Improved detection of melanoma metastases by iodine maps from dual energy CT.
Metastatic disease in melanoma has an unpredictable nature with deposits in rare locations such as musculature. Dual energy CT (DECT) provides high contrast-visualization of enhancement by using spectral properties of iodine. Purpose of this study was to evaluate whether iodine maps from DECT improve lesion detection in staging examinations of melanoma patients. This retrospective study was approved by IRB and written informed consent was obtained from all patients. 75 contrast-enhanced DECT scans (thorax and abdomen) from 75 melanoma patients (n=69 stage IV; n=6 stage III) were analysed. For each patient, conventional CT and iodine maps were reviewed independently by two radiologists. The number of lesions detected by reviewing the iodine maps following conventional CT was recorded. Unweighted Cohens Kappa coefficient (κ) was used for concordance analysis, Wilcoxon test for comparing lesion detection rates. In 26 patients, at least one reader found additional lesions on iodine maps (inter-reader agreement 89%, κ=0.74 (0.742-0.747)). Compared to grey-scale images, mean detection rate for metastases improved from 86% (range 82-90) to 94% (90-99%) (p≤0.01), for muscle metastases from 8% (8-8%) to 99% (98-100%) (p≤0.06). Findings included 2 pulmonary emboli. Iodine maps from DECT improve detection of metastases, especially muscle metastases, and relevant findings in staging examinations of melanoma patients.


Benign human mammary myoepithelioma.
A leiomyoma-like, multifocal tumour developed from intraductal papillomatosis in the breast of a 42 year old woman. The spindle-shaped tumour cells were examined by light, electron and polarizing microscopy, which revealed that they originated from immature "precursor" myoepithelial cells. The author suggests that the tumour be called "myoepithelioma". From the morphological characteristics of the tumour the myoepithelial cells appear to be capable of producing leiomyoma-like benign or malignant tumours. The role that has been attributed by some to the myoepithelial cell in the production of epithelial tumours is problematical, in the light of the present finding.


Patients with burnout in relation to gender and a general population.
The aims of this study were to describe gender differences in patients with burnout and compare these patients with a general population with respect to physical, psychosocial and work variables. Data were collected from a total of 136 patients (96 women and 40 men, 41.6 +/- 7.4 years), diagnosed with stress-related disease and burnout at the Stress Clinic, University Hospital of Umeå. Data on burnout, physical, psychosocial and work characteristics were compared with similar data from a geographical and age-matched population based survey, the 2004 Northern Sweden MONICA study. The survey sample included a total of 573 participants (283 women and 290 men, 40.7 +/- 8.5 years). Women with burnout reported a higher rate of impaired awakening, lower job control, greater proportion of unpaid work and worked to a greater extent "with people" compared to men. Men with burnout had a more restricted social network and reported working more overtime than women. Patients with burnout reported a higher rate of unemployment, a more restricted social network and higher work demands compared to a general population. Women with burnout reported less emotional support, a more sedentary work situation, high job strain and worked to a greater extent "with people" than women from the general population. There are some differences in working conditions and social network between women and men with burnout. Patients with burnout differ from a general population regarding individual and social factors as well as work-related factors.


Primary omental pregnancy with secondary implantation into posterior cul-de-sac: laparoscopic treatment using hemostatic matrix.
Primary omental pregnancy is a rare form of ectopic pregnancy. Only a few reported cases have been treated using laparoscopy. Hemostasis after trophoblast removal can be challenging. A 25-year-old primigravida in week 8 of pregnancy was admitted to our hospital with a diagnosis of missed abortion. An ultrasound scan showed an empty uterine cavity and a gestational sac with a 15-mm embryo dorsal to the uterus, indicative of an ectopic pregnancy. The preoperative serum concentration of human chorionic gonadotropin was 33 600 U/mL. Laparoscopy was performed, which revealed an omental pregnancy invading the peritoneum of the Douglas pouch. After laparoscopic removal of the ectopic pregnancy with partial omentectomy, diffuse bleeding from the crater between both sacrouterine ligaments was treated using the gelatin-thrombin matrix (FloSeal). The final histologic analysis confirmed the omentum as the primary site of the ectopic pregnancy (multiple chorionic villi and decidua within the omental fat). The postoperative period was uneventful. This case expands the classic Studdiford criteria. Secondary peritoneal ectopic pregnancy implantation can occur not only after tubal rupture or expulsion of tubal ectopic pregnancy but also after primary implantation at any other ectopic site. The laparoscopic approach to abdominal pregnancy is safe and feasible if there is sufficient intraoperative hemostasis. The hemostatic matrix facilitates quick and effective control of bleeding.


Immunohistochemical detection of hepatic CEA+ cells: hepatic tumor cell dissemination in colorectal cancer patients--limits of surgery?
Hepatic recurrence following resection of liver metastases occurs in about half of the patients. This is attributed to insufficient margins by some authors, while others accuse the presence of occult tumor cell dissemination. Representative samples of the hepatic margin of 32 patients were examined. Clinicopathologic parameters of the primary tumors of metastatic lesions as well as the width of hepatic resection margin and postoperative adjuvant therapies were recorded. Occult tumor cells were identified in 18 patients (56%). Postoperative adjuvant therapy was associated with longer relapse-free survival. Immunohistochemical detection of occult tumor cells is feasible and a frequent finding in the remaining tissue after hepatic metastasectomy.


Evaluate the impact of COVID-19 prevention policies on supply chain aspects under uncertainty.
Supply chain operations are disrupted due to natural disasters or epidemics. In the recent period, the supply chain suffers from obstacles and major challenges that affect its stages directly due to the spread of the COVID-19 epidemic around the world. The impact of this epidemic on supply chain performance is clear in terms of supply, demand, or logistics. This epidemic is characterized by a rapid spread, so countries have taken preventive policies in an attempt to limit its spread. These policies are direct impacts on the performance of the supply chain in all scopes. The extent of its impact varies from one supply chain to another, according to the activities that the supply chain provides. In order to provide a more accurate study of the impact of the measures taken to limit the spread of the epidemic, this research presents a proposed framework that evaluates the impact of these policies on the three main aspects of the supply chain (supply, demand, and logistics). The proposed framework is build using BWM and TOPSIS based on plithogenic set. Plithogenic set provides a more accurate evaluation result that addresses the uncertainty problem. Supply chain aspects were evaluated for the food industry, electronics industry, pharmaceutical industry, and textile industry.


Aqueous two-phase systems for protein separation: a perspective.
Aqueous two-phase systems (ATPS) that are formed by mixing a polymer (usually polyethylene glycol, PEG) and a salt (e.g. phosphate, sulphate or citrate) or two polymers and water can be effectively used for the separation and purification of proteins. The partitioning between both phases is dependent on the surface properties of the proteins and on the properties of the two phase system. The mechanism of partitioning is complex and not very easy to predict but, as this review paper shows, some very clear trends can be established. Hydrophobicity is the main determinant in the partitioning of proteins and can be measured in many different ways. The two methods that are more attractive, depending on the ATPS used (PEG/salt, PEG/polymer), are those that consider the 3-D structure and the hydrophobicity of AA on the surface and the one based on precipitation with ammonium sulphate (parameter 1/m*). The effect of charge has a relatively small effect on the partitioning of proteins in PEG/salt systems but is more important in PEG/dextran systems. Protein concentration has an important effect on the partitioning of proteins in ATPS. This depends on the higher levels of solubility of the protein in each of the phases and hence the partitioning observed at low protein concentrations can be very different to that observed at high concentrations. In virtually all cases the partition coefficient is constant at low protein concentration (true partitioning) and changes to a different constant value at a high overall protein concentration. Furthermore, true partitioning behavior, which is independent of the protein concentration, only occurs at relatively low protein concentration. As the concentration of a protein exceeds relatively low values, precipitation at the interface and in suspension can be observed. This protein precipitate is in equilibrium with the protein solubilized in each of the phases. Regarding the effect of protein molecular weight, no clear trend of the effect on partitioning has been found, apart from PEG/dextran systems where proteins with higher molecular weights partitioned more readily to the bottom phase. Bioaffinity has been shown in many cases to have an important effect on the partitioning of proteins. The practical application of ATPS has been demonstrated in many cases including a number of industrial applications with excellent levels of purity and yield. This separation and purification has also been successfully used for the separation of virus and virus-like particles.


Diverging times in movement analysis.
In movement analysis, more than one measuring system is often used to record biomechanical variables. Usually, it is desired to assign the occurring events to a common time line, which can be accomplished by synchronizing data acquisition, i.e. using a pulse to trigger a sample on all systems. However, this method is not supported by every system. Alternatively, the measurements of different systems can be started by a common trigger signal with no further synchronization of their sampling clocks during acquisition. With that, two systematic errors may be introduced, namely time lag and time drift. The extents of these errors not only depend on the individual system properties, but also depend on the set of systems combined. In this study, we introduce a simple method to determine time lag and time drift for two systems including cameras and force plates. Our results show that both parameters are present and dependent on chosen sampling frequencies. We conclude that in order to avoid misinterpretation of recorded signals the identified time lag and time drift need to be taken into account for trials of all durations.


Naming speed deficits in reading disability: multiple measures of a singular process.
Speed of word identification is important in the theories of reading proposed by La Berge and Samuels (1974) and Perfetti (1985), and is substantially correlated with reading skill. However, there is controversy about whether disabled readers have a speed deficit that is restricted to the identification of printed words, or if instead, they have a more general speed deficit in retrieving names of even single digits. To investigate this issue, poor and average readers (N = 43) in grade 2 were assessed on several indices of speed of digit and letter naming, using both continuous-list and discrete-trial methodologies. MANCOVA indicated clear effects of reader group on discrete-trial latencies, as well as an interaction between reader group and the speed with which to-be-named items were presented. A series of hierarchical regression analyses explored the amount of shared variance between various measures of digit naming speed and five indices of reading skill. Latency for word identification shares considerable variance with latency for digit naming, and, in general, accounts for the shared variance of naming speed and several other measures of reading skill. Naming speed contributed variance in reading skill. Naming speed contributed variance in reading skill independently of measures of phonological awareness.


Cell responses to cariogenic microorganisms and dental resin materials-Crosstalk at the dentin-pulp interface?
Resin monomers released from unpolymerized dental adhesives or composites and bacterial products like lipopolysaccharide (LPS) or lipoteichoic (LTA) are simultaneously present in specific applications following treatment of deep caries lesions. This review is focused on evidence concerning cell responses as a result of the interactions between adaptive mechanisms activated by resin monomers and signaling pathways of the immune response triggered by LPS or LTA originating from cariogenic microorganisms. Current understanding of dental caries progression and pathways in eukaryotic cells in response to LPS stimulation in a clinical situation as well as cell reactions to oxidative stress caused by resin monomers is analyzed based on publications available through online databases. LPS and LTA activate the redox-sensitive transcription factor NF-κB as a major regulator in immunocompetent dental pulp cells. Cell reactions to LPS/LTA associated with oxidative stress are downregulated by the redox-sensitive transcription factor Nrf2. Thus, activation of Nrf2 through resin monomer-induced oxidative stress due to the increased formation of reactive oxygen species (ROS) could be a molecular mechanism underlying the inhibition of LPS-stimulated responses such as the release of pro- or anti-inflammatory cytokines. Likewise, crosslinking of NF-κB and Nrf2-regulated biocompatibility pathways regulates cell death induced by the interaction of LPS and resin monomers. A multidimensional scenario through independent but linked NF-κB- and Nrf2-regulated pathways is activated in the clinical situation of caries treatment. Unfavorable or beneficial consequences strictly depend on a wide range of combinations and concentrations of bacterial products and resin monomers.


Advancing Cardio-Oncology in Asia.
Cardio-oncology is an emerging multi-disciplinary field, which aims to reduce morbidity and mortality of cancer patients by preventing and managing cancer treatment-related cardiovascular toxicities. With the exponential growth in cancer and cardiovascular diseases in Asia, there is an emerging need for cardio-oncology awareness among physicians and country-specific cardio-oncology initiatives. In this state-of-the-art review, we sought to describe the burden of cancer and cardiovascular disease in Asia, a region with rich cultural and socio-economic diversity. From describing the uniqueness and challenges (such as socio-economic disparity, ethnical and racial diversity, and limited training opportunities) in establishing cardio-oncology in Asia, and outlining ways to overcome any barriers, this article aims to help advance the field of cardio-oncology in Asia.


Contralateral hemimicrencephaly in neonatal hemimegalencephaly.
Identification of abnormalities in the contralateral hemisphere in patients with hemimegalencephaly is critical in their management. In this report, we present a 5-day-old neonate with hemimegalencephaly who demonstrated an enlarged ipsilateral cerebral hemisphere and diffuse volume loss in the contralateral hemisphere on conventional MR imaging sequences. The ipsilateral frontal white matter demonstrated relatively increased NAA, fractional anistropy, and cerebral blood volume values compared to published normative data. In addition, the white matter of the contralateral hemisphere demonstrated elevated lactate and increased mean diffusivity compared to published normative data, supporting the abnormal conventional MR findings. Advanced MR neuroimaging techniques may help further confirm and characterize abnormalities in the smaller contralateral hemisphere in neonatal hemimegalencephaly.


Tissue distribution of 14C-labeled residues of aminocarb in brown bullhead (Ictalurus nebulosus Le Sueur) following acute exposure.
Young brown bullhead (Ictalurus nebulosus) were exposed to aminocarb (4-dimethylamino-3-methylphenyl N-methylcarbamate) at lethal and sublethal concentrations and the tissue distribution of total unspecified residues was examined. The concentration of residues in each tissue increased with the concentration of exposure. The liver and stomach/intestine accumulated the largest concentrations of residues of all the tissues studied except for the abdominal fat deposit, which could not be evaluated at all exposure concentrations. These two tissues also displayed a steady increase in the proportion of the total body burden of aminocarb residues during 4 days of exposure to 0.092 mg aminocarb/liter. The proportion of residues in the carcass at this level of exposure decreased steadily over this same period, but was more similar to that found during exposure at the two lethal concentrations (92.7 and 159.3 mg/liter) as opposed to that found at the intermediate, nonlethal exposure level of 41.1 mg/liter. For all tissues examined, the concentration of residues at the end of 4 days of exposure to 0.092 mg/liter was significantly lower than the peak concentration reached during the exposure period, and clearance of residues was found to be relatively rapid.


Escherichia coli K12 mutants defective in the glycine cleavage enzyme system.
Two routes of one-carbon biosynthesis have been described in Escherichia coli K12. One is from serine via the serine hydroxymethyltransferase (SHMT) reaction, and the other is from glycine via the glycine cleavage (GCV) enzyme system. To isolate mutants deficient in the GCV pathway, we used a selection procedure that is based on the assumption that loss of this enzyme system in strains blocked in serine biosynthesis results in their inability to use glycine as a serine source. Mutants were accordingly isolated that grow with a serine supplement, but not with a glycine supplement. Enzyme assays demonstrated that three independently isolated mutants have no detectable GCV enzyme activity. The absence of a functional GCV pathway results in the excretion of glycine, but has no affect on the cell's primary source of one-carbon units, the SHMT reaction. The new mutations, designated gcv, were mapped between the serA and lysA genes on the E. coli chromosome.


Epidemiological observations on helminth infections of calves in southern Ghana.
This paper describes helminth infections in three groups of calves of different ages grazing naturally infested pastures from March 1987 to May 1988. Calves in which the faecal egg output was followed from birth showed Toxocara vitulorum eggs as early as two days after birth and maximum patency occurred after two months. The fall in Toxocara egg output coincided with a rise in that of the strongylates; Haemonchus spp., Trichostrongylus spp. and Oesophagostumum spp. The influence of rainfall in dictating strongylate nematode infection was clear with high egg output during high rainfall and low egg counts when the rainfall was lower. There was an indication that calves carry the infection from the end of the minor rainy season in November to the beginning of the next rains in March and then contribute to pasture contamination. However, calves born in December may remain uninfected until the onset of the rains.


Understanding drivers of vaccine hesitancy among pregnant women in Nigeria: A longitudinal study.
Vaccine-preventable-diseases are major contributors to disease burden in Sub-Saharan Africa. There is dearth of knowledge on the drivers of childhood vaccine hesitancy in Nigeria and its impact on coverage. Although understudied, pregnant women are a particularly important vulnerable group and very relevant for childhood vaccination decisions. This study's aims are to adapt Confidence, Complacency, Constraints, Calculation, and Collective Responsibility, also known as the 5C psychological antecedence scale for the Nigerian context and to measure predictors of intention to vaccinate among pregnant women (prenatal) and subsequent vaccination behavior (postnatal). It is a longitudinal study that used multi-stage sampling procedure. One healthcare facility was selected from each district in five regional clusters, from which 255 pregnant women were randomly drawn. A standardized questionnaire was used to collect relevant data, including the 5C and some additional variables. Multiple linear regression using backward elimination analysis was performed to identify intention at prenatal and behavior at postnatal. Pregnant women's intention to vaccinate unborn children was lower if they were Muslims, had lower confidence in public health system, if husband approval was important, and if they believed in rumor. At postnatal, vaccination behavior was more likely to follow mothers' religious beliefs, when confidence in vaccine effectiveness was high and when mothers felt responsible for the collective. However, everyday stress (constraints) related to less vaccination behavior, and intention did not predict actual vaccination behavior. The 5C scale needs revision before being widely used in Nigeria. Yet, it is a better tool for measuring vaccination behavior than intention.


Nonneoplastic tracheal and bronchial stenoses.
Nonneoplastic stenosis of proximal airways may result from longstanding intubations or tracheostomy, granulomatous infection, or systemic diseases such as relapsing polychondritis, amyloidosis, Wegener's granulomatosis, sarcoidosis, and inflammatory bowel disease. It also may be caused by saber sheath trachea, tracheobronchopathia osteoplastica, or broncholithiasis. An early diagnosis of the tracheal and bronchial stenosis has become possible with the advent of routine CT imaging. Multiplanar and volume rendering reformations after thin collimation MDCT acquisition help assess the location and extent of the stenosis and characterize the presence, distribution, and type of airway wall thickening. They also help surgeons and endoscopists to select adequate procedures and assess the response to treatment.


[Effectiveness and safety of non-pharmacological interventions for the prevention of venous thromboembolism in stroke patients: an overview of systematic reviews].
Half of the deaths recorded in non-surgical patients attributable to venous thromboembolism (VTE) affect those with stroke. The uncertain benefit of anticoagulant therapy has increased interest in non-pharmacological intervention to prevent VTE. To evaluate the efficacy and safety of non-pharmacological interventions to prevent VTE in stroke patients. Overview of systematic reviews with retrieval of documents in compliance with the PICOS Framework and through a research strategy implemented on 4 April 2019 in six biomedical databases and in the PROSPERO registry. The tools used to assess the methodological quality and the risk of bias were the AMSTAR checklist and the ROBIS tool, respectively. The results have been synthesized with narrative modality. Seven systematic reviews of different methodological quality and risk of bias met the inclusion criteria. The non-pharmacological interventions of prophylaxis used are graduated compression stockings (GCS) and intermittent pneumatic compression devices (IPCD). The first has no effect on VTE and has important side effects, the second is promising in reducing mortality from all causes and decreases the incidence of deep vein thrombosis. The use of IPCD, despite the efficacy observed, should be reserved, after a risk assessment of VTE and a subgroup analysis, for patients who can derive the maximum benefit from the intervention. In stroke patients the use of GCS to prevent VTE is not recommended because it is not superior to standard care and can cause damage. IPCD as a intervention of prophylaxis appears to be effective but further confirmation is needed from future studies.


Growth conditions control the size and order of actin bundles in vitro.
The bonding rules for actin filament bundles do not lead to a particular packing symmetry, but allow for either regular or disordered filament packing. Indeed, both hexagonal and disordered types of packing are observed in vivo. To investigate factors which control bundle order, as well as size, we examined the effect of protein concentration on the growth of actin-fascin bundles in vitro. We found that bundles require 4-8 d to achieve both maximum size and order. The largest and best ordered bundles were grown at low fascin and high actin concentrations (an initial fascin/actin ratio of 1:200). In contrast, a much larger number of poorly ordered bundles were formed at ratios of 1:25 and 1:50, and most surprisingly, no bundles were formed at 1:300 or 1:400. Based on these observations we propose a two-stage mechanism for bundle growth. The first stage is dominated by nucleation, which requires relatively high concentrations of fascin and which is therefore accompanied by rapid growth. Below some concentration threshold, nucleation ceases and bundles enter the second stage of slow growth, which continues until the supply of fascin is exhausted. By analogy with crystallization, we hypothesize that slower growth produces better order. We are able to use this mechanism to explain our observations as well as previous observations of bundle growth both in vitro and in vivo.


P1 variant antithrombins Glasgow (393 Arg to His) and Pescara (393 Arg to Pro) have increased heparin affinity and are resistant to catalytic cleavage by elastase. Implications for the heparin activation mechanism.
The heparin affinity of normal and two P1 variants of antithrombin-III (AT) was studied by gradient elution with NaCl in Tris buffer on heparin-Sepharose. At pH 7.4 normal AT eluted at [Na+] 0.78 mol/l and the variants both showed increased affinity with AT Pescara eluting at [Na+] 0.86 mol/l and AT Glasgow at [Na+] 0.92 mol/l. We have earlier proposed a model for heparin activation in which the native state of AT maintains a salt bridge involving the P1 Arg-393 residue. Binding of heparin induces a higher heparin affinity conformation in which the salt bridge is disrupted to reveal the reactive centre for inhibition of thrombin. The Glasgow and Pescara variants, lacking a reactive centre P1 basic residue, would be unable to form this salt bridge, and we suggested that the high affinity conformation which they adopt as their native state would resemble the heparin induced conformation. To examine this model, we measured the heparin induced fluorescence of two P1 variants and tested the susceptibility of their reactive loops to catalytic cleavage. Both variants had fluorescence spectra indistinguishable from normal AT. In the absence of heparin, neither variant was more susceptible than normal to catalytic cleavage by human neutrophil elastase. These findings suggest that the conformation of these P1 variants is different to that of fully heparinized normal AT.


Acute heat exposure improves microvascular function in skeletal muscle of aged adults.
Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. We hypothesized that acute hot water immersion would improve endothelial-dependent, but not endothelial-independent vasodilation in the microcirculation of the vastus lateralis muscle in healthy aged adults. Participants (70 ± 5 yr) were immersed for 60 min in thermoneutral (36°C) or hot (40°C) water. Ninety minutes following immersion, skeletal muscle microdialysis was used to bypass the cutaneous circulation and directly assess endothelial-dependent and endothelial-independent vasodilation by measuring the local hyperemic response to graded infusions of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. The hyperemic response to 27.5 mM ACh did not differ between thermal conditions (P = 0.9). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, 43.9 ± 23.2 mL/min/100 g vs. hot water immersion, 66.5 ± 25.5 mL/min/100 g; P < 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions (P = 0.3) but was increased following hot water immersion with the infusion of 42 mM SNP (thermoneutral immersion, 48.8 ± 25.6 mL/min/100 g vs. hot water immersion, 90.7 ± 53.5 mL/min/100 g; P < 0.01). These data suggest that acute heat exposure improves microvascular function in skeletal muscle of aged humans.NEW & NOTEWORTHY Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. Using the microdialysis technique to bypass the cutaneous circulation, we demonstrated that heat exposure improves endothelial-dependent and endothelial-independent vasodilation in the microcirculation of skeletal muscle in aged humans.


Digital x-ray imaging: the basics.
This article defines the terminology of digital imaging and presents an introduction to several modalities, with emphasis on digital video subtraction angiography. Topics discussed include special imaging considerations and problems, operating modes, and equipment configuration.


Chick receptor tyrosine phosphatase Psi is dynamically expressed during somitogenesis.
To study the role of receptor tyrosine phosphatases in vertebrate development, in particular somitogenesis, we have cloned chick receptor tyrosine phosphatase Psi (cRPTPPsi). cRPTPPsi is expressed in a dynamic fashion in the somites to-be-formed and uniformly throughout the presomitic mesoderm. In differentiating somites, cRPTPPsi expression gets restricted to the dermomyotome. In addition cRPTPPsi is expressed in the developing intermediate mesoderm, in neurogenic and sensory organs, the limb bud and the developing heart.


Simultaneous relative UV response determination of known liquid drug product degradants by NMR spectroscopy.
Determination of impurity level in weight percent against the claimed active pharmaceutical ingredient (API) in a drug product is of critical importance in drug development. However, authentic material used to determine relative UV response factor (RRF) for impurity quantitation is sometimes not available or not stable. In a particular drug product liquid formulation, three degradants, including one unstable impurity, are consistently observed in stability studies. Here we describe the application of NMR spectroscopy to assist in the determination of RRFs, simultaneously, for all three degradants directly from degraded drug product extracts. This technique was not only effective in determining RRF of an unstable substance, but also in defining RRFs of multiple degradants from a single drug product sample. Overall, this study continues to demonstrate the capabilities of NMR for impurity quantitation in drug development.


Deletions of chromosome 21 restricted to the leukemic cells of children with Down syndrome and leukemia.
Down syndrome (DS) is associated with an increased risk of developing hematological malignancies, but the basis for this predisposition is so far unknown. Using fluorescence in situ hybridization with a panel of locus-specific probes on normal and leukemic metaphases, we have found long-arm interstitial deletions of one of the chromosome 21s in the leukemic cells from five patients with DS and leukemia. This finding provides strong evidence for a gene or genes present on chromosome 21 having an important function in the development of leukemia in individuals with Down syndrome.


Minicell yield and cell division suppression in Bacillus subtilis mutants.
Minicell yield is determined by the probability of a minicell-producing division and the relationship of growth to division in Bacillus subtilis mutants.


Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function Decline and Chronic Kidney Disease in a Community-Dwelling Population.
Whether elevated plasma total homocysteine (tHcy) is a risk factor for the progression of kidney disease in general population has not been well established. The purpose of this study was to investigate the prognostic properties of plasma tHcy for renal function decrement and early chronic kidney disease (CKD) in community-dwelling populations with normal renal function at baseline. A total of 1,426 participants were enrolled and followed for a median of 4.8 years (interquartile range, 4.5-5.2), and estimated glomerular filtration rate (eGFR) was evaluated. One main outcome was the rapid eGFR decline defined as a decline in eGFR of >3 mL/min per 1.73 m2 per year; the other was the new incidence of CKD. At the end of follow-up, the incidence of rapid eGFR decline and new-onset CKD was 20.7 and 5.6%, respectively. In multivariate linear regression analysis, age, central pulse pressure, fasting blood glucose, and concentration of tHcy were independent determinants of the change in eGFR. There was a graded association between tHcy quartiles and eGFR decline. Compared with participants with the lowest quartile of tHcy levels, those with the highest quartile had significantly increased risk for rapid eGFR decline (adjusted odds ratio [aOR] = 1.81; 95% confidence interval [CI]: 1.25-2.94) and new onset of CKD (adjusted hazard ratio = 4.29; 95% CI: 1.42-12.99) after adjusting for various confounders. Similarly, significant associations were also found when baseline tHcy was classified as hyperhomocysteinemia (>15 μmol/L) versus normal tHcy level (≤15 μmol/L). However, there was only association between the change in tHcy levels and new occurrence of CKD but not with rapid eGFR decline (aOR = 0.99, p = 0.613). In this prospective cohort of individuals from community-based population, elevated plasma tHcy emerged as an independent predictor of renal function decline and incident CKD, which might support selection of at-risk individuals.


Synergistic effect of energy drinks and overweight/obesity on cardiac autonomic testing using the Valsalva maneuver in university students.
Obesity and caffeine consumption may lead to autonomic disturbances that can result in a wide range of cardiovascular disorders. To determine autonomic disturbances produced by the synergistic effects of overweight or obesity (OW/OB) and energy drinks. Cross-sectional, analytical. Physiology department at a university in Saudi Arabia. University students, 18-22 years of age, of normal weight (NW) and OW/OB were recruited by convenience sampling. Autonomic testing by the Valsalva ratio (VR) along with systolic and diastolic blood pressure, pulse pressure, and mean arterial blood pressure were measured at baseline (0 minute) and 60 minutes after energy drink consumption. Autonomic disturbance, hemodynamic changes. In 50 (27 males and 23 females) subjects, 21 NW and 29 OW/OB, a significant decrease in VR was observed in OW/OB subjects and in NW and OW/OB females at 60 minutes after energy drink consumption. Values of systolic and diastolic blood pressure, pulse pressure and mean arterial blood pressure were also significantly higher in OW/OB and in females as compared to NW and males. BMI was negatively correlated with VR and diastolic blood pressure at 60 minutes. Obesity and energy drinks alter autonomic functions. In some individuals, OW/OB may augment these effects. Due to time and resource restraints, only the acute effects of energy drinks were examined.


Effectiveness of workplace active rest programme on low back pain in office workers: a stepped-wedge cluster randomised controlled trial.
This study aimed to investigate the effectiveness of workplace active rest programme (WARP) on chronic low back pain (LBP) among office workers. A closed cohort, stepped-wedge cluster randomised trial was conducted. The total duration of the study was 16 weeks (4 weeks for each step). Sequence allocation was randomised, but no one was blinded. This study was conducted in three offices in a Japanese electronics company. One office was for the administrative department, the others are for the engineering department. We recruited 29 office workers with LBP greater than 3 months. LBP due to specific injury or disease was excluded. The median age was 38 years, and 26 (90%) were male. All participants completed the study. In the intervention phase, participants performed WARP comprising frequent stand-up and individualised brief exercise/physical activity during work. Physical therapists held an LBP workshop and developed tailor-made programmes before introducing WARP. We instructed participants to perform WARP at five timings during work. Control phase was set before the intervention and participants stayed as usual. The primary outcome was pain intensity of LBP assessed using the Brief Pain Inventory. The secondary outcomes were work productivity loss measured using the Work Limitations Questionnaire, LBP disability assessed using the Roland-Morris Disability Questionnaire, psychosocial subscale assessed using the STarT Back Screening Tool and physical activity measured using triaxial accelerometers. These outcomes were collected at baseline and at 4-month follow-up evaluation. In the intention-to-treat analysis, WARP did not show any significant effects on pain intensity (β, 0.01; 95% CI -0.50 to 0.52) and on the secondary outcomes. The median adherence to WARP was 28.6% (IQR, 16.8-41.1), which was equal to 1.43 times per day. No adverse effect was observed. The present study was unable to confirm the effectiveness of active rest in improving LBP. Hence, further study needs to investigate its effectiveness. UMIN000033210.


Multi-walled carbon nanotube/hydroxyapatite nanocomposite with leukocyte- and platelet-rich fibrin for bone regeneration in sheep model.
The aim of this study was to evaluate the effects of multi-walled carbon nanotubes/hydroxyapatite (MWCNT/HA) granules with or without leukocyte- and platelet-rich fibrin (L-PRF) on bone regeneration in cancellous bone of sheep model. Totally, 32 cylindrical holes were drilled in female sheep (n = 4) in the distal epiphysis and proximal metaphysis of right and left humerus and femur. The defects were randomly filled with (1) MWCNT/HA, (2) MWCNT/HA mixed with L-PRF, (3) L-PRF, and (4) left empty as control. After 8 weeks, defects were evaluated and compared radiographically using multi-slice computed tomographic (CT) scan and cone beam CT scans, histologically and histomorphometrically. The results showed that there was no significant inflammation (> 10%) or foreign body reaction around the granules. The new lamellar bone was regenerated around the MWCNT/HA nanocomposite granules. Addition of L-PRF to MWCNT/HA demonstrated significantly improvement of new bone formation, about 27.40 ± 1.08%, in comparison with the L-PRF alone, about (12.16 ± 1.46%) (P < 0.01). Also, the rate of new bone formation was significantly greater with the use of MWCNT/HA granules (24.59 ± 1.54%) compared to the control (10.36 ± 1.17%) (P < 0.01). Consequently, both biocompatibility and osteoconductivity of MWCNT/HA nanocomposite were demonstrated in the preclinical sheep model, and the use of L-PRF in combination with MWCNT/HA nanocomposite can improve bone regeneration.


Lacosamide intake during pregnancy increases the incidence of foetal malformations and symptoms associated with schizophrenia in the offspring of mice.
The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers' serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.


Increased purine nucleotides in adenosine deaminase-deficient lymphocytes.
It was found that ATP and cyclic AMP were greatly increased in human blood lymphocytes which were deficient in ADA. Certain other purine and pyrimidine nucleotides were elevated but to a lesser degree. Energy production in these cells may be inhibited by the increase in nucleotides since the ATP:ADP ratio was significantly below normal. Thus it appears that the immunologic deficiency in human ADA deficiency is related to increased nucleotide concentrations in the lymphocytes.


A new treatment for lingual nerve injury: an anatomical feasibility study for using a buccal nerve pedicle graft.
Lingual nerve (LN) palsy is a serious complication in dentistry and repaired by direct suture or a free graft technique. To our knowledge, there has been no study using a (long) buccal nerve (BN) graft as a donor for LN repair. Therefore, we aimed to clarify the location of the BN and investigate if it is feasible to reroute the BN to the LN. Twenty-four sides from 12 fresh-frozen Caucasian cadaveric heads were used in this study. The mean age at death was 73.9 ± 13.4 years. The LN was dissected on the floor of the oral cavity medial to the third molar tooth. Next, the mucosa with the buccinator muscle, pterygomandibular raphe, and superior pharyngeal constrictor muscle on the retromolar area was retracted anteriorly to widen the pathway of the LN. Finally, the BN was cut and transposed to the LN through this widened pathway to its feasibility. The mean diameter of the BN and vertical distance from the horizontal part of the retromolar trigone to the BN was 1.47 ± 0.32 mm and 18.53 ± 6.21 mm, respectively. On all sides, the BN was able to be transposed to the LN without tension. Such a technique might be used for the patients with LN injury and who have lost sensation of the tongue.


Influence of 50 Hz electromagnetic fields in combination with a tumour promoting phorbol ester on protein kinase C and cell cycle in human cells.
It still is an unsolved issue whether exposure to power-line frequency electromagnetic fields (EMF) may promote carcinogenesis and if so whether it does so by influencing the proliferation, the survival, and the differentiation of cells. Since the family of protein kinases C (PKC) takes part in these processes by interacting with signal transduction pathways at several levels including the activation of transcription factors, we evaluated in the present study the effects of exposure of human amniotic fluid cells (AFC) to 50 Hz, 1 mT electromagnetic fields (EMF) alone and in combination with the tumour promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) on the subcellular localization of PKC protein, on PKC enzyme activity, and on the cell cycle distribution. Quantitative analyses of the PKC expression pattern demonstrated the translocation of PKC from the cytosolic to the membrane fraction after exposure to 10, 50, 100 nM, and 1 microM TPA. EMF exposure alone showed no effect on PKC translocation. Co-exposure to 10, 50, and 100 nM TPA and I mT EMF revealed a significant additive effect (25 +/- 50, 66 +/- 29, 22 +/- 50%, respectively) with the most prominent increase at the concentration of 50 nM TPA. At the highest concentration of TPA used (1 microM) no additive effect of EMF could be observed. Data on enzymatic activity indicate that EMF modulate the PKC activity, showing a significant increase of 10 +/- 16% in total PKC activity after co-exposure to 50 nM TPA and 1 mT EMF when compared to 50 nM TPA alone. Flow cytometric analyses showed a transient cell cycle arrest in G0/G1-phase followed by a delayed transit through S-phase in response to TPA, which was, however, not enhanced by co-exposure with EMF. We conclude that in AFC cells TPA at lower concentrations (< or = 100 nM) induces a less than maximum effect on the PKC pathway, which can be enhanced by the applied EMF.


Postoperative Evaluation of Reduction Loss in Proximal Humeral Fractures: A Comparison of Plain Radiographs and Computed Tomography.
To compare postoperative CT images with plain radiographs for measuring prognostic factors of reduction loss of fractures of the proximal part of the humerus. A total of 65 patients who sustained fractures of the proximal humerus treated with locking plates from June 2012 to October 2015 were retrospectively analyzed. There were 24 men and 41 women, with a mean age of 60.0 years (range, 22-76 years). According to the Neer classification system of proximal humeral fracture, there were 26 two-part, 27 three-part and 12 four-part fractures of the proximal part of the humerus, and all fractures were treated with open reduction and internal fixation (ORIF) using locked plating. All postoperative CT images and plain radiographs of the patients were obtained. Prognostic factors of the reduction loss were the change of neck shaft angle (NSA) and the change of humeral head height (HHH). The change of NSA and HHH were evaluated by the difference between postoperative initial and final follow-up measurement. Reduction loss was defined as the change ≥10° for NSA or ≥5 mm for HHH. The NSA and HHH were measured using plain radiographs and 3-D CT images, both initially and at final follow-up. The paired t-test was used for comparison of NSA, change of NSA, HHH, and change of HHH between two image modalities. The differences between two image modalities in the assessment of reduction loss were examined using the χ2 -test (McNemar test). Intraclass correlation coefficients (ICC) were used to assess the intra-observer and inter-observer reliability. 3-D CT images (ICC range, 0.834-0.967) were more reliable in all parameters when compared with plain radiographs (ICC range, 0.598-0.915). Significant differences were found between the two image modalities in all parameters (plain radiographs: initial NSA = 133.6° ± 3.8°, final NSA = 130.0° ± 1.9°, initial HHH = 17.9 ± 0.9 mm, final HHH = 15.8 ± 1.5 mm; 3-D CT: initial NSA = 131.4° ± 3.4°, final NSA = 128.8° ± 1.7°, initial HHH = 16.8 ± 1.2 mm, final HHH = 14.5 ± 1.1 mm; all P < 0.05). In the assessment of reduction loss, the percentage was 16.9% (11/65) for the plain radiographs and 7.7% (5/65) for the 3-D CT scans (P < 0.05). For the 5 patients with reduction loss, which were observed by two imaging modalities, the mean Constant-Murley score was 61.0 ± 1.6. The patients with reduction loss, observed only in plain radiographs but not CT images, had good shoulder function (Constant-Murley score: 82.7 ± 1.0). Our data reveal that 3-D CT images are more reliable than plain radiographs in the assessment of the prognostic factors of reduction loss of fractures of the proximal part of the humerus with treatment of locking plates; this reliable CT technique can serve as an effective guideline for the subsequent clinical management of patients.


Beta-very low density lipoproteins in cholesterol-fed rabbits are of hepatic origin.
When rabbits are fed a cholesterol-rich diet they accumulate beta-migrating very low density lipoprotein (beta-VLDL) in their plasma. beta-VLDL are cholesteryl ester-rich lipoproteins which contain apolipoproteins B and E. There are 2 forms of apolipoprotein B in beta-VLDL. About 90% of apolipoprotein B is present as a 320 000-dalton protein and the remainder is present as a 210 000-dalton protein. These apolipoproteins are tissue specific. Lipoproteins secreted by perfused rabbit livers contain only the 320 000-dalton apolipoprotein B while lipoproteins secreted by the intestine contain only the 210 000-dalton apolipoprotein B. The tissue specificity of apolipoprotein B shows that beta-VLDL is largely of hepatic origin and that only a small fraction is of intestinal origin. The composition of VLDL secreted from the livers of cholesterol-fed rabbits is similar to that of plasma beta-VLDL. Both are cholesteryl ester-rich, in contrast to plasma and perfusate VLDL from normal rabbits which are both triglyceride-rich. This indicates that the cholesteryl ester-rich hepatic VLDL is a direct precursor for plasma beta-VLDL.


Every islet matters: improving the impact of human islet research.
Detailed characterization of human pancreatic islets is key to elucidating the pathophysiology of all forms of diabetes, especially type 2 diabetes. However, access to human pancreatic islets is limited. Pancreatic tissue for islet retrieval can be obtained from brain-dead organ donors or from individuals undergoing pancreatectomy, often referred to as 'living donors'. Different protocols for human islet procurement can substantially impact islet function. This variability, coupled with heterogeneity between individuals and islets, results in analytical challenges to separate genuine disease pathology or differences between human donors from experimental noise. There are currently no international guidelines for human donor phenotyping, islet procurement and functional characterization. This lack of standardization means that substantial investments from multiple international efforts towards improved understanding of diabetes pathology cannot be fully leveraged. In this Perspective, we overview the status of the field of human islet research, highlight the challenges and propose actions that could accelerate research progress and increase understanding of type 2 diabetes to slow its pandemic spreading.


Impact of the physical properties of contact lens materials on the discomfort: role of the coefficient of friction.
Contact Lens Discomfort (CLD) is the main cause in contact lens (CLs) discontinuation, referred in literature as drop-out phenomenon. Despite such evidence was reported in several clinical studies, a relationship between physico-chemical properties of CLs and CLD is not still totally understood. In this regard, the friction of CLs surfaces seems to be related to discomfort feeling events, probably due to an alteration of the lubricate function of the tear film after the CL placement inside the ocular environment. In the last years, many studies have been finalized to the friction measurements of CLs surface, finding conflicting data due to a lack in standardized protocol. The aim of this review is primarily to show evident relationships between CLs surface properties (i.e. wettability, tear evaporation, tear film quality, etc.) and the coefficient of friction (CoF), resulting therefore the most relevant physical quantity in the CLs characterization. In addition, we reported the most recent studies in CLs tribology, which highlight that the introduction of a standard protocol in CoF measurements is necessary to obtain reproducible results, considering the aim to evaluate in a more precise way the relationship between this material surface property and comfort in CLs users.


CT diagnosis of massive hemorrhage from hepatocellular carcinoma.
Massive hemorrhage from rupture of hepatocellular carcinoma is uncommon. We report our experience in two cases diagnosed by CT.


Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy.
To evaluate the subfoveal choroidal thickness in the fellow eyes of patients with CSC, a disease often associated with choroidal vascular hyperpermeability even in eyes without subretinal fluid. In this observational cross-sectional study, we measured the bilateral subfoveal choroidal thickness in patients with unilateral CSC using enhanced depth imaging spectral-domain optical coherence tomography. Areas of choroidal vascular hyperpermeability were visualized with indocyanine green angiography. Sixty-six consecutive Japanese patients (50 men, 16 women; mean age, 52.8 years) with unilateral CSC were examined. The subfoveal choroid in symptomatic eyes was significantly thicker than that in fellow eye (414 ± 109 μm vs. 350 ± 116 μm, P < 0.001, respectively). The subfoveal choroid of eyes with choroidal vascular hyperpermeability was 410 ± 92 μm, which differed significantly (P < 0.001) from the choroid (239 ± 59 μm) of fellow eyes without choroidal vascular hyperpermeability. The subfoveal choroid in the fellow eyes of patients with CSC was thicker in the eyes with choroidal vascular hyperpermeability. Enhanced depth imaging spectral-domain optical coherence tomography can assess the effects of choroidal vascular hyperpermeability by measuring the choroidal thickness noninvasively.


Plasma levels of prolactin and gonadal steroids in relation to multiple-brooding and renesting in free-living populations of the song sparrow, Melospiza melodia.
Plasma levels of testosterone (T), estradiol (E2), and prolactin were measured in samples collected from free-living song sparrows, Melospiza melodia. In males, plasma levels of T were elevated early in the season when territories were established and when females laid the first clutch of eggs. Thereafter, T levels declined and remained low throughout the remainder of the breeding cycle. However, if the first brood was lost to a predator, or by experimental removal of the nest, plasma levels of T increased as renesting, to replace the clutch, occurred. Circulating levels of prolactin in males began to rise during the egg-laying stage of the first brood, reached a maximum toward the end of the incubation stage, remained elevated until breeding was terminated, and then declined throughout the moulting stage to basal values in October. Prolactin levels remained high throughout the breeding season irrespective of whether a brood was raised successfully or whether the nest was lost and renesting occurred. In females, plasma levels of E2 were elevated prior to the egg-laying stage for each brood as is typical of multiple-brooded species. However, prolactin titers rose dramatically during egg-laying for the first clutch (slightly higher than in males) and were maximal by onset of incubation. Only females of this species incubate, although males do feed young. As in males, plasma prolactin in females remained high between broods and during experimentally induced renesting, and then declined to basal by the end of the moult stage in October. These data suggest that there are no differences in the temporal patterns of prolactin concentrations in blood between multiple-brooding and renesting. In a separate experiment, captive male song sparrows were transferred from a short day to artificial long days (18L 6D) and a control group was maintained on 9L 15D. In the long-day group, prolactin levels rose abruptly over the first 20 days, as the testes developed, and remained high well into postnuptial moult after the gonads had regressed. Prolactin remained basal in the control group. These data suggest that the temporal pattern of circulating prolactin levels throughout the breeding season is regulated at least partly by changing photoperiod. However, nonphotoperiodic factors are also important since photoperiodically induced increases in prolactin are significantly less than those seen in free-living individuals. These differences may be related to parental behavior.


Functional expression and molecular characterization of AtUBC2-1, a novel ubiquitin-conjugating enzyme (E2) from Arabidopsis thaliana.
The first member of a novel subfamily of ubiquitin-conjugating E2-proteins was cloned from a cDNA library of Arabidopsis thaliana. Genomic blots indicate that this gene family (AtUBC2) consists of two members and is distinct from AtUBC1, the only other E2 enzyme known from this species to date (M.L. Sullivan and R.D. Vierstra, Proc. Natl. Acad. Sci. USA 86 (1989) 9861-9865). The cDNA sequence of AtUBC2-1 extends over 794 bp which would encode a protein of 161 amino acids and a calculated molecular mass of 18.25 kDa. The protein encoded by AtUBC2-1 is shown to accept 125I-ubiquitin from wheat E1 enzymes, when expressed from Escherichia coli hosts as fusion protein carrying N-terminal extensions. It is deubiquitinated in the presence of lysine and, by these criteria, is considered a functional E2 enzyme.


Methane formation by oxidation of ascorbic acid using iron minerals and hydrogen peroxide.
The possibility of methane formation in an oxidative environment has been intensely debated, especially since the discovery of methane generation by living plants. However, recent studies with animal tissue suggested that under specific conditions aerobic methane formation is also possible. Here, we investigated the generation of methane in an abiotic model system using bioavailable substances. We show formation of methane in a highly oxidative media, using ascorbic acid, ferrihydrite and hydrogen peroxide as reagents. Methane production was shown to be related to reagent ratio, reaction volume and pH. A 2:1 ratio of hydrogen peroxide to ascorbic acid, catalytic amounts of ferrihydrite and acidic conditions (pH 3) enhanced formation of methane. We further show that gaseous oxygen has a strong influence with higher levels found to inhibit methane formation. This study is a first step towards providing an insight for the reaction mechanism of methane formation that would be applicable to aerobic environments.


A TrxR inhibiting gold(I) NHC complex induces apoptosis through ASK1-p38-MAPK signaling in pancreatic cancer cells.
Cancer cells in the advanced stage show aberrant antioxidant capacity to detoxify excessive ROS resulting in the compensation for intrinsic oxidative stress and therapeutic resistance. PDAC is one of the most lethal cancers and often associated with a high accumulation of ROS. Recent studies identified gold(I) NHC complexes as potent TrxR inhibitors suppressing cell growth in a wide spectrum of human malignant cell lines at the low micromolar concentration. However, the mechanism of action is not completely elucidated yet. To understand the biological function of gold(I) NHC complexes in PDAC, we used a recently published gold(I) NHC complex, MC3, and evaluated its anti-proliferative effect in four PDAC cell lines, determined by MTT and SRB assays. In further detailed analysis, we analyzed cellular ROS levels using the ROS indicator DHE and mitochondrial membrane potential indicated by the dye JC-1 in Panc1. We also analyzed cell cycle arrest and apoptosis by FACS. To elucidate the role of specific cell signaling pathways in MC3-induced cell death, co-incubation with ROS scavengers, a p38-MAPK inhibitor and siRNA mediated depletion of ASK1 were performed, and results were analyzed by immunoblotting, ELISA-microarrays, qRT-PCR and immunoprecipitation. Our data demonstrate that MC3 efficiently suppressed cell growth, and induced cell cycle arrest and apoptosis in pancreatic cancer cells, in particular in the gemcitabine-resistant cancer cells Panc1 and ASPC1. Treatment with MC3 resulted in a substantial alteration of the cellular redox homeostasis leading to increased ROS levels and a decrease in the mitochondrial membrane potential. ROS scavengers suppressed ROS formation and rescued cells from damage. On the molecular level, MC3 blocked the interaction of Trx with ASK1 and subsequently activated p38-associated signaling. Furthermore, inhibition of this pathway by using ASK1 siRNA or a p38 inhibitor clearly attenuated the effect of MC3 on cell proliferation in Panc1 and ASPC1. Our results confirm that MC3 is a TrxR inhibitor and show MC3 induced apoptosis in gemcitabine-resistant PDACs. MC3 mediated cell death could be blocked by using anti-oxidants, ASK1 siRNA or p38 inhibitor suggesting that the Trx-ASK1-p38 signal cascade played an important role in gold(I) NHC complexes-mediated cellular damage.


Possible effect of blonanserin on gambling disorder: A clinical study protocol and a case report.
Gambling disorder is characterized by excessive and recurrent gambling and can have serious negative social consequences. Although several psychotherapeutic and pharmacological approaches have been used to treat gambling disorder, new treatment strategies are needed. Growing evidence suggests that dopamine D3 receptor plays a specific role in the brain reward system. To investigate if blonanserin, a dopamine D3 receptor antagonist, would be effective in reducing gambling impulses in patients with gambling disorder. We developed a study protocol to measure the efficacy and safety of blonanserin as a potential drug for gambling disorder, in which up to 12 mg/d of blonanserin was prescribed for 8 wk. A 37-year-old female patient with gambling disorder, intellectual disability, and other physical diseases participated in the pilot study. The case showed improvement of gambling symptoms without any psychotherapy. However, blonanserin was discontinued owing to excessive saliva production. This case suggests that blonanserin is potentially an effective treatment for patients with gambling disorder who resist standard therapies, but it also carries a risk of adverse effects. Further studies are needed to confirm the findings.


A novel thermosensitive persulfate controlled-release hydrogel based on agarose/silica composite for sustained nitrobenzene degradation from groundwater.
The increasing risk of organic contamination of groundwater poses a serious threat to the environment and human health, causing an urgent need to develop long-lasting and adaptable remediation materials. Controlled-release materials (CRMs) are capable of encapsulating oxidants to achieve long-lasting release properties in aquifers and considered to be effective strategies in groundwater remediation. In this study, novel hydrogels (ASGs) with thermosensitive properties were prepared based on agarose and silica to achieve controlled persulfate (PS) release. By adjusting the composition ratio, the gelation time and internal pore structure of the hydrogels were regulated for groundwater application, which in turn affected the PS encapsulated amount and release properties. The hydrogels exhibited significant temperature responsiveness, with 6.8 times faster gelation rates and 2.8 times longer controlled release ability at 10 ℃ than at 30 ℃. The ASGs were further combined with zero-valent iron to achieve long-lasting degradation of the typical nitrobenzene compound 2,4-dinitrotoluene (2,4-DNT), and the degradation performance was maintained at 50 % within 14 PV, which was significantly improved compared with that of the PS/ZVI system. This study provided new concepts for the design of controlled-release materials and theoretical support for the remediation of organic contamination.


Epidemiological surveillance of colonising group B Streptococcus epidemiology in the Lisbon and Tagus Valley regions, Portugal (2005 to 2012): emergence of a new epidemic type IV/clonal complex 17 clone.
This study presents the serotype distribution and the antibiotic resistance profile of 953 colonising group B Streptococcus (GBS) recovered from women of child bearing age (15 to 49 years) between 2005 and 2012 in the Lisbon and Tagus Valley region, Portugal. Overall, serotypes Ia, II, III, and V were the most common, accounting 752 of the 953 isolates (about 80%). However, there were changes in GBS distribution, in particular in the two last years of the study. Of note, the proportion of serotype IV isolates increased from 1% (2/148) in 2006 to 20% (19/97) in 2012. Also, considerable proportions of serotype IV isolates from 2010 to 2012 were respectively resistant to erythromycin (9/43; 21%) or clindamycin (6/43; 14%). The identification of nine serotype IV isolates presenting a novel association with the clonal complex (CC) 17 lineage, involving a putative capsular switch, may accentuate their virulence potential and ecological success. Molecular analysis of this subgroup of isolates revealed the presence of rib, IS (insertion sequence) 861 and GBSi1 group II intron within the C5a peptidase gene (scpB) – laminin-binding protein gene (lmb) region, reflecting high clonality and a putative common origin. A close surveillance of the emergent type IV/CC17 isolates is crucial considering the potential impact over GBS treatment guidelines and capsular vaccine development.


Persistent carriage and infection by multidrug-resistant Escherichia coli ST405 producing NDM-1 carbapenemase: report on the first Italian cases.
We report on the first detection of the NDM-1 carbapenemase in Italy, in Escherichia coli isolated in October 2009. Prolonged colonization and relapsing infection by NDM-1-positive E. coli were observed in a patient (index case) with an indirect epidemiological link with areas of endemicity. Transient colonization was apparently observed in another patient linked with the index case.


Retinopathy screening in children and adolescents with diabetes.
Diabetic retinopathy is a complication of diabetes that affects the blood vessels of the retina. The majority of patients with diabetic retinopathy exhibit background retinopathy. In approximately 10% of patients, background retinopathy will progress to sight-threatening retinopathy. The aims of our study were to measure the prevalence of retinopathy among our population and to assess the optimal time of screening children and adolescents with type 1 diabetes.


Health Disparities Across Lung Cancer Continuum Among Asian Americans: A Systematic Review.
The purpose of this systematic review is to synthesize lung cancer associated health disparities across the cancer continuum among Asian Americans. A systematic review design with the narrative method was used for conducting this study. Electronic literature databases, including PubMed, Google Scholar, and CINAHL, were searched. After applying filter information, inclusion and exclusion criteria, a total of 20 articles were included in the review. Findings related to lung cancer prevention, screening, incidence rates, diagnosis, treatment, survival rates, and mortality rates among Asian Americans were synthesized. Results showed the prevalence of smoking quit attempts in the past year was high among Asian Americans, although the prevalence of receiving advice to quit and using counseling and/or medication services was low among this population. Also, the smoking cessation rate among Asian Americans was the second lowest among all racial groups, although the abstinence rate was highest among this population. Compared with other races, Asian Americans are more likely to be diagnosed with lung cancer at a distant stage of disease, and they tend to be less likely to undergo surgery than other races in the United States. The incidence and mortality rates of lung cancer were low among Asian Americans compared with other races in the United States, while the survival rate of lung cancer was high among this population. Further research focusing on lung cancer associated health disparities in specific Asian American ethnic groups should be conducted. Culturally relevant programs that tackle cultural and genetic factors related to lung cancer risk as well as early screening, diagnosis and treatment in this vulnerable population are also necessary.


Induction of polymyxin resistance in Pseudomonas fluorescens by phosphate limitation.
Shift of Pseudomonas fluorescens NCMB 129 from a a phosphate rich into a phosphate limited medium results in a reduction of the membrane phospholipids phosphatidylethanolamine, phosphatidylglycerol and cardiolipin. Concomitantly a positively charged ornithine amide lipid is synthesized. The gradual increase of this lipid is paralleled by an increasing resistance to polymyxin B. The binding capacities of intact cells, and isolated inner and outer membranes for the antibiotic are reduced in the resistant organisms. It is discussed that the observed effect could be circumstantial evidence that the positively charged polymyxin B needs negatively charged receptors in biological membranes in order to exert its antibiotic activity.


Impacts of environmental change on biodiversity and vegetation dynamics in Siberia.
Biological diversity is the basis for, and an indicator of biosphere integrity. Together with climate change, its loss is one of the two most important planetary boundaries. A halt in biodiversity loss is one of the UN Sustainable Development Goals. Current changes in biodiversity in the vast landmass of Siberia are at an initial stage of inventory, even though the Siberian environment is experiencing rapid climate change, weather extremes and transformation of land use and management. Biodiversity changes affect traditional land use by Indigenous People and multiple ecosystem services with implications for local and national economies. Here we review and analyse a large number of scientific publications, which are little known outside Russia, and we provide insights into Siberian biodiversity issues for the wider international research community. Case studies are presented on biodiversity changes for insect pests, fish, amphibians and reptiles, birds, mammals and steppe vegetation, and we discuss their causes and consequences.


The reticuloendothelial system and aging: a review.
This review represents an attempt to summarize and evaluate the literature data on the changes occurring in the reticuloendothelial system (RES) during aging. The RES is briefly introduced with emphasis on cellular composition, function, physiology, regulation and the methods employed for assessment of its functions. The age-related changes in the RES are discussed in terms of endocytotic capacity, antimicrobial and antitumor activity and morphology. In addition, the cooperation between the RES and the immune system in the defence of the body against disease agents is discussed in relation to the increased susceptibility to infectious diseases and tumorigenesis in both man and experimental animals during aging.


Dihydro-β-agarofuran-type sesquiterpenoids from the seeds of Celastrus virens with lifespan-extending effect on the nematode Caenorhabditis elegans.
Twelve dihydro-β-agarofuran-type sesquiterpenoids, including five new ones (1-5), were purified from the seeds of Celastrus virens (Wang et Tang) C. Y. Chent et T. C. Kao. Their chemical structures were characterized via comprehensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and computational prediction of ECD, as well as comparison of observed and reported NMR spectral data. Among the isolates, nine abundant dihydro-β-agarofuran-type sesquiterpenoids were evaluated for their lifespan-extending activity using the nematode Caenorhabditis elegans model. As a result, compounds 1, 2, 5, 6, 8, and 9 (50 μM) significantly extended the mean survival time of C. elegans, respectively, compared with the blank control group (p < 0.05). Further Quantitative RT-PCR showed that the prolonging of lifespan mediated by compounds 1, 6, 8, and 9 were dependent on the transcription factors skn-1 and hsf-1.


Effects of altering aminoglycoside structures on bacterial resistance enzyme activities.
Aminoglycoside-modifying enzymes (AMEs) constitute the most prevalent mechanism of resistance to aminoglycosides by bacteria. We show that aminoglycosides can be doubly modified by the sequential actions of AMEs, with the activity of the second AME in most cases unaffected, decreased, or completely abolished. We demonstrate that the bifunctional enzyme AAC(3)-Ib/AAC(6')-Ib' can diacetylate gentamicin. Since single acetylation does not always inactivate the parent drugs completely, two modifications likely provide more-robust inactivation in vivo.


Prolonged therapy with ACE inhibitors induces a regression of left ventricular hypertrophy of dialyzed uremic patients independently from hypotensive effects.
Left ventricular hypertrophy (LVH), which frequently occurs in chronic uremia, may be due in part to factors other than arterial hypertension, chronic anemia, and/or other well-known loading conditions inherent to the uremic state. Angiotensin-converting enzyme (ACE) inhibitors may be able to reverse LVH by mechanisms independent of their antihypertensive effects. In this study, 18 subjects free of arterial hypertension or severe anemia were selected from 170 chronically hemodialyzed uremic patients after fulfilling the criterion of a supranormal left ventricular mass (LVM). Ten subjects agreed to undergo treatment with 2.5 to 20 mg lisinopril every other day over a period of 2 years, during which annual determinations of the LVM by echocardiography and of the 24-hour blood pressure with a portable device were carried out. Eight patients unwilling to undergo the treatment served as controls. The average resting left ventricular mass index (LVMi) of the overall group was 178 +/- 30 g/m2 body surface area (+/- SD), and did not differ between the two subgroups. Lisinopril treatment significantly decreased the LVM of eight of 10 treated subjects and actually even completely normalized it in three. The LVM of the untreated group remained unchanged. Systolic and diastolic blood pressures were 138 +/- 5 mm Hg and 78 +/- 6 mm Hg in the treated group and 133 +/- 9 mm Hg and 75 +/- 4 mm Hg in the untreated group, respectively (P = NS), and did not vary over the following 2 years. This study indicates that a mild degree of LVH, which is seemingly independent of arterial blood pressure load, does exist in a tight subset of uremic patients. This study also demonstrates that this type of LVH is apparently nonprogressive. ACE inhibitors given at doses not affecting blood pressure are able to reverse it.


Optimization of therapeutic antibodies by predicting antigen specificity from antibody sequence via deep learning.
The optimization of therapeutic antibodies is time-intensive and resource-demanding, largely because of the low-throughput screening of full-length antibodies (approximately 1 × 103 variants) expressed in mammalian cells, which typically results in few optimized leads. Here we show that optimized antibody variants can be identified by predicting antigen specificity via deep learning from a massively diverse space of antibody sequences. To produce data for training deep neural networks, we deep-sequenced libraries of the therapeutic antibody trastuzumab (about 1 × 104 variants), expressed in a mammalian cell line through site-directed mutagenesis via CRISPR-Cas9-mediated homology-directed repair, and screened the libraries for specificity to human epidermal growth factor receptor 2 (HER2). We then used the trained neural networks to screen a computational library of approximately 1 × 108 trastuzumab variants and predict the HER2-specific subset (approximately 1 × 106 variants), which can then be filtered for viscosity, clearance, solubility and immunogenicity to generate thousands of highly optimized lead candidates. Recombinant expression and experimental testing of 30 randomly selected variants from the unfiltered library showed that all 30 retained specificity for HER2. Deep learning may facilitate antibody engineering and optimization.


Ca2+ transport systems mediating the high K+/low Na+-induced uptake of Ca2+ into rat atrium.
The effect of high K+/low Na+-Tyrode's solution on Ca2+ uptake into neonatal rat atrium was studied using 45Ca2+. Substitution of 60-129 mM Na+ in Tyrode's solution by equimolar concentrations of K+ or choline, significantly (with the exception of 60 mM choline substitution) increased Ca2+ uptake above control. Furthermore, the Ca2+ uptake stimulated by K+ substitution was significantly greater than that stimulated by choline substitution at the corresponding concentrations. The choline/low Na+-induced Ca2+ uptake (i.e. that above the Ca2+ uptake measured in normal Tyrode's solution) was increased by pre-exposure to either ice-cold Tyrode's solution for 1 h (approximately 36% increase) or to K+-free Tyrode's solution for 3 h (approximately 100% increase). The choline/low Na+-induced Ca2+ uptake was abolished by the hypertonic addition of NaCl (returning the bathing Na+ concentration to normal), increased (approximately 140%) by the addition of 1.8 mM PO4(3-)-free Hepes buffered choline/low Na+ media, but unaffected by 0.2 mM cadmium. The high K+/low Na+-induced Ca2+ uptake (i.e. that above the Ca2+ uptake measured in normal Tyrode's solution) was relatively insensitive to pre-exposure to cold (0% change) or K+-free media (11% increase) and only 50% inhibited by the hypertonic addition of NaCl (returning the bathing Na+ concentration to normal). However, the high K+/low Na+-induced Ca2+ uptake was 57% inhibited by 0.2 mM cadmium and approximately 30% inhibited by the addition of 1.8 mM PO4(3-) to HCO3-/PO4(3-)-free Hepes buffered high K+/low Na+ media.(ABSTRACT TRUNCATED AT 250 WORDS)


Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome.
Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly).


Discussing Mild Cognitive Impairment.
Dr. Purganan reports that her spouse has served on an advisory board for Dova Pharmaceuticals and Targeted Oncology, has served as a speaker for the Chronic Liver Disease Foundation/Focus Medical Communications, has received research funding from Arrowhead Pharmaceuticals, and has received sponsored travel for research support from Arrowhead Pharmaceuticals and Genfit/Covance.


Role of phospholipid transfer protein on the plasma distribution of amphotericin B following the incubation of different amphotericin B formulations.
The purpose of this study was to investigate the role of phospholipid transfer protein (PLTP) on the plasma distribution of amphotericin B (AmpB) following incubation with different AmpB formulations in human plasmas with varying lipid profiles. In a first set of experiments, plasma distribution profiles of AmpB were determined following the incubation of Fungizone and lipid-based formulations (Abelcet and AmBisome) at a concentration of 20 microg AmpB/mL for 5-120 min at 37 degrees C in the plasma obtained from six different individuals (total cholesterol concentrations range between 62 and 332 mg/dL). In a second set of experiments, Abelcet, and AmBisome at a concentration of 20 microg AmpB/mL were incubated for 5 min at 37 degrees C in human plasma (total cholesterol = 163 mg/dL) that had been pretreated with an antibody raised up against PLTP (1:400 v/v dilution from stock solution) for 20 min at 37 degrees C. Following incubation, the human plasma was separated into its lipoprotein and lipoprotein-deficient fractions by density gradient ultracentrifugation and analyzed for AmpB content by high-performance liquid chromatography. The majority of AmpB was covered in the lipoprotein-deficient plasma and high-density lipoprotein (HDL) fractions following incubation of Fungizone in human plasma. The majority of AmpB (48.7-87.2%) was recovered in the HDL fraction following incubation of Abelcet and AmBisome in human plasma. The presence of the PLTP antibody resulted in a 20% decrease in the percentage AmpB recovered in the HDL fraction following the incubation of Abelcet. However, the plasma distribution of AmpB remained unchanged following the incubation of AmBisome in plasma containing the PLTP antibody. Taken together, these findings suggest indirect evidence that PLTP may play an important role in the plasma distribution profile of AmpB following the incubation of Abelcet and may be one of the factors responsible for the preferential association of AmpB with HDL when administered as Abelcet.


Inflammatory bowel disease and risk of urinary cancers: a systematic review and pooled analysis of population-based studies.
The aim of this study is to elucidate the risk of urologic cancers in patients with Crohn's disease (CD) and ulcerative colitis (UC). Electronic databases including PubMed, the Cochrane Library, Embase and Web of Science, and manual retrieval were conducted from inception to June 2020. Two reviewers independently searched the above databases and selected the studies using prespecified standardized criteria. The Newcastle-Ottawa Scale was used to assess the risk of bias in the included studies, and this meta-analysis was completed by STATA version 14.2. A total of 12 cohort studies and 4 case-control studies were included in this meta-analysis. Overall, patients with inflammatory bowel disease (IBD) were at significantly increased risk of renal cancer (RCa) [standardized incidence ratio (SIR): 1.53; 95% confidence interval (CI): 1.25-1.80; I2=42.4%], but not at increased risk of prostate cancer (PCa), bladder cancer (BCa) and male genital cancer. In the subgroup analysis, CD patients had a significantly higher RCa risk (SIR: 1.95; 95% CI: 1.45-2.44; I2=39.9%). Besides, CD patients seemed to be at borderline significantly increased risks of PCa (SIR: 1.07; 95% CI: 0.93-1.20; I2=15.1%) and BCa (SIR:1.19; 95% CI: 0.94-1.44; I2=0%), and UC patients seemed to be at borderline significantly increased risks of RCa (SIR:1.31; 95% CI: 0.94-1.67; I2=48.0%) and PCa (SIR: 1.13; 95% CI: 0.93-1.33; I2=73.5%). Notably, we observed that IBD patients in Eastern countries have significantly increased PCa risk (SIR: 2.66; 95% CI: 1.52-3.81; I2=13.6%), especially for UC patients (SIR: 3.01; 95% CI: 1.75-4.27; I2=0.0%). Our findings indicate that IBD patients with special reference to CD patients increase the risk of RCa. Besides, IBD patients in Asian countries have significantly increased risk of PCa, especially for UC patients. Further studies are warranted to elucidate the potential mechanism of RCa associated with IBD and the differences of the risk of urinary cancers between Eastern and Western countries.


Surgical Site Infection after Bone Tumor Surgery: Risk Factors and New Preventive Techniques.
The management of malignant bone tumors requires multidisciplinary interventions including chemotherapy, radiation therapy, and surgical tumor resection and reconstruction. Surgical site infection (SSI) is a serious complication in the treatment of malignant bone tumors. Compared to other orthopedic surgeries, the surgical treatment of malignant bone tumors is associated with higher rates of SSIs. In patients with SSIs, additional surgeries, long-term administrations of antibiotics, extended hospital stays, and the postponement of scheduled adjuvant treatments are required. Therefore, SSI may adversely affect functional and oncological outcomes. To improve surgical outcomes in patients with malignant bone tumors, preoperative risk assessments for SSIs, new preventive techniques against SSIs, and the optimal use of prophylactic antibiotics are often required. Previous reports have demonstrated that age, tumor site (pelvis and tibia), extended operative time, implant use, body mass index, leukocytopenia, and reconstruction procedures are associated with an increased risk for SSIs. Furthermore, prophylactic techniques, such as silver and iodine coatings on implants, have been developed and proven to be efficacious and safe in clinical studies. In this review, predictive factors of SSIs and new prophylactic techniques are discussed.


Ending genetic essentialism through genetics education.
Genetic concepts are regularly used in arguments about racial inequality. This review summarizes research about the relationship between genetics education and a particular form of racial prejudice known as genetic essentialism. Genetic essentialism is a cognitive form of prejudice that is used to rationalize inequality. Studies suggest that belief in genetic essentialism among genetics students can be increased or decreased based on what students learn about human genetics and why they learn it. Research suggests that genetics education does little to prevent the development of genetic essentialism, and it may even exacerbate belief in it. However, some forms of genetics education can avert this problem. In particular, if instructors teach genetics to help students understand the flaws in genetic essentialist arguments, then it is possible to reduce belief in genetic essentialism among biology students. This review outlines our knowledge about how to accomplish this goal and the research that needs to be done to end genetic essentialism through genetics education.


[The role of malnutrition and other medical factors in the evolution of patients with hip fracture].
As the population progressively ages, hip fractures have become increasingly common and are associated with high morbidity and mortality and a pronounced decline in functional status. Hip fractures frequently occur in elderly patients with a high rate of comorbidity and polymedication. Patients hospitalised with hip fractures often display signs of protein malnutrition and may develop medical complications requiring intrahospital care. These factors, more than simply surgical ones, unfavourably influence the vital status and functional outcome of these patients. For this reason, it is necessary to improve the management of pre-existing conditions during hospitalisation, assess and treat malnutrition and prevent medical complications to achieve optimal outcomes for these patients. With this objective, we believe that care should be provided by multidisciplinary teams in close partnership with internists.


Effects of verapamil on pharmacokinetics and pharmacodynamics of digitoxin in patients.
Investigations by various teams have shown that combined treatment with verapamil and digoxin may result in a marked increase in digoxin plasma concentrations, necessitating a reduction in the dose of digoxin. This is mainly due to an impairment of the renal digoxin excretion. Unlike digoxin, the excretion of digitoxin is independent of renal function. A prospective clinical study was therefore planned to investigate the influence of a daily dose of 240 mg of verapamil on pharmacokinetics and the cardiac effect of digitoxin after a single dose (n = 3) and under steady-state conditions (n = 10). While pretreatment with verapamil did not alter pharmacokinetics of digitoxin in the single-dose study, there was a slight rise of digitoxin plasma concentrations (an average of 35% in 8 out of 10 patients) following administration of verapamil for a period of 4 to 6 weeks. Renal excretion of digitoxin, however, was not changed significantly. Simultaneous with a rise of digitoxin plasma concentrations and until a new steady state was reached, PQ interval was prolonged and T wave flattening intensified. On the other hand, the antagonistic effect on contractility which was initially observed after verapamil administration was diminished. Based on these observations, it can be concluded that the risk of digitalis overdose after combined treatment with verapamil and digitoxin may be less pronounced than after digoxin, and that this glycoside can prove a valuable alternative.


Continuous intravenous infusion of prostaglandin E1 improves myocardial perfusion reserve in patients with ischemic heart disease assessed by positron emission tomography: a pilot study.
Recent investigation has demonstrated that prostaglandin E(1) (PGE(1)) therapy increased capillary density in explanted hearts. Dynamic (13)N-ammonia positron emission tomography (PET) is reliable for non-invasive measurement of myocardial blood flow and myocardial perfusion reserve (MPR). The aim of this study was to investigate the effects of PGE(1) therapy during 4 weeks on reduction of myocardial perfusion abnormalities and increase of MPR in the patients with ischemic heart disease. In this double-blind, placebo-controlled trial, we randomly assigned 11 patients who had symptomatic heart failure and documented myocardial ischemia to 4 weeks intravenous infusion of PGE(1) (2.5 ng/kg/min; 8 patients, age 60 ± 13 years) or saline (3 patients, age 57 ± 13 years). Dynamic (13)N-ammonia PET scans at rest and during adenosine stress were obtained at baseline and 12 weeks after treatment completion. Quantitative size/severity of perfusion defects and MPR change from baseline to follow-up PET were determined using a 17-segment model. Compared with the control group, baseline MPR in the PGE(1) group was significantly lower (1.96 ± 0.78 vs. 2.71 ± 0.73; P < 0.001). MPR significantly improved 12 weeks after completion of PGE(1) infusion (1.96 ± 0.78 to 2.16 ± 0.77; P < 0.001). In contrast, MPR declined significantly in the placebo group (2.71 ± 0.73 to 2.01 ± 0.58, P < 0.001). Four weeks of PGE(1) infusion sustained MPR improvement in patients with ischemic heart disease. This may be an attractive therapeutic approach for no-option patients with severe ischemic cardiomyopathy.


A major role for capsule-independent phagocytosis-inhibitory mechanisms in mammalian infection by Cryptococcus neoformans.
The antiphagocytic polysaccharide capsule of the human fungal pathogen Cryptococcus neoformans is a major virulence attribute. However, previous studies of the pleiotropic virulence determinant Gat201, a GATA family transcription factor, suggested that capsule-independent antiphagocytic mechanisms exist. We have determined that Gat201 controls the mRNA levels of ∼1100 genes (16% of the genome) and binds the upstream regions of ∼130 genes. Seven Gat201-bound genes encode for putative and known transcription factors--including two previously implicated in virulence--suggesting an extensive regulatory network. Systematic analysis pinpointed two critical Gat201-bound genes, GAT204 (a transcription factor) and BLP1, which account for much of the capsule-independent antiphagocytic function of Gat201. A strong correlation was observed between the quantitative effects of single and double mutants on phagocytosis in vitro and on host colonization in vivo. This genetic dissection provides evidence that capsule-independent antiphagocytic mechanisms are pivotal for successful mammalian infection by C. neoformans.


Total knee arthroplasty: Latest robotics implantation techniques.
The recent introduction of new robotic systems for total knee arthroplasty (TKA) has created somewhat of a craze. Nevertheless, we can ask ourselves whether it is justified to use these new but very costly technologies. The results and limitations of these robotic tools must be analyzed systematically before confirming their benefits. Most of the newest robotic systems are interactive ones. These systems can accurately restore the mechanical axis and can improve the ligament balance and implant positioning. Theoretically, this can lead to better survival, function and outcomes. Recent studies have shown that use of robotics for TKA implantation does not increase the surgery time and does not cause more complications. Nevertheless, the long-term advantages of robotics use in this context remains to be proven. This task will be more difficult since there is currently no consensus as to the ideal positioning of TKA implants for a given patient. The aim of this study is to summarize this topic by answering the following questions: What are the different types of robots that can be used for TKA implantation? Which steps of the TKA surgical procedure are done with robotic arm assistance? What are the outcomes of these new implantation techniques? What are the limitations of these new implantation techniques? LEVEL OF EVIDENCE: V; expert opinion.


Sulbactam/ampicillin versus metronidazole/gentamicin in the treatment of severe pelvic infections.
The clinical efficacy and safety of sulbactam/ampicillin versus metronidazole/gentamicin were compared in 39 patients with severe pelvic infections. 30 patients had severe acute pelvic inflammatory disease with peritonitis, 3 tubo-ovarian abscesses, 4 endomyometritis, and 2 posthysterectomy pelvic cellulitis. Aerobic and anaerobic cultures from the sites of infection yielded 259 micro-organisms from 38 patients; an average of 6.8 bacteria per infection (3.9 anaerobes and 2.9 aerobes). The most frequent isolates were Bacteroides spp. (21), B. bivius (13), B. disiens (8), Fusobacterium spp. (9), Peptostreptococcus anaerobius (15), P. asaccharolyticus (8), anaerobic Gram-positive cocci (17), Gardnerella vaginalis (24), Neisseria gonorrhoeae (14), alpha-haemolytic streptococci (6) and Escherichia coli (3). Clinical cure was noted in 19 of 20 patients treated with sulbactam/ampicillin and 16 of 19 treated with metronidazole/gentamicin. The sulbactam/ampicillin failure was a patient with pelvic inflammatory disease with a positive Chlamydia trachomatis culture who required antichlamydial therapy. The metronidazole/gentamicin failures included a patient with a tubo-ovarian abscess requiring surgical drainage and 2 patients with pelvic inflammatory disease requiring antichlamydial treatment. No adverse haematological, renal, or hepatic effects were noted with either regimen.


Assessment of biotoxicity of three types of landfilled foundry waste on the basis of dehydrogenase activity.
The microbiological activity of three types of landfilled foundry wastes, i.e. biologically reclaimed foundry waste (BFW), foundry waste landfilled since the 1990s (LFW) and fresh foundry waste (FFW), was investigated. The wastes originated from a Polish iron and steel foundry which uses organic binders based on phenol-formaldehyde resins and mineral binders to casting production. The physical and chemical properties and dehydrogenase activity (DHA) were determined in the waste samples and local soils. In addition, a pot experiment was performed to determine the effect of the addition of FFW with no microbial activity on soils. Additional correlation analysis was conducted between DHA and other parameters. It was found that biologically reclaimed foundry waste (BFW) showed the highest microbial activity, similar to soils from garden allotments and agricultural fields. The DHA in LFW was about a half lower than BFW. On the other hand, FFW did not show any microbial activity. A pot experiment showed that increasing the percentage of foundry waste relative to soil had a negative effect on DHA, probably as a result of soil dilution rather than the inhibitory effect of contaminants. It was concluded that the optimum addition of FFW to soils is 10% wt, due to the highest value of DHA among the other variants.


An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.
Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.


Thyroid hormone signaling specifies cone photoreceptor subtypes during eye development: Insights from model organisms and human stem cell-derived retinal organoids.
Cones are the color-detecting photoreceptors of the vertebrate eye. Cones are specialized into subtypes whose functions are determined by the expression of color-sensitive opsin proteins. Organisms differ greatly in the number and patterning of cone subtypes. Despite these differences, thyroid hormone is an important regulator of opsin expression in most vertebrates. In this chapter, we outline how the timing of thyroid hormone signaling controls cone subtype fates during retinal development. We first examine our current understanding of cone subtype specification in model organisms and then describe advances in human stem cell-derived organoid technology that identified mechanisms controlling development of the human retina.