gobiid species (Bathygobius fuscus, Chaenogobius annularis and C. gulosus). Null models based on the results of single-species experiments were used to assess interspecific spatial use and coexistence on two different scales: (i) microhabitats within a tidepool ('microhabitat' scale); and (ii) distribution among a set of tidepools ('habitat-wide' scale). 2. Patterns of microhabitat use varied from single to paired treatments, depending on paired species. Realized overlap of microhabitat use was smaller than would be expected from single-individual situations for intraspecific combinations, but not for interspecific ones. 3. Patterns of tidepool occupancy (a measure of spatial niche breadth) in the mesocosm were influenced by interspecific interactions. Two Chaenogobius species, but not B. fuscus, decreased tidepool occupancy in the hetero-specific treatments compared with the mono-specific ones. For all interspecific combinations, spatial overlap (habitat-wide scale) was significantly lower than the values expected from mono-specific situations. The results also indicated a possible trade-off between competitiveness and growth efficiency in these fishes. 4. Interspecific spatial overlap in the field was similar to that in the mesocosm experiment and the pattern of coexistence of gobiids can be explained by the results of our experiments. 5. This study demonstrates that niches of intertidal fishes may experience modifications under the influence of species interactions and that null models based on controlled experiments can greatly facilitate the deciphering of such changes in niche structure.


A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.
Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.


Outcome Analysis of Reduction and Nonreduction Dismembered Pyeloplasty in Ureteropelvic Junction Obstruction: A Randomized, Prospective, Comparative Study.
The objective of this study is to compare the changes in renal function and drainage following open dismembered pyeloplasty with and without renal pelvis reduction. Randomized prospective study of children with ureteropelvic junction obstruction undergoing pyeloplasty with (Group 1) and without (Group 2) pelvis reduction over an 18-month period. Postoperative function and drainage were assessed by ethylene dicysteine (EC) scan and intravenous urography (IVU) and renal pelvis size by ultrasonography. Forty-two patients (2 months-11 years) participated. The mean preoperative EC scan function was Group 1: 45.88% ± 14.42% (5%-80%) and Group 2: 39.22% ± 9.75% (21%-53%). (P = 0.117). The mean postoperative EC scan function of Group 1 was 42.64% ± 9.62% (17%-54%) and 43.75% ± 9.88% (17%-58%) and of Group 2 was 44.77% ± 12.82% (20%-68%) and 42.25% ± 8.56% (23%-58%) at 3 months (P = 0.584) and ≥ 1year (P = 0.385), respectively, with no significant difference. None required re-do pyeloplasty. The number of patients with slow drainage, especially at 3 months and also at ≥1-year postoperative period on EC scan was slightly higher in Group 2 compared to Group 1 but did not attain statistical significance. There was postoperative improvement in function and drainage on IVU with no significant difference between the two groups, (P = 0.214; P = 0.99, respectively). At a mean follow-up of 45.5 months, Group 2 also showed significant reduction in pelvis size on ultrasound (P = 0.011). Postoperative function remained stable in both groups. More number of patients achieved unobstructed drainage by 3 mo postoperative after reduction pyeloplasty but drainage patterns were mostly similar between reduction and nonreduction of pelvis group in late follow-up.


Cell wall thickness and the molecular mechanism of heterogeneous vancomycin-intermediate Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) with reduced sensitivity to vancomycin (VAN) has caused many clinical cases of VAN treatment failure, but the molecular mechanism underlying the reduced sensitivity to VAN is still unclear. We isolated a heterogeneous VAN-intermediate Staphylococcus aureus (hVISA), which was also a MRSA strain with reduced sensitivity to VAN. To investigate the molecular mechanism underlying the reduced sensitivity to VAN exhibited by the hVISA strain, we compared the hVISA strain with a VAN-sensitive MRSA strain, known as the N315 strain. The images captured by transmission electron microscopy showed that the cell wall of the hVISA strain was significantly thicker than that of the N315 strain (36·72 ± 1·04 nm vs 28·15 ± 1·25 nm, P < 0·05), and the results of real-time quantitative PCR analysis suggested that the expression levels of the cell wall thickness related genes (glmS, vraR/S, sgtB, murZ and PBP4) of the hVISA strain were significantly higher than those of the N315 strain (P < 0·05). In conclusion, this study indicated that the upregulation of the expression of the genes related to cell wall synthesis might be the molecular mechanism underlying the cell wall thickening of the hVISA strain and might be related to its resistance to VAN.


Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock.
Mice lacking mCry1 and mCry2 are behaviorally arrhythmic. As shown here, cyclic expression of the clock genes mPer1 and mPer2 (mammalian Period genes 1 and 2) in the suprachiasmatic nucleus and peripheral tissues is abolished and mPer1 and mPer2 mRNA levels are constitutively high. These findings indicate that the biological clock is eliminated in the absence of both mCRY1 and mCRY2 (mammalian cryptochromes 1 and 2) and support the idea that mammalian CRY proteins act in the negative limb of the circadian feedback loop. The mCry double-mutant mice retain the ability to have mPer1 and mPer2 expression induced by a brief light stimulus known to phase-shift the biological clock in wild-type animals. Thus, mCRY1 and mCRY2 are dispensable for light-induced phase shifting of the biological clock.


Enantioselective total synthesis of (-)-blennolide A.
Blennolide A can be synthesized through an enantioselective domino-Wacker/carbonylation/methoxylation reaction of 7a with 96 % ee and an enantioselective Wacker oxidation of 7b with 89 % ee. Further transformations led to the α,β-unsaturated ester (E)-17, which was subjected to a highly selective Michael addition, introducing a methyl group to give 18a. After a threefold oxidation and an intramolecular acylation, the tetrahydroxanthenone 4 was obtained, which could be transformed into (-)-blennolide A (ent-1) in a few steps.


Thrombocytopenia with Absent Radii (TAR) Syndrome Without Significant Thrombocytopenia.
Thrombocytopenia with absent radii (TAR) syndrome is a rare genetic syndrome that occurs with a frequency of about 0.42 cases per 100,000 live births. It is characterized by hypo-megakaryocytic thrombocytopenia with bilateral absent radii and the presence of both thumbs. The thrombocytopenia is initially very severe, manifesting in the first few weeks to months of life, but subsequently improves with time to reach near normal values by one to two years of age. We present a case of a newborn with TAR syndrome with an atypical presentation of mild thrombocytopenia in the first week of life, with early normalization of platelet counts in the neonatal period. The patient deviates from the normal pattern in which 95% of patients with TAR syndrome usually develop significant thrombocytopenia (platelet counts of less than 50 x 10 9 platelets/L) within the first four months of life. Additionally, the absence of hypo-megakaryocytes on peripheral smear sets this patient apart from the typical cases of TAR syndrome. TAR syndrome is often associated with significant morbidity and mortality secondary to severe thrombocytopenia, which occurs with the highest frequency in the first 14 months of life. The most common cause of mortality is due to a severe hemorrhagic event occurring in the brain, gastrointestinal tract, and other organs. Therefore, all patients with TAR syndrome should be monitored closely for symptomatic thrombocytopenia with platelet transfusions being implemented as the first-line therapy for the treatment of severe or symptomatic disease.


Cues to care: Chronic disease diagnosis in young adult trauma patients.
Prevention of chronic disease necessitates early diagnosis and intervention. In young adults, a trauma admission may be an early contact with the health care system, representing an opportunity for screening and intervention. This study estimates the prevalence of previously diagnosed disease and undiagnosed disease (UD)-diabetes mellitus, hypertension, obesity, and alcohol and substance use-in a young adult trauma population. We determine factors associated with UD and examine outcomes in patients with UD. This is a multicenter, retrospective cohort study of adult trauma patients 18 to 40 years old admitted to participating Level I trauma centers between January 2018 and December 2020. Three Level 1 trauma centers in a single state participated in the study. Trauma registry data and chart review were examined for evidence of previously diagnosed disease or UD. Patient demographics and outcomes were compared between cohorts. Multivariable regression modeling was performed to assess risk factors associated with any UD. The analysis included 6,307 admitted patients. Of these, 4,843 (76.8%) had evidence of at least 1 UD, most commonly hypertension and obesity. In multivariable models, factors most associated with risk of UD were age (adjusted odds ratio [aOR], 0.98; 95% confidence interval [CI], 0.98-0.99), male sex (aOR, 1.43; 95% CI, 1.25-1.63), and uninsured status (aOR, 1.57; 95% CI, 1.38-1.80). Only 24.5% of patients had evidence of a primary care provider (PCP), which was not associated with decreased odds of UD. Clinical outcomes were significantly associated with the presence of chronic disease. Of those with UD and no PCP, only 11.2% were given a referral at discharge. In the young adult trauma population, the UD burden is high, especially among patients with traditional sociodemographic risk factors and even in patients with a PCP. Because of short hospital stays in this population, the full impact of UD may not be visible during a trauma admission. Early chronic disease diagnosis in this population will require rigorous, standard screening measures initiated within trauma centers. Prognostic and Epidemiological; Level IV.


PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance.
Engineered oncolytic viruses are used clinically to destroy cancer cells and have the ability to boost anticancer immunity. Phosphatase and tensin homolog deleted on chromosome 10 loss is common across a broad range of malignancies, and is implicated in immune escape. The N-terminally extended isoform, phosphatase and tensin homolog deleted on chromosome 10 alpha (PTENα), regulates cellular functions including protein kinase B signaling and mitochondrial adenosine triphosphate production. Here we constructed HSV-P10, a replicating, PTENα expressing oncolytic herpesvirus, and demonstrate that it inhibits PI3K/AKT signaling, increases cellular adenosine triphosphate secretion, and reduces programmed death-ligand 1 expression in infected tumor cells, thus priming an adaptive immune response and overcoming tumor immune escape. A single dose of HSV-P10 resulted in long term survivors in mice bearing intracranial tumors, priming anticancer T-cell immunity leading to tumor rejection. This implicates HSV-P10 as an oncolytic and immune stimulating therapeutic for anticancer therapy.


Burns, inflammation, and intestinal injury: protective effects of an anti-inflammatory resuscitation strategy.
Intestinal barrier breakdown after severe burn can lead to intestinal inflammation, which may act as the source of the systemic inflammatory response. In vitro intestinal cell studies have shown that mitogen-activated protein kinase (MAPK) signaling is an important modulator of intestinal inflammation. We have previously observed that pentoxifylline (PTX) attenuates burn-induced intestinal permeability and tight junction breakdown. We hypothesized that PTX would limit intestinal barrier breakdown and attenuate inflammatory signaling via the MAPK pathway. Male balb/c mice underwent 30% total body surface area full-thickness steam burn. Immediately after burn, animals received an intraperitoneal injection of PTX (12.5 mg/kg) in normal saline or normal saline alone. In vivo intestinal permeability to 4 kDa fluorescein isothiocyanate-dextran was measured. Intestinal extracts were obtained to measure interleukin-6 by enzyme-linked immunosorbent assay, and phosphorylated p38 MAPK, p38 MAPK, phosphorylated extracellular signal-related kinase (1/2) (ERK (1/2)), and ERK (1/2) by immunoblotting. Acute lung injury was assessed by histology at 24 hours after burn. Administration of PTX immediately after injury attenuated burn-induced intestinal permeability. PTX also decreased the burn-induced phosphorylation of p38 MAPK and decreased phosphorylation of ERK (1/2) at 2 hours and 24 hours after injury. Animals given PTX had decreased intestinal interleukin-6 levels. A single dose of PTX also decreased histologic lung injury at 24 hours after burn. PTX attenuates burn-induced intestinal permeability and subsequent intestinal inflammation. Use of PTX after burn was also associated with decreased acute lung injury. Because of its compelling anti-inflammatory effects, PTX may be an ideal candidate for use as an immunomodulatory adjunct to resuscitation fluid.


Larval desperation and histamine: how simple responses can lead to complex changes in larval behaviour.
Some marine invertebrate larvae expand the range of settlement cues to which they will respond as they age. How do relatively simple larvae achieve such complex changes in behaviour? Larvae of the Australian sea urchin Holopneustes purpurascens settle and metamorphose specifically in response to a settlement cue, dissolved histamine, produced by the host alga Delisea pulchra. Older H. purpurascens larvae appear to accept a wider range of host algae, which contain far less histamine than D. pulchra, than newly competent larvae. We tested the hypothesis that older H. purpurascens larvae accept a greater range of host algae by metamorphosing in response to lower concentrations of histamine. We compared the response of newly competent and older larvae to a range of histamine concentrations in settlement assays. Larval age strongly affected the minimum concentration of histamine that induced metamorphosis in H. purpurascens, with older larvae responding to lower concentrations of histamine than newly competent larvae. Older larvae were more sensitive to lower concentrations of histamine yet still maintained a stringent requirement for exposure to histamine in order to metamorphose. In addition, older larvae metamorphosed after shorter exposure periods to histamine than did younger larvae. By using histamine concentration as a proxy for specific habitat cues, H. purpurascens larvae appear to expand their range of settlement preferences with age by simply changing their sensitivity to a single settlement cue. Overall, our results show that marine invertebrate larvae can exhibit surprisingly complex changes in behaviour via simple changes in their response to a single cue.


Hospital Contracting Reforms: The Lebanese Ministry of Public Health Experience.
Abstract-Since 2009, the Ministry of Public Health (MoPH) in Lebanon has been going through a major reform initiative to improve its contracting system with private and public hospitals. The private sector is the main provider of hospital care in the country and the main contractor to the MoPH for the provision of curative care. As an "insurer of last resort," the MoPH plays an important role in providing hospital coverage to 53% of the population who lack coverage by private or public insurance schemes, through contractual arrangements with the private sector. Historically, the MoPH used hospital accreditation as the basis for contracting and for determining the reimbursement rate. However, recent studies by the MoPH showed that reimbursing hospitals solely on accreditation results was not appropriate and led to an unfair and inefficient reimbursement system. The reform program included the development of several components, in particular, an automated billing system, a utilization review function, standardized admission criteria, and a hospital case mix index that accounts for case complexity. In 2014, the MoPH started implementing a new mixed-model contracting system with private and public hospitals. Preliminary evaluation of the new model suggests that the system incentivized hospitals to admit fewer inappropriate cases and more cases that are more complex/serious. This article shares one experience of how to introduce a merit-based system to face the common practice of political clientelism and confessional/religious-based favoritism in Lebanon. It highlights the importance of stakeholder engagement in a framework of networking and participatory governance that proved to be a key element behind the resilience of a diversified health system.


Bacteriology of Chronic Supporative Otitis Media (CSOM) at a Tertiary Care Hospital, Mymensingh.
Chronic suppurative otitis media (CSOM) is a notorious infection in developing countries causing serious local damage and threatening complications. It was a cross sectional observational study to isolate and identify aerobic bacteria and to analyze the susceptibility pattern of the aerobic bacterial isolates. It was carried out from March 2017 to July 2018 in the department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh. Samples were collected from Outpatient of ENT department, MMCH. Out of a total 300 patients with CSOM were enrolled in this study and 209 were culture positive. Among them gram negative organisms were 129(61.72%) and gram positive organisms were 70(33.49%). The most frequently isolated organism in this study was Pseudomonas aeruginosa 72(34.44%), gram positive organisms S. aureus 63(30.14%), E. coli 21(10.04%), other Pseudomonas spp (other than P. aeruginosa) 15(7.17%), mixed bacterial infectios 10(4.78%), Proteus spp 9(4.30%), CoNS 7(3.34%), Klebsiela lspp 7(3.34%), Acinetobactor spp 5(2.39%). P. aeruginosa isolates had least resistant to imipenem and colistin, S. aureus were showed high sensitivity to Vancomycin and Linezolid and E. coli were sensitive to imipenem and amikacin, ciprofloxacin and amikacin respectively. Pseudomonas aeruginosa was the most common bacteria isolated from chronic discharging ears followed by Staphylococcus aureus. Piperacillin-Tazobactum, Ciprofioxacin, Gentamicin and Amikacin were found to be the most suitable drug for Pseudomonas aeruginosa, S. aureus and E. coli. The resistance against ceftriaxone and aztreonam was found to be very high.


Efficacy and safety of azithromycin 1.5% eye drops in paediatric population with purulent bacterial conjunctivitis.
To determine the efficacy and safety of azithromycin 1.5% eye drops in a paediatric population with purulent bacterial conjunctivitis. This was a multicentre, international, randomised, investigator-masked study in 286 children with purulent discharge and bulbar conjunctival injection. Patients received either azithromycin 1.5% eye drops (twice daily for 3 days) or tobramycin 0.3% eye drops (every 2 h for 2 days, then four times daily for 5 days). Clinical signs were evaluated on day (D) 0, 3 and 7, and cultures on D0 and D7. The primary variable was the clinical cure (absence of bulbar conjunctival injection and discharge) on D3 in the worse eye for patients with positive cultures on D0. 286 patients (mean age 3.2 years; range 1 day-17 years) were included; 203 had positive cultures on D0. Azithromycin was superior to tobramycin in clinical cure rate on D3 (47.1% vs 28.7%, p=0.013) and was non-inferior to tobramycin on D7 (89.2% vs 78.2%, respectively). Azithromycin treatment eradicated causative pathogens, including resistant species, with a similar resolution rate to tobramycin (89.8% vs 87.2%, respectively). These results were confirmed in a subgroup of patients younger than 24 months old. Azithromycin 1.5% eye drops provided a more rapid clinical cure than tobramycin 0.3% eye drops in the treatment of purulent bacterial conjunctivitis in children, with a more convenient twice-a-day dosing regimen.


[Intraoperative aortic injury caused by arterial perfusion cannula during extended aortoplasty in a patient with Williams syndrome].
An 8-year-old girl with Williams syndrome underwent repair of supravalvular aortic stenosis by extended aortoplasty (Doty technique). Although she was weaned from bypass successfully, direct epiaortic ultrasound scanning disclosed the acute luminal narrowing of the ascending aorta at the level of aortic cannulation. The perfusion was restarted through the tube graft anastomosed to the left carotid artery and the ascending aorta was cross-clamped. The longitudinal incision at the site of prior aortic cannulation disclosed the intramural hematoma at the posterior wall of the ascending aorta. The stenosis was repaired with the patch enlargement of the anterior wall. As the dysplastic wall of the ascending aorta in patients with this syndrome may be injured by arterial cannula, an appropriate positioning of the cannula is mandatory to lessen the risk of intimal injury.


Studies on the determination and degradation of pyrimethamine in mammals.
Treatment of pyrimethamine with blood plasma in vitro yields a metabolite which is also produced when the drug is administered through intravenous injection in the rat. A thin layer liquid chromatographic method for quantitative and qualitative determination of pyrimethamine and its metabolite in plasma and biological tissues is described.


Recovery of vision after transcranial decompression of pituitary apoplexy characterized by third ventricular hemorrhage.
The authors present a case of pituitary apoplexy characterized by massive third ventricular hemorrhage. This rare complication, which caused total blindness in the patient, a 67-year-old man, was treated with transcranial decompression of the pituitary tumor and removal of a blood clot from the third ventricle. After surgery, the patient totally recovered his vision. To the best of our knowledge, this is the first case of a patient with pituitary apoplexy that ruptured into the third ventricle (diagnosed by imaging studies) who was treated by emergency transcranial decompression.


The pharmacological cost of COPD during Greek economic crisis.
The economic crisis in Greece has substantially affected patients with COPD. The reduction of disposable income has its consequences on patients' ability to afford their medication. The aim of the study is to evaluate the cost of treatment for patients with COPD and the influence of the financial crisis to the patients. Data were collected from 189 patients (male: 178, mean age: 70.1±8.4) who visited the outpatient department of University Hospital of Larissa in 2014 and 2015. The pharmacological cost of treatment was calculated based on national pharmaceutical formulary prices. COPD patients were classified into four stages according to Global Initiative for Chronic Obstructive Lung Disease (GOLD): 7.4% were in stage I, 43.4% in stage II, 34.4% in stage III, and 14.8% in stage IV. Patients were graded as per GOLD as follows: 18% as grade A, 14.3% as B, 23.3% as C, and 44.4% as D. The annual cost of COPD maintenance treatment per patient was €952.92 (±398.01), of which €239.91 were patients' expenses. The annual treatment cost for stable disease ranged from €615.44 to €1302.03 depending on disease stages (GOLD stages I-IV) and from €715.01 to €1101.05 depending on GOLD grades (grades A-D). The cost of maintenance medication was statistically and significantly higher for patients with advanced disease (GOLD stages III-IV) and for patients at high risk (GOLD grades C-D [P=0.000]). The pharmacological cost of treatment for COPD patients seems to be considerably high, in all disease stages. As the average income is decreased, patients face difficulties to afford inhaled medication.


Ocular distribution, spectrum of activity, and in vivo viral neutralization of a fully humanized anti-herpes simplex virus IgG Fab fragment following topical application.
Herpes simplex ocular infection is a major cause of corneal blindness. Local antiviral treatments exist but are associated with corneal toxicity, and resistance has become an issue. We evaluated the biodistribution and efficacy of a humanized anti-herpes simplex virus (anti-HSV) IgG FAb fragment (AC-8; 53 kDa) following repeated topical administration. AC-8 was found in the corneal epithelium, anterior stroma, subepithelial stromal cells, and retinal glial cells, with preferential entry through the ocular limbus. AC-8 was active against 13 different strains of HSV-1, with 50% and 90% mean effective concentrations (MEC(50) and MEC(90), respectively) ranging from 0.03 to 0.13 μg/ml, indicating broad-spectrum activity. The in vivo efficacy of AC-8 was evaluated in a mouse model of herpes-induced ocular disease. Treatment with low-dose AC-8 (1 mg/ml) slightly reduced the ocular disease scores. A greater reduction of the disease scores was observed in the 10-mg/ml AC-8-treated group, but not as much as with trifluridine (TFT). AC-8 treatment reduced viral titers but less than trifluridine. AC-8 did not display any toxicity to the cornea or other structures in the eye. In summary, topical instillation of an anti-HSV FAb can be used on both intact and ulcerated corneas. It is well tolerated and does not alter reepithelialization. Further studies to improve the antiviral effect are needed for AC-8 to be considered for therapeutic use.


Presentation and revascularization patterns of patients admitted for acute coronary syndromes in France between 2004 and 2008 (from the National Observational Study of Diagnostic and Interventional Cardiac Catheterization [ONACI]).
Patients with acute coronary syndrome (ACS) comprise a heterogeneous group. Despite clear guidelines, the management of ACS in clinical practice is variable. We aimed to evaluate clinical characteristics and myocardial revascularization patterns of patients presenting with ACS from a large French nationwide registry. The National Observational Study of Diagnostic and Interventional Cardiac Catheterization is a multicenter registry including all interventional cardiology procedures performed since 2004. Patient demographics and co-morbidities, invasive parameters, treatment options, and procedural techniques were prospectively collected. The present study is focused on data collected between 2004 and 2008. Patients were recruited in 99 hospitals (55% in private clinics, 45% in public institutions). Over a 5-year period, 64,932 patients with ACS were included (mean age 65.7 ± 13.3; 73% men, 31% ST-elevation myocardial infarction [STEMI]). Patients presenting with unstable angina pectoris and non-ST-elevation myocardial infarction weresimilar with regards to clinical presentation and coronary artery disease (CAD) extension. Overall, these patients were older, had a higher cardiovascular risk profile, and had more severe CAD compared with STEMI patients. In-hospital mortality during the first 24 hours was higher in STEMI patients. Patient's characteristics and CAD were highly dependent on the type of ACS. Patients with unstable angina/non-STEMI were older and had a more severe CAD. In-hospital complications were higher in STEMI patients.


Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling.
Megakaryocyte (MK) is the naturally polyploid cell that gives rise to platelets. Polyploidization occurs by endomitosis, which was a process considered to be an incomplete mitosis aborted in anaphase. Here, we used time-lapse confocal video microscopy to visualize the endomitotic process of primary human megakaryocytes. Our results show that the switch from mitosis to endomitosis corresponds to a late failure of cytokinesis accompanied by a backward movement of the 2 daughter cells. No abnormality was observed in the central spindle of endomitotic MKs. A furrow formation was present, but the contractile ring was abnormal because accumulation of nonmuscle myosin IIA was lacking. In addition, a defect in cell elongation was observed in dipolar endomitotic MKs during telophase. RhoA and F-actin were partially concentrated at the site of furrowing. Inhibition of the Rho/Rock pathway caused the disappearance of F-actin at midzone and increased MK ploidy level. This inhibition was associated with a more pronounced defect in furrow formation as well as in spindle elongation. Our results suggest that the late failure of cytokinesis responsible for the endomitotic process is related to a partial defect in the Rho/Rock pathway activation.


An NBD-armed tetraaza macrocyclic lysosomal-targeted fluorescent probe for imaging copper(II) ions.
An NBD-armed tetraaza macrocyclic lysosomal-targeted fluorescent probe for detecting Cu(2+) was synthesized and used for fluorescence imaging in HeLa cells. The probe was specifically localized in lysosomes and successfully applied to visualize Cu(2+) as well as to monitor Cu(2+) level changes in the lysosomes of living cells.


Investigation of Spatial Heterogeneity of Salt Disproportionation in Tablets by Synchrotron X-ray Diffractometry.
Tablets which were binary mixtures of pioglitazone hydrochloride (PioHCl) with magnesium stearate (MgSt), croscarmellose sodium (CCS), microcrystalline cellulose, or lactose monohydrate were prepared. Two sets of experiments, using intact tablets, were performed. (i) Tablets containing PioHCl (90% w/w) and MgSt were exposed to 25 or 40 °C and 75% RH in a custom-built temperature/humidity chamber. In situ spatiotemporal mapping of disproportionation was performed by transmission-mode synchrotron X-ray diffractometry (SXRD; Argonne National Laboratories). Tablets were scanned in radial direction starting from the top edge of the tablet and moving, in increments of 300 μm, toward the center. There was evidence of disproportionation after 10 min (at 40 °C). The reaction was initiated on the tablet surface and progressed toward the core. (ii) SXRD of tablets stored for a longer time (up to 15 days) enabled the simultaneous quantification of the reactants and products of disproportionation and provided insight into the reaction progression. The influence of sorbed water and microenvironmental acidity on the disproportionation reaction was investigated. The most pronounced reaction was observed in the presence of MgSt followed by CCS. The transformation was solution-mediated, and the spatial heterogeneity in disproportionation could be explained by the migration of sorbed water. There was a good correlation between microenvironmental acidity (pHeq) and extent of PioHCl disproportionation.


Early vs late cranioplasty: what is better?
Cranioplasty is the surgical repair of skull defects, which commonly is performed after traumatic skull injuries due to tumor removal or decompressive craniectomy. Several studies reported improvement in cognitive functions following cranioplasty in patients with severe brain damage. The reasons why exist such clinical improvement is not completely understood, although the increase in cerebrospinal fluid hydrodynamics with the potential improvement of local and global cerebral hemodynamics, blood flow, and metabolism may play a pivotal role. We investigated whether the cranioplasty improved neurological recovery and the whole array of cognitive functions or just some specific domains. A total of 30 consecutive brain-injured subjects with craniectomy were enrolled and underwent a structured neuropsychological assessment immediately before the cranioplasty, 1 month after the cranioplasty and 1 year after the surgical procedure. Our results showed that cranioplasty may facilitate the cognitive recovery, independently from the surgical timing. Particularly, we observed an important cognitive recovery in the period immediately after cranioplasty, while the improvement trend settles after a lapse of time, and the recovery starts to slow down. Cranioplasty seems to significantly improve neuropsychological and motor status in the patients with skull defects, independently from cranioplasty timing and patient's clinical status.


Effect of Oxygen on the Contribution of Respiration to the CO(2) Compensation Point in Wheat and Bean Leaves.
The CO(2) compensation point at 21% O(2) (Gamma(21)) and at 2% O(2) (Gamma(2)), and the rate of dark CO(2) efflux at 21% O(2) (R(n)) were measured in adult wheat (Triticum aestivum L, cv Gabo) leaves at the end of the night and after a period of photosynthesis of 5 h at 800 mubar CO(2). The values of Gamma(21) and R(n) significantly increased after the light period, due to the stimulation of respiration by carbohydrates. In contrast, Gamma(2) did not increase after the same period of photosynthesis, suggesting that the respiratory component of Gamma(2) was not stimulated by carbohydrates. In a different experiment, Gamma(21), Gamma(2), and R(n) were studied during the growth period of bean (Phaseolus vulgaris L, cv Hawkesbury Wonder) leaves. The values of Gamma(21) and R(n) were high in young leaves, and decreased rapidly in parallel during maturation. However, Gamma(2) presented relatively low values in growing bean leaves, and a model predicted that the observed values of Gamma(2) should have been considerably higher if their respiratory component was considered to be as large as that of Gamma(21). The results suggest that the rate of respiration in the light contributing to the CO(2) compensation point in wheat and bean leaves is smaller at low O(2) levels than at ambient levels.


Role of splenectomy in immune (idiopathic) thrombocytopenic purpura.
Idiopathic thrombocytopenic purpura (ITP) is an immune disorder, which causes an acute or chronic thrombocytopenia, and may result in potentially life-threatening hemorrhage. Splenectomy is one of the treatment options that needs to be weighed in the treatment of ITP, particularly in cases that have shown response failure to medical modalities such as prednisone, i.v.Ig, or anti-D globulin therapy. Although most studies demonstrate good early response following splenectomy, the long-term outcome is less favorable. Furthermore, other negative factors, such as rendering the patient ineligible for anti-D globulin or oral tolerance therapy and vulnerable to possible life-threatening sepsis, must be weighed prior to splenectomy.


Monitoring APC/C activity in the presence of chromosomal misalignment in unperturbed cell populations.
Chromosome segregation is under strict control of the spindle assembly checkpoint (SAC). The SAC regulates anaphase-promoting complex/cyclosome (APC/C)-dependent proteolysis of securin and cyclin B. Unattached or misaligned chromosomes trigger SAC-mediated mitotic delay by stabilizing securin and cyclin B due to inhibition of APC/C until the problem is solved. Here we present a hitherto unavailable model facilitating the simultaneous depiction of chromosome movements and pulse-chased cyclin B proteolysis in every single cell within a cell population. During chromosome misalignment, we observed slow cyclin B degradation, which changed to fast degradation once the SAC was satisfied, initiating chromosome separation and mitotic exit. Slow degradation during a SAC-mediated mitotic delay is part of a tightly regulated balance between cyclin B synthesis and degradation. Since chromosomal misalignment is a rare event, the ability to study entire cell populations enabled us to monitor for the first time SAC surveillance in living cells without the need of highly artificial perturbation by spindle poisons.


Gender differences in pharmacokinetics of antipyrine in a simulated weightlessness rat model.
Gender differences in gastrointestinal physiology and hepatic metabolizing enzyme systems may potentially modify drug absorption and disposition during spaceflight. This study evaluated the effect of simulated weightlessness on gender-related pharmacokinetic differences of intravenously administered antipyrine, a marker compound for hepatic oxidative metabolism, using the tail-suspended (TS) rat model for microgravity. TS rats were suspended at a 45 degrees angle from the cage floor for 3 d prior to and for 8 h after antipyrine administrations. Control and TS jugular vein-cannulated male and female Sprague-Dawley rats received a 20 mg x kg(-1) intravenous dose of antipyrine. Serial blood samples (0.25 ml) were collected from each rat at 14 predetermined times. Plasma drug concentrations were measured by a HPLC method. Plasma antipyrine concentration-time data were analyzed using noncompartmental pharmacokinetic methods. Statistical comparisons were made using the nonparametric Mann-Whitney U-test. In male rats, simulated weightlessness appreciably and significantly reduced the mean total body clearance of antipyrine by 44.7% and increased the mean residence time of antipyrine by 58.3%, but had no significant effect on the apparent volume of distribution of the drug. In striking contrast to that observed in male rats, simulated weightlessness had no significant effect on the disposition kinetics of antipyrine in female rats. Significant gender difference exists in microgravity-induced changes in drug disposition, where simulated weightlessness apparently has more of an effect in male versus female rats in terms of hepatic enzymatic functions.


Pan-Cancer DNA Methylation Analysis and Tumor Origin Identification of Carcinoma of Unknown Primary Site Based on Multi-Omics.
The metastatic cancer of unknown primary (CUP) sites remains a leading cause of cancer death with few therapeutic options. The aberrant DNA methylation (DNAm) is the most important risk factor for cancer, which has certain tissue specificity. However, how DNAm alterations in tumors differ among the regulatory network of multi-omics remains largely unexplored. Therefore, there is room for improvement in our accuracy in the prediction of tumor origin sites and a need for better understanding of the underlying mechanisms. In our study, an integrative analysis based on multi-omics data and molecular regulatory network uncovered genome-wide methylation mechanism and identified 23 epi-driver genes. Apart from the promoter region, we also found that the aberrant methylation within the gene body or intergenic region was significantly associated with gene expression. Significant enrichment analysis of the epi-driver genes indicated that these genes were highly related to cellular mechanisms of tumorigenesis, including T-cell differentiation, cell proliferation, and signal transduction. Based on the ensemble algorithm, six CpG sites located in five epi-driver genes were selected to construct a tissue-specific classifier with a better accuracy (>95%) using TCGA datasets. In the independent datasets and the metastatic cancer datasets from GEO, the accuracy of distinguishing tumor subtypes or original sites was more than 90%, showing better robustness and stability. In summary, the integration analysis of large-scale omics data revealed complex regulation of DNAm across various cancer types and identified the epi-driver genes participating in tumorigenesis. Based on the aberrant methylation status located in epi-driver genes, a classifier that provided the highest accuracy in tracing back to the primary sites of metastatic cancer was established. Our study provides a comprehensive and multi-omics view of DNAm-associated changes across cancer types and has potential for clinical application.


Inhibition of fibronectin binding to matrix components by nonenzymatic glycosylation.
We examined the effect of nonenzymatic glycosylation on the ability of fibronectin, an extracellular glycoprotein that interacts with cell surfaces and matrix components, to bind to collagen and heparin. Nonenzymatic glycosylation was accomplished by incubation of the protein with glucose, both cold and [14C]-labeled, and documented by measurement of ketoamine-bound carbohydrate with the thiobarbituric acid assay. Effect on binding was assessed with affinity chromatography on heparin-Sepharose and gelatin-Sepharose, and with an in vitro assay that detects complexation of fibronectin with [3H]-heparin. Glycosylated fibronectin did not bind to these immobilized matrix components, and in vitro binding of the glycosylated protein was reduced compared with that of nonglycosylated fibronectin. Inhibition of heparin binding in the in vitro assay was observed even with levels of glycosylation about threefold those of control, which is comparable to the degree of glycosylation determined in fibronectin isolated from plasma of two patients with uncontrolled diabetes. The findings indicate that nonenzymatic glycosylation of fibronectin inhibits its binding to connective tissue components, and suggest that this process contributes to faulty integrity of extracellular matrices in diabetes.


Intraductal ultrasonography of traumatic neuroma of the bile duct.
We report a case of a 70-year-old female with traumatic neuroma of the bile duct. Transpapillary intraductal ultrasonography showed a cystic duct stump, from which a smooth and homogeneous hypoechoic mass arose; the adjacent bile duct wall had a normal structure. Intraductal ultrasonography is useful for distinguishing traumatic neuroma from bile duct carcinoma.


The increased iron deposition of the gray matter over the whole brain in chronic migraine: An exploratory quantitative susceptibility mapping study.
Prior studies identified iron deposition in deep brain nuclei and the periaqueductal gray matter region in chronic migraine, and less is known about the cerebral iron deposition over the whole cerebral gray matter in CM. The aim of this case-control study is to investigate the cerebral iron deposition of gray matter in CM using an advanced quantitative susceptibility mapping. A multi-echo gradient echo MR sequence was used to obtain raw quantitative susceptibility mapping data from 12 CM patients and 18 normal controls and the quantitative susceptibility mapping were reconstructed. Three dimensional T1 images were segmented and the gray matter mask was generated to extract the susceptibility value of gray matter over the whole brain. The independent t test and receiver operating characteristic curve Receiver operating characteristics was used to investigate the iron deposition changes in CM patients. CM presented a higher susceptibility value (1.44 × 10-3 ppm) compared with NC group (0.47 × 10-3 ppm) (p < 0.0001) over the whole cerebral gray matter. There was no correlation between susceptibility value and the clinical variables including disease duration, Visual Analog Scale (VAS), Migraine Disability Assessment Scale (MIDAS), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Montreal Cognitive Assessment (MoCA) scores (p > 0.05). ROC analysis demonstrated the susceptibility had a high diagnostic efficacy (AUC 0.949, sensitivity 77.78% and specificity 100%) in distinguishing CM from NC. CM patients had increased iron deposition in total cerebral gray matter which could be considered as a potential diagnostic and evaluated imaging biomarker in CM.


Fulminant amebic colitis: analysis of 55 cases.
Fulminant amebic colitis is a rare disease with high morbidity and mortality. This study was designed to identify the most frequent clinical and histopathologic features of fulminant amebic colitis and to analyze results of surgical treatment and the existence of risk factors for mortality. A retrospective analysis was conducted of clinical and histopathologic data of 55 patients with fulminant amebic colitis. Data were obtained from the files of autopsies and surgical operations that had been performed at a referral center in Mexico from 1943 through 1994. Median age was 52 (range, 18-79) years. There were 34 men (62 percent) and 21 women (38 percent). Diabetes mellitus and chronic alcoholism were the most frequent diseases in association with fulminant amebic colitis (40 and 31 percent, respectively). The most frequent clinical manifestations were abdominal pain, diarrhea, rectal bleeding, and fever. There was a coexistent amebic liver abscess in 54 percent of patients. The main histopathologic characteristics were necrosis, presence of trophozoites, and acute and/or chronic inflammation. Of 25 patients who underwent surgery, only six survived (operative mortality, 76 percent; overall mortality, 89 percent). The variables that correlated with mortality were longer duration of symptoms, lower count of leukocytes, nonsurgical treatment, nonresective surgical procedure, hospital admission before 1971, and invasion of trophozoites into or through the muscularis. The results may help to obtain an earlier diagnosis and establish proper treatment of fulminant amebic colitis.


Adherence to heart failure management medications following cardiac resynchronization therapy.
Objective: The purpose of this study is to assess the real-world impact of cardiac resynchronization therapy (CRT) on adherence to heart failure (HF) medications.Methods: MarketScan administrative health care claims data from 2008 to 2014 among patients with HF were used. The date of first CRT implantation served as the index date. Adherence to guideline-directed medical therapy (GDMT) classes were compared during pre- and post-index periods using proportion of days covered (PDC). Comparisons between the two periods were made using the Wilcoxon sign-rank test for continuous PDC and McNemar's test for dichotomized PDC.Results: Increases in medication adherence were observed for major classes of HF GDMT medications. Specifically, adherence to angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), beta blockers (BB), and furosemide increased by 22, 24, 32, and 28% (all p < .001), respectively, in the 12 months pre to 12 months post-CRT. Large increases between the pre- and post-CRT period were also observed when considering adherence as dichotomized PDC ≥0.80 in the 12 months pre- versus post-CRT.Conclusion: Adherence to HF medications significantly improved among HF patients post-CRT implantation. Further research is needed to better understand the underlying determinants of this effect, including whether the effect is attributable to factors such as enhanced patient monitoring and improved access to high-quality specialized HF care among patients receiving CRT.


Pulmonary mechanical ventilation at home: a reasonable and less expensive alternative.
The long-term care of ventilator-dependent patients often presents financial and moral burdens. During a 38-month period, January 1978 through February 1981, we provided home care for 10 ventilator-dependent patients, four of whom were completely ventilator-dependent, 24 hours a day, at the time of their discharge from the hospital. Four patients had amyotrophic lateral sclerosis, three had restrictive chest wall disease, and three had miscellaneous disorders (chronic polyneuropathy, multiple sclerosis, and alveolar hypoventilation). The length of their home care during our observation period ranged from 2 to 38 months. As our home care program evolved, our conception of home care ventilation expanded from its being a necessity for getting certain patients discharged from institutional care to its being an alternative to institutional care or death. A team approach by physician, psychiatrist, nurse, respiratory therapist, physical therapist, occupational therapist, and social worker facilitated home care. Home care proved to be less costly by far than institutional care; estimated savings during our observation period from the use of home care for these 10 patients was approximately $2.8 million. We learned that a long-term psychological evaluation process is vitally important to the success of a home care program. Further support for this type of health care by third-party payers and professional societies is necessary to establish criteria and standards for the provision of services and reimbursement for them.


Scleromyxedema-like syndrome with systemic involvement in a cat.
Scleromyxedema--the generalized form of lichen myxedematosus, a primary mucinosis--is a rare disease in human patients. It is characterized by dermal mucin deposits, increased numbers of fibroblasts, and variable fibrosis in the absence of thyroid disease. It is accompanied in 80% of cases by a monoclonal gammopathy. To date, scleromyxedema with systemic involvement has not been documented in domestic animals. This is the first report of a scleromyxedema-like syndrome in a cat, which had a substantial deposition of mucin in the dermis of the head and paws with a mild gammaglobulinemia of 2.25 g/dl (reference range, 1.39-2.22 g/dl). At necropsy, multiple nodules of connective tissue intermingled with mucin deposits were conspicuous on the surface of thoracic and abdominal organs. Such severe systemic accumulations of mucin have not been reported in human or veterinary medicine.


Alpinia calcarata Roscoe: a potent antiinflammatory agent.
Alpinia calcarata Roscoe (Family: Zingiberaceae) rhizomes are often used in Sri Lankan traditional systems of medicine as a remedy for bronchitis, cough, respiratory ailments, diabetics, asthma and arthritis. Generally drugs that are used for arthritis have antinociceptive and antiinflammatory properties. However, validity of the antiinflammatory activity has not been scientifically investigated so far. Therefore, the aim of this study was to investigate the antiinflammatory potential of Alpinia calcarata rhizomes using hot water extract (AWE) and hot ethanolic extract (AEE). The antiinflammatory activity of Alpinia calcarata was evaluated by use of the carrageenan-induced paw oedema model in rats. In addition, the mechanism/s by which Alpinia calcarata is mediated the antinflammatory activity was assessed by determining its effects on (a) membrane stabilizing, (b) antihistamine and (c) prostaglandin synthesis inhibition activity. All the tested doses of AWE and AEE (250, 500, 750, and 1000 mg/kg) produced a significant (P≤0.05) inhibition of the inflammation, most pronounced at 4h after the injection of carrageenan. The antiinflammatory effect induced by 500 mg/kg of AEE was superior than the reference drug, indomethacin at 4h. Inhibition of histamine and prostaglandin synthesis production is probable mechanisms by which Alpinia calcarata mediates its antiinflammatory action. These findings rationalize the traditional usage of Alpinia calcarata as an antiinflammatory agent for the first time.


Aetiology and clinical signs of bacterial meningitis in children admitted to Goroka Base Hospital, Papua New Guinea, 1989-1992.
Children aged 1-59 months admitted to Goroka Base Hospital with signs suggestive of meningitis were recruited to determine what proportion of such children have clinical or bacterial meningitis and to investigate the bacterial aetiology. A laboratory classification of definite, probable, possible, indeterminate and no meningitis was established. Thirty per cent of 697 children had a final clinical diagnosis of meningitis, 12% had culture-proven bacterial meningitis (case fatality rate 34%) and 10% had probable or possible meningitis. Inability to feed, vomiting, drowsiness, "staring eyes" and haemoglobin < 9 g/dl in addition to the classical signs of meningitis were associated with increased mortality. Isolates from cerebrospinal fluid were 62 pneumococci, 22 Haemophilus influenzae type b (Hib) and one Neisseria meningitidis. Including blood culture-proven and antigen-proven Hib disease, Hib and pneumococci accounted for 44% and 46% of bacterial meningitis, respectively, and 23% of pneumococci were intermediately resistant to penicillin. Inability to feed, bulging fontanelle, convulsions in young children, neck stiffness, fever and "staring eyes" were all independently associated with bacterial meningitis. Conjugate Hib vaccine must be given to infants as early as possible. Conjugate pneumococcal vaccines, maternal immunization with 23-valent vaccine and pneumococcal protein vaccines are under investigation for prevention of pneumococcal disease.


On the Assembly of Microreactors with Parallel Enzymatic Pathways.
Cell mimicry aims to create artificial structures capable of mimicking certain functions of living cells. However, cell mimics are tremendously simpler than their natural role models. Thus, increasing their complexity is of great importance for the advancement of cell mimicry concepts and for further understanding of biological intracellular processes. Here, the successful co-encapsulation of two enzymatic pathways with up to five enzymes into compartmentalized microreactors is reported. The microreactors are assembled by combining polymer layers and enzyme-loaded liposomal subunits, which physically separate the two encapsulated enzymatic pathways. Specifically, this report confirms the activity of an encapsulated enzymatic cycle that conjugates the actions of glutamate dehydrogenase and glutathione reductase, using NADP+ /NADPH as a common co-factor, as well as an encapsulated enzymatic cascade combining β-galactosidase, glucose oxidase, and catalase. This work represents a relevant advancement in encapsulated catalysis toward the assembly of therapeutic cell mimics.


Prediction of Postoperative Delirium after Gastrointestinal Surgery Using the Mie Constructional Apraxia Scale.
Postoperative delirium (POD) is a transient postoperative complication that occurs after surgical procedures. Risk factors reported for POD include dementia and cognitive decline. The purpose of this study was to identify predictors of POD by examining the use of preoperative neuropsychological tests, including the Mie Constructional Apraxia Scale (MCAS), and patient background factors. The study was performed as a retrospective cohort study. The subjects were 33 patients (mean age, 75.8 ± 10.9 years; male:female ratio, 26:7) who underwent gastrointestinal surgery at Matsusaka City Hospital between December 2019 and April 2021. Data were collected retrospectively from medical records. The study was started after receiving approval from the institution's ethics committee. The survey items included general patient information, nutritional assessment, surgical information, and neuropsychological tests. Subjects were classified into 2 groups according to the presence or absence of POD. If a significant difference was observed between the 2 groups, the sensitivity, specificity, and area under the curve were calculated using a receiver operating characteristic (ROC) curve. There were 10 patients in the POD group (male:female ratio, 6:4) and 23 patients in the non-POD group (20:3). The POD group had a shorter education history (p = 0.047) and significantly higher MCAS scores (p = 0.007) than the non-POD group. The ROC curve showed a sensitivity of 90%, a specificity of 69%, and an area under the curve of 0.798 when the MCAS cutoff value was set at 3 points. Preoperative MCAS results were capable of predicting the occurrence of POD after gastrointestinal surgery. In addition, a relatively short education background was also considered a risk factor for POD.


Preclinical Pharmacokinetics and Acute Toxicity in Rats of 5-{[(2E)-3-Bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic Acid: A Novel 5-Aminosalicylic Acid Derivative with Potent Anti-Inflammatory Activity.
Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.


Buffer capacities of leaves, leaf cells, and leaf cell organelles in relation to fluxes of potentially acidic gases.
Since environmental pollution by potentially acidic gases such as SO(2) causes proton release inside leaf tissues, homogenates of needles of spruce (Picea abies) and fir (Abies alba) and of leaves of spinach (Spinacia oleracea) and barley (Hordeum vulgare) were titrated and buffer capacities were determined as a function of pH. Titration curves of barley leaves were compared with titration curves of barley mesophyll protoplasts. From the protoplasts, chloroplasts and vacuoles were isolated and subjected to titration experiments. From the titration curves, the intracellular distribution of buffering capacities could be deduced. Buffering was strongly pH-dependent. It was high at the extremes of pH but still significant close to neutrality. Owing to its large size, the vacuole was mainly responsible for cellular buffering. However, on a unit volume basis, the cytoplasm was much more strongly buffered than the vacuole. Potentially acidic gases are trapped in the anionic form. They release protons when trapped. The magnitude of diffusion gradients from the atmosphere into the cells, which determines flux, depends on intracellular pH. In the light, the chloroplast stroma, as the most alkaline leaf compartment, has the highest trapping potential. Acidification of the chloroplast stroma inhibits photosynthesis. The trapping potential of the chloroplast is followed by that of the cytosol. Compared with the cytoplasm, the vacuole possesses little trapping potential in spite of its large size. It is particularly small in the acidic vacuoles of conifer needles. In the physiological pH range (slightly above neutrality), chloroplast buffering was about 1 microequivalents H(+) per milligram chlorophyll per pH unit or 35 microequivalents H(+) per milliliter per pH unit in barley or spinach chloroplasts. This compares with SO(2)-generated H(+) production of somewhat more than 1 microequivalent H(+) per milligram chlorophyll per hour, which results from observed SO(2) uptake of leaves when stomata were open and the atmospheric SO(2) concentration was 0.4 microliters per liter (GE Taylor Jr, DT Tingey 1983 Plant Physiol 72: 237-244). At lower SO(2) concentrations, similar H(+) generation inside the cells requires correspondingly longer exposure times.


Malignant Epithelioid Soft Tissue Tumours- A Pathologist's Perspective With Review of Literature.
Background Soft tissue tumours with epithelioid morphology have many differential diagnoses, which include epithelioid sarcoma, malignant extrarenal rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, epithelioid leiomyosarcoma, epithelioid angiosarcoma and sclerosing epithelioid fibrosarcoma. There are other rare entities also. They often express characteristic patterns of immunohistochemical markers that can be used to identify these tumours. Materials and methods This retrospective study comprises 22 cases of malignant soft tissue tumours with epithelioid differentiation diagnosed over a period of four years. Findings regarding clinical presentation, cytological findings, histopathological findings and immunohistochemical profile of the tumours were noted and analyzed. Results A total of 22 cases were included in the study including five cases of epithelioid sarcoma (conventional and proximal), three cases of epithelioid angiosarcoma and epithelioid myxofibrosarcoma, two cases of epithelioid malignant peripheral nerve sheath tumour, epithelioid gastrointestinal stromal tumour and clear cell sarcoma each, one case of epithelioid leiomyosarcoma, sclerosing epithelioid fibrosarcoma, malignant extrarenal rhabdoid tumour, monophasic synovial sarcoma and malignant and malignant perivascular epithelioid cell tumour each. Conclusion Pathologists should be aware of the various differential diagnoses of soft tissue tumours with epithelioid morphology. Over and above the clinical findings and morphological features, ancillary methods like immunohistochemistry help to arrive at a definitive diagnosis in most cases.


Femoral anatomy described in cylindrical coordinates using computed tomography.
A new method, which describes the femoral anatomy in terms of angles and distances is presented. Primary data are obtained from CT and reduced to cylindrical coordinates by a computer program. The approach yields rotational angles for the entire shaft and demonstrates the limitation of conventional measurements of the anteversion angle. The method is proposed as a generalized technique for measurement of rotation in orthopedic radiology.


The Public Health Legacy of Polio Eradication in Africa.
The legacy of polio in Africa goes far beyond the tragedies of millions of children with permanent paralysis. It has a positive side, which includes the many well-trained polio staff who have vaccinated children, conducted surveillance, tested stool specimens in the laboratories, engaged with communities, and taken care of polio patients. This legacy also includes support for routine immunization services and vaccine introductions and campaigns for other diseases. As polio funding declines, it is time to take stock of the resources made available with polio funding in Africa and begin to find ways to keep some of the talented staff, infrastructure, and systems in place to work on new public health challenges. The partnerships that helped support polio eradication will need to consider funding to maintain and to strengthen routine immunization services and other maternal, neonatal, and child health programs in Africa that have benefitted from the polio eradication infrastructure.


[Effects of two antigens for IgM detection of toxoplasmosis].
To observe the effects of recombinant Toxoplasma gondii P30 antigen and soluble antigen for IgM detection of toxoplasmosis. Recombinant Toxoplasma gondii P30 antigen and soluble antigen were coated on two nitrocellulose membranes (NC) respectively. They were combined with the corresponding antibodies in the testing sera. The gold-labeled rabbit anti-human IgM(s) were detected for corresponding antibodies and the positive visualized. The sera of toxoplasmosis, rheumatoid arthritis, Mycoplasma pneumonia, schistosomiasis patients and healthy persons were tested. A total of five kinds of 166 serum samples were detected with dot immunogold filtration assay (DIGFA) of the two antigens respectively. In 38 serum samples of Toxoplasma gondii infection, the sensitivity of P30-DIGFA was 92.1% (35/38) and soluble antigen-DIGFA 81.6% (31/38). There was no significant difference (P > 0.05). Totally 63 normal serum samples showed negative, so the specificity was 100%. In 30 serum samples of rheumatoid arthritis patients, 2 cases were positive in P30-DIGFA and 3 positive in soluble antigen-DIGFA. Totally 25 serum samples of schistosomiasis patients and 10 serum samples of Mycoplasma pneumonia patients showed negative. Recombinant Toxoplasma gondii P30 antigen may be developed into clinical diagnostic kits for detection of early or acute toxoplasmosis.