Can we ameliorate quality of life in chronic kidney disease? The nephrologist's point of view.
Despite admirable technical progress in dialysis procedure, rehabilitation of dialysis patients is far from optimal, in part because of deficiencies in the dialysis modality, in part because of the limited access to kidney transplantation, which is a superior method of treatment, and in part because of demographic reasons, particularly the ageing of the dialysis population. Chronic dialysis treatment creates a particular "microcosmos" in which interpersonal relations and psychological problems carry particular weight.


Error optimization of a three-dimensional magnetic resonance imaging tagging-based cartilage deformation technique.
Three-dimensional strain fields in articular cartilage subjected to compressive loading can be determined using a recently developed MRI-based cartilage deformation by tag registration technique. The objective of this study was to determine the experimental variables that minimize the technique error, which has not been previously reported. Error (strain bias and precision) was determined using direct experiments and Monte Carlo simulations for four variables: spatial resolution, tag line spacing, applied nominal strain, and number of control points used to describe tag lines in a B-spline model. The important results include the following: (1) bias was not significantly different from zero, (2) precision increased with image resolution and with tag line spacing, (3) precision was independent of applied nominal strain, and (4) error was a minimum (absolute precision = 0.41% strain) for the following values: spatial resolution = 0.05 x 0.05 mm2; tag line spacing = 2.0 mm; control points = 6. With these results the technique can now be used in various applications while minimizing error.


Comparison of homozygous sickle cell disease in northern Greece and Jamaica.
The clinical and haematological features of homozygous sickle cell (SS) disease were compared in 30 Greek and 310 Jamacian patients. Deletional alpha-thalassaemia, which modifies SS disease, is rare among Greek patients, so only Jamacian patients with four alpha-globin genes were included in the control group. Greek patients had higher total haemoglobin concentration and red cell counts, and lower mean cell haemoglobin concentration (MCHC) and reticulocyte counts. They also had a more normal body build and more adults had persistent splenomegaly. Fewer had a history of leg ulceration or priapism but more reported acute chest syndrome. The comparatively mild disease in Greek patients is consistent with less haemolysis and sickling and therefore less bone marrow expansion. In the absence of amelioriating factors such as high HbF concentration or alpha-thalassaemia, these findings may be explained by the low MCHC.


Early detection of psychosis: helpful or stigmatizing experience? A qualitative study.
Despite the large scientific debate concerning potential stigmatizing effects of identifying an individual as being in an at-risk mental state (ARMS) for psychosis, studies investigating this topic from the subjective perspective of patients are rare. This study assesses whether ARMS individuals experience stigmatization and to what extent being informed about the ARMS is experienced as helpful or harmful. Eleven ARMS individuals, currently participating in the follow-up assessments of the prospective Basel Früherkennung von Psychosen (FePsy; English: Early Detection of Psychosis) study, were interviewed in detail using a semistructured qualitative interview developed for this purpose. Data were analysed using Interpretative Phenomenological Analysis. Most individuals experiencing first symptoms reported sensing that there was 'something wrong with them' and felt in need of help. They were relieved that a specific term was assigned to their symptoms. The support received from the early detection centre was generally experienced as helpful. Many patients reported stigmatization and discrimination that appeared to be the result of altered behaviour and social withdrawal due to the prepsychotic symptoms they experienced prior to contact with the early detection clinic. The results suggest that early detection services help individuals cope with symptoms and potential stigmatization rather than enhancing or causing the latter. More emphasis should be put on the subjective experiences of those concerned when debating the advantages and disadvantages of early detection with regard to stigma. There was no evidence for increased perceived stigma and discrimination as a result of receiving information about the ARMS.


Let's do it together! The role of interaction in false belief understanding.
From the interaction theory perspective, we aimed to verify whether the interactive context in which theory of mind is measured can allow children younger than 4 years to pass the verbal false belief task (FBT). Therefore, an interactive FBT (iFBT) was devised, in which children were actively engaged in the story, and was used to test 210 children twice: first when they were 3 years old and again when they were 3.5 years old. Most 3-year-olds were unable to pass the iFBT (28% passed), but a half year later their performance was enhanced and they passed at a rate above chance level (59% passed). In addition, among 3.5-year-olds, passing the iFBT increases the chance of passing the standard FBT by four times. We conclude that the interactive mode of the FBT facilitates false belief understanding in children under 4 years of age.


Interference between concurrent resistance and endurance exercise: molecular bases and the role of individual training variables.
Concurrent training is defined as simultaneously incorporating both resistance and endurance exercise within a periodized training regime. Despite the potential additive benefits of combining these divergent exercise modes with regards to disease prevention and athletic performance, current evidence suggests that this approach may attenuate gains in muscle mass, strength, and power compared with undertaking resistance training alone. This has been variously described as the interference effect or concurrent training effect. In recent years, understanding of the molecular mechanisms mediating training adaptation in skeletal muscle has emerged and provided potential mechanistic insight into the concurrent training effect. Although it appears that various molecular signaling responses induced in skeletal muscle by endurance exercise can inhibit pathways regulating protein synthesis and stimulate protein breakdown, human studies to date have not observed such molecular 'interference' following acute concurrent exercise that might explain compromised muscle hypertrophy following concurrent training. However, given the multitude of potential concurrent training variables and the limitations of existing evidence, the potential roles of individual training variables in acute and chronic interference are not fully elucidated. The present review explores current evidence for the molecular basis of the specificity of training adaptation and the concurrent interference phenomenon. Additionally, insights provided by molecular and performance-based concurrent training studies regarding the role of individual training variables (i.e., within-session exercise order, between-mode recovery, endurance training volume, intensity, and modality) in the concurrent interference effect are discussed, along with the limitations of our current understanding of this complex paradigm.


A corrosion-resistant RuMoNi catalyst for efficient and long-lasting seawater oxidation and anion exchange membrane electrolyzer.
Direct seawater electrolysis is promising for sustainable hydrogen gas (H2) production. However, the chloride ions in seawater lead to side reactions and corrosion, which result in a low efficiency and poor stability of the electrocatalyst and hinder the use of seawater electrolysis technology. Here we report a corrosion-resistant RuMoNi electrocatalyst, in which the in situ-formed molybdate ions on its surface repel chloride ions. The electrocatalyst works stably for over 3000 h at a high current density of 500 mA cm-2 in alkaline seawater electrolytes. Using the RuMoNi catalyst in an anion exchange membrane electrolyzer, we report an energy conversion efficiency of 77.9% and a current density of 1000 mA cm-2 at 1.72 V. The calculated price per gallon of gasoline equivalent (GGE) of the H2 produced is $ 0.85, which is lower than the 2026 technical target of $ 2.0/GGE set by the United Stated Department of Energy, thus, suggesting practicability of the technology.


Transferring Fragments of Paternal Metabolism to the Offspring.
Paternal diet influences offspring metabolism, yet the underlying epigenetic mechanisms are unclear. Recently, Chen et al. (2016) and Sharma et al. (2016) identified tRNA fragments in sperm and the male reproductive tract as possible inherited factors altered by paternal diet that lead to gene misexpression and altered metabolism in offspring.


Tocopherols in canned entrées and vended sandwiches.
Determination was made of alpha-, beta-plus-gamma-, and delta-tocopherol contents of brand-name canned entrées from a supermarket and from vending machines on a college campus, of several home-prepared entrées, and of sandwiches from vending machines in Spokane, Washington. Amounts of total tocopherols in canned entrées were small, ranging from none detected to 0.66 mg. per 100 gm. food. Similar home-prepared entrées, however, contained 0.41 mg. to 1.55 mg. Tocopherols in vended sandwiches ranged from 0.05 mg. to 1.86 mg. per 100 gm. sandwich. Results are also expressed as total tocopherols per serving (I.U.). These convenience foods contribute only a small amount to the day's intake of vitamin E.


Newt lungs: a versatile system for the study of mucociliary transport.
Lungs of the newt, Taricha granulosa, provide a versatile system for studying mucociliary transport. The mucociliary epithelium is restricted to a ventral strip of epithelium which extends the entire length of the lung. The transport process can be studied in the isolated lung or in a variety of functional components derived from it. These components include: (1) isolated sheets of the mucociliary epithelium, (2) flattened epithelial sheets grown in long term primary culture, (3) dissociated ciliated and mucous cells, (4) functional, demembranated ciliary tufts, and (5) isolated populations of discrete, demembranated axonemes. The latter two models can be reactivated with MgATP and made to beat at frequencies comparable to those measured in intact cells. Featuring large cells (25-30 microns in diameter) and cilia (12-13 microns in length) in comparison to other mucus-transporting systems, coupled with the ability to perform 'physiological' experiments at ambient temperatures, newt lungs afford a convenient system to study mechanisms involved in the control of ciliary beat frequency, waveform and coordination at several levels of organization.


Rhoptry neck protein RON2 forms a complex with microneme protein AMA1 in Plasmodium falciparum merozoites.
Erythrocyte invasion is an essential step in the establishment of host infection by malaria parasites, and is a major target of intervention strategies that attempt to control the disease. Recent proteome analysis of the closely-related apicomplexan parasite, Toxoplasma gondii, revealed a panel of novel proteins (RONs) located at the neck portion of the rhoptries. Three of these proteins, RON2, RON4, and RON5 have been shown to form a complex with the microneme protein Apical Membrane Protein 1 (AMA1). This complex, termed the Moving Junction complex, localizes at the interface of the parasite and the host cell during the invasion process. Here we characterized a RON2 ortholog in Plasmodium falciparum. PfRON2 transcription peaked at the mature schizont stage and was expressed at the neck portion of the rhoptry in the merozoite. Co-immunoprecipitation of PfRON2, PfRON4 and PfAMA1 indicated that the complex formation is conserved between T. gondii and P. falciparum, suggesting that co-operative function of the rhoptry and microneme proteins is a common mechanism in apicomplexan parasites during host cell invasion. PfRON2 possesses a region displaying homology with the rhoptry body protein PfRhopH1/Clag, a component of the RhopH complex. However, here we present co-immunoprecipitation studies which suggest that PfRON2 is not a component of the RhopH complex and has an independent role. Nucleotide polymorphism analysis suggested that PfRON2 was under diversifying selective pressure. This evidence suggests that RON2 appears to have a fundamental role in host cell invasion by apicomplexan parasites, and is a potential target for malaria intervention strategies.


Cord blood porphyrins. A quantitative assay in newborn infants.
A quantitative assay of free erythrocyte porphyrins was done in umbilical cord blood of 30 newborn babies by a spectrophotometric method. The mean value of free erythrocyte protoporphyrin in umbilical cord blood was found to be 74.58 microng/100 ml packed erythrocytes and that of free erythrocyte coproporphyrin to be 0.77 microng/100 ml packed erythrocytes with a standard deviation of +/-29.99 and +/-1.48 respectively. Relationship between free erythrocyte protoporphyrin and free erythrocyte comproporphyrin and their correlations with birth weight and sex of the newborn baby were found to be statistically significant.


Council-tip catheter facilitates vesicourethral anastomotic suture placement.
The use of a transurethrally placed Council-tip catheter facilitates urethral suture placement when performing the urethral-vesical anastomosis following radical retropubic prostatectomy. The technique for use of this catheter is described.


Endothelin antagonists: evaluation of 2,1,3-benzothiadiazole as a methylendioxyphenyl bioisoster.
The methylendioxyphenyl group is present in a number of endothelin receptor antagonists thus far reported. By means of a Kohonen neural network we discovered with a benzothiadiazole a bioisosteric replacement instead. This group should be devoid of the negative metabolic interactions with cytochrome P450 ascribed to methylendioxyphenyl in vivo. The synthesis of a potent benzothiadiazole analogue EMD 122801 together with in vitro studies of different methylendioxyphenyl, benzothiadiazole and benzofurazan derivatives is described.


Modification of carbon nanotubes with redox hydrogel: improvement of amperometric sensing sensitivity for redox enzymes.
This study demonstrated that redox hydrogel-modified carbon nanotube (CNT) electrodes can be developed as an amperometric sensor that are sensitive, specific and fast and do not require auxiliary enzymes. A redox polymer, poly(vinylimidazole) complexed with Os(4,4'-dimethylbpy)(2)Cl (PVI-dmeOs) was electrodeposited on Ta-supported multi-walled CNTs. The resulted PVI-dmeOs thin film did not change the surface morphology of the CNTs, but turned the CNT surface from hydrophobic to hydrophilic, as studied by scanning electron microscopy (SEM) and static water contact angle measurements. Cyclic voltammetry measurements in a Fe(CN)(6)(3-) solution and electrochemical impedance measurements in an equimolar Fe(CN)(6)(3-/4-) solution demonstrated that the PVI-dmeOs hydrogel thin film was electronic conductive with a resistance of about 15Omega. The PVI-dmeOs/CNT electrodes sensed rapidly, sensitively and specifically to model redox enzymes (glucose oxidase (GOD) and lactate oxidase (LOD)) in amperometric experiments in electrolyte solutions containing the substrates of the measured redox enzymes. Both the CNT substrate and the thin PVI-dmeOs film enhanced the sensing sensitivities. Exploration of the mechanisms suggests that the PVI-dmeOs film may enhance the sensing sensitivities by wiring the enzyme molecules through the redox centers tethered on the mobile redox polymer backbones to the CNT electrodes.


Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells.
The nuclear Ki-67 protein (pKi-67) has previously been shown to be exclusively expressed in proliferating cells. As a result, antibodies against this protein are widely used as prognostic tools in cancer diagnostics. Here we show, that despite the strong downregulation of pKi-67 expression in non-proliferating cells, the protein can nevertheless be detected at sites linked to ribosomal RNA (rRNA) synthesis. Although this finding does not argue against the use of pKi-67 as a proliferation marker, it has wide ranging implications for the elucidation of pKi-67 function. Employing the novel antibody TuBB-9, we could further demonstrate that also in proliferating cells, a fraction of pKi-67 is found at sites linked to the rRNA transcription machinery during interphase and mitosis. Moreover, chromatin immunoprecipitation (ChIP) assays provided evidence for a physical association of pKi-67 with chromatin of the promoter and transcribed region of the rRNA gene cluster. These data strongly suggest a role for pKi-67 in the early steps of rRNA synthesis.


Blood flow heterogeneity in the heart.
Local deposition density of microspheres is heterogeneous in histologically homogeneous myocardium under physiological conditions. The underlying biological heterogeneity must be distinguished from a methodological heterogeneity which depends preferentially on the number of microspheres injected, blood flow to a particular myocardial region and sample mass. As the variables space (spat), time (temp), and method (meth) are independent of each other, the observed (obs) variability may be approximated using the coefficients of variation (CV) of the individual variables: CVobs = (CV2spat+CV2temp+CV2meth)0.5. Studies in which these different variables have been quantified indicate that the largest fraction of the observed variability of microsphere deposition density is contributed by spatial flow heterogeneity which exists independent of the myocardial layer. Spatial flow heterogeneity increases with decreasing sample mass and decreasing mean flow. Fractal and autocorrelation analyses have shown that adjacent myocardial flows are spatially correlated and nonrandom. Local blood flow was shown to correlate with various metabolic and transport rates, while no differences were found between low and high flow regions with respect to several metabolic markers of tissue hypoxia. In conclusion, the evidence available to date indicates that 1) in histologically homogeneous myocardium there exists a spatial blood flow heterogeneity which 2) is temporally stable, 3) resolution dependent, 4) largely layer-independent, 5) nonrandom, and 6) related to local aerobic metabolism.


Surgical outcomes and optimal approach to treatment of aortic valve endocarditis with aortic root abscess.
To evaluate the impact of aortic root abscess (ARA) on the postoperative outcomes of surgically managed infective endocarditis (IE) and to inform optimal surgical approach. Between 2009 and 2020, 143 consecutive patients who underwent surgical management for aortic-valve IE were included in a retrospective cohort study. Multivariable and propensity-weighted analyses were used to adjust for demographic imbalances between those without (n = 93; NARA) and with an ARA (n = 50). Additionally, empirical subgroup analysis appraised the two most used surgical techniques; patch reconstruction (PR) and aortic root replacement (ARR). Demographic characteristics were similar between ARA and NARA except for logistic EuroSCORE, previous valve surgery, and multivalvular infection. In-hospital mortality was 8% and 12% in NARA and ARA, respectively (p = .38), with mortality rates consistently nonsignificantly higher in ARA across all time periods. The overall reoperation rate was also higher in ARA (27% vs. 14%; p = .09) and ARA was shown to be associated with late reoperation (odds ratio [OR] = 2.74; 95% confidence interval [CI] = 1.18-6.36). Patients treated with an ARR showed a 16% increase in late mortality when compared with PR (40% vs. 24%; p = .27) and a 17% lower reoperation rate (14% vs. 31%; p = .24). Propensity-weighted analysis identified ARR as a significant protective factor for reoperation (hazard ratio = 0.05; 95% CI = 0.01-0.34). The presence of an ARA in aortic valve endocarditis was not associated with significantly higher early and late mortality but is linked with a higher reoperation rate at our institution. ARR in ARA is protective from reoperation so should be considered best practice in this setting.


Carrier envelope phase noise in stabilized amplifier systems.
At present most laser systems for generating phase-stabilized high-energy pulses are chirped pulse amplifier systems that involve the selection and subsequent amplification of pulses from a phase-stabilized seed oscillator. We investigate the effect of the picking process on the carrier envelope phase stability and how the phase noise of the picked pulse sequence can be estimated from the phase noise properties of the seed oscillator. All noise components from the original pulse train above the picking frequency are aliased into the picked pulse train and therefore cannot be neglected.


Small-Scale Dynamic Aurora.
Small-scale dynamic auroras have spatial scales of a few km or less, and temporal scales of a few seconds or less, which visualize the complex interplay among charged particles, Alfvén waves, and plasma instabilities working in the magnetosphere-ionosphere coupled regions. We summarize the observed properties of flickering auroras, vortex motions, and filamentary structures. We also summarize the development of fundamental theories, such as dispersive Alfvén waves (DAWs), plasma instabilities in the auroral acceleration region, ionospheric feedback instabilities (IFI), and the ionospheric Alfvén resonator (IAR). The online version contains supplementary material available at 10.1007/s11214-021-00796-w.


Desensitization of capsaicin-evoked neuropeptide release--influence of Ca2+ and temperature.
Capsaicin-induced stimulation and desensitization of neuropeptide release from primary afferent neurons was investigated in the rat urinary bladder in-vitro. The capsaicin (5 min contact time)-evoked release of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR) was dose-dependent; threshold to produce detectable release was 0.1 mumol/l, the EC50 was 0.17 mumol/l. Pre-exposure of tissues to capsaicin (0.1-1.0 mumol/l, 5 min contact time) caused a dose-dependent reduction of the amount of CGRP-IR which was released by a second exposure to capsaicin. At 0.1 and 0.3 mumol/l, capsaicin was less effective to inhibit the subsequent K(+)-evoked release than that evoked by a second capsaicin exposure. Pre-exposure to 1 mumol/l capsaicin completely prevented subsequent K(+)- or capsaicin-evoked release of CGRP-IR. Exposure of the preparation to capsaicin (0.3 mumol/l) in a Ca2(+)-free, EDTA-containing medium did not produce release of CGRP-IR. A subsequent stimulation with capsaicin in a 2.5 mmol/l Ca2(+)-containing superfusion solution was not less effective to release CGRP-IR than in tissues which had not been pre-exposed to capsaicin. At 18 degrees C, the capsaicin-evoked release of CGRP-IR was reduced to 20% of the value obtained by the same dose (0.3 mumol/l for 5 min) of capsaicin at 37 degrees C. Comparison of the desensitizing effect of 0.3 and 0.1 mumol/l capsaicin at 18 degrees C and 37 degrees C, respectively, showed significant inhibition of desensitization at 18 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)


Lead optimization of novel quinolone chalcone compounds by a structure-activity relationship (SAR) study to increase efficacy and metabolic stability.
Many agents targeting the colchicine binding site in tubulin have been developed as potential anticancer agents. However, none has successfully made it to the clinic, due mainly to dose limiting toxicities and the emergence of multi-drug resistance. Chalcones targeting tubulin have been proposed as a safe and effective alternative. We have shown previously that quinolone chalcones target tubulin and maintain potent anti-proliferative activity vis-à-vis colchicine, while also having high tolerability and low toxicity in mouse models of cancer and refractivity to multi-drug resistance mechanisms. To identify the most effective anticancer chalcone compound, we synthesized 17 quinolone-chalcone derivatives based on our previously published CTR-17 and CTR-20, and then carried out a structure-activity relationship study. We identified two compounds, CTR-21 [((E)-8-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] and CTR-32 [((E)-3-(3-(2-ethoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one)] as potential leads, which contain independent moieties that play a significant role in their enhanced activities. At the nM range, CTR-21 and CTR-32 effectively kill a panel of different cancer cells originated from a variety of different tissues including breast and skin. Both compounds also effectively kill multi-drug resistant cancer cells. Most importantly, CTR-21 and CTR-32 show a high degree of selectivity against cancer cells. In silico, both of them dock near the colchicine-binding site with similar energies. Whereas both CTR-21 and CTR-32 effectively prevents tubulin polymerization, leading to the cell cycle arrest at G2/M, CTR-21 has more favorable metabolic properties. Perhaps not surprisingly, the combination of CTR-21 and ABT-737, a Bcl-2 inhibitor, showed synergistic effect in killing cancer cells, since we previously found the "parental" CTR-20 also exhibited synergism. Taken together, CTR-21 can potentially be a highly effective and relatively safe anticancer drug.


Self-administration of medication during hospitalization-a randomized pilot study.
Self-administration of medication (SAM) during hospitalization is a complex intervention where patients are involved in their course of treatment. The study aim was to pilot test the SAM intervention. The objectives were to assess the feasibility of conducting a randomized controlled trial on the safety and cost-consequences of SAM during hospitalization. The study was performed in a Danish cardiology unit.Patients ≥ 18 years capable of self-administering medication during hospitalization were eligible. Patients were excluded if they did not self-administer medication at home, were incapable of self-administering medication, were not prescribed medication suitable for self-administration, did not bring their medication, or were unable to speak Danish.Feasibility was assessed as part of the pilot study. A future randomized controlled trial was considered feasible if it was possible to recruit 60 patients within 3 months, if outcome measurement method was capable of detecting dispensing errors in both groups, and if patients in the intervention group were more satisfied with the medication management during hospitalization compared to the control group.Forty patients were recruited to gain experience about the intervention (self-administration). Additionally, 20 patients were randomized to the intervention or control group (nurse-led dispensing) to gain experience about the randomization procedure.Dispensing error proportions were based on data collected through disguised observation of patients and nurses during dispensing. The error proportion in the control group was used for the sample size calculation. Patient acceptability was assessed through telephone calls. Of the 60 patients recruited, one withdrew and 11 were discharged before observation resulting in analysis of 39 patients in the intervention group and nine in the control group. A dispensing error proportion of 3.4% was found in the intervention group and 16.1% in the control group. A total of 91.7% of patients in the intervention group and 66.7% in the control group were highly satisfied with the medication management during hospitalization. The overall protocol worked as planned. Minor changes in exclusion criteria, intervention, and outcome measures were considered. It may be feasible to perform a pragmatic randomized controlled trial of the safety and cost-consequences of self-administration of medication during hospitalization. ClinicalTrials.gov, NCT03541421, retrospectively registered on 30 May 2018.


Mechanism associated with the positive effect of nanocellulose on nitrogen retention in a manure composting system.
Additives can play important roles in effectively inhibiting nitrogen losses during livestock manure composting due to the activities of microbes. This study investigated the effects of adding nanocellulose at 300 mg/kg, 600 mg/kg, and 900 mg/kg (NC900) on nitrogen conversion, nitrogen conversion functional genes, and related microorganisms during composting. The results showed that compared with the control, nanocellulose hindered the ammoniation reaction. In addition, NC900 promoted nitrification, interfered with the denitrification process, and reduced the abundance of the nirK gene, thereby increasing the nitrate nitrogen content and decreasing ammonia spillover. NC900 promoted nitrogen fixation by increasing the abundance of members of Rhizobiales, which play important roles in nitrogen fixation. In general, compared with the control, NC900 improved the retention of nitrogen by controlling ammonia emissions. The results obtained in this study demonstrate that nanocellulose can be applied in the treatment of organic solid waste and agricultural production.


MANAGEMENT OF ACUTE RENAL FAILURE WITH DELAYED HYPERCALCEMIA SECONDARY TO SARCOCYSTIS NEURONA-INDUCED MYOSITIS AND RHABDOMYOLYSIS IN A CALIFORNIA SEA LION (ZALOPHUS CALIFORNIANUS).
A 3-yr-old captive-born California sea lion (Zalophus californianus) developed Sarcocystis neurona-induced myositis and rhabdomyolysis that led to acute renal failure. The sea lion was successfully managed with fluid therapy, antiprotozoals, antibiotics, anti-inflammatories, antiemetics, gastroprotectants, and diuretics, but developed severe delayed hypercalcemia, a syndrome identified in humans after traumatic or exertion-induced rhabdomyolysis. Treatment with calcitonin was added to the management, and the individual recovered fully. The case emphasizes that animals with rhabdomyolysis-induced renal failure risk developing delayed hypercalcemia, which may be life threatening, and calcium levels should be closely monitored past the resolution of renal failure.


VEGF-mediated STAT3 activation inhibits retinal vascularization by down-regulating local erythropoietin expression.
Avascular, hypoxic retina has been postulated to be a source of angiogenic factors that cause aberrant angiogenesis and intravitreal neovascularization (IVNV) in retinopathy of prematurity. Vascular endothelial growth factor (VEGF) is an important factor involved. However, VEGF is also required for normal retinal vascular development, which raises concerns about inhibiting its activity to treat IVNV in retinopathy of prematurity. Therefore, understanding the effects that VEGF has on other factors in the development of avascular retina is important to prevent aberrant angiogenesis and IVNV. Here, we show that STAT3 was activated by increased retinal VEGF in the rat 50/10 oxygen-induced retinopathy model. Phospho-STAT3 colocalized with glutamine synthetase-labeled Müller cells. Inhibition of STAT3 reduced avascular retina and increased retinal erythropoietin (Epo) expression. Epo administered exogenously also reduced avascular retina in the model. In an in vitro study, hypoxia-induced VEGF inhibited Epo gene expression by STAT3 activation in rat Müller cells. The mechanism by which activated STAT3 regulated Epo was by inhibition of Epo promoter activity. Together, these findings show that increased retinal VEGF contributes to avascular retina by regulating retinal Epo expression through Janus kinase/STAT signaling. Our results suggest that rescuing Epo expression in the retina before the development of IVNV may promote normal developmental angiogenesis and, therefore, reduce the stimulus for later pathologic IVNV.


Disease patterns in experimental allergic neuritis (EAN) in the Lewis rat. Is EAN a good model for the Guillain-Barré syndrome?
Lewis rats develop experimental allergic neuritis (EAN) when injected with bovine dorsal root (BDR) emulsified in complete Freund's adjuvant (CFA). In this study the susceptibility to EAN and subsequent relapse was studied in animals ranging from 4 to 25 weeks of age. Older animals exhibited a severe acute illness which was monophasic over the period of observation, whereas younger animals developed a less severe and frequently relapsing illness. Very young animals often relapsed more than once and sometimes to a more severe degree than shown in their first attack. Older animals which were in the late recovery stage of EAN (44 days after injection with BDR/CFA) were completely resistant to a second challenge with antigen. Young adult animals also developed resistance but not as strongly as the older animals. Animals first injected at weaning developed resistance as in the adults, but the analysis is complicated by the occurrence of spontaneous relapses. Because of differences in disease pattern between EAN and acute inflammatory polyneuropathy (Guillain-Barré syndrome) in man, caution should be exercised in drawing too close a parallel between the animal model and the human disease. The affinities may be closer to chronic relapsing inflammatory polyradiculopathy in man.


Perifocal Zone of Brain Gliomas: Application of Diffusion Kurtosis and Perfusion MRI Values for Tumor Invasion Border Determination.
(1) Purpose: To determine the borders of malignant gliomas with diffusion kurtosis and perfusion MRI biomarkers. (2) Methods: In 50 high-grade glioma patients, diffusion kurtosis and pseudo-continuous arterial spin labeling (pCASL) cerebral blood flow (CBF) values were determined in contrast-enhancing area, in perifocal infiltrative edema zone, in the normal-appearing peritumoral white matter of the affected cerebral hemisphere, and in the unaffected contralateral hemisphere. Neuronavigation-guided biopsy was performed from all affected hemisphere regions. (3) Results: We showed significant differences between the DKI values in normal-appearing peritumoral white matter and unaffected contralateral hemisphere white matter. We also established significant (p < 0.05) correlations of DKI with Ki-67 labeling index and Bcl-2 expression activity in highly perfused enhancing tumor core and in perifocal infiltrative edema zone. CBF correlated with Ki-67 LI in highly perfused enhancing tumor core. One hundred percent of perifocal infiltrative edema tissue samples contained tumor cells. All glioblastoma samples expressed CD133. In the glioblastoma group, several normal-appearing white matter specimens were infiltrated by tumor cells and expressed CD133. (4) Conclusions: DKI parameters reveal changes in brain microstructure invisible on conventional MRI, e.g., possible infiltration of normal-appearing peritumoral white matter by glioma cells. Our results may be useful for plotting individual tumor invasion maps for brain glioma surgery or radiotherapy planning.


Alternatives for detoxification of diluted-acid lignocellulosic hydrolyzates for use in fermentative processes: a review.
Acid hydrolysis of lignocellulosic materials produces several inhibitory compounds, such as sugar and lignin degradation products, compounds derived from the lignocellulosic structure, and heavy metal ions. Their toxicity is a major factor limiting bioconversion processes that utilize hydrolyzates. The identification of these compounds and the choice of the best hydrolyzate detoxification method are important for improving the efficiency of the fermentative processes. A variety of biological, physical, and chemical techniques have been proposed to reduce the concentration of these compounds in lignocellulose hydrolyzates. However, the efficiency of any detoxification method depends both on the hydrolyzate composition, which differs according to the raw material used, and on the hydrolysis conditions employed. This review describes the effects of the inhibitory compounds on fermentation yield and productivity, as well as various detoxification methods for treating the hydrolyzates.


Halomonas campaniensis sp. nov., a haloalkaliphilic bacterium isolated from a mineral pool of Campania Region, Italy.
A Gram-negative, aerobic, motile and rod-shaped haloalkaliphilic bacterial strain 5AGT (DSM 15293 and ATCC BAA-966) was isolated from water with algal mat of a mineral pool in Malvizza site (Campania-Italy) and was subjected to a polyphasic study. The isolate grew at temperature of 10.0-43.0 degrees C with an optimum at 37.0 degrees C. Strain 5AGT grew optimally in the presence of 10% NaCl and grew also in the absence of salt. The isolate grew in the pH range 7.0-10.0 with an optimum at pH 9.0. It accumulated glycine-betaine, ectoine, and glutamate, as osmoprotectants. Strain 5AGT was also characterized chemotaxonomically by having ubiquinone-8 (Q8) as the predominant isoprenoid quinone, phosphoethanolamine (PEA), phosphatidylglycerol (PG) and diphosphatidylglycerol (DPG), as major polar lipids and aiC16:0 and C18:1cis as the major fatty acids. The DNA G+C content was 63.7mol%. Phylogenetic analyses based on 16S rRNA gene sequence showed that the isolate belonged to the genus Halomonas. The DNA-DNA hybridization of the type strain 5AGT with the most related Halomonas campisalis showed a re-association value of 35.0%. On the basis of phenotypic properties and phylogeny, strain 5AGT should be placed in the genus Halomonas as a member of a novel species for which we propose the name Halomonas campaniensis sp. nov.


The evolution of adult height across Spanish regions, 1950-1980: a new source of data.
We present new evidence concerning the evolution of adult height across Spanish regions for the 1950-1980 male and female birth cohorts, using the augmented sample of the European Community Household Panel (ECHP) for Spain. This augmented sample, available only for the year 2000, contains self-reported height data representative at the Autonomous Community level. The average heights of these two sets of birth cohorts, female and male, are found to increase by 1.7 and 1.6cm/decade, respectively. Making available a new dataset of quinquennial mean heights will allow researchers to study the determinants of population heights by means of a within-country analysis.


Experiences of LGBTQ student-athletes in college sports: A meta-ethnography.
This study aimed to explore and describe the experiences of LGBTQ student-athletes to identify ways in which athletic staff, coaches, and others can support LGBTQ youth's safe participation in sports. Guided by the preferred reporting items for systematic reviews (PRISMA) and eMERGe reporting guidance. We conducted a meta-ethnography to synthesize qualitative research focused on student-athletes' experiences. Fourteen studies were included in the meta-ethnography published between 1973 and 2022. Four themes were identified: (1) experiences of discrimination and violence; (2) perceived stigma; (3) internalized prejudice; and (4) coping and team support, and they were used to generate a line of argument model, which explains the stress process of LGBTQ student-athletes in the sports. LGBTQ student-athletes experience persistent discrimination in college sports, which poses a significant risk to their mental health. Meanwhile, this study identified that qualitative research on LGBTQ youth sports participation is lacking in many regions of the world and lacks knowledge of the sports participation experience of bisexual, gay, and transgender students. These findings revealed a way for research on LGBTQ-related issues and future policy and practice on LGBTQ youth-related issues in sports.


Rapid, on-site quantitative determination of higenamine in functional food using a time-resolved fluorescence microsphere test strip.
Higenamine (HIG), a benzyltetrahydroisoquinoline alkaloid found naturally in plants, is classified as an S3 Prohibited Substance in the 2020 World Anti-Doping Agency (WADA) report. To avoid problems such as doping violations in competitive events, it is necessary to develop rapid and sensitive detection methods. In this study, a highly-sensitive anti-HIG monoclonal antibody (mAb) was prepared and a time-resolved fluorescent microsphere immunochromatographic test strip (TRFM-ICTS) was established for the rapid quantitative detection of HIG in functional foods. Under optimized conditions, the TRFM-ICTS was compared with colloidal gold immunochromatographic test strip (CG-ICTS), and the half-maximal inhibitory concentration (IC50) of TRFM-ICTS was 1.37 ng/mL. The spiked recoveries ranged from 86.4% to 105.3%, which was consistent with the results of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the detection of real functional food. Therefore, TRFM-ICTS can be a candidate method for doping monitoring in functional foods and a powerful tool for HIG quantification.


Early elevation of serum thrombopoietin levels and subsequent thrombocytosis in healthy preterm infants.
To verify pathophysiological mechanisms underlying thrombocytosis in low-birth-weight (LBW) preterm babies, we evaluated kinetic changes in platelet counts and thrombopoietic cytokines including thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 in 24 uncomplicated preterm infants. Platelet counts in cord blood (CB) (265 +/- 64 x 10(9)/l) were similar to adult levels, increased by d 14 (473 +/- 140 x 10(9)/l), and then remained fairly constant. Thrombocytosis (> 500 x 10(9)/l) was observed in 9/24 (38%) subjects. Mean TPO level in CB was 5.11 +/- 1.51 fmol/ml, peaked at d 2 (7.64 +/- 3.28 fmol/ml), decreased at d 5 (3.93 +/- 1.67 fmol/ml), and thereafter kept fairly constant during the remaining neonatal period. Compared with term infants, mean TPO levels of preterm infants in CB and at d 2 were significantly higher (P < 0.01). There was an inverse correlation between platelet counts and TPO levels (r = 0.45, P < 0.001, n = 88). Preterm neonates with thrombocytosis had significantly higher TPO values in CB than those without thrombocytosis (P < 0.05). There was no significant relationship between platelet counts and IL-6. IL-11 was not detectable. These results suggest that an early elevation of serum TPO levels is related to the subsequent thrombocytosis in LBW preterm infants.


Urinary albumin excretion in renal transplant donors.
Twenty-four hour urinary albumin excretion was measured using sensitive methods in 129 renal transplant donors 1 to 22 years (mean 7.3 years) after kidney donation. The 24 hour urinary albumin excretion values for the donor group was 6 +/- 9.9 mg (mean +/- standard deviation) (range of 0.1 to 65.2 mg) and was 7.7 +/- 4.5 mg for the control group. Five donors (3.9 percent) had 24 hour urinary albumin excretion levels of 25.5 to 65.2 mg 6 to 13 years after donation, values that were greater than a single value from any member of the control group. Elevated diastolic blood pressure (90 mm Hg or greater) was present in these five donors, and in three, labile or established hypertension was present at the time of donation. It is likely that more careful screening of potential donors with labile or fixed hypertension would further reduce the incidence of microalbuminuria in the renal transplant donor. We conclude that urinary albumin excretion values are within the normal range in most renal transplant donors studied several years after renal donation.


Secondary nonresponsiveness to botulinum toxin type A in patients with oromandibular dystonia.
Intramuscular injection of botulinum toxin type A is the treatment of choice for most cases of oromandibular dystonia. We report on five patients with oromandibular dystonia that developed secondary nonresponsiveness to botulinum toxin type A following multiple injections over a 6-year period.


Health-related quality of life, emotional burden, and neurocognitive function in the first generation of metastatic melanoma survivors treated with pembrolizumab: a longitudinal pilot study.
The aim of this study was to assess the evolution of health-related quality of Life (HRQoL), emotional burden, and neurocognitive function in the first-generation metastatic melanoma survivors treated with pembrolizumab. Survivors were defined as patients who achieved a durable remission for at least 6 months after initiating pembrolizumab in a single-center observational study (N = 141). A semi-structured interview was performed at baseline. Neurocognitive computerized testing and patient-reported outcomes were collected at 4 time points to assess HRQoL using the EORTC QLQ-C30 and the HADS to assess anxiety and depression. Out of 35 eligible patients, 25 were recruited and completed baseline assessment (18 female; median age 58 years [range 28-86]; 24 completed the 1-year follow-up phase. Median time since diagnosis was 30 months (range 12-84); median time since initiation of pembrolizumab was 19 months (range 6-42). At all visits, survivors reported a significantly lower global HRQoL, lower physical, emotional, cognitive, role, and social functioning compared with the European Mean of the healthy population. Fifteen patients (64%) had clinical levels of anxiety/depression at one time point during follow-up. The clinical interview revealed that 12 patients (48%) suffered from Cancer-Related-Post-Traumatic-Stress disorder, of whom 7 (28%) developed transient suicidal ideation, 1 patient made a suicide attempt. Neurocognitive testing revealed cognitive impairment in 8 patients (32%). Metastatic melanoma survivors, treated successfully with pembrolizumab, are at risk for suffering from emotional distress and neurocognitive impairment with a persistent impact on their HRQOL. Timely detection in order to offer tailored care is indicated.


[Practice improvement: workshops for caregivers].
The transmission of good practices is one of the missions of the mobile geriatric outreach teams (EMGE). In this context, the EMGE Centre-Nord 92 has proposed two activities for caregivers in residential care facilities for the dependent elderly (Ehpad) in a concrete and participatory form, called "workshop". The purpose of the workshop on handling hearing aids is to help caregivers handle these technologies used to correct hearing loss in the elderly. The etymology-card game workshop is designed to help caregivers review and use medical vocabulary.


Detection of FOXL2 C134W Mutation Status by a Novel BaseScope In Situ Hybridization Assay is Highly Sensitive and Specific for Adult Granulosa Cell Tumors.
Adult granulosa cell tumors (AGCTs) are a molecularly distinct group of malignant ovarian sex cord-stromal tumors (SCSTs) characterized by a nearly ubiquitous c.402C>G/p.C134W mutation in FOXL2 (hereafter referred to as "C134W"). In some cases, AGCT exhibits marked morphologic overlap with other SCSTs and has an identical immunophenotype, and molecular testing may be necessary to help confirm the diagnosis. However, molecular testing is time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an in situ hybridization (ISH) custom BaseScope assay for the detection of the FOXL2 C134W mutation. We evaluated 106 ovarian SCSTs, including 78 AGCTs, 9 juvenile granulosa cell tumors, 18 fibromas (cellular and conventional), and 1 SCST, not otherwise specified, as well as 53 epithelial ovarian tumors (42 endometrioid carcinomas and 11 carcinosarcomas) and 1 STK11 adnexal tumor for the presence or absence of FOXL2 wild-type and FOXL2 C134W RNA expression via BaseScope-ISH. Fifty-one tumors had previously undergone DNA sequencing of the FOXL2 gene. Across the entire cohort, the FOXL2 C134W probe staining was positive in 77 of 78 (98.7%) AGCTs. Two of 81 (2.5%) non-AGCTs also showed positive staining, both of which were epithelial ovarian tumors. The assay worked in tissue from blocks >20 years old. There was 100% concordance between the FOXL2 sequencing and BaseScope-ISH results. Overall, assessment of FOXL2 mutation status by custom BaseScope-ISH demonstrated 98.7% sensitivity and 97.5% specificity for the diagnosis of AGCT. BaseScope-ISH for FOXL2 C134W represents a reasonable alternative to sequencing, is quicker and less expensive, and is more easily incorporated than molecular testing into many pathology laboratories. It also has the advantage of requiring less tissue, and the neoplastic cells can be directly visualized on stained sections.


The use of prostaglandin F2-alpha in selective pancreatic and left gastric angiography.
Prostaglandin F2-Alpha has been used in 10 superselective angiographic studies of the pancreas and 10 left gastric studies. Injection of Prostaglandin into the dorsal pancreatic or gastroduodenal artery increased opacification of small pancreatic vessels and better demonstrated the angiographic changes in three cases of carcinoma of the pancreas. Injection of the drug into the left gastric artery increased opacification of the left gastric vein, allowed identification of the direction of flow of the contrast medium and enhanced demonstration of gastro-oesophageal varices. It is concluded that Prostaglandin improves the quality of pancreatic and left gastric angiographic studies.


Threshold based on bone mineral density for therapeutic decision-making in postmenopausal women and men over 50 years old under glucocorticoid therapy.
T-score bone mineral density (BMD) thresholds may influence guidance for treatment in patients under glucocorticoid (GC) therapy. Different BMD thresholds have been described but there is no international consensus. The aim of this study was to find a threshold to help in treatment decision-making in the population under GC therapy. A working group representing three scientific societies from Argentina was convened. The first team was formed by specialists with expertise in glucocorticoid-induced osteoporosis (GIO) who voted according to summary of evidence. The second team was constituted by a methodology group who coordinated and supervised each stage. We conducted two systematic reviews to synthesize the evidence. The first included trials of drugs used in GIO to analyze the BMD cut-off used as inclusion criteria. In the second, we analyzed the evidence regarding the densitometric thresholds to discriminate between fractured and non-fractured patients under GC treatment. In the first review, 31 articles were included for qualitative synthesis and more than 90% of the trials included patients regardless of their densitometric T-score or range of osteopenia. In the second review, 4 articles were included and more than 80% of the T-scores were in the range -1.6 to -2.0. The summary of findings was analyzed and put to a vote. With more than 80% agreement of the voting expert panel, a T-score≤-1.7 was considered the most appropriate for treatment in postmenopausal women and men over 50 years of age under GC therapy. This study could help in treatment decision-making in patients under GC therapy without fractures but other fracture risk factors should certainly be considered.


Strategies to avoid the mis-identification of anatoxin-a using mass spectrometry in the forensic investigation of acute neurotoxic poisoning.
Anatoxin-a (AN) is a potent neurotoxin, produced by a number of cyanobacterial species, and consumption of freshwater contaminated with this toxin has led to animal deaths. Forensic investigations of suspected AN poisonings are frequently hampered by difficulties in detecting this toxin in biological matrices due to its rapid decay. In addition, detection of AN using single quadrupole mass spectrometry (MS) is suspect due to the presence of the amino acid, phenylalanine (Phe), since these compounds are isobaric and elute similarly in reversed phase liquid chromatography (LC). Approaches to prevent the misidentification of AN that have been explored in these studies included: (a) fluorimetric LC following derivatisation using 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F); (b) methylation using diazomethane prior to LC-MS determination; (c) multiple tandem MS using a quadrupole ion-trap (LC-MS3); and (d) hybrid quadrupole time-of-flight (QqTOF). Interference from Phe was not observed in any of procedures, (a)-(c), and the high mass accuracy obtained in method (d), readily distinguished between AN (165.11536) and Phe (165.07898). LC-MSn was also employed to study the fragmentation pathway of Phe and multi-stage MS spectra provided characteristic fragmentation information that clearly distinguished between AN and Phe. The difficulties associated with the over reliance on low resolution MS without MS/MS data in forensic toxicology are discussed.


Ulvan inhibits α-synuclein fibrillation and disrupts the mature fibrils: In vitro and in vivo studies.
Misfolding and aggregation of α-synuclein (α-syn) play a key role in the pathogenesis of Parkinson's disease (PD). Herein, the inhibitory effect of ulvan on α-syn fibrillogenesis was studied using thioflavin T fluorescence and atomic force microscope assays. It is shown that ulvan could inhibit α-syn fibrillogenesis in a dose-dependent manner. Based on the circular dichroism results, it is found that ulvan delays greatly the conformational transition from its initial random coil to β-sheet rich structure. The protective effect of ulvan against celllular death induced by α-syn aggregates was investigated by MTT colorimetric and cellular staining methods. It is found that ulvan protects greatly PC12 cells from α-syn fibril-induced cytotoxicity. In addition, ulvan disaggregates preformed α-syn fibrils and reduces cytotoxicity in a dose-dependent manner. Thereafter, the inhibitory effects of ulvan against α-syn fibrillogenesis were probed using Caenorhabditis elegans model NL5901 expressing human α-syn. It is found that ulvan extends the lifespan of NL5901 and recovers the lipid deposition by reducing the accumulation of α-syn. Finally, the molecular interactions between ulvan and α-syn pentamer was also explored using molecular docking. These findings suggest that ulvan can be pursued as a novel candidate drug for treatment of PD.


Genetic dissection of pyrimidine biosynthesis and salvage in Leishmania donovani.
Protozoan parasites of the Leishmania genus express the metabolic machinery to synthesize pyrimidine nucleotides via both de novo and salvage pathways. To evaluate the relative contributions of pyrimidine biosynthesis and salvage to pyrimidine homeostasis in both life cycle stages of Leishmania donovani, individual mutant lines deficient in either carbamoyl phosphate synthetase (CPS), the first enzyme in pyrimidine biosynthesis, uracil phosphoribosyltransferase (UPRT), a salvage enzyme, or both CPS and UPRT were constructed. The Δcps lesion conferred pyrimidine auxotrophy and a growth requirement for medium supplementation with one of a plethora of pyrimidine nucleosides or nucleobases, although only dihydroorotate or orotate could circumvent the pyrimidine auxotrophy of the Δcps/Δuprt double knockout. The Δuprt null mutant was prototrophic for pyrimidines but could not salvage uracil or any pyrimidine nucleoside. The capability of the Δcps parasites to infect mice was somewhat diminished but still robust, indicating active pyrimidine salvage by the amastigote form of the parasite, but the Δcps/Δuprt mutant was completely attenuated with no persistent parasites detected after a 4-week infection. Complementation of the Δcps/Δuprt clone with either CPS or UPRT restored infectivity. These data establish that an intact pyrimidine biosynthesis pathway is essential for the growth of the promastigote form of L. donovani in culture, that all uracil and pyrimidine nucleoside salvage in the parasite is mediated by UPRT, and that both the biosynthetic and salvage pathways contribute to a robust infection of the mammalian host by the amastigote. These findings impact potential therapeutic design and vaccine strategies for visceral leishmaniasis.


Outcomes and prognostic factors of post-irradiation and de novo sarcomas of the head and neck: a histologically matched case-control study.
This study was designed to compare post-irradiation sarcomas (PIS) and de novo sarcomas (DN) of the head and neck in terms of tumor characteristics, prognostic factors, and survival outcomes. All (N=83) head and neck sarcoma patients treated at National Cancer Centre, Singapore (Feb 2002-May 2011) were included: DN (N=60; 72%); PIS (N=23; 28%). Clinicopathologic features and outcomes of all patients and histologically matched pairs were compared. Prognostic factors were identified using univariate and multivariate analyses. Median age, gender, smoking status, and tumor size were not significantly different. Significant differences were seen in histology (most prevalent: PIS-sarcoma-NOS; DN-angiosarcoma) and tumor subsite (most prevalent: PIS-nasal cavity and sinuses; DN-skin). Median latency of PIS development was 16.7 years. PIS patients had shorter overall survival (OS) and disease-specific survival (DSS) compared with DN patients, most clearly seen on histologically matched pair analysis: 2-year OS (PIS: 54%; DN: 83%; P=0.028). Multivariate analyses showed that age>50 years (hazard ratio (HR)=3.68; P=0.007), ever-smokers (HR=2.79; P=0.017), and larger tumor-size (cm) (HR=1.12; P=0.045) were associated with worse OS, and age at >50 years (HR=2.77; P=0.04) and ever-smokers (HR=2.94; P=0.021) were associated with worse DSS. When treated with curative intent, no significant survival difference was noted between DN and PIS patients. In our cohort, PIS constituted 28% of head and neck sarcomas. Poorer prognosis traditionally associated with PIS compared with DN was not seen amongst patients treated with curative intent.


Nucleotide sequence and expression of the sn-glycerol-3-phosphate dehydrogenase gene in Locusta migratoria.
The sn-glycerol-3-phosphate dehydrogenase gene (Gpdh) in the locust (Locusta migratoria) encodes three mature transcripts and a number of isozymes. Gpdh expression is tissue- and developmentally regulated such that two transcripts are unique to flight muscle. Identical proteins are encoded by two transcripts which are generated by alternative splicing downstream of the stop codon in the penultimate exon.


Early Surgery Versus Watchful Waiting Strategy for Infantile Abdominoscrotal Hydrocele.
Infantile abdominoscrotal hydrocele is generally managed with early surgery. However, whether these patients actually benefit from an initial watchful waiting strategy is yet to be determined. This single-center, comparative observational analysis included 36 consecutive patients (9 bilateral cases) diagnosed between January 1998 and December 2019. Initial 16 patients (21 lesions) underwent surgical repair shortly after diagnosis (Group A) at a mean (SD) age of 8 (4) months. Remaining 20 patients (24 lesions) underwent initial nonoperative management (Group B). Overall follow-up was 82.74 (63.84) months. Six lesions of Group B spontaneously regressed at a mean age of 23.8 (7.8) months. Remaining 18 hydroceles underwent surgical management at a mean age of 18.7 (12.6) months. Early postoperative morbidity was high (43%) in both groups (Clavien-Dindo grade I-II). During follow-up, there were 1 recurrent hydrocele and 1 testicular atrophy, both events occurring in Group A patients. Group B patients required a higher need for concomitant ipsilateral orchidopexy (61% versus 14%; p = 0.001), and developed a higher rate of ipsilateral inguinal hernia (39% versus 5%; p = 0.01), occurring within 8.3 (3.53) months of surgery. On multivariable analysis, nonoperative management was associated with unplanned second surgery (odds ratio 5.5, 95% CI 1.25-24.17, p = 0.02), regardless of the type of hydrocelectomy performed. Nonoperative management provides effective spontaneous resolution in about 25% of infantile abdominoscrotal hydrocele. Clinicians must balance the potential benefits of such strategy against the impact of pressure induced detrimental effects on the success of future surgery when dealing with longstanding lesions. III.


Presence of an essential lysine residue in a GDP-fucose protected site of the alpha 1----3fucosyltransferase from human small cell lung carcinoma NCl-H69 cells.
The NCI-H69 cell alpha 1----3fucosyltransferase has been purified from a 0.2% Triton X-100R solubilized enzyme fraction by GDP-hexanolamine-Sepharose affinity chromatography and Superose 12 gel filtration. Photoaffinity labeling experiments with 125I-GDP-hexanolaminyl-4-azidosalicylic acid present in concentrations equivalent to 0.5 and 1 times Ki of the inhibitor for the enzyme indicated that labeling of the 45-kDa protein band could be inhibited by addition of 400 microM GDP-fucose but was not effected by similar concentrations of either GDP-mannose or GDP-glucose. The purified enzyme was applied to studies intended to define catalytically essential amino acid residues of the protein. Incubation of the enzyme in the presence of increasing concentrations of pyridoxal 5'-phosphate was found to result in irreversible inactivation of the enzyme after NaBH4 reduction. The donor substrate, GDP-fucose, was found to protect the enzyme from inactivation. Little or no protection was found for either GDP-mannose or the acceptor substrate nLc4. Pyridoxal 5'-phosphate was shown to behave as a competitive inhibitor with respect to GDP-fucose with a Ki of 105 microM. Labeling with 3H-pyridoxal 5'-phosphate resulted in the incorporation of approximately 8 mol pyridoxal 5'-phosphate per mole subunit. Parallel experiments containing GDP-fucose indicated protection of one site per subunit correlated with GDP-fucose binding. Acid hydrolysis and chromatographic analysis of the 3H-pyridoxylated protein indicated greater than 95% of the 3H label was recovered as pyridoxyl-lysine irrespective of whether GDP-fucose was present or not during labeling. These studies indicate the presence of a catalytically essential lysine residue associated with GDP-fucose binding to this enzyme. This information will be of value in further studies of this and other alpha 1----3fucosyltransferases and may suggest a practical basis for modulation of enzyme activity in the cell.


Beta-arrestin 2 is required for lysophosphatidic acid-induced NF-kappaB activation.
Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-kappaB. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-kappaB is not fully defined. In this work, we found that beta-arrestin 2, but not beta-arrestin 1, is required for LPA-induced NF-kappaB activation and interlukin-6 expression. Mechanistically, we found that beta-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-kappaB activation, suggesting that beta-arrestin 2 may recruit CARMA3 to LPA receptors. Although beta-arrestin 2 deficiency did not affect LPA-induced IKKalpha/beta phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKKalpha/beta activation but not for the inducible phosphorylation of IKKalpha/beta. Together, our results provide the genetic evidence that beta-arrestin 2 serves as a positive regulator in NF-kappaB signaling pathway by connecting CARMA3 to GPCRs.


Anterior cervical decompression and fusion with plate fixation as an outpatient procedure.
Outpatient cervical spine surgery has previously been described for posterior laminoforaminotomy and anterior microdiscectomy with allograft fusion. Anterior cervical discectomy and fusion (ACDF) with plate fixation has not, to our knowledge, been described as an outpatient procedure. The objective of this study was to evaluate the safety and feasibility of ACDF with instrumentation when performed as an outpatient in a free-standing ambulatory surgical center. Additionally, the authors sought to determine any patient selection bias and its effect on outcome. This study is a retrospective medical record review. The sample included all patients who underwent one or two level ACDF with plate fixation at levels C4-5 or below as an adjunct to autogenous iliac crest bone graft or structural allograft from 1998 to 2002 by the two senior authors. Complications were assessed clinically with special attention to dysphagia and respiratory complications. Inpatient lengths of stay and postoperative hospital admission or readmission were also measured. Thirty consecutive patients were treated at a free-standing ambulatory surgery center, whereas two control groups, each of 30 consecutive patients, had surgery performed in the hospital and were admitted overnight for observation. The first control group consisted of admitted patients before the commencement of patient selection for the outpatient group; the second control group was comprised of admitted patients who had surgery performed concurrently with the outpatient group. The study group was evaluated on the first postoperative day and 3 weeks after surgery. Ninety patients underwent ACDF plate fixation at 140 different levels. Forty patients were treated at one level, and 50 were treated at two levels. The three groups were comparable in age, sex, and body mass index. There were no major complications. Seven patients (13%) had minor postoperative complications among the controls: transient dysphagia in three (5%) and graft donor site pain in four (14%). Three patients (10%) in the outpatient group had minor complications (all had dysphagia). Among the controls, four patients (7%) had increased length of stay owing to complications. Four patients (7%) in the combined control group were readmitted for early complications; no patient was admitted for a complication after outpatient surgery. In the present study, selection criteria for outpatient surgery included one or two level involvement C4-5 or lower, absence of myelopathy, subjective neck size, and estimated operative time. The data did not otherwise suggest a difference in the surgical populations. The outpatient group had a lower complication rate compared with the controls. This was likely the result of selection bias. Transient dysphagia was the most prevalent complication in the outpatient group.


Molecular identification and genotyping of Acinetobacter baumannii isolated from burn patients by PCR and ERIC-PCR.
Acinetobacter baumannii is one of the most important agents of hospital infections. Rapid and accurate identification and genotyping of A. baumannii is very important, especially in burn hospitals in order to prevent the spread of related nosocomial infections and to further epidemiological studies. For two months, 82 A. baumannii isolates were collected from burn wound swabs of patients in a major burn hospital in Tehran. A. baumannii isolates were identified by conventional microbiological test and polymerase chain reaction (PCR) using the primers of blaOXA-51 gene, while the genetic linkage of A. baumannii isolates was investigated by enterobacterial repetitive intragenic consensus (ERIC)-PCR technique. Similarity, a cut-off of ⩾ 95% was considered for classifying the genotypes. The molecular test (PCR) confirmed 97.56% of phenotypic results for the detection of A. baumannii isolates. ERIC-PCR results revealed 14 different ERIC patterns (ERIC-types) including 11 common types and three unique types. Our findings show that we can simply and quickly detect A. baumannii isolates by PCR using blaOXA genes and genetic diversity by ERIC-PCR, respectively. These rapid and simple techniques for the routine screening and identification of clinical A. baumannii isolates could be useful with epidemic potential.


Maximum acceptable level for the determination of ECAP and ESRT in a paediatric population.
Two of the most used objective measures are electrically evoked action potentials (ECAPs) and electrically evoked stapedius reflex thresholds (ESRTs). Although stimuli used for these measures differ considerably, both measures are influenced by subjective loudness percept. We focus on the subjective maximum acceptable loudness (MAL) to investigate if loudness sensitivity varied along the electrode array during ECAP recordings. In addition, we explored how the MAL reached during an ECAP recording related to the postoperative ESRT. Uni- and bilaterally implanted young CI users (n = 15, average age = 9 y, age range 3-18 y) underwent ECAP and ESR recordings using the clinical software MAESTRO (MED-EL, Innsbruck, Austria) and a commercially available immittance instrument (PATH MEDICAL GmbH, Germering, Germany). Loudness tolerance during ECAP recordings was lowest at the two apical-most electrode contacts (number 1 and 2). There was a moderate correlation between the MAL achieved during ECAP recordings and ESR maximum stimulation amplitudes. (r: 0.44344). ECAP recordings should commence at basal or medial contacts to increase the users' comfort and loudness tolerance, especially in young CI users. A higher maximum stimulation appears to increase the chance of the automatic determination of ECAP thresholds for all electrode contacts.


Mean-field theory of globally coupled integrate-and-fire neural oscillators with dynamic synapses.
We analyze the effects of synaptic depression or facilitation on the existence and stability of the splay or asynchronous state in a population of all-to-all, pulse-coupled neural oscillators. We use mean-field techniques to derive conditions for the local stability of the splay state and determine how stability depends on the degree of synaptic depression or facilitation. We also consider the effects of noise. Extensions of the mean-field results to finite networks are developed in terms of the nonlinear firing time map.


Human chromosome 21-encoded cDNA clones.
We have employed two strategies to isolate random cDNA clones encoded by chromosome 21. In the first approach, a cDNA library representing expressed genes of WA17, a mouse-human somatic cell hybrid carrying chromosome 21 as its sole human chromosome, was screened with total human DNA to identify human chromosome 21-specific cDNAs. The second approach utilized previously characterized single-copy genomic fragments from chromosome 21 as probes to retrieve homologous coding sequences from a human fetal brain cDNA library. Six cDNA clones on chromosome 21 were obtained in this manner. Two were localized to the proximal long arm of chromosome 21, two to the distal portion of the long arm, and one to the region of 21q22 implicated in the pathology of Down syndrome.


Neutrophils exacerbate tuberculosis infection in genetically susceptible mice.
Mice of the I/St inbred strain genetically hyper-susceptible to TB infection and prone to form neutrophil-abundant necrotic lung lesions and relatively resistant mice of the C57BL/6 (B6) strain were infected with 100 CFU of M. tuberculosis H37Rv. To verify the role of neutrophils in TB immunity, we selectively depleted neutrophils from infected mice with highly specific 1A8 anti-Ly6G antibodies at day 2 and 6 post-challenge. Depletion of neutrophils resulted in reduced lung tissue pathology, mycobacterial CFU counts and an increase of the survival time in genetically susceptible I/St, but not in B6 mice. Furthermore, we demonstrated that in vivo neutrophil depletion at the onset of TB infection results in a significant increase in numbers of mycobacteria-specific IFN-γ-producing T-cells at the time point when the acquired immunity to mycobacteria is fully developed. These results suggest antagonistic activity of neutrophils and immune T-cells in the course of TB infection and provide further evidence of deleterious rather than protective role of the former.


Translesion DNA Synthesis and Carcinogenesis.
Tens of thousands of DNA lesions are formed in mammalian cells each day. DNA translesion synthesis is the main mechanism of cell defense against unrepaired DNA lesions. DNA polymerases iota (Pol ι), eta (Pol η), kappa (Pol κ), and zeta (Pol ζ) have active sites that are less stringent toward the DNA template structure and efficiently incorporate nucleotides opposite DNA lesions. However, these polymerases display low accuracy of DNA synthesis and can introduce mutations in genomic DNA. Impaired functioning of these enzymes can lead to an increased risk of cancer.


Parents' attitudes as mediators between knowledge and behaviours in unintentional injuries at home of children aged 0-3 in Shanghai, Eastern China: a cross-sectional study.
Parental behaviours are important in preventing unintentional injury at home among young children. Previous research showed an inconsistent relationship between knowledge and behaviours, indicating that the mechanisms may vary for different behaviours. This study aimed to examine the mediating roles of different attitudes in the mechanism of knowledge acting on different behaviours. Cross-sectional study. Eastern China. Participants were recruited using stratified community-based sampling. A total of 488 parents of children aged 0-3 years participated in the study and 476 (97.5%) valid questionnaires were recovered. Parents' knowledge, attitudes (including injury attribution, preventability and responsibility) and behaviours (including supervision behaviours, risky behaviours and providing a safe home environment). The results of mediation analysis showed that the mediator variables were different for different behaviours and that all associations were positive. Parents' knowledge (β 0.19, 95% CI 0.13 to 0.24) and attitude of injury attribution (β 0.37, 95% CI 0.21 to 0.46) were directly associated with risky behaviours. Attitude of preventability was directly associated with parents' supervision behaviour (β 0.27, 95% CI 0.14 to 0.40). Parents' attitude of preventability mediated the positive association between knowledge, attitudes of injury attribution and responsibility, and supervision behaviours, as well as providing a safe home environment. In addition, the occurrence of child injuries at home was directly associated with home environment (β -0.41, 95% CI -0.82 to -0.01). The current findings confirm that attitudes play varying mediating roles between knowledge and different behaviours. An important recommendation is that parents' attitudes, especially towards preventability and responsibility, need to be considered when health providers develop health education programmes targeted at improving parental supervision behaviours and providing a safe home environment.


Role of MgO nanoparticles in the suppression of Meloidogyne incognita, infecting cowpea and improvement in plant growth and physiology.
Root-knot disease, caused by Meloidogyne spp., alters histology as well as physiology of the roots thus influencing metabolism of vegetative and reproductive parts leading to huge losses in crop productivity. The experimental plant, Vigna unguiculata L. (cowpea of Fabaceae family) var. Gomti is an economically important pulse crop plant. An experiment was conducted to evaluate the effects of different concentrations (0, 25, 50 or 100 ppm) and various modes of applications (root dip, soil drench or foliar spray) of MgO nanoparticles on cowpea infected with M. incognita. The MgO nanoparticles were synthesized chemically and characterized by transmission and scanning electron microscopy (TEM, SEM), UV-Vis spectroscopy, X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The scanning electron microscopy images of second stage juveniles of M. incognita treated with MgO nanoparticles (50 and 100 ppm) exhibited indentations, roughness and distortions in the cuticular surface, in comparison to the control untreated juveniles. MgO nanoparticles, in varying concentrations (50, 100 and 200 ppm), were dispensed into the plants by root dip, soil drench and foliar spray methods and their efficacy was assessed in terms of morphological characteristics, yield parameters and biochemical attributes of M. incognita infected plants. In planta trials revealed that 100 ppm dose of MgO nanoparticles, as root dip application, demonstrated reduced nematode fecundity, decreased number and smaller size of galls; enhanced plant growth, increased chlorophyll, carotenoid, seed protein, and root and shoot nitrogen contents. From these findings it could be inferred that MgO nanoparticles played twin roles, first as a nematicidal agent and the other as growth promotion inducer.


Immunological study of complex formation between soluble transferrin receptor and transferrin.
Transferrin receptor (TfR) is a dimeric transmembrane protein that provides iron transport from plasma to cells by binding and internalization of iron-loaded transferrin (Tf). Soluble transferrin receptor (sTfR) is an extracellular part of the TfR molecule that is truncated from the cell surface and released into the blood stream. Using monoclonal antibodies (HyTest Ltd., Turku, Finland), immunofluorescent methods for sTfR and sTfR-Tf complex determination were developed. Soluble TfR was isolated from human plasma, and complex formation between sTfR and Tf was studied by stepwise complex construction and by FPLC gel filtration. It was found that sTfR could bind two Tf molecules step by step when the sTfR-Tf complex is constructed in the plate wells. FPLC gel filtration of sTfR-Tf mixtures and analysis of sTfR and sTfR-Tf immunological activities in collected fractions showed that sTfR can form different complexes with TF depending upon the ratios between them: a 291-kDa compound is assumed to be a 2:1 sTfR/Tf complex, and a 345-kDa compound is assumed to be a 2:2 sTfR/Tf complex. Isolated sTfR eluted as a 237-kDa protein. FPLC gel filtration of serum revealed that all sTfR in serum is bound to Tf in a 2:2 complex, and no isolated sTfR can be found in serum. This raises the question as to the nature of the bonds that hold two molecules of sTfR together to form a dimer.


Cell confluence induces switching from proliferation to migratory signaling by site-selective phosphorylation of PDGF receptors on lipid raft platforms.
Platelet derived growth factor receptors (PDGFR) play an important role in tumor pathogenesis and are frequently overexpressed in glioblastoma. Earlier we have shown that only confluent glioblastoma cell cultures exhibit a biphasic calcium transient upon PDGF stimulation. Here, we examined how the change in cell density leads to differential cellular responses to the same PDGF stimulus. PDGF beta receptors and their specific phosphotyrosine residues were fluorescently co-labeled on A172 and T98G glioblastoma cells. The distribution in cell membrane microdomains (lipid rafts) and the phosphorylation state of PDGFR was measured by confocal microscopy and quantitated by digital image processing. Corresponding bulk data were obtained by Western blotting. Activation of relevant downstream signaling pathways was assessed by immunofluorescence in confocal microscopy and by Western blot analysis. Functional outcomes were confirmed with bulk and single cell proliferation assays and motility measurements. In non-confluent (sparse) cultures PDGF-BB stimulation significantly increased phosphorylation of Tyr716 specific for the Ras/MAPK pathway and Tyr751 specific for the phosphoinositide 3-kinase/Akt pathway. As cell monolayers reached confluence, Tyr771 and Tyr1021 were the prominently phosphorylated residues. Tyr771 serves as adaptor for Ras-GAP, which inactivates the MAPK pathway, and Tyr1021 feeds into the phospholipase C-gamma/PKC pathway. Coherent with this, MAPK phosphorylation, Ki-67 positivity and proliferation dominated in dispersed cells, and could be abolished with inhibitors of the MAPK pathway. At the same time, RhoA activation, redistribution of cortactin to leading edges, and increased motility were the prominent output features in confluent cultures. Importantly, the stimulus-evoked confluence-specific changes in the phosphorylation of tyrosine residues occurred mainly in GM1-rich lipid microdomains (rafts). These observations suggest that the same stimulus is able to promote distinctly relevant signaling outputs through a confluence dependent, lipid raft-based regulatory mechanism. In particular, cell division and survival in sparse cultures and inhibition of proliferation and promotion of migration in confluent monolayers. In our model, the ability to switch the final output of the same stimulus as a function of cell density could be a key to the balance of proliferation and invasion in malignant glioblastoma.


Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28.
G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.


Gestures-enhanced anatomy teaching: A literature review of an educational strategy with promising outcomes.
The educational use of gestures has resulted in positive outcomes in several fields. We performed a literature review to investigate the outcomes of the use of gestures to enhance the existing anatomy education methods. PubMed, SCOPUS, ERIC and Cochrane databases were searched for papers with purpose to investigate the outcomes of the use of gestures (either seeing or performing them or both) as adjuncts to existing anatomy education methods. Six articles were included. Three studies comprised both seeing and performing gestures by the students, while the remaining three studies only comprised either seeing or performing gestures by the students. Most studies evaluated the acquisition of anatomical knowledge after the educational intervention and demonstrated that the addition of gestures resulted in significant benefit compared to control groups, while positive students' perceptions were recorded. It was not clarified whether seeing or performing gestures by the students leads to better educational outcomes. Gestures-enhanced anatomy education seems to be a promising teaching strategy, given that it has led to significantly increased acquisition of anatomical knowledge compared to no gestures-enhanced modalities. The addition of gestures to existing anatomy education modalities seems able to increase their potential without increasing their cost. Further research is needed to determine if seeing or performing gestures by the students is more effective.


Erratum to: Cognitive and mood improvements following acute supplementation with purple grape juice in healthy young adults.
In the original publication of the article, on page 7, paragraph "Discussion", line 12, 'blackcurrant has been observed to increase digit vigilance reaction time' should read as 'blackcurrant has been observed to decrease digit vigilance reaction time'.


Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer's disease.
Alzheimer's disease (AD) is the leading progressive neurodegenerative disorder afflicting 35.6 million people worldwide. There is no therapeutic agent that can slow or stop the progression of AD. Human studies show that besides loss of cognition/learning ability, neuropsychological symptoms such as anxiety and seizures are seen as high as 70 and 17 % respectively in AD patients, suggesting dysfunction of GABAergic neurotransmission contributes to pathogenesis of AD. Dihydromyricetin (DHM) is a plant flavonoid and a positive allosteric modulator of GABAARs we developed recently (Shen et al. in J Neurosci 32(1):390-401, 2012 [1]). In this study, transgenic (TG2576) and Swedish transgenic (TG-SwDI) mice with AD-like pathology were treated with DHM (2 mg/kg) for 3 months. Behaviorally, DHM-treated mice show improved cognition, reduced anxiety level and seizure susceptibility. Pathologically, DHM has high efficacy to reduce amyloid-β (Aβ) peptides in TG-SwDI brain. Further, patch-clamp recordings from dentate gyrus neurons in hippocampal slices from TG-SwDI mice showed reduced frequency and amplitude of GABAAR-mediated miniature inhibitory postsynaptic currents, and decreased extrasynaptic tonic inhibitory current, while DHM restored these GABAAR-mediated currents in TG-SwDI. We found that gephyrin, a postsynaptic GABAAR anchor protein that regulates the formation and plasticity of GABAergic synapses, decreased in hippocampus and cortex in TG-SwDI. DHM treatment restored gephyrin levels. These results suggest that DHM treatment not only improves symptoms, but also reverses progressive neuropathology of mouse models of AD including reducing Aβ peptides, while restoring gephyrin levels, GABAergic transmission and functional synapses. Therefore DHM is a promising candidate medication for AD. We propose a novel target, gephyrin, for treatment of AD.


Isolation of an extracellular neutral proteinase from Pseudomonas fragi.
A single proteolytic enzyme (EC 3.4.4.-) was isolated from culture supernatants of Pseudomonas fragi with 20% yielded and 60-fold purification by means of stepwise DEAE-Sephadex batch adsorption, ammonium sulfate precipitation, gel filtration and DEAE-cellulose chromatography. The enzyme was Zn-2+ activated and Ca-2+ stabilized, had optimum activity at pH 6.5--8.0 and 40 degrees C. The molecular weight range was 40 000--50 000 as determined by dodecylsulfate gel electrophoresis, gel filtration and Zn assay. This proteinase has properties similar to other extracellular bacterial neutral proteinases.


Carbamyl phosphate: glucose phosphotransferase and glucose-6-phosphate phosphohydrolase of nuclear membrane. Interrelationships between membrane integrity, enzymic latency, and catalytic behavior.
The presence of carbamyl-phosphate:glucose phosphotransferase in liver nuclei of five species of mammals and birds is demonstrated. The activity is confined to nuclear membranes and is due exclusively to multifunctional glucose-6-phosphatase-phosphotransferase (D-glucose-6-phosphate phosphohydrolase; EC 188.8.131.52). The nuclear enzyme constitutes approximately 16 to 19 percent of total hepatic glucose-6-phosphatase-phosphotransferase. Carbamyl-phosphate:glucose phosphotransferase and glucose-6-P phosphohydrolase activities of membrane of chicken liver nuclei are shown to be catalytically identical with the maximally activated microsomal enzyme. A correspondence is seen in two-substrate kinetic double reciprocal plots, K-m or apparent K-m values for the various substrates, K-i values for the competitive inhibitors P-i and ATP, and pH-activity profiles. Comparative studies were carried out with various intact, disrupted, and detergent-dispersed membranous preparations by a combination of enzyme kinetic and electron microscopic techniques. It is concluded that (a) intimate interrelationships exists between catalytic behavior of this enzyme and morphological integrity of membranes of which the enzyme is a part; (b) activities of the enzyme of nuclear membrane appear quite available for physiological phosphorylative functions; and (c) interrelationships between membrane morphology and catalytic behavior of this membrane-bound enzyme may well be involved in the bioregulation of this complex, multifunctional enzyme system.


Sphaeranthus senegalensis DC: Evaluation of chemical constituents, oral safety, gastroprotective activity, and mechanism of action of its hydroethanolic extract.
Sphaeranthus senegalensis DC is a seasonal herb with a spicy smell that grows wild in wet grounds of tropical Africa and Asia. The plant is used in folk medicine for the treatment of various diseases; that includes its use to treat gastric ulcers. This study aimed to investigate the chemical constituents of the hydroethanolic extract of Sphaeranthus senegalensis DC and evaluate its oral safety, gastroprotective activity, and mechanisms of action using laboratory models in rats and mice. Hydroethanolic extract (70%) of the powdered whole dried material was prepared, and chemical constituents of the resultant extract (denoted HESs) standardized using the high-performance liquid chromatography (HPLC) method. The safety profile of HESs was assessed using 2000 mg/kg, oral (p.o.) for Hippocratic screening in mice, and 800 mg/kg, p.o. for 28 days subchronic toxicity assay in rats. The gastroprotective effect of HESs (25, 100, and 400 mg/kg, p.o.) was investigated using acidified ethanol, piroxicam, water immobilization stress, and acetic acid-induced ulcer models. The gastroprotective mechanisms of HESs were evaluated using its effect on gastric mucus protection, nitric oxide modulation, gastric juice secretory parameters, catalase and myeloperoxidase activities. Histological analysis of the stomach tissues was also carried out. The HPLC analysis indicated the presence of 25.94% phenolics (gallic acid, caffeic acid, and ferulic acid) and 14.53% flavonoids (rutin, morin, luteolin, quercetin, and apigenin). Hippocratic screening and the 28 days subchronic study indicated that HESs is generally safe. Result shows that oral administration of HESs (25, 100 and 400 mg/kg) alleviated the severity of the gastric ulcers induced by acidified ethanol by 35.65% (p < 0.05), 48.70% (p < 0.05) and 78.02% (p < 0.001) respectively; exhibited gastroprotective effect against the gastric lesions induced by piroxicam by 37.97% (p < 0.05), 53.27% (p < 0.05) and 76.23% (p < 0.001) respectively; and decreased the severity of the water immobilization stress-induced gastric ulcers by 32.43% (p < 0.05), 55.26% (p < 0.01) and 74.05% (p < 0.001) respectively, when compared to the vehicle control group. The mechanisms of action assays indicated that the gastroprotective activity was mediated mainly through gastroprotection, antisecretory, and antioxidant activities. Histological analysis showed it inhibited epithelial cell loss, vascular damage, and leucocyte infiltration. HESs contains useful phytochemicals, is safe, and exhibited significant gastroprotective action. The results provided justification for its claim in the treatment of gastric ulcers and its evaluation for potential application as a gastroprotective agent.


Intraoperative technical difficulty during laparoscopy-assisted surgery as a prognostic factor for colorectal cancer.
Laparoscopy-assisted surgery has technical drawbacks compared with open surgery, although laparoscopic surgery has become widely adopted with evidence of oncological safety for colon cancer treatment. The oncological risk of technical difficulties during laparoscopic surgery for colorectal cancer has not been previously reported. We aimed to investigate whether a technical difficulty encountered during laparoscopic surgery can be considered a recurrence-related factor for colorectal cancer. Data from 427 patients who underwent laparoscopic surgery for colorectal cancer between May 2003 and December 2007 were analyzed. An intraoperative technical difficulty was defined as a significant deviation from the ordinary surgical procedure. All conversions to open surgery and iatrogenic bowel perforation during laparoscopic surgery were included as technical difficulties. The Cox proportional-hazards regression model was used to evaluate the recurrence-related factor in the various risk factors including technical difficulty. Technical difficulties were found in 44 (10.3%) patients, which included 17 (3.9%) conversions to open surgery and 10 (2.4%) with iatrogenic bowel injury. Technical difficulties were encountered more frequently in men compared with women (13.5% vs 6.0%, P = .013), and for cancers located in the mid and low rectum, splenic flexure, and descending colon. The recurrence rates were higher in patients with technical difficulties (local recurrence, 2.6% vs 6.7%, P < .05; systemic recurrence, 6.3% vs 13.6%, P < .05) with a mean follow-up duration of 45.9 months. Multivariate analysis by the Cox proportional-hazards regression model showed that a technical difficulty was an independent factor related to recurrence after laparoscopic surgery (odds ratio, 2.374; 95% CI, 1.006-5.600; P = .048). This study has demonstrated that a technical difficulty during laparoscopy-assisted surgery jeopardizes oncological safety. It is suggested that surgeons should be prepared to minimize technical difficulties during laparoscopy-assisted surgery.


Modified behavioural tests to detect white matter injury- induced motor deficits after intracerebral haemorrhage in mice.
Motor function deficit induced by white matter injury (WMI) is one of the most severe complications of intracerebral haemorrhage (ICH). The degree of WMI is closely related to the prognosis of patients after ICH. However, the current behavioural assessment of motor function used in the ICH mouse model is mainly based on that for ischaemic stroke and lacks the behavioural methods that accurately respond to WMI. Here, a series of easy-to-implement behavioural tests were performed to detect motor deficits in mice after ICH. The results showed that the grip strength test and the modified pole test not only can better distinguish the degree of motor dysfunction between different volumes of blood ICH models than the Basso Mouse Scale and the beam walking test but can also accurately reflect the severity of WMI characterized by demyelination, axonal swelling and the latency of motor-evoked potential delay induced by ICH. In addition, after ICH, the results of grip tests and modified pole tests, rather than the Basso Mouse Scale and the beam walking test, were worse than those observed after intraventricular haemorrhage (IVH), which was used as a model of brain haemorrhage in non-white matter areas. These results indicate that the grip strength test and the modified pole test have advantages in detecting the degree of motor deficit induced by white matter injury after ICH in mice.


The success of nanomedicine.
In recent years, the promise and prospects of nanomedicine have been controversially discussed. We here argue that nanomedicine has undeniably been successful, not only academically and preclinically, but also industrially and clinically. To ensure that we keep on making progress, we have to move away from over-focusing on nano and on materials, towards more holistic approaches that address real medical problems, in a realistic manner.


Circulating concentration of interleukin-37 in Helicobacter pylori-infected patients with peptic ulcer: Its association with IL-37 related gene polymorphisms and bacterial virulence factor CagA.
The immunopathologic responses play a major role in the development of H. pylori (HP)-related gastrointestinal diseases. IL-37 is an anti-inflammatory cytokine with potent suppressive effects on innate and adaptive immune responses. Here, we investigated the IL-37 levels and two single nucleotide polymorphisms (SNPs) including rs3811047 and rs2723176 in IL-37 gene in HP-infected peptic ulcer (PU) patients to identify any relationship. Three groups, including 100 HP-infected PU patients, 100 HP-infected asymptomatic (AS) subjects and 100 non-infected healthy control (NHC) subjects were enrolled to study. Serum IL-37 levels and the genotyping at rs3811047 and rs2723176 were determined using ELISA and SSP-PCR methods, respectively. Significantly higher IL-37 levels were observed in PU patients compared with AS and NHC groups (P < 0.0001). In both PU and AS groups, the CagA+ HP-infected participants displayed higher IL-37 levels compared with those infected with CagA- strains (P < 0.0001). There were significant differences between PU, AS and NHC groups regarding the distribution of genotypes and alleles at rs3811047 and rs2723176 SNPs. The genotype GG and allele G at IL-37 rs3811047 SNP, and the genotype CC and allele C at IL-37 rs2723176 SNP more frequently expressed in PU patients than total healthy subjects (AS + NHC groups) and were associated with an increased risk of PU development (genotype GG: RR = 3.08, P < 0.009; allele G: RR = 2.94, P < 0.01; genotype CC: RR = 5, P < 0.01; and allele C: RR = 5.0, P < 0.02, respectively). The PU patients with allele A at IL-37 rs2723176 SNP expressed higher amounts of IL-37 compared with patients carried allele C at the same position (P < 0.05). In AS carriers and NHC individuals, the IL-37 levels in subjects carried genotype AA or allele A at IL-37 rs2723176 SNP were higher than those carried genotype CC or allele C at the same location (P < 0.01 and P < 0.02 for AS group; P < 0.0001 and P < 0.001 for NHC subjects, respectively). The increased IL-37 levels may be considered as a valuable marker of PU development in HP-infected individuals. The SNPs rs3811047 and rs2723176 were associated with PU development. The CagA status of HP and IL-37 rs2723176 SNP may affect the IL-37 levels.