A digital fluoroscopic imaging device for radiotherapy localization.
We have been developing a digital fluoroscopic imaging system to replace the portal films that are currently used to verify patient positioning during radiotherapy treatments. Our system has a number of modifications compared to previously reported devices. The detector, which consists of a copper plate with Gd2O2S:Tb phosphor bonded directly to the copper, has been designed to maximize light output from the phosphor by increasing the phosphor thickness. The operation of the T.V. camera has been modified so that the light signal is accumulated on the target of the T.V. camera for periods of 0.2-2.0 seconds. Accumulation of the light increases the video signal relative to the fixed noise current generated by the camera, and thus minimizes the camera noise. The resulting image quality is comparable to film, so the imaging system represents a promising alternative to film as a method of verifying patient positioning in radiotherapy.


A bifunctional probe reveals increased viscosity and hydrogen sulfide in zebra fish model of Parkinson's disease.
Altered H2S levels and intracellular viscosity have both been seen in Parkinson's disease (PD). However, how H2S and intracellular viscosity are involved in PD pathogenesis remains unknown. Herein, a dual-function fluorescent probe DF was designed and synthesized to analyze intracellular viscosity and hydrogen sulfide. It is a near-infrared fluorescence probe with improved photostability and large Stokes shift (110 nm). The probe reveals increased viscosity and hydrogen sulfide in zebrafish model of PD for the first time.


Magnetic Resonance Thermometry Targeting for Magnetic Resonance-Guided Histotripsy Treatments.
The potential of transcranial magnetic resonance (MR)-guided histotripsy for brain applications has been described in prior in vivo studies in the swine brain through an excised human skull. The safety and accuracy of transcranial MR-guided histotripsy (tcMRgHt) rely on pre-treatment targeting guidance. In the work described here, we investigated the feasibility and accuracy of using ultrasound-induced low-temperature heating and MR thermometry for histotripsy pre-treatment targeting in ex vivo bovine brain. A 15-element, 750-kHz MRI-compatible ultrasound transducer with modified drivers that can deliver both low-temperature heating and histotripsy acoustic pulses was used to treat seven bovine brain samples. The samples were first heated to an approximately 1.6°C temperature increase at the focus, and MR thermometry was used to localize the target. Once the targeting was confirmed, a histotripsy lesion was generated at the focus and visualized on post-histotripsy MR images. The accuracy of MR thermometry targeting was evaluated with the mean/standard deviation of the difference between the locus of peak heating identified by MR thermometry and the center of mass of the post-treatment histotripsy lesion, which was 0.59/0.31 mm and 1.31/0.93 mm in the transverse and longitudinal directions, respectively. This study determined that MR thermometry could provide reliable pre-treatment targeting for transcranial MR-guided histotripsy treatment.


Overexpression of Holocarboxylase Synthetase Predicts Lymph Node Metastasis and Unfavorable Prognosis in Breast Cancer.
Holocarboxylase synthetase (HLCS) catalyzes the specific attachment of biotin onto biotin-dependent carboxylases (BDCs) which play important roles in intermediary metabolism. Previous studies show that BDCs are overexpressed in many cancer types. However, expression of HLCS in cancerous tissues has not been reported. Immunohistochemistry was used to investigate HLCS expression in breast tissue obtained from 65 Thai patients, and the correlation between its expression and key clinical-pathological parameters was assessed. The role of HLCS in supporting invasion was investigated in HLCS-knockdown MCF-7 cells. Overexpression of HLCS was significantly associated with metastasis of breast cancer cells to other lymph nodes but not the sentinel and axillary lymph nodes - a finding supported in cellular invasion assays using HLCS knockdown cells. Furthermore, overexpression of HLCS reduced survival time of patients with breast cancer. HLCS appears to be a prognostic marker for patients with breast cancer.


Palladium(II)-η3 -Allyl Complexes Bearing N-Trifluoromethyl N-Heterocyclic Carbenes: A New Generation of Anticancer Agents that Restrain the Growth of High-Grade Serous Ovarian Cancer Tumoroids.
The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η3 -allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02-0.5 μm). By choosing 1,3,5-triaza-7-phosphaadamantane (PTA) as co-ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2-methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3 -allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids.


Occult and obscure gastrointestinal bleeding: causes and clinical management.
Occult gastrointestinal bleeding, defined as bleeding that is unknown to the patient, is the most common form of gastrointestinal bleeding and can be caused by virtually any lesion in the gastrointestinal tract. Patients with occult gastrointestinal bleeding include those with fecal occult blood and iron-deficiency anemia (IDA). In men and postmenopausal women, IDA should be considered to be the result of gastrointestinal bleeding until proven otherwise. Indeed, the possibility of gastrointestinal tract malignancy in these patients means that gastrointestinal evaluation is nearly always indicated. Obscure gastrointestinal bleeding is defined as obvious bleeding from a difficult to identify source and is always recurrent. This form of bleeding accounts for approximately 5% of all cases of clinically evident gastrointestinal bleeding and is most commonly caused by bleeding from the small intestine. Capsule endoscopy and deep enteroscopy have had a major impact on the way that patients with occult and, in particular, obscure bleeding are managed. In this Review the causes, diagnostic evaluation and treatment of occult and obscure gastrointestinal bleeding are discussed.


CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated p38/CHOP/death receptor 5 signaling pathways.
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows little or no toxicity in most normal cells and preferentially induces apoptosis in a variety of malignant cells. However, patients develop resistance to TRAIL, therefore, sensitizing agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are necessary. In this study, we investigated the effect of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), an useful flavonoid, to overcome the TRAIL-resistant triple negative breast cancer (TNBC) cells. We found that CSC-3436 potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells and this correlated with the upregulation of death receptors (DR)-5 and down-regulation of decreased decoy receptor (DcR)-1 expression. When examined for its mechanism, we found that the decreased expression of anti-apoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, Survivin, and XIAP. CSC-3436 would increase the expression of Bax and promoted the cleavage of bid. In addition, the induction of DR5 by CSC-3436 was found to be dependent on the modulation of reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results indicated that CSC-3436 could potentiate the apoptotic effects of TRAIL through down-regulation of cell survival proteins and upregulation of DR5 via the ROS-mediated upregulation of CHOP protein.


Quantitative magnetic resonance imaging in geriatric depression and primary degenerative dementia.
Quantitative magnetic resonance imaging (MRI) was used to investigate volumes of different brain structures in 19 patients with late-onset major depression (DSM-III-R), 27 patients with Alzheimer's disease (NINCDS-ADRDA criteria) and 13 age matched controls. 3-D MRI sequences were acquired using a Siemens 1.5 T scanner. Whole brain volume, CSF volume, volume of the frontal and temporal lobes and the volume of the amygdala-hippocampus complex were assessed using the software NMR Win. Compared to the controls, depressed patients showed a significantly lower whole brain volume and a significantly higher CSF volume, whereas volumes of the frontal and temporal lobes as well as the amygdala-hippocampus complex volumes were not significantly decreased. In addition, depressed patients exhibited a higher ventricle-brain ratio suggesting a higher degree of central atrophy compared to healthy individuals. In contrast, Alzheimer patients showed significantly lower volumes than depressed patients and controls with respect to all volumetric parameters. Although the findings indicate the presence of brain atrophy in patients with late-onset depression, the pattern of volumetric changes in these patients differs markedly from that observed in patients with primary degenerative dementia.


HIV-associated tuberculosis and cryptococcosis in resource-limited settings.
Tuberculosis (TB) and cryptococcosis are common infectious complications in HIV in resource-limited settings and contribute substantial morbidity and mortality. The increasing access to highly active antiretroviral treatment (HAART) has invited numerous challenges such as timing of HAART, cotreatment (drug dosages and interaction), immune reconstitution syndromes, and withdrawal of chemoprophylaxis. Numerous small studies propose the feasibility of concomitant TB/HIV treatment that needs to be confirmed in large, randomized trials. Treatment of acute cryptococcocal meningo-encephalitis with amphoterecin B is fraught with logistic problems in resource-limited settings. An effective safe dose of fluconazole as monotherapy needs to be determined in phase II studies. Current management guidelines extrapolated from developed countries may not necessarily apply and need validation in resource-limited settings.


An ecological and evolutionary perspective on human-microbe mutualism and disease.
The microbial communities of humans are characteristic and complex mixtures of microorganisms that have co-evolved with their human hosts. The species that make up these communities vary between hosts as a result of restricted migration of microorganisms between hosts and strong ecological interactions within hosts, as well as host variability in terms of diet, genotype and colonization history. The shared evolutionary fate of humans and their symbiotic bacteria has selected for mutualistic interactions that are essential for human health, and ecological or genetic changes that uncouple this shared fate can result in disease. In this way, looking to ecological and evolutionary principles might provide new strategies for restoring and maintaining human health.


In vitro inhibition of transthyretin aggregate-induced cytotoxicity by full and peptide derived forms of the soluble receptor for advanced glycation end products (RAGE).
Familial amyloidotic polyneuropathy is a neurodegenerative disorder characterized by systemic extracellular deposition of transthyretin (TTR) amyloid fibrils. The latter have been proposed to trigger neurodegeneration through engagement of the receptor for advanced glycation end products (RAGE). Here we show that TTR interaction with RAGE is conserved across mouse and human species and is not dependent on RAGE glycosylation. Moreover, strand D of TTR structure seems important for the TTR-RAGE interaction as well as a motif in RAGE (residues 102-118) located within the V-domain; this motif suppressed TTR aggregate-induced cytotoxicity in cell culture.


Endothelial keratoplasty without Descemet's stripping in eyes with previous penetrating corneal transplants.
To evaluate techniques, outcomes and complications of endothelial keratoplasty (EK) without Descemet's stripping in eyes with previous penetrating keratoplasty (PK). A retrospective, consecutive analysis of patients who underwent EK in eyes with previous PK. 33 eyes of 31 consecutive patients underwent EK without Descemet's stripping in eyes with previous PK. All 33 eyes were followed for an average of 14.2 ± 4.4 months. The reason for EK was either graft rejection (n=9) or endothelial failure (n=24). 32/33 (97.0%) eyes remained clear at the last follow-up visit. Visual acuity improved in 28/33 (84.8%) patients with 19/28 (67.9%) of these patients having more than three lines of visual acuity improvement. The average postoperative vision in this group was 20/60 (range 20/25-20/100). Pre-cut donor tissue was used for all cases with an average thickness of 127 μm. Endothelial cell density declined by 35% at 3 months and was stable at 1 year. 2/33 (6%) eyes had graft dislocations. One eye was successfully treated by a re-bubble. The other case failed EK revision and required a repeat PK. No patients developed EK or PK graft failure/rejection. EK without Descemet's membrane stripping in eyes with previous PK graft failure/rejection is a valuable alternative to a repeat full thickness PK.


Low-Dose-Rate versus High-Dose-Rate intracavitary brachytherapy in cervical cancer - Final Results of a Phase III randomized trial.
Intracavitary brachytherapy using High-Dose-Rate (HDR) and Low-dose-rate (LDR) in cervical cancer has been utilized. We report the long-term final results of a large randomized trial in terms of toxicities and efficacy. Between 1996 to 2005, 816 patients were randomized to LDR (n = 441 patients) or HDR brachytherapy (n = 369 patients) stratified by FIGO Stage grouping. Patients with Stage I-II received external irradiation of 40 Gy in 20 fractions (with midline block (MLB)) followed by either 2 LDR Intracavitary applications of 30 Gy to point A (2-3 weeks apart) or 5 HDR Intracavitary applications of 7 Gy to point A once weekly. Patients with Stage III received 50 Gy in 25 fractions (with MLB after 40 Gy) followed by either one application of LDR 30 Gy to point A or three applications of HDR 7 Gy to point A once weekly. With a median follow-up was 64 months (interquartile range [IQR]: 21 - 111), moderate to severe rectal and bladder complications were higher in LDR arm as compared to HDR arm (9.7% vs. 3.6%; p = 0.02) and (10.5% vs. 5.5%; p = 0.06) for Stage I-II. No difference in rectal or bladder complications for Stage III patients. Disease free and overall survivals were similar in both the arms for all stages. HDR intracavitary brachytherapy with 7 Gy per fraction weekly is superior to LDR in terms of late rectal and bladder complications. Local control rates and survivals are similar irrespective of stages.


Heterochromatin and molecular characterization of DsmarMITE transposable element in the beetle Dichotomius schiffleri (Coleoptera: Scarabaeidae).
Cytogenetic studies of the Neotropical beetle genus Dichotomius (Scarabaeinae, Coleoptera) have shown dynamism for centromeric constitutive heterochromatin sequences. In the present work we studied the chromosomes and isolated repetitive sequences of Dichotomius schiffleri aiming to contribute to the understanding of coleopteran genome/chromosomal organization. Dichotomius schiffleri presented a conserved karyotype and heterochromatin distribution in comparison to other species of the genus with 2n = 18, biarmed chromosomes, and pericentromeric C-positive blocks. Similarly to heterochromatin distributional patterns, the highly and moderately repetitive DNA fraction (C 0 t-1 DNA) was detected in pericentromeric areas, contrasting with the euchromatic mapping of an isolated TE (named DsmarMITE). After structural analyses, the DsmarMITE was classified as a non-autonomous element of the type miniature inverted-repeat transposable element (MITE) with terminal inverted repeats similar to Mariner elements of insects from different orders. The euchromatic distribution for DsmarMITE indicates that it does not play a part in the dynamics of constitutive heterochromatin sequences.


Oxidation and reduction of membrane-bound cytochrome c in Hemophilus parainfluenzae. Reaction with oxygen, hydrogen peroxide and nitrate.
Cytochromes of the a-, b-, c- and d-type become reduced when intact cells of Hemophilus parainfluenzae have become anaerobic following respiration with substrates such as formate or succinate, as shown previously (J. Biol. Chem. (1970) 254, 5096-5100). In the presence of formate after depletion of O2, there is an unusual two-step time course of reduction of the membrane-bound cytochrome c. The proportion of the cytochrome c which is reduced during the second stage is oxidizable by either nitrate or H2O2 and is reduced again when the nitrate or H2O2 have been depleted. We conclude that the observed two-stage reduction of cytochrome c results from the presence of an oxidant, probably H2O2, produced by reaction of formate dehydrogenase with O2. This was shown by the effects of cyanide, catalase and O2. In addition, no evidence for the production of the oxidant is seen when succinate is the substrate oxidized. Although measurements of absorption spectra indicated only one species of cytochrome c, kinetic evidence is presented for some separation of the cytochrome c into more than one electron transport pathway.


Interoceptive awareness selectively predicts timing accuracy in irregular contexts.
Awareness of psychophysiological changes has been proposed to play a role in duration perception; however, evidence on whether interoceptive awareness affects timing is mixed, and it is not clear which task features favor the reliance on bodily changes to track time. Here we tested the hypothesis that interoceptive awareness is selectively involved in timing when the context does not provide reliable cues on elapsed time. We developed a novel paradigm assessing interval reproduction in two conditions: 1) with regularly spaced stimuli during the encoding/reproduction phase (regular condition), 2) with irregularly spaced stimuli during the encoding/reproduction phase (irregular condition). Interoceptive awareness was assessed using the "Self-Awareness Questionnaire", investigating the frequency of common bodily sensations. Interoceptive awareness predicted timing accuracy in the irregular, but not in the regular condition; also, the contribution was specifically due to awareness of visceral sensations rather than somatosensory sensations. Overall, results suggest that individual differences in interoception differently affect timing according to contextual features, consistently with evidence that different mechanisms mediate timing in different conditions.


Distribution and polarity of actin in the sensory hair cells of the chinchilla cochlea.
The distribution and polarity of actin in sensory hair cells of the chinchilla cochlea has been determined by decoration of actin filaments with myosin subfragment S1. Decorated actin filaments of the same polarity were present within the stereocilia above the cuticular plate. However the filaments in the rootlets and the thin filaments projecting laterally from the rootlets into the cuticular plate did not decorate with S1. Decorated actin filaments were present within the cuticular plate, and near the plasma-membrance filaments of opposite polarity were observed. In the cross-striated region at the base of the cuticular plate of inner hair cells, decorated filaments were present in the dense bands of the cross-striations but the thin filaments perpendicular to the dense bands were not decorated. These results are discussed with respect to the two mechanisms that have been suggested for actin-myosin mediated movement of the stereocilia of inner-ear sensory cells.


Electrochemical generation of microbubbles by carbon nanotube interdigital electrodes to increase the permeability and material uptakes of cancer cells.
Artificial cavitation as a prerequisite of sonoporation, plays an important role on the ultrasound (US) assisted drug delivery systems. In this study, we have proposed a new method of microbubble (MB) generation by local electrolysis of the medium. An integrated interdigital array of three-electrode system was designed and patterned on a nickel-coated quartz substrate and then, a short DC electrical pulse was applied that consequently resulted in distributed generation of microbubbles at the periphery of the electrodes. Growth of the carbon nanotube (CNT) nanostructures on the surface of the electrodes approximately increased the number of generated microbubbles up to 7-fold and decreased their average size from ∼20 µm for bare to ∼7 µm for CNT electrodes. After optimizing the three-electrode system, biocompatibility assays of the CNT electrodes stimulated by DC electrical micropulses were conducted. Finally, the effect of the proposed method on the sonoporation efficiency and drug uptake of breast cells were assessed using cell cycle and Annexin V/PI flow cytometry analysis. These results show the potential of electrochemical generation of MBs by CNT electrodes as an easy, available and promising technique for artificial cavitation and ultrasound assisted drug delivery.


COVID-19 Pandemic Influence on Diabetes Management in Croatia.
The study aims to investigate the effects of the COVID-19 pandemic on diabetes management and diabetes patients' healthcare utilization patterns in Croatia. Using data contained in the Croatian diabetes registry (CroDiab), Central Health Information System of the Republic of Croatia (CEZIH), and the Croatian hospitalization database (BSO), indicators including the total number of registered diabetes patients, number of newly diagnosed diabetes cases, number of diabetes-related primary care visits and hospitalizations, and key diabetes control indicators were analyzed. Yearly values from 2017 until 2020 were compared. The age-adjusted prevalence rate increased significantly from 2017 until 2019 (2017: 6,858/100,000; 2018: 7,053/100,000; 2019: 7,160/100,000). In 2020 the age-adjusted prevalence rate was 7,088/100,000, but the decrease was insignificant compared to 2019. The age-adjusted rate of new cases decreased from 2017 until 2019 (2017: 910/100,000; 2018: 876/100,000; 2019: 845/100,000), with a significant decrease in 2020 (692/100,000) compared to 2019. The number of diabetes panels increased from 2017 (117,676) to 2018 (131,815), with a slight decrease in 2019 (127,742) and a sharp decrease in 2020 (104,159). A similar trend was observed regarding the numbers of diabetes patients with panels, visits to primary healthcare providers for diabetes-related problems and diabetes patients who visited their primary healthcare provider. A slightly different trend was observed regarding diabetes-related hospitalizations. In 2017 there were 91,192 diabetes-related hospitalizations; the number decreased to 83,219 in 2018, increased again to 102,087 in 2019 and decreased to 85,006 in 2020. The number of hospitalized diabetes patients displayed a similar tendency. The COVID-19 pandemic has had a negative effect on the utilisation of healthcare by diabetes patients, which may have long-term consequences for their general health.


Systems-level perspective of sudden infant death syndrome.
Sudden infant death syndrome (SIDS) remains one of the primary causes of infant mortality in developed countries. Although the causes of SIDS remain largely inconclusive, some of the most informative associations implicate molecular, genetic, anatomical, physiological, and environmental (i.e., infant sleep) factors. Thus, a comprehensive and evolving systems-level model is required to understand SIDS susceptibility. Such models, by being powerful enough to uncover indirect associations, could be used to expand our list of candidate targets for in-depth analysis. We present an integrated WikiPathways model for SIDS susceptibility that includes associated cell systems, signaling pathways, genetics, and animal phenotypes. Experimental and literature-based gene-regulatory data have been integrated into this model to identify intersecting upstream control elements and associated interactions. To expand this pathway model, we performed a comprehensive analysis of existing proteomics data from brainstem samples of infants with SIDS. From this analysis, we discovered changes in the expression of several proteins linked to known SIDS pathologies, including factors involved in glial cell production, hypoxia regulation, and synaptic vesicle release, in addition to interactions with annotated SIDS markers. Our results highlight new targets for further consideration that further enrich this pathway model, which, over time, can improve as a wiki-based, community curation project.


Antinociceptive pharmacological profile of Dysphania graveolens in mouse.
This work evaluates the potential antinociceptive activity of Dysphania graveolens, traditional medicinal plant used in Mexico to treat stomach pain. A CH2Cl2-MeOH extract, infusion and essential oil from aerial parts of Dysphania graveolens were evaluated in hot plate and writhing tests in mice. The metabolites pinostrobin, pinocembrin and chrysin were isolated from the Dysphania graveolens infusion; next, they were evaluated in both nociceptive tests. To confirm the antinociceptive activity and explore the possible participation of opioid, GABA and serotonin receptors in the pharmacological mechanism, a formalin test was used. Oral administration of Dysphania graveolens CH2Cl2-MeOH extract, infusion and essential oil (31-316mg/kg) produced an antinociceptive response to thermic and chemical algesic stimuli. Essential oil was the most active partition of this plant. In addition, the secondary metabolites pinostrobin, pinocembrin and chrysin possess a significant antinociceptive effect. This response was confirmed by the formalin test for the CH2Cl2-MeOH extract of Dysphania graveolens and chrysin. In both cases, the antinociceptive activity was reverted in the presence of naltrexone, flumazenil and bicuculline antagonists. The 5-HT2A/2C receptors did not participate in the antinociceptive response of this plant. The overall information tends to support the efficacy of Dysphania graveolens as an analgesic and its cultural use in abdominal pain.


Parental hypertension and cardiac alterations in normotensive children and adolescents.
The objective of this investigation was the examination of the relation of left ventricular mass (LVM) and function with cardiovascular response to exercise in normotensive adolescents at risk for hypertension. Carried out was a prospective, cross-sectional study of 47 subjects (age, 10 to 18 years), who underwent dynamic and isometric exercise, 24-hour Holter monitoring, and echocardiography. Twenty-nine had normotensive parents (group 2, "at risk"). Both groups were similar for age, race, sex, body mass index, blood pressures, and resting heart rates. Group 2 had a higher E/A ratio (2.3 +/- 0.5 vs 2.0 +/- 0.5; p = 0.039) and higher heart rates during stage IV of dynamic exercise (188 +/- 20 beats/min vs 176 +/- 18 beats/min; p = 0.046). The LVM, 24-hour heart rates, and exercise systolic blood pressures (SBP) were similar in both groups. Only in group 2, SBP at peak dynamic and isometric exercise correlated best with LVM (r = 0.74, p < 0.002; r = 0.82, p < 0.001). It is concluded that altered hemodynamic regulatory mechanisms may exist before the establishment of hypertension in normotensive subjects with parental hypertension.


Bilateral chronic ureteritis associated with Serratia marcescens.
To our knowledge this is the first case of bilateral obstructive uropathy caused by nonspecific chronic ureteritis to be reported. Prior to operation the bilateral involvement was throught to be due to a tuberculous infection or retroperitoneal fibrosis. The diagnostic difficulties were similar to those previously reported in the unilateral involvement. The focus of the infective organism found was Serratia marcescens which originated in the right kindey.


Development and validation of indirect RP-HPLC method for enantiomeric purity determination of D-cycloserine drug substance.
A new chiral purity method was developed for D-cycloserine (D-cys) by reverse phase HPLC and validated. Chiral derivatizing reagents, viz., o-phthalaldehyde and N-acetyl-L-cysteine were utilized in this method. The resultant diastereomers were resolved using Zorbax SB Phenyl HPLC column under isocratic elution. A mobile phase of 95:05 (v/v), 20mM Na(2)HPO(4) (pH 7), and acetonitrile, respectively, was used with the flow rate of 1.0 mL/min and UV detection at 335 nm. The method development with different chiral stationary phases and chiral derivatization reagents were also investigated. The stability of diastereomer derivative and influence of organic modifier and pH of the mobile phase were studied and optimized. The stability-indicating capability of the method was established by performing stress studies under acidic, basic, oxidation, light, humidity and thermal conditions. The detection and quantitation limit of L-cycloserine (L-cys) were 0.015 and 0.05% (w/w), respectively. A linear range from 0.05 to 0.30% (w/w) was obtained with the coefficient of determination (r(2)) 0.998. The recovery obtained for L-cys was between 92.9 and 100.2%. This method was applied successfully in pharmaceutical analysis to determine the content of L-cys in D-cys bulk drug.


Cardiovascular disease care and outcomes in West and South European countries.
Variations in cardiovascular disease (CVD) burden between West and South European countries are rarely reported. To address this knowledge gap, The Lancet Regional Health-Europe convened experts from a broad range of countries to assess the current state of knowledge of cardiovascular disease inequalities across Europe. This Review is specifically focused on West and South European countries. Mortality, risk factor and economic data for nine West European and six South European countries were sourced from the World Health Organisation, the Global Burden of Disease study and the World Bank. Healthcare data were collected by survey of participating countries. A key finding was of declines in age-standardised mortality rates (ASMRs) across all countries since 1990. In 2019 rates per 100,000 were lower in West European countries in males (279.7 (264.1-335.9) vs 337.2 (323.7-367.2)) and females (196.2 (183.3-228.8) vs 247.3 (232.2-268.3)). Differences in risk factor exposures were small, with the exception of physical activity and dietary factors, but across all countries the prevalence of obesity has increased, affecting >20% of adults in 2019. Healthcare delivery in 2019 showed inequalities with cardiovascular procedure rates lower in South compared with West European countries. Further declines in ASMRs in West and South European countries will require population strategies to reduce obesity and address inequalities in physical activity and dietary factors. Reducing the gap in procedure rates is unlikely to match the beneficial effects of population strategies for reducing CVD burden in South European countries.


Autobiographical Memories for Very Negative Events: The Effects of Thinking about and Rating Memories.
In three related experiments, 250 participants rated properties of their autobiographical memory of a very negative event before and after writing about either their deepest thoughts and emotions of the event or a control topic. Levels of emotional intensity of the event, distress associated with the event, intrusive symptoms, and other phenomenological memory properties decreased over the course of the experiment, but did not differ by writing condition. We argue that the act of answering our extensive questions about a very negative event led to the decrease, thereby masking the effects of expressive writing. To show that the changes could not be explained by the mere passage of time, we replicated our findings in a fourth experiment in which all 208 participants nominated a very negative event, but only half the participants rated properties of their memory in the first session. Implications for reducing the effects of negative autobiographical memories are discussed.


Heat shock proteins as gatekeepers of proteolytic pathways-Implications for age-related macular degeneration (AMD).
Age-related macular degeneration (AMD) is the major diagnosis for severe and irreversible central loss of vision in elderly people in the developed countries. The loss of vision involves primarily a progressive degeneration and cell death of postmitotic retinal pigment epithelial cells (RPE), which secondarily evokes adverse effects on photoreceptor cells. The RPE cells are exposed to chronic oxidative stress from three sources: their high levels of oxygen consumption, their exposure to the high levels of lipid peroxidation derived from the photoreceptor outer segments and their exposure to constant light stimuli. Cells increase the expression of heat shock proteins (HSPs) in order to normalize their growth conditions in response to various environmental stress factors, e.g. oxidative stress. The HSPs function as molecular chaperones by preventing the accumulation of cellular cytotoxic protein aggregates and assisting in correct folding of both nascent and misfolded proteins. Increased HSPs levels are observed in the retina of AMD patients, evidence of stressed tissue. A hallmark of RPE cell aging is lysosomal lipofuscin accumulation reflecting a weakened capacity to degrade proteins in lysosomes. The presence of lipofuscin increases the misfolding of intracellular proteins, which evokes additional stress in the RPE cells. If the capacity of HSPs to repair protein damages is overwhelmed, then the proteins are mainly cleared in proteasomes or in lysosomes. In this review, we discuss the role of heat shock proteins, proteasomes, and lysosomes and autophagic processes in RPE cell proteolysis and how these might be involved in development of AMD. In addition to classical lysosomal proteolysis, we focus on the increasing evidence that, HSPs, proteasomes and autophagy regulate protein turnover in the RPE cells and thus have important roles in AMD disease.


Induction of eosinophilic colonies by interleukin-5 on acute myeloblastic leukaemic cells.
The effect of interleukin-5 (IL-5) on blast colony formation of acute myeloblastic leukaemia (AML) cells was studied. IL-5 showed a weak but significant colony stimulatory effect in one out of six cases studied. IL-5 induced eosinophilic colony growth in this case, and chromosomal and histochemical analyses strongly suggested that these eosinophilic colonies were derived from leukaemic blast progenitor cells. To our knowledge, this is the first report that IL-5 induces eosinophilic colonies on fresh AML cells. A possible induction of differentiation of AML blast cells by IL-5 is suggested.


Carbonic anhydrase IX in malignant pleural mesotheliomas: a potential target for anti-cancer therapy.
Malignant mesothelioma is a neoplasm deriving from mesothelial cells, which line the body cavities. The most common type is malignant pleural mesothelioma (MPM), which is a locally aggressive malignancy with poor prognosis. To improve both the clinical diagnostics and treatment it is necessary to identify novel molecular targets which are characteristic for MPM. Although carbonic anhydrase (CA) enzymes have been linked to pH regulation and spread of cancer cells, they have not been thoroughly studied in MPM specimens. We investigated by immunohistochemistry the expression of CA isozymes II, VII, IX, and XII in a series of 27 histological MPM tumor samples. CA IX was absent in the normal lung alveolar cells, whereas it was abundantly expressed in the normal pleural mesothelium and malignant mesothelioma cells. CA VII also showed weak or moderate reactions in several cases of mesotheliomas. Neither high expression of CA VII nor CA IX did correlate significantly with the survival of the patients. The very high expression of CA IX in MPM suggests that it could represent a novel molecular target for cancer research applications.


Bone Metastases Pattern in Newly Diagnosed Metastatic Nasopharyngeal Carcinoma: A Real-World Analysis in the SEER Database.
To evaluate the prevalence rate and survival situation of bone metastases in initial nasopharyngeal carcinoma (NPC) patients and the hazard and forecast elements of bone metastases NPC patients. Patients and Methods. The data collected from Surveillance, Epidemiology, and End Results (SEER) program between 2010 and 2016 were evaluated. Univariate and multivariable logistic analysis and the Cox regression were carried out to estimate predictors and elements of the being of bone metastases at diagnosis, respectively. The overall survival of different subgroups were appraised by log-rank tests and the Kaplan-Meier analysis. Factors including male sex, higher N stage, presence of liver, and brain or lung metastases were largely related to the occurrence of bone metastases. The median survival time for bone metastasis NPC patients was 14.0 months. A factor of more than one primary sequence number predicted worse survival. The data offer corresponding risks and prognostic indicators of bone metastases for NPC patients.


Hierarchical and simultaneous utilization of carbon substrates: mechanistic insights, physiological roles, and ecological consequences.
Bacteria grown on a mixture of carbon substrates exhibit two utilization patterns: hierarchical utilization (HU) and simultaneous utilization (SU). How and why cells adopt these different behaviors remains poorly understood despite decades of research. Recent studies address various open questions from multiple viewpoints. From a mechanistic perspective, it was found that flux sensors play a central role in the regulation of substrate utilization, accounting for the known dependences on single-substrate growth rates, substrate concentrations, and the point where the substrate enters central metabolism. From a physiological perspective, several recent studies suggested HU or SU as growth-optimizing strategies through efficient allocation of essential proteome resources. However, other studies demonstrate that a significant fraction of the proteome is dedicated to functions apparently unnecessary for growth, casting doubt on explanations based on slight efficiency gains. From an ecological perspective, recent theoretical studies suggest that HU can help increase species diversity in bacterial communities.


The role of C-Reactive protein as an inflammatory marker to predict prolonged QTc interval in rifampicin-resistant tuberculosis patients: A case-control study.
long-term use of anti-tuberculosis drugs (ATD) increases the risk of QTc prolongation, while C-reactive protein (CRP) can be used as an inflammatory marker of Mycobacterium tuberculosis infection.Objective: correlation of CRP on the QTc interval in Rifampicin-resistant tuberculosis (RR-TB) patients with the short regimen. An observational study was conducted in Rifampicin-resistant tuberculosis (RR-TB) patients from 2 groups, patients on intensive phase and patients on continuation phase. CRP levels were measured from blood samples and measured automatically using the immunoturbidimetric assay. QTc interval was calculated using electrocardiography. Levels of CRP levels and QTc interval between the 2 groups were analyzed. The statistical analysis used includes the independent t-test, Mann Whitney test, and Rank Spearman test with p = 0.05. Forty-five eligible RR-TB patients were included in this study. CRP levels and QTc intervals between 2 groups (intensive and continuation phase) showed significant difference with p < 0.001 but found no significant correlation of CRP levels and QTc interval in both intensive and continuation phase with p = 0.226 and 0.805, respectively. A higher level of CRP strongly indicated the inflammation caused by RR-TB infection at the early phase of the disease, but not correlated with QTc interval in RR-TB patients. Levels of CRP and QTc interval do not correlate in RR-TB patients and can not be used to be the marker of QTc prolongation in RR-TB Patients.


[Learning vascular microsurgical techniques on an animal model].
The aim of this study was to assess the progress of an operator, during microsurgical training, on a bilateral carotid revascularization in the rat. In this prospective study, nine rats underwent bilateral carotid revascularization. An end-to-end graft of the right carotid artery by the facial vein and an end-to-side bypass of left carotid artery by the jugular external vein were performed. Anastomoses were carried out with 10/0 thread, based on the technique of the symmetric bi-angulation. At the end of procedure, a permeability test was performed on each anastomosis. Duration of survival of the animal, permeability of anastomosis, and evolution of the operating periods during the training were collected and respectively analyzed with a Fisher's and Student's t tests. In cases of procedure success, anastomoses were remotely controlled and a brain dissection was performed in order to seek a possible ischemia due to carotid clamping. In the event of failure, the rat was sacrificed and anastomoses were opened in order to establish the cause of thrombosis. Two thirds of the revascularization procedures were successful. A total of 83.3% of the anastomoses were patent. Of the six rats preserved for remote evaluation of anastomoses, three died. Remotely controlled anastomoses remained all permeable. No cerebral ischemia, associated with carotid clamping (approximately 45 minutes), was highlighted by brain dissection. With the growing experience of the operator, an improvement in results in mastery of the technique was objectively observed. Operative durations were reduced between the beginning and the end of the training: -54 minutes (P=0.001). Microsurgical laboratory training seems to be essential in order to acquire the dexterity, ease and experience necessary for performing microsurgical procedures in humans.


Assessment of the Cytotoxicity of Peptide Modifications of Doxorubicin on Tetrahymena pyriformis.
The cytotoxicity of doxorubicin (Dox) and its peptide modifications Z-Gly-Pro-Dox and Boc-Gly-Pro-Dox were studied. Tetrahymena pyriformis was used as a test system, which made it possible, due to the short life cycle and high reproduction rate of ciliates, to trace their response to the effects of toxicants over several generations. It was found that peptide modification of the Dox molecule markedly reduces its cytotoxic and cytostatic effect. The Z-Gly-Pro-Dox modification has less cytotoxic and cytostatic effect compared to Boc-Gly-Pro-Dox. When determining the ability of drugs (at a concentration of 100 μM) to prevent bacterial contamination of samples, it was shown that the smallest degree of overgrowth was recorded in the presence of Dox (OD600nm 81.1). Boc-Gly-Pro-Dox also had a bacteriostatic effect, though less pronounced (OD600nm 93.8). The degree of overgrowth in the presence of Z-Gly-Pro-Dox was close to that of distilled water. The results obtained on ciliates did not contradict the data obtained in similar studies on mice.


Fresh embryo transfer after in vitro insemination of fresh vs. cryopreserved anonymous donor oocytes: which has a better live birth rate? A Society for Assisted Reproductive Technology Clinic Outcome Reporting System analysis.
To determine if transfer of fresh embryos derived from fresh or cryopreserved donor oocytes yields a higher live birth rate. Historical cohort study. Society for Assisted Reproductive Technology Clinic Outcome Reporting System database. A total of 24,663 fresh embryo transfer cycles of donor oocytes. None. The primary outcome was live births per number of embryos transferred on day 5. The secondary outcomes included number of infants per embryo transfer, surplus embryos cryopreserved, and characterization of US oocyte recipients. A total of 16,073 embryo transfers were from fresh oocytes and 8,590 were from cryopreserved oocytes. Recipient age, body mass index (BMI), gravidity, and parity were similar between the groups. Most recipients were of White non-Hispanic race (66.9%), followed by Asian (13.7%), Black non-Hispanic (9.3%), and Hispanic (7.2%). Fresh oocyte cycles were more likely to use elective single embryo transfer (42.5% vs. 37.8%) or double embryo transfer (53.2% vs. 50.4%) and resulted in more surplus embryos for cryopreservation (4.6 vs. 1.2). The live birth rate from fresh oocytes was 57.5% vs. 49.7% from cryopreserved oocytes. Negative predictors of live birth included the use of cryopreserved oocytes (odds ratio [OR] 0.731, 95% confidence interval [CI] 0.665-0.804), Black non-Hispanic race (OR 0.603, 95% CI 0.517-0.703), Asian race (OR 0.756, 95% CI 0.660-0.867), and increasing recipient BMI (OR 0.982, 95% CI 0.977-0.994) after controlling for recipient age, number of embryos transferred on day 5, and unexplained infertility diagnosis. The proportion of multifetal deliveries was greater in cycles utilizing fresh (26.4%) vs. cryopreserved (20.6%) oocytes. The live birth rate is higher with use of fresh oocytes vs. cryopreserved oocytes in fresh embryo transfer cycles. Negative live birth predictors include recipient Black non-Hispanic or Asian race and increasing BMI.


Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry.
Systemic therapies (ATHs) in early breast cancer have improved the survival of breast cancer (BC) patients in recent decades. The magnitude of the changes in overall, metastasis-free (MFS) and post-metastatic (PMS) survival and in the metastasis (MET) pattern will be described. We analysed 60,227 patients with a diagnosis of T-N-M0 BC between 1978 and 2013 and 11,983 patients with metastases (MET) in the Munich Cancer Registry. Patients will be divided into four time periods to identify relationships between BC and METs. Survival was estimated using Kaplan-Meier curves, and Cox proportional hazards models were used to explore the impact of the BC subtype and MET status on survival with the time periods as surrogate markers for ATH evolution. During the observation period, 5-year relative survival has improved from 80.3 to 93.6% with an adjusted hazard ratio of 0.54 (P < 0.0001). Successful implementation of ATH has changed the MET pattern. The percentage of liver and CNS METs has more than doubled, the rate of lung METs remains stable, and the rate of bone METs has been reduced by approximately 50%. MFS has been prolonged with a hazard ratio 0.75 (P < 0.0001), but PMS has declined (hazard ratio 1.36; P < 0.0001); however, effects of adjuvant and palliative treatments cannot be separated. These results do not contradict improvements in advanced BC and do not suggest alterations of MET tumour biology by ATH. Over the past three decades, ATHs have dramatically improved patient survival after BC diagnosis-most likely, by eradicating prevalent micro-METs; as a result, the MET pattern has changed. Eradicating only a portion of the first METs results in delaying the onset of subsequent MET, which leads to an apparently paradoxical effect: an extension of the MET-free interval and a reduction in PMS.


Aspects of visual avatar appearance: self-representation, display type, and uncanny valley.
The visual representation of human-like entities in virtual worlds is becoming a very important aspect as virtual reality becomes more and more "social". The visual representation of a character's resemblance to a real person and the emotional response to it, as well as the expectations raised, have been a topic of discussion for several decades and have been debated by scientists from different disciplines. But as with any new technology, the findings may need to be reevaluated and adapted to new modalities. In this context, we make two contributions which may have implications for how avatars should be represented in social virtual reality applications. First, we determine how default and customized characters of current social virtual reality platforms appear in terms of human likeness, eeriness, and likability, and whether there is a clear resemblance to a given person. It can be concluded that the investigated platforms vary strongly in their representation of avatars. Common to all is that a clear resemblance does not exist. Second, we show that the uncanny valley effect is also present in head-mounted displays, but-compared to 2D monitors-even more pronounced.


Comparative study between different schedules for sclerosing oesophageal varices.
There were no significant differences between the one week and the 2 weeks interval groups with regard to total number of sclerotherapy sessions, total volume of the sclerosant used (5% ethanolamine oleate) or rate of complications such as pyrexia, stricture ulcer and/or slough formation. Neither early nor recurrent bleeding occurred in any patient in the two (2) groups. Eradication of varices in the 2-week interval group was achieved significantly earlier (P less than 0.05) than in the one week interval group.


The Effect of Probiotics Use on Salivary Cariogenic Bacteria in Orthodontic Patients with Various Caries Risk Status.
The purpose of this study was to evaluate the change in intraoral cariogenic bacteria density after probiotic use in patients with orthodontic treatment, and to compare the impact of probiotics in patients with various caries risk status. Patients that planned to receive orthodontic treatment were recruited according to this study's inclusion/exclusion criteria. A probiotic prescription (Lactobacteria 3 mg, Glycobacteria 2 mg) was started one month after the initial orthodontic treatment. Saliva sampling and cultures using a CRT kit (caries risk test) were performed at three time points (T0, T1, T2). Mutans streptococci (MS) and Lactobacilli (LB) density were evaluated and scored using the interpretation chart in the CRT kit to evaluate the change in bacteria density at three time points, to define the high and low caries risk prior to orthodontic treatment, and to evaluate if there were differences in probiotics between the high and low caries risk groups. Thirty-three orthodontic patients were enrolled, twenty-two classified as high caries risk and eleven as low caries risk. After undergoing treatment for one month, the densities of MS and LB increased significantly (p = 0.011, p = 0.001); probiotics for one month decreased the density of MS and LB, but the differences were statistically nonsignificant (p = 0.109, p = 0.109). Patients classified as low risk of caries demonstrated an increase in MS and LB density one month after orthodontic treatment (p = 0.024, p = 0.001), probiotic use did not result in a significant reduction in bacteria density (p = 1000, p = 0.933). In patients with high caries risk, there were no statistically significant changes in MS count between the three time points (p = 0.127); a significant change in LB density occurred at T0-T1 (p = 0.011) only. Supplemental use of probiotic oral tablets during orthodontic treatment aimed at reducing cariogenic bacteria count in saliva did not achieve significant differences, regardless of patients' risk status for caries.


Radiotherapy in prostate cancer after kidney transplant in 6 cases.
Patients who received a kidney transplant (KT) are described in literature as a group with a higher incidence of malignant neoplasms compared to the general population. Cancer development after KT has become a major issue, as a remarkable percentage of patients are diagnosed with cancer. Treatment of prostate cancer (PCa) in renal transplant recipients (RTRs) is a challenging issue that has been discussed by many authors over the years, but evidence is sparse and often includes conflicting reports. Among the therapeutic options for PCa in these patients, prostate irradiation represents a valuable alternative to surgery or other systemic therapies, as RTRs are often ineligible for these treatments. To report six cases treated at our institution between 1998 and 2017 and discuss the available literature. Patients' characteristics were reported along with biochemical status at diagnosis, type of immunosuppressive treatment, radiation therapy technique, and dose to transplanted kidney. Overall, prostate irradiation was delivered respecting the dose constraints and patients showed good tolerance with no reports of acute or late transplanted kidney injury. Our experience confirms that prostate radiotherapy for RTRs is feasible and effective and represents a valid option that should be considered by the multidisciplinary team.


Association study of childhood obesity with eight genetic variants recently identified by genome-wide association studies.
Being overweight or obese is becoming increasingly common in low- and middle-income countries. The present study aimed to examine association of eight genetic variants with obesity and to estimate the cumulative effects of these variants in Chinese children. We conducted the case-control study in a total of 2,030 subjects. Genotyping of seven novel variants was performed with matrix-assisted laser desorption ionization time of flight mass spectrometry, while rs9939609 was genotyped with tetra-primer amplification refractory mutation system analysis. The association of two fat mass and obesity-associated gene (FTO) single-nucleotide polymorphisms (SNPs; rs9939609 and rs62048402) with body mass index (BMI) or obesity reached nominal significance at P < 0.05. We found a cumulative effect of five SNPs on the risk of overweight and obesity (odds ratio (OR) = 1.197, 95% confidence interval (CI) = 1.068-1.342, P = 0.002). Subjects carrying 9 or more effect alleles had a 127% increased risk of overweight and obesity (OR = 2.270, 95% CI = 1.403-3.671, P = 0.001) compared with subjects who carry 6 or fewer effect alleles. We confirmed two FTO SNPs (rs62048402 and rs9939609) had nominal significant effects on BMI or obesity. We identified the cumulative effect of five SNPs on risk of overweight and obesity. The results provided evidence for identifying genetic factors related to childhood obesity.


Anti-tumor effects of an ID antagonist with no observed acquired resistance.
ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.


Evaluation of the BioFire® COVID-19 test and Respiratory Panel 2.1 for rapid identification of SARS-CoV-2 in nasopharyngeal swab samples.
The BioFire® COVID-19 Test and Respiratory Panel 2.1 (RP2.1) are rapid, fully automated assays for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs. In the case of the RP2.1, an additional 21 viral and bacterial pathogens can be detected. Both tests have received emergency use authorization from the U.S. Food & Drug Administration and Interim Order authorization from Health Canada for use in clinical laboratories. We evaluated the performance characteristics of these tests in comparison to a laboratory-developed real-time PCR assay targeting the viral RNA-dependent RNA polymerase and E genes. A total of 78 tests were performed using the BioFire COVID-19 Test, including 30 clinical specimens and 48 tests in a limit of detection study; 57 tests were performed using the RP2.1 for evaluation of SARS-CoV-2 detection, including 30 clinical specimens and 27 tests for limit of detection. Results showed 100% concordance between the BioFire assays and the laboratory-developed test for all clinical samples tested, and acceptable performance of both BioFire assays at their stated limits of detection. Conclusively, the BioFire COVID-19 Test and RP2.1 are highly sensitive assays that can be effectively used in the clinical laboratory for rapid SARS-CoV-2 testing.


Effects of micro-sized polyethylene spheres on the marine microalga Dunaliella salina: Focusing on the algal cell to plastic particle size ratio.
There is increasing concern about how microplastics (MPs) are impacting marine ecosystems. In particular, studies on how MPs impact microalgae are required because of the abundance of MPs and importance of green microalgae as primary producers. This study investigated how MPs that are larger (200 μm) than algal cells impact them, using the marine microalga Dunaliella salina as the test species. The microalga was exposed to polyethylene MPs for 6 days. Of interest, the growth and photosynthetic activity of D. salina was enhanced with exposure to MPs, while cell morphology (size and granularity) was not impacted. This phenomenon might be explained by trace concentrations of additive chemicals (endocrine disruptors, phthalates, stabilizers) that possibly leached from MPs promoting the growth and photosynthetic activity of D. salina. We also confirmed that MP size contributes towards determining how plastics affect microalgae. Specifically, as MP size shrinks compared to algal cell size, MPs have increasingly adverse effects. MPs of very small size (like nanoplastics) induce particularly adverse effects on algae. Further studies are required to establish the relationship between algal cell size and MP size.


Mid-term results after in situ pinning and hip arthroscopy for mild slipped capital femoral epiphysis: a minimum five-year follow-up.
In situ pinning of mild slipped capital femoral epiphysis (SCFE) results in an aspherical head-neck junction and arthroscopic osteochondroplasty can successfully correct the head-neck junction. However, whether the correction stays stable over at least five years remains unknown. In a retrospective and consecutive series, 11 patients with a mean age of 12 years (range, 10 years to 15 years) were included. All patients were treated for mild SCFE with in situ pinning and staged hip arthroscopy correcting the head-neck junction. All patients were assessed clinically and radiographically (radiograph and magnetic resonance imaging (MRI)) pre-operatively, 12 weeks and at least five years' post-operatively. The mean range of motion (ROM) for flexion and internal rotation was stable over time with 100° (sd 4) and 21° (sd 6), respectively at the last follow-up. The mean alpha angle decreased from pre-operative 64° (range 61° to 68°) to 12 weeks post-operative 49° (range 46° to 52°; p = 0.001) and stayed stable over time. New superficial cartilage damage on either the acetabular or femoral side was seen in each three patients. Progressive labral degeneration was present in two patients. In situ pinning and staged hip arthroscopy for the correction of mild SCFE is safe, restores normal alpha angles and reveals stable morphological correction at mid-term follow-up. Furthermore, the clinical results were excellent with almost normalized internal hip rotation at mid-term follow-up in patients who had reached adulthood. However, there was some joint deterioration, but without negative impact on subjective and clinical outcome after at least five years. IV.


Obstetric fractures in caesarean delivery and risk factors as evaluated by paediatric surgeons.
Obstetric fractures usually occur after complicated births and are sent to paediatric orthopaedics for treatment and follow-up. Clavicle fractures represent the most common orthopaedic birth injury, involving approximately 0.2 to 3.5% of births. Caesarean delivery, elective or necessary, along with the type of presentation, may play a determinant role in the aetiology of obstetric fractures. We chose to do a retrospective study to determine possible risk factors for this type of injury that may manifest in either delivery. Our aim was to deepen our knowledge in order to have a better prediction and a better management of this condition. Data gathered included parity, gestity, type of delivery, presentation, shoulder dystocia, type of fracture, birth weight, and APGAR score. We followed 136 patients that were diagnosed with Allman type I clavicle fracture, 32 of them also having brachial plexus birth palsy (BPBP) type 1 (Duchenne-Erb). Natural birth with a pelvic presentation imposes a relative risk of 6.2 of associated pathology compared to cranial presentation. Caesarean delivery and cranial presentation increase the risk of related pathology by 5.04 compared to natural birth. Statistically, pelvic presentation is 5.54 times more likely to develop related pathology than cranial presentation. Type of delivery and presentation correlate with associated pathology of clavicle fractures. Caesarean delivery brings risks for the newborn and should be practiced only when necessary. Predictive modeling in obstetrics in third-trimester evaluations may statistically predict risks of birth complications like fracture and BPBP.


Covalent Coupling assisted Hydrophilic Perovskite Spheres for Ratiometric Fluorescent Visual Multichannel Immunoassay.
Quantitative fluorescence immunoassay is essential for the construction of biosensing mechanisms and the quantification of trace markers. But the interference problems caused by low fluorescence efficiency and broad fluorescence spectrum of fluorescent probes have hindered the continued development of ratiometric fluorescence sensing in biosensing. Perovskite materials, with ultra-high color purity (FWHM < 30 nm) and photoluminescence quantum yield (close to 100%), are expected to be next-generation fluorescent probes. However, their poor water stability and biocompatibility are still non-negligible in biosensor applications. In this work, hyperstatic perovskite fluorescent microspheres prepared by swelling-shrinking method can be used as ratiometric fluorescence signals and biological immunoassay platforms. Meanwhile, inspired by p-aminophenol controlled synthesis and the catalytic reaction of 4-aminophenol phosphate triggered by alkaline phosphatase (ALP), we propose a strategy to prepare fluorescent nanoparticles as fluorescence signals for ALP detection. Most importantly, we propose for the first time to combine this enzymatic fluorescence with perovskite materials using covalent linkage to create a novel cascade immunoassay and use it for quantitative and visualization determination of hepatitis B surface antigen for application verification. These results indicate the biosensing potential of perovskite materials, and provide a pathway for high sensitivity enzyme detection and enzyme triggered immune detection. This article is protected by copyright. All rights reserved.


Febrile neutropenia in patients with acute myeloid leukemia: Outcome in relation to qSOFA score, C-reactive protein, and blood culture findings.
To evaluate quick Sequential Organ Failure Assessment (qSOFA) score during febrile neutropenia (FN) in adult patients receiving intensive chemotherapy for acute myeloid leukemia (AML). qSOFA score, as well as the association of qSOFA score with ICU admission, infectious mortality, blood culture findings, and C-reactive protein (CRP) measurements during FN were assessed among 125 adult AML patients with 355 FN periods receiving intensive chemotherapy in a tertiary care hospital from November 2006 to December 2018. The multivariate model for qSOFA score ≥ 2 included CRP ≥ 150 mg/L on d0-2 [OR 2.9 (95% CI 1.1-7.3), P = .026], Gram-negative bacteremia [OR 2.7 (95% CI 1.1-6.9), P = .034], and treatment according to AML-2003 vs more recent protocols [OR 2.7 (95% CI 1.0-7.4), P = .047]. Age or gender did not gain significance in the model. qSOFA score ≥ 2 was associated with ICU treatment and infectious mortality during FN with sensitivity and specificity of 0.700 and 0.979, and 1.000 and 0.971, respectively. qSOFA offers a useful tool to evaluate the risk of serious complications in AML patients during FN.


Perinatal and neonatal outcomes of twin pregnancies in Turkey.
This study was conducted for the purpose of assessing, in the light of results of other research carried out in the present researchers' clinic and in Turkey, the status of twin pregnancies in Turkey, the incidence of twin births, perinatal and mortality rates associated with twin pregnancies, and the problems experienced in Turkey in cases of multiple and twin pregnancies. The outcomes of twin births that occurred at the researchers' clinic during the period 2001-2009 were studied retrospectively. Seventeen studies conducted in Turkey on multiple and twin pregnancies during the years 1991-2010 were included in the study. It was observed that the mean multiple pregnancy rate in Turkey is 1.9% and the mean twin birth rate is 1.7%. It was also observed that a large majority (80-97.3%) of multiple pregnancies in Turkey are twin pregnancies. It was noted from Turkish literature that the mean gestational age of twins at birth varies between 33-36.2 weeks and that mean birthweights are 2065-2327 grams for the first-born twin and 1887-2262 grams for the second-born. These findings were observed to be lower than what is indicated in the literature. Perinatal and neonatal mortality, at 58-156/1000 and 40-98/1000 respectively, were seen to be higher than in the literature. It can be seen that preterm birth rates for twin pregnancies in Turkey are higher than what is indicated in the literature and that prenatal and neonatal mortality rates are also similarly higher.


Gli-fully Halting the Progression of Fibrosis.
Activating triggers, selective markers, and the residual regenerative potential of scar-forming myofibroblasts are largely determined by their origin. In this issue of Cell Stem Cell, Schneider et al. report that bone marrow myofibroblasts derive from Gli1+ mesenchymal stromal cells and that a Gli inhibitor targets them for elimination in mice and humans, ameliorating fibrosis.


Prevalence and Determinants of Atrial Fibrillation-Associated In-Hospital Ischemic Stroke in Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.
Atrial fibrillation (AF) is an established risk factor ischemic stroke (IS) and is commonly encountered in patient hospitalized with acute myocardial infarction (AMI). Uncommonly, IS can occur as a complication resulting from percutaneous coronary intervention (PCI). There is limited real world data regarding AF-associated in-hospital IS (IH-IS) in patients admitted with AMI undergoing PCI. We queried the National Inpatient Sample database from January 2010 to December 2014 to identify patients admitted with AMI who underwent PCI. In this cohort, we determined the prevalence of AF associated IH-IS and compared risk factors for IH-IS between patients with AF and without AF using multivariable logistic regression models. IH-IS was present in 0.46% (n = 5,938) of the patients with AMI undergoing PCI (n = 1,282,829). Prevalence of IH-IS in patients with AF was higher compared with patients without AF (1.05% vs 0.4%; adjusted odds ratio: 1.634, 95% confidence interval: 1.527 to 1.748, p <0.001). Regardless of AF status, prevalence and risk of IH-IS was higher in females and increased with advancing age. There was significant overlap among risk-factors associated with increased risk of IH-IS in AF and non-AF cohorts, except for obesity in AF patients (adjusted odds ratio: 1.268, 95% confidence interval: 1.023 to 1.572, p = 0.03) in contrast to renal disease, malignancy, and peripheral vascular disease in non-AF patients. In conclusion, IH-IS is a rare complication affecting patients undergoing PCI for AMI and is more likely to occur in AF patients, females, and older adults, with heterogeneity among risk factors in patients with and without AF.


Molecular detection of Torque teno sus virus in lymphoid tissues in concomitant infections with other porcine viral pathogens.
In this study, 40 pigs with respiratory and wasting disorders from Cuban swine herds were screened by PCR for the presence of TTSuV1, TTSuV2, PCV-2, PPV and CSFV in spleen samples. The variability of the porcine TTSuV sequences obtained was investigated by phylogenetic analysis. This study showed for the first time that TTSuV1 and TTSuV2 were present in Cuban swine herds. The investigation revealed the following infection rates: TTSuV1 40%, TTSuV2 37.5%, PCV-2 70%, PPV 37.5% and CSFV in 52.5%. The presence of two or more of these viruses at different rates in the same spleen samples was revealed. Also, a higher genetic diversity of TTSuV2 sequences was observed regarding TTSuV1 sequences.


Microplate selection technique (MPST). A new method for selecting mouse transfectants expressing human gene products.
This paper examines the analytical power of fluorescence activated cell sorting and immunorosetting technique as compared with the newly devised microplate selection technique in identifying transfected murine L cells expressing human surface molecules. The microplate selection technique relies on the mechanical transfer of transfected cells to a terasaki microplate, where an indirect immunofluorescence assay is carried out. It is a simple procedure not requiring costly equipment and with a detection capacity equivalent to that of the fluorescence activated cell sorter. The microplate selection technique proved to be sensitive enough to detect all the transfectants produced during the present study.


Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice.
Previous data demonstrate that traumatic brain injury (TBI) activates autophagy, and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining mainly in neurons. However, the role of autophagy in traumatic brain damage remains elusive. The aim of the present study was to investigate the autophagic mechanisms participating in traumatic brain injury. The autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (BFA) were administered with a single i.c.v. injection before TBI. We first examined the protein levels of Beclin-1 and LC3 II, which have been found to promote autophagy previously. Immunoblotting analysis showed that 3-MA pretreatment reduced post-TBI Beclin-1 and LC3-II levels, and maintained p62/SQSTM1 (p62) levels. In addition, double immunolabeling showed that the increased punctate LC3-II dots colocalizing with Propidium Iodide (PI)-stained nuclei at 24 h after injury, were partially inhibited by 3-MA pretreatment. Furthermore, inhibition of autophagy could reduce TBI-induced cell injury assessed with i.p. injection of PI and lesion volume, and attenuate behavioral outcome evaluated by motor test and Morris water maze. The neuroprotective effects were associated with an inhibition on TBI-induced up-regulation of LC3, Beclin-1, cathepsin B, caspase-3 and the Beclin-1/Bcl-2 ratio. Taken together, these data imply that the autophagy pathway is involved in the pathophysiologic responses after TBI, and inhibition of this pathway may help attenuate traumatic damage and functional outcome deficits.


Zuogui pills maintain the stemness of oogonial stem cells and alleviate cyclophosphamide-induced ovarian aging through Notch signaling pathway.
Zuogui pills (ZGP), a classical prescription of traditional Chinese medicine, have been widely used in the treatment of ovarian aging. Previous studies have demonstrated its efficacy on protecting ovarian aging, and the mechanisms were mostly relevant to inhibiting the apoptosis of follicles and activating the primordial follicles. However, whether ZGP could stimulate the oogonial stem cells (OSCs) to refresh the follicle pool remains poorly understood. To investigate the effects of ZGP on the stemness of OSCs in cyclophosphamide (Cy)-induced ovarian aging. Female Sprague-Dawley (SD) rats were randomly divided into 8 groups: control group, model group, ZGP groups (low / high dose groups), estradiol valerate (EV) groups (low / high dose groups), DAPT group and DAPT+ZGP-L group. After modeling with Cy, the ZGP groups and EV groups were treated with ZGP and EV for 8 weeks respectively. Meanwhile, the DAPT groups were treated with DAPT twice a week. Additionally, OSCs were also isolated after modeling, and then treated with drug serum containing ZGP or EV. Ovarian volume and the ratio of weight of total ovaries to the body weight were measured. The serum hormones were measured by ELISA. Quantities and location of OSCs in ovaries were detected by flow cytometry and immunofluorescence. Cell viability was measured by CCK8. And OSCs were identified by immunofluorescence. Biomarkers of germ cells, stem cells and associated to differentiation and meiosis were detected by qPCR and western blot. Proteins in Notch signaling pathway were detected by western blot and immunofluorescence. After treating with ZGP, ovarian volume and the ratio of weight of total ovaries to the body weight increased. ZGP could increase serum AMH and E2 level and decrease serum FSH level. Quantities and cell viability of OSCs increased after ZGP treatment in vivo and in vitro. In addition, treatment with ZGP could increase not only the expression of MVH, Oct4 and DAZL, but also the expression of ZP1 and ZP2. Furthermore, ZGP could up-regulate the expression of Notch intracellular domain (NICD), HES1 and HES5. After blocking the Notch signaling pathway, ZGP could increase not only the expression of NICD, HES1 and HES5, but also the expression of MVH, Oct4, DAZL, ZP1 and ZP3. In conclusion, the mechanism of ZGP on treating ovarian aging may be relevant to maintain the stemness of OSCs by up-regulating Notch signaling pathway, which added the mechanism of ZGP on the perspective of OSCs at first time.


Molecular response to induction chemotherapy and its correlation with treatment outcome in head and neck cancer patients by means of NMR-based metabolomics.
The aim of this prospective study is to identify the biomarkers associated with the effects of induction chemotherapy (iCHT) in terms of the favorable/weaker response to the treatment in locally advanced head and neck squamous cells carcinomas (LA-HNSCC). The studied group consisted of 53 LA-HNSCC patients treated with iCHT. The treatment tolerance was measured by the Common Terminology Criteria for Adverse Events (CTCAE). The response to the treatment was evaluated by the clinical, fiberoptic and radiological examinations made before and after iCHT (the TNM Classification of Malignant Tumors was used for classifying the extent of cancer spread). Proton nuclear magnetic resonance (1H NMR) serum spectra of the samples collected before and after iCHT were acquired with a 400 MHz spectrometer and analyzed using the multivariate and univariate statistical methods. The molecular response to iCHT involves an increase of the serum lipids which is accompanied by the simultaneous decrease of alanine, glucose and N-acetyl-glycoprotein (NAG). Furthermore, in males, the iCHT induced changes in the lipid signals and NAG significantly correlate with the regression of the primary tumor. The OPLS-DA multivariate model identified two subgroups of the patients with a weaker metabolic and clinical response. The first one consisted of the patients with a significantly lower initial nodal stage, the second one showed no differences in the initial clinical and metabolic statuses. The NMR-based metabolomic study of the serum spectra revealed that iCHT induces the marked changes in the LA-HNSCC patients' metabolic profiles and makes it possible to stratify the patients according to their response to iCHT. These effects are sex dependent. Further studies on a larger scale accounting for sex and the clinical and metabolic factors are warranted.


Digital Leg Volume Quantification: Precision Assessment of a Novel Workflow Based on Single Capture Three-dimensional Whole-Body Surface Imaging.
Whole-body three-dimensional surface imaging (3DSI) offers the ability to monitor morphologic changes in multiple areas without the need to individually scan every anatomical region of interest. One area of application is the digital quantification of leg volume. Certain types of morphology do not permit complete circumferential scan of the leg surface. A workflow capable of precisely estimating the missing data is therefore required. We thus aimed to describe and apply a novel workflow to collect bilateral leg volume measurements from whole-body 3D surface scans regardless of leg morphology and to assess workflow precision. For each study participant, whole-body 3DSI was conducted twice successively in a single session with subject repositioning between scans. Paired samples of bilateral leg volume were calculated from the 3D surface data, with workflow variations for complete and limited leg surface visibility. Workflow precision was assessed by calculating the relative percent differences between repeated leg volumes. A total of 82 subjects were included in this study. The mean relative differences between paired left and right leg volumes were 0.73 ± 0.62% and 0.82 ± 0.65%. The workflow variations for completely and partially visible leg surfaces yielded similarly low values. The workflow examined in this study provides a precise method to digitally monitor leg volume regardless of leg morphology. It could aid in objectively comparing medical treatment options of the leg in a clinical setting. Whole-body scans acquired using the described 3DSI routine may allow simultaneous assessment of other changes in body morphology after further validation.


Extracellular matrix regulation of drug resistance in small-cell lung cancer.
Lung cancer is the leading cause of cancer deaths in the developed world. Small cell lung cancer (SCLC) has the worst prognosis due to the emergence of resistance to chemotherapy. This article will review recent work that has defined mechanisms of chemo-resistance focusing on the role of integrins. SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) and high levels of expression correlate with poor prognosis. ECM protects SCLC cells against chemotherapy-induced cell death by activating beta1 integrins leading to activation of phosphoinositide-3-OH kinase (PI3-kinase), which prevents etoposide-induced caspase-3 activation and subsequent apoptosis. Engagement of ECM prevents etoposide and radiation induced G2/M cell cycle arrest in SCLC cells by blocking the up-regulation of p21Cip1/WAF1 and p27Kip1 and the down-regulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signalling. Thus, ECM via beta1 integrin-mediated PI3-kinase activation allows SCLC cells to survive treatment induced cell cycle arrest and apoptosis with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance. Novel therapeutic strategies may therefore be directed at inhibiting integrin-mediated cell survival signals improving response rates and cure in this devastating cancer.


An unusual location of the origin of an adenosine-sensitive atrial tachycardia: The lateral mitral annulus.
A 56-year-old woman underwent an electrophysiological study and radiofrequency catheter ablation of a narrow QRS tachycardia. Programmed atrial extrastimulation reproducibly induced the tachycardia. During the tachycardia, differential atrial overdrive pacing exhibited no ventriculoatrial (VA) linking, and ventricular overdrive pacing exhibited VA dissociation. Entrainment of the tachycardia with atrial overdrive pacing was not demonstrable because the tachycardia cycle length varied from 262 to 320 ms. An intravenous bolus of 5 mg of adenosine reproducibly terminated the tachycardia without atrioventricular (AV) block. Based on these findings, the clinical tachycardia was diagnosed as an adenosine-sensitive atrial tachycardia (AT). Activation mapping during the AT using the EnSite Precision system and Advisor HD Grid mapping catheter (Abbott, Minneapolis, MN, USA) exhibited a centrifugal pattern with the earliest activation along the lateral mitral annulus. A radiofrequency application at the earliest activation during the AT successfully terminated the AT. Adenosine-sensitive ATs generally originate from the vicinity of the AV node and tricuspid annulus. We present a case with an unusual location of the origin of an adenosine-sensitive AT, which was successfully ablated at the lateral mitral annulus. Since the AT was sensitive to adenosine, the AT substrate appeared to have been calcium channel-dependent tissue along the mitral annulus. <Learning objective: Adenosine-sensitive atrial tachycardias (ATs) generally originate from the right-sided atrioventricular (AV) annulus and are eliminated by ablation at the vicinity of the AV node, tricuspid annulus, proximal coronary sinus, and non-coronary sinus of Valsalva. This case report described a rare type of an adenosine-sensitive AT originating from the lateral mitral annulus. A radiofrequency application targeting the earliest activation on the activation map during the AT terminated the AT.>.


Rapid development of hepatic alpha1-antitrypsin globules after liver transplantation for chronic hepatitis C.
A 37-year-old man undergoing liver transplantation for cirrhosis caused by chronic hepatitis C and alcoholism developed large numbers of alpha1-antitrypsin (AAT) globules within hepatocytes of the transplanted liver during a 5-month period. This finding occurred simultaneously with severe recurrent hepatitis C. The AAT phenotype of this patient changed from MM before transplantation to MZ after transplantation; AAT levels in serum did not change significantly. After a second liver transplantation 6 months after the first, the AAT phenotype reverted to MM and globules were not detectable in the second transplanted liver. Severe recurrent hepatitis C and the appearance of AAT globules within the liver allograft of a heterozygous donor may be related. The recurrent infection may have induced accumulation of AAT protein, or, alternatively, the MZ liver may have been more susceptible to injury from recurrent viral infection.


Comparison of corneal sensation following photorefractive keratectomy and laser in situ keratomileusis.
To evaluate the effect of photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) on corneal sensation. Eye Institute, Medical School of the University of Crete, Heraklion, Greece, and Orasis, Hellenic Eye Center of Athens, Greece. In a masked study, corneal sensation was measured with the Cochet-Bonnet aesthesiometer in 40 consecutive patients 6 to 12 months following PRK and LASIK (60 mm constitutes normal reading and < 40 mm, abnormal). After 6 to 12 months, the mean corneal sensation following PRK was 39.2 mm (range 30 to 55 mm) (mean 9.5 months) and after LASIK, 53.6 mm (range 40 to 60 mm) (mean 9.3 months). The mean correction attempted for PRK was 7.05 diopters (D) (range 2.5 to 12.0 D) and for LASIK, 11.71 D (range 6.0 to 20.0 D). In this group of patients, with correction of primarily severe myopia, corneal sensation was significantly greater after LASIK than after PRK.


Graves' ophthalmopathy and tongue cancer complicated by peg-interferon α-2b and ribavirin therapy for chronic hepatitis C: A case report and review of the literature.
Hepatitis C virus (HCV) infection induces not only chronic liver disease, but also extrahepatic manifestations such as thyroid disease and oral cancer. Thyroid dysfunction is also a complication known to be associated with interferon (IFN) therapy for HCV infection. We report on a 69-year-old Japanese man who developed Graves' ophthalmopathy and tongue cancer (malignant transformation of leukoplakia) while receiving peg-interferon (Peg-IFN) α-2b and ribavirin (RBV) treatment for chronic hepatitis C. This patient had no history of thyroid disease before the combination therapy, but did have bilateral leukoplakia of the tongue. The leukoplakia lesions did not change until 20 weeks after the start of the combination therapy, and ophthalmopathy was not diagnosed until 47 weeks later. As ophthalmopathy is considered to be a severe adverse event induced by Peg-IFN α-2b plus RBV, therapy was discontinued after 47 weeks. The patient received a partial glossectomy to remove the malignant neoplasm as well as extraocular muscle surgery for the ophthalmopathy, and was treated with an antithyroid agent and steroids. In conclusion, it is necessary to clinically examine organs other than the liver in patients with HCV infection.


The pharmacokinetics and safety of single escalating oral doses of eletriptan.
The pharmacokinetics, safety, and tolerability of the 5-HT(1B/1D) agonist eletriptan were characterized in a randomized, double-blind, placebo-controlled, dose escalation study. Healthy males received single oral doses of 10 to 120 mg. Following screening and baseline measurements, plasma and saliva eletriptan concentrations were measured at intervals over 48 hours and 24 hours, respectively. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection. Both the maximum plasma concentration and the area under the plasma eletriptan concentration-time curve showed an essentially linear relationship to the administered dose. Eletriptan exhibited a median time to maximum plasma concentration of 1 to 1.25 hours and a mean elimination half-life of 3.6 to 7.0 hours. Mean salivary-plasma ratios for pharmacokinetic parameters generally remained constant across the 30 to 90 mg dose range. Eletriptan was well tolerated, with mostly mild and transient adverse events. In conclusion, oral doses of eletriptan in the therapeutic range were rapidly absorbed and exhibited essentially linear plasma and saliva pharmacokinetics.


Association between posttraumatic stress disorder and lack of exercise, poor diet, obesity, and co-occuring smoking: A systematic review and meta-analysis.
Research has shown that posttraumatic stress disorder (PTSD) increases the risk of development of cardiometabolic disease (CMD) including cardiovascular disease and diabetes. Whether PTSD is also associated with behavioral risk factors (e.g., diet, exercise, smoking and obesity) for CMD, is less clear. PubMed, Web of Science, and Scopus databases were searched to obtain papers published between 1980-2016. Studies were reviewed for quality using the Quality of Cohort screen. Significance values, odds ratios (OR), 95% confidence intervals (CI), and tests of homogeneity of variance were calculated. A total of 1,349 studies were identified from our search and 29 studies met all eligibility criteria. Individuals with PTSD were 5% less likely to have healthy diets (pooled adjusted OR = 0.95; 95% CI: 0.92, 0.98), 9% less likely to engage in physical activity (pooled adjusted OR = 0.91; 95% CI: 0.88, 0.93), 31% more likely to be obese (pooled adjusted OR = 1.31; 95% CI:1.25, 1.38), and about 22% more likely to be current smokers (pooled adjusted OR = 1.22; 95% CI: 1.19, 1.26), than individuals without PTSD. Evidence shows PTSD is associated with reduced healthy eating and physical activity, and increased obesity and smoking. The well-established association between PTSD and metabolic and cardiovascular disease may be partly due to poor diet, sedentary lifestyle, high prevalence of obesity, and co-occurring smoking in this population. The well-established association of PTSD with CMD is likely due in part to poor health behaviors in this patient population. (PsycINFO Database Record


Abnormal proinsulin congeners as autoantigens that initiate the pathogenesis of Type 1 diabetes.
Exposure of concentrated and purified monomeric insulin solutions to inorganic oxidants as iodine and chlorine lead to the appearance of a minor peak on gel chromatography that was disulfide cross-linked. It exhibited a 20-fold reduction in bioactivity, a markedly decreased immunoreactivity and a different electrophoretic pattern as compared to the starting material. The covalent dimer was formed by way of aggregation. These findings were reproduced by incubating monomeric insulin in normal blood spiked to hyperglycemic levels. In contrast, normoglycemic blood used as incubating medium failed to induce dimerization. Since the conformation of proinsulin is similar to that of insulin, involving the exposure of the anterior A7-B7 disulfide bridge, the authors hypothesize that proinsulin dimers rather than insulin dimers might be formed in Type 1 diabetes (TD1), leading to the autoimmune destruction of pancreatic B-cells. Proinsulin is present in a soluble aggregate state in the coated granule and may further accumulate allowing disulfide exchange due to abnormalities of the processing enzymes. This might be caused by inborn errors in genetically susceptible children or perhaps secondary to viral infection, whereas crystallization of insulin in mature granules is unlikely to be conducive to dimerization. Dimeric proinsulin would then migrate to pancreatic B-cell membranes to be taken up by surface immunoglobulins on B-lymphocytes that would in turn present it to cytotoxic T lymphocytes. The abnormal configuration of this congener would not be recognized as self by the immune system, triggering a selective destruction of pancreatic B-cells in the early pre-clinical development of TD1, resulting eventually in clinical disease. Since proinsulin is continuously converted to insulin in the coated granules of Type 2 diabetics, dimerization is unlikely in this condition. As pointed out by earlier investigators, TD1 is not a homogeneous disease, since several of its clinical features are different in children up to 6 years of age as compared to older patients. It is thus conceivable that there are subsets of TD1 triggered by dissimilar autoantigens and we propose in the present hypothesis that a conformationally altered congener of native proinsulin might play such a role.


Designing a purification process for chromium-, copper- and arsenic-contaminated wood.
The disposal of chromated copper arsenate (CCA)-treated wood is becoming a serious problem in many countries due to increasing levels of contamination by the hazardous elements, chromium, copper and arsenic. The present experiment was conducted as a preliminary step toward one-step solvent extraction of CCA-treated wood. Because chromium, copper and arsenic have different chemical characteristics, it is best to consider them separately prior to designing a one-step extraction process. As a basis, various two-step extraction processes were first designed and tested experimentally to determine feasibility. Among these combinations, the treatment combining oxalic acid as the 1st step and a sodium oxalate solution under acidic conditions (pH 3.2) as the 2nd step was found to be an effective way of extracting CCA elements from treated wood. Extraction efficiency reached 100% for arsenic and chromium and 95.8% for copper after a 3-h sodium oxalate treatment, following a 1-h pre-extraction process with oxalic acid. On the other hand, the same combination under alkaline conditions (pH 11.2) during the 2nd step was ineffective for copper removal, indicating that pH plays an important role in complexation with sodium oxalate solution. The present results suggest that the extraction of CCA elements using a combination of oxalic acid and acidic sodium oxalate solution is a promising basis for application to a one-step extraction method.


Tissue-specific Cd and Pb accumulation in Peruvian scallop (Argopecten purpuratus) transplanted to a suspended and bottom culture at Sechura Bay, Peru.
In order to understand the effect of different culture systems on Cd and Pb accumulation, suspended long-line and bottom cultures of Argopecten purpuratus were conducted during January until April 2010 (120 days). The Cd tissue levels were the highest at the middle of the experiment (30-d till 70-d) for suspended-cultured individuals, while bottom-cultured individuals showed an increasing trend. Gonad Pb levels were also higher during the same period for all cultures, while adductor muscle exhibited no considerable variations. Cd and Pb tissue concentrations were mainly greater in deeper cultures. There were no significant differences in Cd and Pb accumulation between individual sizes. The Cd and Pb levels in edible tissue (gonad+adductor muscle) did not exceed the EU and FDA maximum levels. Based on the target hazard quotient (THQ) and the provisional tolerance weekly intake (PTWI), no risk (THQ<1 and %PTWI<30) was found for human consumption.


An innovation in the subcutaneous island pedicle flap for cutaneous reconstruction.
The aim of this study was to describe an innovation of the transposition pedicle island flap for reconstruction of the medium-sized skin defects in the face, neck and hand. Twenty-seven cases of skin tumours and scars were surgically excised and reconstructed with this island flap. ALL flap survived with primary healing postoperatively. With a follow-up from 1 to 22 months, functionally and cosmetically satisfactory outcomes were achieved. This modification of transposition island flap provides a competitive repair alternative for the treatment of medium-sized skin defects.


Development of in vitro cardiovascular tissue models within capillary circuit microfluidic devices fabricated with 3D Stereolithography printing.
Human cardiovascular tissue and diseases are difficult to study for novel drug discovery and fundamental cellular/molecular processes due to limited availability of physiologically-relevant models in vitro.[1-3] Animal models may resemble human heart structure, however there are significant differences from human cardiovascular physiology including biochemical signaling, and gene expression.[4-6] In vitro microfluidic tissue models provide a less expensive, more controlled, and reproducible platform for better quantification of isolated cellular processes in response to biochemical or biophysical stimulus.[6-12] The capillary driven-flow microfluidic device in this study was manufactured with a 3D stereolithography (SLA) printed mold and is a closed circuit system operating on principles of capillary action allowing continuous fluid movement without external power supply. Human umbilical vein endothelial cells (HUVECs) and human cardiomyocytes (AC16) were encapsulated into a fibrin hydrogel to form vascular (VTM) and cardiac (CTM) tissue models respectively. To determine response to biophysical stimulus, the 3D cardiovascular tissue was directly loaded into the device tissue culture chambers that either had no microposts (DWoP) or microposts (DWPG) for 1, 3 and 5 days. The tissues were analyzed with fluorescent microscopy for morphological differences, average tube length, and cell orientation between tissues cultured in both conditions. In DWPG VTMs displayed capillary-like tube formation with visible cell alignment and orientation, while AC16s continued to elongate around microposts by day 5. VTM and CTM models in devices with posts (DWPG) displayed cell alignment and orientation after 5 days, indicated the microposts induced biophysical cues to guide cell structure and specific organization.


[Isolated intracranial relapse in previously treated Hodgkin's disease].
Isolated brain relapse is uncommon in Hodgkin's lymphoma and often linked with advanced or refractory disease. We report two patients with stage IV Hodgkin's disease, previously treated with chemotherapy, who later developed neurological symptoms. Brain MRI demonstrated two different types of lesions. Histological findings were consistent with intracranial location of Hodgkin lymphoma. Both of the patients presented only with isolated CNS relapse of the lymphoma. The two cases demonstrated the MRI appearance of intracranial involvement can be varied and mimic other disease processes in patients with a previous history of Hodgkin's lymphoma. Thus, a biopsy is necessary for diagnosis and correct treatment.


Cloning and sequencing of nifBHDKENX genes of Paenibacillus massiliensis T7 and its nif promoter analysis.
A 324 bp of nifH fragment was PCR amplified from Paenibacillus massiliensis T7 using the universal degenerate primers. The PCR-amplified nifH fragment was labeled with DIG and then used as a probe in Southern blot analysis. Southern blot result showed that there were two positive signals, indicating that there might be two copies of nifH in P. massiliensis T7. A total of 10254 bp DNA sequence containing purD and nifBHDKENX was obtained by five rounds of inverse-PCR amplification. The predicted proteins of nifBHDKENX had high homology with those from other nitrogen-fixing bacteria. Only one putative sigma54-dependent promoter sequence was detected upstream of the nifB gene and nifBHDKENX were likely to be organized in one operon. Assays of 3-galactosidase activity of P. massiliensis T7PB carrying a nifB-lacZ fusion under different concentrations of NH4+ and O2 showed that the expression of nifB-lacZ was strongly inhibited by O2.