Descriptive Proteome Analysis to Investigate Context-Dependent Treatment Responses to OXPHOS Inhibition in Colon Carcinoma Cells Grown as Monolayer and Multicellular Tumor Spheroids.
We have previously identified selective upregulation of the mevalonate pathway genes upon inhibition of oxidative phosphorylation (OXPHOS) in quiescent cancer cells. Using mass spectrometry-based proteomics, we here investigated whether these responses are corroborated on the protein level and whether proteomics could yield unique insights into context-dependent biology. HCT116 colon carcinoma cells were cultured as monolayer cultures, proliferative multicellular tumor spheroids (P-MCTS), or quiescent (Q-MCTS) multicellular tumor spheroids and exposed to OXPHOS inhibitors: nitazoxanide, FCCP, oligomycin, and salinomycin or the HMG-CoA-reductase inhibitor simvastatin at two different doses for 6 and 24 h. Samples were processed using an in-depth bottom-up proteomics workflow resulting in a total of 9286 identified protein groups. Gene set enrichment analysis showed profound differences between the three cell systems and confirmed differential enrichment of hypoxia, OXPHOS, and cell cycle progression-related protein responses in P-MCTS and Q-MCTS. Treatment experiments showed that the observed drug-induced alterations in gene expression of metabolically challenged cells are not translated directly to the protein level, but the results reaffirmed OXPHOS as a selective vulnerability of quiescent cancer cells. This work provides rationale for the use of deep proteome profiling to identify context-dependent treatment responses and encourages further studies investigating metabolic processes that could be co-targeted together with OXPHOS to eradicate quiescent cancer cells.


Agricultural conservation may not help Midwestern US freshwater biodiversity in a changing climate.
Global climate change and agricultural disturbance often drive freshwater biodiversity changes at the regional level, particularly in the Midwestern US. Agricultural conservation practices have been implemented to reduce sediment and nutrient loading (e.g., crop rotation, cover crops, reduced tillage, and modified fertilizer application) for long-term economic sustainability and environmental resilience. However, the effectiveness of these efforts on freshwater biodiversity is not conclusive. In this study, we used the Kaskaskia River Watershed, Illinois as an example to evaluate how agricultural conservation practices affects both taxonomic and functional diversity under climate changes. The measures of trait-based functional diversity provide mechanistic explanations of biological changes. In specific, we model and predict 1) species richness (SR), 2) functional dispersion (FDis), and 3) functional evenness (FEve). FDis and FEve were based on ecology (life history, habitat preference, and trophic level) and physiology (thermal preference, swimming preference, etc.). The best random-forest regression models showed that flow, temperature, nitrate, and the watershed area were among the top predictors of the three biodiversity measures. We then used the models to predict the changes of SR and FDis under RCP8.5 climate change scenarios. SR and FDis were predicted to decrease in most sites, up to 20 % and 4 % by 2099, respectively. When agricultural conservation practices were considered together with climate changes, the decreasing trends of SR and FDis remained, suggesting climate change outweighed potential agriculture conservation efforts. Thus, climate-change effects on temperature and flow regimes need to be incorporated into the design of agricultural practices for freshwater biodiversity conservation.


Successful treatment of life-threatening bleeding after cesarean section with recombinant activated factor VII.
Hemorrhagic shock developed in a 29-year-old nullipara without coagulopathy after emergency caesarean section. Treatment with uterotonic drugs, prostaglandins, and conservative procedures with transfusion of packed red cells and fresh-frozen plasma failed to control the diffuse vaginal and uterine bleeding. Finally an intravenous bolus injection of 90 microg/kg recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark), was given and showed success within 20 minutes after administration, without any side effects.


Optimising management of complex regional pain syndrome to improve clinical outcomes throughout the therapy care pathway in England: Protocol for a qualitative interview and observational study with patients and clinicians.
Complex Regional Pain Syndrome (CRPS) is a disabling and distressing chronic pain condition characterised by a range of sensory, motor, autonomic and trophic symptoms. Guidelines recommend early referral for therapies that promote movement of the painful limb. However, evidence suggests a lack of defined therapy pathways for CRPS. The current study aims to explore CRPS therapy management in centres of excellence in England, and outside of these settings, to understand what facilitates and hinders best practice. The overall aim is to develop a draft stratified package of care to expedite patient access to optimal CRPS therapy across the management pathway. Semi-structured interviews will be conducted with therapists working in CRPS centres of excellence and with therapists in other settings. Observations of therapy interventions in CRPS centres of excellence and interviews with patients who have received this care, will also help to identify potential key care package components. Interview data will be analysed using thematic analysis, mapped to the Theoretical Domains Framework (TDF), and Intervention Mapping Adapt (IMA) framework. Observations will be described and documented using the TDF headings. A triangulation protocol for qualitative health research will be used to integrate all data. Online stakeholder events will be held using consensus methods to agree a draft package of care for future implementation following further refinement, testing and evaluation. The trial was registered with ISRCTN registry on 24 February 2022 (ISRCTN16917807).


Bleb morphology of glaucoma drainage devices on magnetic resonance imaging.
To evaluate bleb morphology features of different glaucoma drainage devices (GDD) using magnetic resonance imaging (MRI). Prospective cohort study of GDD and bleb morphology in consecutive glaucoma patients implanted with Ahmed Glaucoma Valve (AGV), Paul Glaucoma Implant (PGI), Baerveldt Glaucoma Implant (BGI) and Ahmed ClearPath (ACP) devices. Thirty-six eyes from 30 consecutive patients underwent standardized GDD implantation followed by MRI at least 1 month after surgery. Main outcomes included bleb volume and endplate position relative to the optic nerve. Secondary outcomes included intraocular pressure (IOP), medication and surgical complications during a 12-month follow-up. Seven eyes were implanted with the AGV (19%), 5 with BGI (14%), 16 with PGI (44%) and 8 with ACP (22%). MRI scans were obtained 85 ± 66 days after surgery. Mean total bleb volume was 563 ± 390 mm3 . This bleb volume was inversely correlated with early post-operative IOP (day 7; rs = -0.3326, p = 0.0475) but positively correlated with IOP at 12 months (rs = 0.3592, p = 0.0341). No significant difference in total bleb volume was found between GDD types (p = 0.1223). A double-layered bleb was observed in 34 eyes (94%). The inferior bleb volume was significantly larger in PGI devices versus other GDD types (380 ± 205 vs. 193 ± 161 mm3 ; p = 0.0043). Distance from the endplate to the optic nerve was 9.5 ± 4.0 mm, similar across GDDs (p = 0.2519). Double-layered blebs are a common finding with GDDs. Bleb volume showed different correlations with IOP at distinct timepoints and the PGI device formed larger blebs. A standardized GDD implantation technique ensures a safe distance from the GDD endplate to the optic nerve.


Genetics of esterases in Drosophila. IV. Slow-migrating S-esterase in Drosophila of the virilis group.
A slow-migrating beta-esterase (S-esterase) is described which has been detected in Drosophila montana, Drosophila imeretensis, and some stocks of Drosophila virilis when mixtures of alpha- and beta-naphthyl acetate are used as substrates in histochemical reactions after electrophoresis. Sexual dimorphism for S-esterase has been demonstrated. This esterase is contained in male genitalia only, predominantly in the ejaculatory bulb (waxy plug). It appears 3-4 days after emergence of flies. In hybrids between S+ and So species, the activity of the slow esterase is either decreased or inhibited. An autonomous synthesis of the S- esterase in the ejaculatory bulb was established by transplantation of imaginal genital discs into larvae of different Drosophila stocks. Based on analysis of physiochemical and immunochemical properties, S-esterase is suggested to be an independent fraction of esterase, possibly dimeric, which does not cross-react with beta-esterase antiserum.


Thinning of the Lamina Cribrosa and Deep Layer Microvascular Dropout in Patients With Open Angle Glaucoma and High Myopia.
Lamina cribrosa (LC) thinning (thickness of ≤128.00 µm) helps to distinguish open angle glaucoma from high myopia, which was associated with the presence of microvasculature dropout and elevated intraocular pressure. The purpose of this study was to analyze the factors associated with LC thickness in highly myopic eyes with and without open angle glaucoma. In total, 240 highly myopic eyes with γ-zones (194 eyes without and 46 eyes with open angle glaucoma) were examined, and the LC center, externally oblique border, an abrupt change of scleral curvature (scleral step), deep layer microvasculature dropout and global retinal nerve fiber layer thickness were investigated on optical coherence tomography and optical coherence tomography angiography. LC were thinner in highly myopic open angle glaucoma compared with high myopia alone (107.76±9.86 vs. 137.07±18.51 µm, P <0.001), which was associated with deep layer microvasculature dropout and elevated intraocular pressure. The areas under the receiver operating characteristic curve for detecting open angle glaucoma from the LC thickness was 0.964, which was statistically higher ( P <0.05) than from the global retinal nerve fiber layer thickness (0.921) and vertical cup-to-disc ratio (0.902). A LC thickness cutoff value of 128 µm provided 100% sensitivity for detecting open angle glaucoma with 84% specificity. Highly myopic eyes with open angle glaucoma appear to have a thinner LC, which was associated with elevated intraocular pressure and deep layer microvasculature dropout. LC thinning (≤128.00 µm) helps distinguish open angle glaucoma from high myopia with an abnormal retinal nerve fiber layer thickness distribution and unclear shallow disc cupping.


Minimal invasive right ventricular and atrial pacemaker lead repositioning as a first alternative is superior in avoiding pocket complications with passive fixation leads.
Lead dislocations of pacemaker systems are reported in all and even in high-volume centers. Repeated procedures necessitated by lead dislocations are associated with an increased risk of complications. We investigated a minimal invasive method for right atrial and ventricular lead repositioning. The minimal invasive method was applied only when passive fixation leads were implanted. During the minimal invasive procedure, a steerable catheter was advanced through the femoral vein to move the distal end of the lead to the appropriate position. Retrospective data collection was conducted in all patients with minimal invasive and with conventional method, at a single center between September 2006 and December 2012. Forty-five minimal invasive lead repositionings were performed, of which eight were acutely unsuccessful and nine electrodes re-dislocated after the procedure. One hundred two leads were repositioned with opening of the pocket during the same time, including the ones with unsuccessful minimal invasive repositionings. One procedure was acutely unsuccessful in this group and four re-dislocations happened. A significant difference of success rates was noted (66.6% vs. 95.1%, p = 0.001). One complication was observed during the minimal invasive lead repositionings (left ventricular lead microdislodgement). Open-pocket procedures showed different types of complications (pneumothorax, subclavian artery puncture, pericardial effusion, hematoma, fever, device-associated infection which necessitated explantation, atrial lead dislodgement while repositioning the ventricular one, deterioration of renal function). The minimal invasive method as a first alternative is safe and feasible. In those cases when it cannot be carried out successfully, the conventional method is applicable.


Sensitivity of identified medial hypothalamic neurons to GABA, glycine and related amino acids; influence of bicuculline, picrotoxin and strychnine on synaptic inhibition.
Medial hypothalamic neurons in pentobarbital anesthetized rats were identified by location and response to electrical stimulation of the amygdala, medial preoptic area, midbrain periaqueductal gray and median eminence. Cells were then examined for their sensitivity to microiontophoretic applications of GABA, glycine and 3 related amino acids, i.e. beta-guanidinopropionic acid, delta-aminovaleric acid and beta-alanine. Application of all agents decreased the spontaneous and glutamate or aspartate evoked activity of the majority of neurons in all identified categories. The majority of neurons were more sensitive to beta-guanidinopropionate, delta aminovalerate and GABA than to glycine and beta-alanine. Bicuculline and picrotoxin produced a selective and reversible antagonism of depressions evoked by GABA and GABA-like amino acids whereas strychnine produced a selective and reversible antagonism of depressions evoked by glycine and beta-alanine. Bicuculline and picrotoxin, but not strychnine, were observed to diminish synaptic inhibition evoked by electrical stimulation of several sites when these agents were administered by microiontophoresis and by i.v. injections in convulsive doses. These observations suggest that many medial hypothalamic neurons have both GABA and glycine receptors but that GABA may have the more important role as a neurotransmitter common to afferent or recurrent inhibitory hypothalamic pathways.


Comment on Theeuwes's Characterization of Visual Selection.
Theeuwes (2018, this issue) argues that the classic dichotomy describing the factors that guide attention (bottom-up and top-down) is inadequate and should be replaced by a trichotomy (bottom-up, top-down, and selection history). In contrast, I argue that top-down is a broad category that comfortably includes selection history. While one can certainly choose to subdivide broad categories, there is no obvious stopping point for such an endeavor; how long can it be before this trichotomy turns into a "quadchotomy"?


Methionine-80-sulfoxide cytochrome c: preparation, purification and electron-transfer capabilities.
In order to explore the electron-transferring properties of methionine-80-sulfoxide cytochrome c, the pure, chromatographically homogeneous methionine-80-sulfoxide cytochrome c was previously published procedure (Ivanetich, K.M., Bradshaw, J.J. and Kaminsky, L.S. (1976) Biochemistry 15, 1144-1153) was found to produce a mixture of products. In the pure derivative, visible spectroscopy indicates that the 695 nm band indicative of the Met-80-Fe coordination is missing, amino acid analysis indicates that only one methionine is modified to the sulfoxide, and the E0' is found to be 240 mV vs. N.H.E. For succinate cytochrome c reductase activity, the Km for modified cytochrome was about one-ninth that of the native protein, while the maximum turnover number of the reductase with the modified protein was only about 54% of that with native protein. In contrast, the activity with cytochrome oxidase measured polarographically using ascorbate and TMPD under two different buffer/pH conditions, gave Km values that were very similar for both the native and modified cytochromes c, but the maximum turnover numbers of the oxidase with the modified protein were less than 40% of native in either buffer. It is concluded that the Met-80-sulfoxide cytochrome c in the reduced form is able to maintain substantially its heme crevice structure and thus maintain Km values similar to those of native protein. However, the low maximum turnover numbers for oxidase activity with the modified protein in the reduced state indicate that electron transfer itself has been significantly decreased, probably because the parity of acid/base and electrostatic interactions of Met-80 sulfur with the Fe in the two redox states has been disrupted.


Studies on adenosine 3',5'-phosphate-binding and adenosine 3',5-phosphate-dependent protein kinase activities associated with subcellular fractions of Chinese hamster ovary cells.
Both cyclic AMP-binding and cyclic AMP-dependent protein kinase activities exist in Chinese hamster ovary cell extract. Competition experiments demonstrate that the binding is specific for cyclic AMP. All cellular elements including nucleus, mitochondria, plasma membrane, microsome, ribosome and cytosol contain both activities. Binding activity is highest in the cytosol and lowest in the nucleus. Each fraction contains endogenous protein kinase activity which is insensitive to cyclic AMP activation. When histone was used as a substrate, protein kinase activity in all fractions was stimulated by cyclic AMP (with the highest in cytosol and lowest in the nucleus) and inhibited by Walsh's protein kinase inhibitor.


Using latent class analysis to estimate the test characteristics of the γ-interferon test, the single intradermal comparative tuberculin test and a multiplex immunoassay under Irish conditions.
Considerable effort has been devoted to improving the existing diagnostic tests for bovine tuberculosis (single intradermal comparative tuberculin test [SICTT] and γ-interferon assay [γ-IFN]) and to develop new tests. Previously, the diagnostic characteristics (sensitivity, specificity) have been estimated in populations with defined infection status. However, these approaches can be problematic as there may be few herds in Ireland where freedom from infection is guaranteed. We used latent class models to estimate the diagnostic characteristics of existing (SICTT and γ-IFN) and new (multiplex immunoassay [Enferplex-TB]) diagnostic tests under Irish field conditions where true disease status was unknown. The study population consisted of herds recruited in areas with no known TB problems (2197 animals) and herds experiencing a confirmed TB breakdown (2740 animals). A Bayesian model was developed, allowing for dependence between SICTT and γ-IFN, while assuming independence from the Enferplex-TB test. Different test interpretations were used for the analysis: SICTT (standard and severe interpretation), γ-IFN (a single interpretation), and a range of interpretations for the Enferplex-TB (level-1 [high sensitivity interpretation] to level-5 [high specificity interpretation]). The sensitivity and specificity (95% posterior credibility intervals; 95% PCI) of SICTT[standard] relative to Enferplex-TB[level-1] and γ-IFN were 52.9-60.8% and 99.2-99.8%, respectively. Equivalent estimates for γ-IFN relative to Enferplex-TB[level-1] and SICTT were 63.1-70.1% and 86.8-89.4%, respectively. Sensitivity of Enferplex-TB[level-1] (95% PCI: 64.8-71.9%) was superior to the SICTT[standard], and specificity of the Enferplex-TB[level-5] was superior to γ-IFN (95% PCI: 99.6-100.0%). These results provide robust measures of sensitivity and specificity under field conditions in Ireland and suggest that the Enferplex-TB test has the potential to improve on current diagnostics for TB infection in cattle. The extent of that potential will be assessed in further studies.


Paced auditory serial addition test (PASAT): a very difficult test even for individuals with high intellectual capability.
To assess the difficulty of paced auditory serial addition test (PASAT) in a population of high intellectual level, under ideal cognitive testing circumstances. One hundred medical students underwent PASAT testing. They had slept well the night before, they had eaten before the assessment, they were not using any drugs that could affect the central nervous system and they did not have depression, anxiety or any chronic disease. The average result from the three-second version of PASAT was 57.5% and, from the two-second version, it was 44.3%. Even under ideal circumstances, PASAT is a very difficult test for the general population. It may not be ideal for neurologists to screen, assess and follow up patients with cognitive function in multiple sclerosis.


Morphine, haloperidol and hyoscine N-butyl bromide combined in s.c. infusion solutions: compatibility and stability. Evaluation in terminal oncology patients.
The administration of drugs by subcutaneous infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is common for two or more drugs to be combined in subcutaneous solutions. The combination of an opioid with other drugs (haloperiol lactate and hyoscine N-butyl bromide) can be very valuable. Unfortunately, the compatibility and stability of morphine hydrochloride, haloperidol lactate and hyoscine N-butyl bromide combined in the same solution has not yet been determined. Therefore, this study examined the stability of ternary solutions containing morphine HCl, haloperidol lactate and hyoscine N-butyl bromide at different dose ranges. Twelve different solutions were assessed for 15 days after preparation in polypropylene syringes using 0.9% saline as diluent. Triplicate syringes were stored at 25 degrees C. HPLC was the analytical technique used to measure morphine HCl, haloperidol lactate and hyoscine N-butyl bromide. Initial concentration ranges were 1.67-10.0 mg/ml for morphine HCl, 0.417-0.625 mg/ml for haloperidol lactate and, 5.0-6.67 mg/ml for hyoscine N-butyl bromide. All three drugs were very stable (>92.5%) when stored at 25 degrees C. The clinical performance of the admixture was retrospectively assessed in 21 terminal oncology patients. Total symptom control was achieved in 17 out of 21 patients with very good local tolerance.


Low vitamin B6 status associated with slow growth in healthy breast-fed infants.
To evaluate the effect of vitamin B6 status on infant growth, we studied longitudinally anthropometry and the erythrocyte parameters that reflect long-term vitamin B6 status [erythrocyte pyridoxal 5'-phosphate concentration (EPLP), erythrocyte aspartate transaminase basal activity (EAST0), and its activation co-efficient (alpha EAST)] in 44 infants. The infants were exclusively breast-fed for 6 mo, given additional solids according a uniform schedule from 6-9 mo, and formula after 9 mo, if needed. In seven of these infants, a low vitamin B6 status (EPLP < 10th, and EAST0 > 10th or alpha EAST > 90th percentile for these values in reference infants) was observed between 4 and 6 mo of age. These seven infants showed slower length velocity (0.30 +/- 0.05 versus 0.40 +/- 0.02 mm/d, p < or = 0.02) and deeper fall in length-for-age (-0.69 +/- 0.20 versus -0.25 +/- 0.07 SD score, p < or = 0.03) from 6 to 9 mo of age than the similarly fed infants with higher vitamin B6 status. Preceding vitamin B6 status remained a significant explanatory factor for length velocity and change in length-for-age in addition to preceding and concomitant weight velocity, when sex, birth size, preceding length gain, and mid-parent height were taken into account. Change in weight-for-age alone explained 16% and 18% and, together with vitamin B6 status, 23 and 27% of the variation in length velocity and in change in length-for-age, respectively. Thus, in healthy breast-fed infants, according to our results, low vitamin B6 status is associated with reversibly reduced gain in length.


Acute polyhydramnios associated with chorioangioma. A case report.
A case of acute polyhydramnios occurred at 26 weeks' gestation. Prenatal sonography demonstrated a placental chorioangioma. Acute polyhydramnios is clinically distinct from nonacute polyhydramnios and carries a high perinatal mortality rate. As in our case, fetal death often results from complications of prematurity.


Concentrations and Toxic Equivalency of Polycyclic Aromatic Hydrocarbons (PAHs) and Polychlorinated Biphenyl (PCB) Congeners in Groundwater Around Waste Dumpsites in South-West Nigeria.
Polyaromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in groundwater and leachate around selected waste dumpsites from two southwestern states of Nigeria were investigated. Samples were Soxhlet-extracted using hexane/methylene chloride mixture and cleaned-up with preconditioned solid-phase extraction cartridges. The ∑PAHs (PCBs) (all in µg/L) in the boreholes, leachate, and hand-dug well across all locations ranged from below detection limit (BDL) to 0.62 (BDL to 0.067), 1.16 to 9.96 (0.003 to 0.041), and BDL to 0.01 (0.001-0.031), respectively. Low molecular weight-PAHs accounted for ≥61% of ∑PAHs detected across all locations. The highly chlorinated hexa-PCBs [2,2',3,4,4',5'-HeCB(#180), 2,2',3,4',5',6-HeCB(#34) and 2,2',4,4',5,5'-HeCB(#153)] dominated the entire congener profiles. Pyrene and 2,3',4,4',5-PeCB(#118) constituted 56% and 58% of the ∑PAHs and ∑PCBs, respectively. Sampled water is not adequately safe for drinking and may pose cancer risk. This study should be sustained for health risk and sustenance of an enduring ecological integrity.


Depression of maximum rate of depolarization of guinea-pig ventricular action potentials by metabolites of encainide.
1. Standard microelectrode methods have been used to record action potentials from guinea-pig ventricular myocardium and dog Purkinje fibres, and to study the effects of the two major metabolites of encainide, O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). 2. In concentrations similar to those found in patients during chronic encainide therapy, neither ODE nor MODE produced significant depression of maximum rate of depolarization (Vmax) of action potentials in unstimulated tissue. Repetitive stimulation, however, was associated with depression of Vmax which increased with increasing driving rates (rate-dependent block, RDB). At the fastest rate studied (interstimulus interval = 300 ms) ODE 1 microM depressed Vmax by 47.5 +/- 5.7% and MODE 1 microM, reduced Vmax by 52.2 +/- 12%. 3. The onset and offset kinetics of this rate-dependent block were very slow. Full development of RDB during a train required over 100 action potentials and the time constants of recovery of Vmax from RDB were 86.4 +/- 37 s for ODE and 100.4 +/- 18 s for MODE. The amount of RDB and its rate of onset increased with drug concentration. The recovery time constants were independent of inter-stimulus interval or drug concentration. Both metabolites also produced rate-dependent depression of conduction velocity in canine Purkinje fibres, but no evidence of selective depression of conduction of interpolated premature potentials was seen. 4. Early afterdepolarizations occurred spontaneously in three preparations in the presence of MODE, 1 microM and one preparation in ODE, 1 microM. 5. It is concluded that these metabolites of encainide may play a role in producing both its antiarrhythmic and its proarrhythmic effects.


In Vivo Investigation of Gene Function in Muscle Stem Cells by CRISPR/Cas9-Mediated Genome Editing.
Skeletal muscle satellite cells (SCs) are adult stem cells responsible for muscle development and injury-induced muscle regeneration. Functional elucidation of intrinsic regulatory factors governing SC activity is constrained partially by the technological limitations in editing SCs in vivo. Although the power of CRISPR/Cas9 in genome manipulation has been widely documented, its application in endogenous SCs remains largely untested. Our recent study generates a muscle-specific genome editing system leveraging the Cre-dependent Cas9 knockin mice and AAV9-mediated sgRNAs delivery, which allows gene disruption in SCs in vivo. Here, we illustrate the step-by-step procedure for achieving efficient editing using the above system.


Deep_CNN_LSTM_GO: Protein function prediction from amino-acid sequences.
Protein amino acid sequences can be used to determine the functions of the protein. However, determining the function of a single protein requires many resources and a tremendous amount of time. Computational Intelligence methods such as Deep learning have been shown to predict the proteins' functions. This paper proposes a hybrid deep neural network model to predict an unknown protein's functions from sequences. The proposed model is named Deep_CNN_LSTM_GO. Deep_CNN_LSTM_GO is an Integration between Convolutional Neural network (CNN) and Long Short-Term Memory (LSTM) Neural Network to learn features from amino acid sequences and outputs the three different Gene Ontology (GO). The gene ontology represents the protein functions in the three sub-ontologies: Molecular Functions (MF), Biological Process (BP), and Cellular Component (CC). The proposed model has been trained and tested using UniProt-SwissProt's dataset. Another test has been done using Computational Assessment of Function Annotation (CAFA) on the three sub-ontologies. The proposed model outperforms different methods proposed in the field with better performance using three different evaluation metrics (Fmax, Smin, and AUPR) in the three sub-ontologies (MF, BP, CC).


Impact of Knee Injuries on Post-retirement Pain and Quality of Life: A Cross-Sectional Survey of Professional Basketball Players.
Professional basketball players are at increased risk for knee injuries. Epidemiologic data exist on the prevalence of such injuries in players in the National Basketball Association (NBA), but little is known about how these injuries affect athletes before after retirement. The goals of this study were to evaluate the rates and characteristics of knee injury before and during NBA players' careers and how those injuries correspond to knee injury, pain, or surgery, as well as quality of life, after retirement. A cross-sectional survey study was performed. The survey instrument was designed with the aid of a multidisciplinary focus group. Data collected included patient demographics; length of professional career; injuries before, during, and after the athletes' NBA careers; and post-retirement quality of life, assessed using the EQ-5D and Tegner Activity Scale. The survey was distributed electronically to 900 retired NBA athletes. Descriptive statistics were used to present means and proportions, and multiple regression analysis was performed to assess for potential factors correlated to injury. One hundred eight retired NBA players participated (a response rate of 12%). Almost a third (32.4%) sustained a knee injury before starting their NBA career; 51 (47.2%) sustained knee injury during professional play in the NBA, and nearly two-thirds of those players (62.7%) needed surgery. Among those who reported knee injuries during their NBA career, a majority had knee pain that continued until retirement (72.5%). Two-thirds (67%) reported having knee pain currently (at the time of the survey). More than a third (34.0%) underwent knee surgery after retirement, which included nine total knee arthroplasties (8.3%). A majority of retired NBA athletes in our study had knee pain, and many needed operative management during and after their NBA careers. NBA players score lower on quality-of-life measures than average North American men of similar age. Further research is needed to elucidate the best strategies for recognizing and treating knee injuries in these athletes.


Determination and risk assessment of toxic metals in lipsticks from Europe and China.
The presence of toxic toxic metals in lipstick can pose a health risk to many consumers of this type of cosmetics, especially for women. Thus, the aim of this study was to assess consequences attributed to dermal and oral exposure to toxic metals in lipsticks manufactured in China and Europe as determined by non-cancer and cancer risks assessment models from SCCS and USEPA, respectively. The treatment of the samples was carried out by calcination using muffle furnaces and the determination of Al, Cd and Pb were determined by inductively coupled plasma optical emission spectrometry (ICP-OES). The concentration of Cd and Pb in the study samples does not exceed the limits stablished for the FDA (00,228 mg kg-1·day-1 for Cd and 000,343 mg kg-1·day-1 for Pb, respectively) but they do not comply with the Regulation of the European Parliament, which prohibits the presence of these two metals in cosmetics. Neither European Union nor United States have established maximum levels for Al in cosmetics. The cancer risk assessment of Cd and Pb metals resulted in a total cancer risk less than 1. The results of non-cancer oral risk assessment for Pb had a MoS result of 88 for China and 62 for Europe, suggesting that Pb poses a risk for the human health, especially in samples manufactured in Europe.


Clinical Implications of Combined Lymphocyte and Neutrophil Count in Locally Advanced Rectal Cancer After Preoperative Chemoradiotherapy.
There are controversies about the ability of neutrophil to lymphocyte ratio to predict the recurrence and survival in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation. The objective of this study is to investigate the prognostic potential of combined lymphocyte count (LC) and neutrophil count (NC) in LARC patients treated with chemoradiotherapy (CRT) followed by curative surgery. Patients with LARC who underwent surgical resection between January 2010 and December 2017 were reviewed retrospectively. We divided the patients into three groups: high LC and low NC, low LC and high NC, and the remaining patients. The cut-off values of LC and NC were determined by receiver operating characteristic curve analysis and log-rank test statistics. We compared the disease-free survival (DFS) rate between the groups. A total of 176 consecutive patients were included in this study. The 5 year DFS rate was significantly different among the three groups in pathologic node (pN)+ patients (73.2% vs. 61.9% vs. 14.2%; P = 0.025). Cox multivariate analysis for pN+ patients demonstrated that combination of low LC and high NC (hazard ratio, 3.630; 95% confidence interval [CI], 1.306-10.093; P = 0.013) was significantly correlated with decreased DFS. This study showed that the combination of LC and NC is a powerful predictive factor for disease recurrence in pN+ LARC patients who underwent CRT.


[Causality analysis of a low-viscosity bone cement in orthopaedic surgery following serious adverse events].
Low-viscosity bone cement impregnated with gentamicin is frequently used to fix femoral prostheses. Three cardiac arrests occured successively during cementoplasty oh hip replacements, leading to the death of two patients. The objective of this study is to describe the actions undertaken to establish a potential link between the use of the bone cement and the occurrence of these serious adverse events (SAE). A mortality and morbidity review was organised in order to study the causality of bone cement and to propose improvement actions, following 3 considered SAE associated to materiovigilance reporting. All three SAE occurred following the injection of the same reference of bone cement. The incriminated batches were rapidly placed in quarantine. Analysis by the manufacturer revealed no defects in production quality requirements but suggested the possibility of Bone Cement Implantation Syndrome (BCIS). A literary review on BCIS confirmed that this rare intraoperative complication was plausible in all three cases. Management of these SAE via a health care safety process enabled to provide a rapid answer concerning the causality of the cement and practice deviations of its use. Systemic analysis completed by the manufacturer's analysis provided corrective actions for professional practices. Implementation and efficacy of these actions will be monitored as part of the facility's programme for the improvement of quality and patient safety.


Double immunofluorescent evidence that oxidative stress-associated activation of JNK/AP-1 signaling participates in neuropeptide-mediated appetite control.
Amphetamine (AMPH), an appetite suppressant, alters expression levels of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. This study explored the potential role of cJun-N-terminal kinases (JNK) in appetite control, mediated by reactive oxygen species (ROS) and activator protein-1 (AP-1) in AMPH-treated rats. Rats were given AMPH daily for 4 days. Changes in feeding behavior and expression levels of hypothalamic NPY, CART, cFos, cJun, phosphorylated JNK (pJNK), as well as those of anti-oxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione S-transferase (GST), were examined and compared. Following AMPH treatment, food intake and NPY expression decreased, whereas the other proteins expression and AP-1/DNA binding activity increased. Both cerebral cJun inhibition and ROS inhibition attenuated AMPH anorexia and modified detected protein, revealing a crucial role for AP-1 and ROS in regulating AMPH-induced appetite control. Moreover, both pJNK/CART and SOD/CART activities detected by double immunofluorescent staining increased in hypothalamic arcuate nucleus in AMPH-treated rats. The results suggested that pJNK/AP-1 signaling and endogenous anti-oxidants participated in regulating NPY/CART-mediated appetite control in rats treated with AMPH. These findings advance understanding of the molecular mechanism underlying the role of pJNK/AP-1 and oxidative stress in NPY/CART-mediated appetite suppression in AMPH-treated rats.


Delivery through the bladder during cesarean section.
A case is reported of simultaneous incision of the anterior and posterior bladder walls during cesarean section. Despite the serious surgical occurrence delivery was accomplished through the bladder, which was repaired successfully.


Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action.
Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagon-like peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 double-knockout mice. Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.


Low-dimensional compounds containing cyano groups. VII. (Dicyanamido-kappaN1)bis(1,10-phenanthroline-kappa2N,N')copper(II) trifluoromethanesulfonate.
The title compound, [Cu(C(2)N(3))(C(12)H(8)N(2))(2)](CF(3)SO(3)), is formed by discrete [Cu(phen)(2)(N(CN)(2)))](+) complex cations (phen is 1,10-phenanthroline) and uncoordinated CF(3)SO(3)(-) anions. The Cu centre is five-coordinated in the form of a distorted trigonal bipyramid to two phen molecules and one dicyanamide ligand, which is coordinated through one nitrile N atom in the equatorial plane at a distance of 1.990 (2) A. The two axial Cu-N distances are similar (mean 1.993 A) and are substantially shorter than the two equatorial Cu-N bonds (mean 2.125 A).


Unprecedented binding and activation of CS2 in a dinuclear copper(I) complex.
The first structural characterisation of a copper-carbondisulfide complex revealed a hitherto unknown binding mode for CS(2): it interacts with two metal centres (Cu(I)) simultaneously via both C=S π bonds. DFT calculations showed that complex formation occurs mainly due to a donation of electron density from the copper centres into the C=S π* orbitals.


[Genetic study of saccharomycete yeast sensitivity to the lethal and mutagenic action of nitrous acid. III. Relation between mitochondrial genome variability and the unstable sensitivity of yeast cells to inactivation by nitrous acid].
The sensitivity of the yeast Saccharomyces cerevisiae to nitrous acid (NA) is significantly influenced by various spontaneous mutations of the mitochondrial (mt) genome as well as by the nuclear mutation mmg 1 leading to a decrease in the spontaneous mutability of the mt genome. The mmg 1 locus and the mt genome most probably interact and this nucleo-cytoplasmic interaction plays a role in determining the NA sensitivity of yeast cells. A significant subclonal variation of the NA sensitivity has already been reported for the strains under study. Here we show this variability to decrease significantly when the cells are devoid of the mt DNA or carry the mmg 1 mutation. These data suggest a direct relation between the unstable NA sensitivity and the variability of the mt genome.


[Effectiveness of hearing aid provision for severe hearing loss].
In practice, the unilateral monosyllabic speech recognition score with hearing aid (WRS65(HA)) is often below the maximum word recognition score with headphones (WRSmax), in particular for subjects with severe hearing loss. The aim of this study was to evaluate the efficiency factor Q of hearing aid provision, the ratio WRS65(HA)/WRSmax, in patients with severe to profound hearing loss. Data from real-ear measurements (REM), pure tone and speech audiogram, and speech recognition with and without hearing aid of 93 ears in 64 patients were examined. The patients visited the authors' hearing center for hearing aid evaluation in 2019. Deviations of the real-ear measured frequency-dependent output level values from the prescription targets NAL-NL2 and DSL v5.0 were analyzed. Spearman correlation coefficients for the speech intelligibility index (SII) were calculated for the parameters WRS65(HA) and Q. In more than 67% of the hearing aid fittings, output level values matched the target curves of NAL-NL2 or DSL v5.0 in the range of ±5 dB for frequencies from 0.5 to 4 kHz at 65 dB SPL. Nevertheless, WRSmax was not achieved with hearing aid at conversational speech levels of 65 dB SPL (mean deviations: 34.4%). However, WRS65(HA) and Q were best when target values for DSL v5.0 were achieved at 65 dB SPL, which is associated with a higher SII. For patients with severe to profound hearing loss, the prescription targets of NAL-NL2 and DSL v5.0 do not provide sufficient amplification for WRSmax to be achieved at a normal speech level of 65 dB SPL. It remains to be investigated whether alternative prescriptions with better audibility for input levels of 50 and 65 dB SPL might improve the effectiveness of hearing aid provision.


Patient-derived lung cancer "sandwich cultures" with preserved tumor microenvironment.
In the past, different spheroid-, organotypic-, and three-dimensional (3D) bioprinting lung cancer models were established for in vitro drug testing and personalized medicine. These tissue models cannot depict the tumor microenvironment (TME) and therefore research addressing tumor cell-TME interactions is limited. To overcome this hurdle, we applied patient-derived lung tumor samples to establish new in vitro models. To analyze the tissue model properties, we established two-dimensional (2D) and 3D co-culture tissue models exposed to static and dynamic culture conditions that afforded tissue culture for up to 28 days. Our tissue models were characterized by hematoxylin eosin staining, M30 ELISA, and immunofluorescence staining against specific lung cancer markers (TTF-1 and p40/p63), cancer associated fibroblast (CAF) markers (α-SMA and MCT4), and fibronectin (FN). The 3D models were generated with higher success rate than the corresponding 2D model. The cell density of the static 3D model increased from 21 days to 28 days whereas the apoptosis decreased. The dynamic 3D model possessed an even higher cell density than the static 3D model. We identified lung cancer cells, CAFs, and FN. Therefore, a novel in vitro 3D lung cancer model was established, which simulated the TME for 28 days and possessed a structural complexity.


Myosin light chain compositions of the interatrial and interventricular septa of sheep heart.
The myosin light chain composition of sheep interatrial and interventricular septa were analysed by one- and two-dimensional polyacrylamide gel. The interventricular septum has myosin light chain composition indistinguishable from that of ventricular myosin. Myosin from the interatrial septum contains three light chains, two of which co-migrated with the two atrial light chains (ALC1 and ALC2), while the third co-migrated with ventricular light chain 2 (VLC2). ALC1 are more abundant than ALC2 or VLC2 suggesting a mixed myosin population. Myosin with ALC1 and VLC2 light chain composition may be present, and its possible relationship with cardiac "conducting" cells is discussed.


Diabetic retinopathy and OCT angiography: clinical findings and future perspectives.
In diabetic retinopathy (DR), macular involvement can present as either macular edema or ischemia. Fluorescein angiography remains the gold standard in the evaluation of retinal vascular perfusion and diagnosis of macular ischemia. However, it is a costly, time-consuming technique, it requires venipuncture, and reports of anaphylaxis and death related to fluorescein injections have been documented, despite their rarity. Optical coherence tomography (OCT) provides a fast and non-invasive method to assess retinal structures at a microscopic level. OCT angiography permits the noninvasive study of retinal and choroid circulation via motion contrast imaging. Split-spectrum amplitude decorrelation angiography combined with OCT angiography has furthered the understanding of retinal and choroidal vascular diseases, allowing the evaluation of retinal microvasculature and identification of subsequent disorders, including DR. Previous studies using OCT angiography have demonstrated that it may demonstrate DR findings such as microaneurysms, arteriolar wall staining, retinal neovascularization, and intraretinal microvascular abnormalities. The purpose of this article is to describe and discuss different concepts regarding OCT angiography, as well as its role in the diagnosis of DR and maculopathy.


Apical pressures generated by several canal irrigation methods: A laboratory study in a maxillary central incisor with an open apex.
A laboratory study to determine the apical pressure generated by seven canal irrigation methods in an anterior tooth with an open apex. Canal irrigation was performed on a 3D-printed central maxillary incisor with an open apex (maximum diameter of 2.1 mm). Ultrasonically activated irrigation (UAI), sonic activation (EDDY), negative pressure irrigation (EndoVac), the self-adjusting file (SAF) and the XP-endo Finisher were employed at tooth length (TL), TL-1 mm, TL-2 mm and TL-3 mm. UAI was tested at three intensity levels additionally. Hydrodynamic irrigation with RinsEndo was performed in the pulp chamber, at the canal orifice, the coronal third, the middle of the canal and at TL. Er:YAG laser activation, at four frequency settings, was performed in the pulp chamber and at the orifice of the canal. The pressure of the fluid towards the canal terminus generated by activation was directly transferred to a pressure sensor with a range of 0 to 120 mmHg and a response time of ≤0.5 ms. The critical threshold for apical extrusion of the irrigant was set at 5.73 mmHg (lower limit of the central venous pressure: 5.88 ± 0.15 mmHg). Each experiment was repeated ten times. The tests were followed by descriptive analyses (maximum, mean, standard deviation, 95% confidence interval). EndoVac, the SAF, the XP-endo Finisher, and UAI never exceeded the critical threshold at any insertion depth or intensity level. Er:YAG laser activation exceeded the critical threshold exclusively at frequency settings that varied from the manufacturer's recommendation. EDDY at TL and RinsEndo at any insertion depth exceeded the critical threshold in 100% of the measurements. EDDY at TL-1,-2, and-3 mm crossed the critical threshold in 30%, 10%, and 20% of the measurements, respectively. In a simulated maxillary central incisor with an open apex, irrigation with EndoVac, Er:YAG laser activation, UAI, the SAF, and the XP-endo Finisher generated apical pressures below the critical threshold of 5.73 mmHg. By contrast, using EDDY and RinsEndo for irrigation produced higher apical pressures that exceeded the critical threshold.


Variations in seasonal phytoplankton assemblages as a response to environmental changes in the surface waters of a hypo saline coastal station along the Bhagirathi-Hooghly estuary.
Due to the close proximity of the Bay of Bengal and the freshwater inflow of Bhagirathi-Hooghly, Diamond Harbour appeared as an important coastal station of the Bhagirathi-Hooghly estuary. The spatial and temporal composition and abundance of microphytoplankton species was examined in relation to physical and chemical surface water variables (i.e., salinity, nutrient, and temperature).The primary objective of the study was to observe the variations in phytoplankton species assemblages as a response to environmental variables. Hierarchical cluster analysis and non-metric multidimensional scaling were used to find out distinct seasonal groups based on the composition of phytoplankton. The results indicate that several key environmental factors like temperature, DIN content, and molar ratio of nutrients like DIN-DIP and DIN-DSi influenced seasonal phytoplankton assemblages within the estuary. The distribution of phytoplankton population showed two main groups where the blue-green and green algal populations favored the warmer conditions of summer and monsoon months, whereas the diatom population primarily flourished in the cooler months of autumn and winter.


Primary malignant melanoma of rectum: A rare case report.
Malignant melanoma of the gastrointestinal tract is an extremely rare event of which 50 % occurs in anorectal region. The lesion can easily be misdiagnosed as rectal-carcinoma, which comprises >90 % of rectal tumors and has a different treatment. The behavior of the anorectal melanoma is very aggressive and has very poor prognosis with fatal outcome. A 48-year-old man presented complaining of rectal bleeding of two months' duration, without any other significant history. Colonoscopy showed a polypoidal mass in the rectum that was in favor of adenocarcinoma. The microscope examination of biopsy tissue showed sheets of poorly differentiated malignant neoplasm. Immuno-histochemical (IHC) staining showed negativity of pan Cytokeratin and CD31. IHC for HMB45 showed diffuse and strong positivity in neoplastic cells, confirming the diagnosis of malignant melanoma. According to a report by the National Cancer Database of the United States, primary rectal melanoma is very rare. Mucosal surface of the body is third most common site for primary melanoma after skin and eye. The first case of anorectal melanoma was reported in 1857. Histopathological examinations are gold standard for diagnosis, but histopathology examination without immunohistochemistry will misdiagnose some cases as poorly differentiated adenocarcinoma which has completely different treatment. Surgical resection has been reported as the most useful treatment option. Malignant melanoma of the rectum is extremely rare and difficult to diagnose in low resources settings. Histopathologic examination with IHC stains can differentiate poorly differentiated adenocarcinoma from melanoma and other rare tumors of anorectal region.


Diagnostic performance of intraoperative cone beam computed tomography compared with postoperative magnetic resonance imaging for detecting hemorrhagic transformation after endovascular treatment following large vessel occlusion.
Early detection of hemorrhagic transformation (HT) in patients with large vessel occlusion (LVO) after endovascular treatment is important for postoperative patient management. We investigated the diagnostic performance of intraoperative cone beam computed tomography (CBCT) with reference standard magnetic resonance imaging (MRI) for detecting HT. Consecutive patients with LVO treated by endovascular treatment who underwent intraoperative CBCT and postoperative MRI were included. Two observers evaluated all images for the presence of HT. Sensitivity and specificity for detecting HT were calculated with MRI as reference standard. The observers classified HT according to the European Cooperative Acute Stroke Study (ECASS). Inter-method and inter-rater agreement for the detection of HT and for the ECASS classification were assessed using kappa or weighted Brennan-Prediger (wBP) statistics. Images of 106 procedures (94 for anterior circulation) were analyzed. The sensitivity and specificity for detecting HT on CBCT were 0.77 and 0.83, respectively, for all procedures and 0.83 and 0.8, respectively, for anterior circulation. The inter-method agreement for HT detection (κ = 0.63 overall, κ = 0.69 anterior circulation) and ECASS classification (wBP = 0.67 overall, wBP = 0.77 anterior circulation) were substantial. The inter-rater agreement for HT detection (κ = 0.87 overall, κ = 0.85 anterior circulation) and for ECASS classification (wBP = 0.95 overall, wBP = 0.92 anterior circulation) were almost perfect. The diagnostic performance of CBCT for the detection of HT in stroke patients treated for LVO was acceptable with excellent inter-rater agreement. Intraoperative CBCT may be useful to trigger early interventions if HT is detected, although detailed classifications of HT may be difficult.


Effect of adhesive strategy of universal adhesives in noncarious cervical lesions - an updated systematic review and meta-analysis.
To determine the effect of adhesive strategy (total etch or self-etch) of universal adhesives in non-carious cervical lesions. A search was made in PubMed, Scopus, Cochrane, Web Of Science, Open Gray, Clinical Registries. Randomized Controlled Clinical Trials, studies on non-carious cervical lesions restored using Universal Adhesives, and studies in which universal adhesives have been used in total etch and self -etch strategies were included in this systematic review. A total of 17 articles were included in the systematic review and 13 in the meta-analysis. Meta-analysis was conducted to assess the clinical performance of NCCLs in terms of retention, marginal adaptation, marginal discoloration, secondary caries and post-operative sensitivity at 18, 24, 36 month follow-up using USPHS as well as FDI criteria, separately. Overall there was no significant difference between total etch and self etch adhesive strategies for any of the five outcome measures using either the FDI or the USPHS criteria. p > 0.05, 95% CI, I2 value of 0%. A strongly suspected publication bias in the retention domain was seen at 18 month follow up under FDI criteria. Most universal adhesives show acceptable clinical performance. There is no significant effect of the adhesive strategy of universal adhesives on their clinical performance according to the results of our meta-analysis.


(Z)-1-(3-Mesityl-3-methyl-cyclo-but-yl)-2-(morpholin-4-yl)ethanone oxime.
In the title compound, C(20)H(30)N(2)O(2), the cyclo-butane ring is puckered, with a dihedral angle of 19.60 (13)° between the two planes. In the crystal, the mol-ecules are linked by inter-molecular O-H⋯N and weak C-H⋯O hydrogen bonds, as well as a C-H⋯π hydrogen-bonding association.


Long-term results of the metal-cancellous cementless Lübeck total hip arthroplasty: a critical review at 12.8 years.
The influence of a spongy metal surface total hip arthroplasty (THA) (S&G, ESKA, Lübeck, Germany) on the clinical, psychometric, and radiograhic long-term results were examined. An amount of 137 THA with the cementless spongy metal Lübeck hip prosthesis were evaluated long-term, radiographically and clinically, with a mean follow-up time of 12.8 years (range 10.1-14.9 years). The MOS SF-36 was used to assess the health-related quality of life (HRQL). Cumulative survival rates were 90% (+/-8%) for the cups and 86% (+/-5%) for the stems at 14.9 years. Four stems fractured at the middle part (3%) without major trauma. In the remaining patients the clinical results expressed as Harris Hip Score (HHS) averaged 88 (range 34-100). Patients above 60 years undergoing THA had no significant difference in HRQL (MOS SF-36) in comparison to the age-matched healthy population (P>0.05). Patients younger than 60 years had scores lower than normal in the physical function domains (P<0.01), but were comparable in the mental health domains (P>0.05). Radiolucent lines and bone atrophy related to stress shielding by distal fixation were found in the periprosthetic Gruen Zone I (19.8, 16.8%) and VII (10.3, 27.1%) of the proximal femur. Whereas the rate of aseptic cup failures of the cementless spongy metal Lübeck hip prosthesis is among the best, the failure rate of the stems is attributable to osteolysis of the proximal femur. The fractures of the stem may be attributed to the combination of the lack of proximal support, the fully porous stem made of a cast cobalt-chrome-molybdenum alloy, and the narrow dimension of the stem core. The long-term results of the spongy metal cup are good, whereas the high loosening and fracture rate of fully coated stem are a source of concern especially with regard to the difficult revision scenario with frequent massive bone loss.


Intraoperative administration of systemic/epidural/intrathecal morphine on the quality of recovery following substitutional urethroplasty with buccal mucosal graft: A randomized control trial.
Substitutional urethroplasty with buccal mucosal grafting for urethral stricture is associated with significant pain, and thus inappropriate perioperative pain management could delay postoperative recovery. The objective of our research was to determine the effects of analgesia with systemic or epidural or intrathecal morphine on quality of recovery (QoR) in patients undergoing substitutional urethroplasty with buccal mucosal grafting. This prospective, double-blinded, randomized control trial was conducted over 2 years in ASA I and II patients who underwent substitutional urethroplasty with buccal mucosal graft. Patients were randomized into three groups, and Group A received systemic morphine (0.1 mg/kg), Group B received epidural morphine (3 mg), and Group C received intrathecal morphine (150 μg). The QoR between the groups were compared postoperatively using the 40-item QoR questionnaire, and the hemodynamic variations, time taken for ambulation, resumption of oral intake, and incidence of complications were also compared. Out of the recruited 93 patients, 88 patients were analyzed. The QoR score for each domain was comparable between the three groups. The total QoR score for systemic, epidural, and intrathecal morphine groups were 189 (185-191), 189 (187-191), and 185 (183-189), respectively. Additionally, the hemodynamic variations, time taken for ambulation, and resumption of oral intake were comparable between all three groups except the incidence of postoperative nausea and vomiting (PONV) and pruritis, which were higher in the intrathecal group. All three modalities, namely systemic morphine (0.1 mg/kg), epidural morphine (3 mg), and intrathecal morphine (150 μg), offer similar QoR after substitutional urethroplasty. However, the incidence of PONV and pruritis was higher with the administration of intrathecal morphine.


Long-term follow-up of infants and children treated with extracorporeal membrane oxygenation (ECMO): a preliminary report.
Extracorporeal Membrane Oxygenation (ECMO) has been used clinically as a life-saving treatment modality in infants and children who are dying of respiratory insufficiency. From 1973 to 1980 47 children less than 10 years of age were treated in a study to determine the feasibility and effectiveness of ECMO in the pediatric population. Despite a predicted mortality of 90% or greater, 24 patients survived. Eighteen of those patients have been seen in long-term follow-up. Thirteen patients (72%) demonstrate basically normal growth and development. Five patients (28%) have definite handicaps which are severe in two. Despite ligation of one common carotid artery and systemic heparinization, the risk of intracranial hemorrhage and/or neurodevelopmental problems appears to be no higher in this ECMO group and may even be lower than in the high-risk population treated with conventional therapy. The incidence of chronic respiratory problems, especially bronchopulmonary dysplasia, is zero in this group of patients. Only one patient (4%) has a defect that lateralizes to the right hemisphere which may have been affected by ligation of the carotid artery. Further study is required; however, it appears that ECMO offers life-saving intervention without increasing morbidity in select children with severe respiratory insufficiency.


ANALYSIS OF THE GENETIC STRUCTURE OF LIFE HISTORY OF DROSOPHILA MELANOGASTER USING RECOMBINANT EXTRACTED LINES.
A model for the evolution of senescence known as "antagonistic pleiotropy" makes the specific prediction that there should be a negative genetic correlation between early- and late-age traits associated with fitness. This model has previously been tested by classical quantitative-genetic means including sib-analysis and artificial selection. We used the approach of chromosome extraction, which has both advantages and disadvantages compared to classical techniques, to test the model further. From four isogenic lines of Drosophila melanogaster, four sets of recombinant extracted lines were constructed using standard balancer-chromosome techniques. The four parental lines and 53 recombinants were reared under controlled laboratory conditions and isolated as pairs for scoring daily fecundity and longevity. Even though the design is not optimal for estimating classical components of genetic variance, it afforded a uniquely direct test of the magnitude of environmental covariances, while giving a detailed genetic picture of part of the genome. There were clear differences among the recombinant series in the distribution of mean longevity and early fecundity. The genetic correlation between early fecundity (sum of egg production for the first five days posteclosion) and female longevity was significantly negative in only one of the recombinant series. When all lines were considered together, the phenotypic correlation between these traits was significantly negative (P < 0.02), while the broad-sense genetic correlation was -0.219 (P < 0.11). This result may be viewed as weakly consistent with the model of antagonistic pleiotropy, but other aspects of the data are at odds with the model.


Comparison of Road Traffic Noise prediction models: CNOSSOS-EU, Nord2000 and TRANEX.
Road traffic noise is the most pervasive source of ambient outdoor noise pollution in Europe. Traffic noise prediction models vary in parameterisation and therefore may produce different estimates of noise levels depending on the geographical setting in terms of emissions sources and propagation field. This paper compares three such models: the European standard, Common Noise Assessment Methods for the EU Member States (hereafter, CNOSSOS), Nord2000 and Traffic Noise Exposure (TRANEX) model based on the UK methodology, in terms of their source and propagation characteristics. The tools are also compared by analysing estimated noise (LAeq) from CNOSSOS, Nord2000 (2006 version), and TRANEX for more than one hundred test cases (N = 111) covering a variety of source and receiver configurations (e.g. varying source to receiver distance). The main aim of this approach was to investigate the potential pattern in differences between models' performance for certain types of configurations. Discrepancies in performance may thus be linked to the differences in parameterisations of the CNOSSOS, Nord2000, and TRANEX (e.g. handling of diffraction, refraction). In most cases, both CNOSSOS and TRANEX reproduced LAeq levels of Nord2000 (2006 version) within three to five dBA (CNOSSOS: 87%, TRANEX: 94%). The differences in LAeq levels of CNOSSOS, compared to Nord2000, can be related to several shortcomings of the existing CNOSSOS algorithms (e.g. ground attenuation, multiple diffractions, and mean ground plane). The analyses show that more research is required in order to improve CNOSSOS for its implementation in the EU. In this context, amendments for CNOSSOS proposed by an EU Working Group hold significant potential. Overall, both CNOSSOS and TRANEX produced similar results, with TRANEX reproducing Nord2000 LAeq values slightly better than the CNOSSOS. The lack of measured noise data highlights one of the significant limitations of this study and needs to be addressed in future work.


Improving the feasibility of aquaculture feed by using microalgae.
The aquaculture industry is an efficient edible protein producer and grows faster than any other food sector. Therefore, it requires enormous amounts of fish feed. Fish feed directly affects the quality of produced fish, potential health benefits, and cost. Fish meal (FM), fis oil (FO), and plant-based supplements, predominantly used in fish feed, face challenges of low availability, low nutritional value, and high cost. The cost associated with aquaculture feed represents 40-75% of aquaculture production cost and one of the key market drivers for the thriving aquaculture industry. Microalgae are a primary producer in aquatic food chains. Microalgae are expanding continuously in renewable energy, pharmaceutical pigment, wastewater treatment, food, and feed industries. Major components of microalgal biomass are proteins with essential amino acids, lipids with polyunsaturated fatty acids (PUFA), carbohydrates, pigments, and other bioactive compounds. Thus, microalgae can be used as an essential, viable, and alternative feed ingredient in aquaculture feed. In recent times, live algae culture, whole algae, and lipid-extracted algae (LEA) have been tested in fish feed for growth, physiological activity, and nutritional value. The present review discusses the potential application of microalgae in aquaculture feed, its mode of application, nutritional value, and possible replacement of conventional feed ingredients, and disadvantages of plant-based feed. The review also focuses on integrated processes such as algae cultivation in aquaculture wastewater, aquaponics systems, challenges, and future prospects of using microalgae in the aquafeed industry.


Larvicidal efficacy of Jatropha curcas and bacterial insecticide, Bacillus thuringiensis, against lymphatic filarial vector, Culex quinquefasciatus Say (Diptera: Culicidae).
The present study explored the effects of Jatropha curcas leaf extract and Bacillus thuringiensis israelensis larvicidal activity against the lymphatic filarial vector, Culex quinquefasciatus. Wights were selected for investigating the larvicidal potential against the first to fourth instar larvae of the laboratory-reared mosquito species, C. quinquefasciatus Say, in which the major lymphatic filariasis was used. The medicinal plants were collected from the area around Bharathiar University, Coimbatore. The dried plant materials were powdered by an electric blender. From the powder, 100 g of the plant materials was extracted with 300 ml of organic solvents of methanol for 8 h, using a Soxhlet apparatus, and filtered. The crude plant extracts were evaporated to dryness in a rotary vacuum evaporator. The plant extract showed larvicidal effects after 24 h of exposure; however, the highest larval mortality was found in the leaf extract of methanol J. curcas against the first to fourth instar larvae of values LC(50) = 1.200%, 1.290%, 1.358%, and 1.448% and LC(90) = 2.094%, 2.323%, 2.444%, and 2.544% and B. thuringiensis israelensis against the first to fourth instar larvae of values LC(50) = 9.332%, 9.832%, 10.212%, 10.622% and LC(90) = 15.225%, 15.508%, 15.887%, and 15.986% larvae of C. quinquefasciatus, respectively. No mortality was observed in the control. These results suggest methanol extracts of J. curcas and B. thuringiensis israelensis have potential to be used as an ideal eco-friendly approach for the control of the major lymphatic filarial vector, C. quinquefasciatus.


Thermosensitive chitosan-Pluronic hydrogel as an injectable cell delivery carrier for cartilage regeneration.
Injectable hydrogels have been studied for potential applications for articular cartilage regeneration. In this study, a thermosensitive chitosan-Pluronic (CP) hydrogel was designed as an injectable cell delivery carrier for cartilage regeneration. The CP conjugate was synthesized by grafting Pluronic onto chitosan using EDC/NHS chemistry. The sol-gel phase transition and mechanical properties of the CP hydrogel were examined by rheological experiments. The CP solution underwent a sol-gel transition around 25 degrees C at which the storage modulus (G') approaches 10(4)Pa, highlighting the potential of this material as an injectable scaffold for cartilage regeneration. The CP hydrogel was formed rapidly by increasing the temperature. The morphology of the dried CP hydrogel was observed by scanning electron microscopy. In vitro cell culture was performed using bovine chondrocytes. The proliferation of bovine chondrocytes and the amount of synthesized glycosaminoglycan increased for 28 days. These results suggested that the CP hydrogel has potential as an injectable cell delivery carrier for cartilage regeneration and could serve as a new biomaterial for tissue engineering.


Disparities in colonoscopy utilization for lower gastrointestinal bleeding in rural vs urban settings in the United States.
Lower gastrointestinal bleeds (LGIB) is a very common inpatient condition in the United States. Gastrointestinal bleeds have a variety of presentations, from minor bleeding to severe hemorrhage and shock. Although previous studies investigated the efficacy of colonoscopy in hospitalized patients with LGIB, there is limited research that discusses disparities in colonoscopy utilization in patients with LGIB in urban and rural settings. To investigate the difference in utilization of colonoscopy in lower gastrointestinal bleeding between patients hospitalized in urban and rural hospitals. This is a retrospective cohort study of 157748 patients using National Inpatient Sample data and the Healthcare Cost and Utilization Project provided by the Agency for Healthcare Research and Quality. It includes patients 18 years and older hospitalized with LGIB admitted between 2010 and 2016. This study does not differentiate between acute and chronic LGIB and both are included in this study. The primary outcome measure of this study was the utilization of colonoscopy among patients in rural and urban hospitals admitted for lower gastrointestinal bleeds; the secondary outcome measures were in-hospital mortality, length of stay, and costs involved in those receiving colonoscopy for LGIB. Statistical analyses were all performed using STATA software. Logistic regression was used to analyze the utilization of colonoscopy and mortality, and a generalized linear model was used to analyze the length of stay and cost. Our study found that 37.9% of LGIB patients at rural hospitals compared to approximately 45.1% at urban hospitals received colonoscopy, (OR = 0.730, 95%CI: 0.705-0.7, P > 0.0001). After controlling for covariates, colonoscopies were found to have a protective association with lower in-hospital mortality (OR = 0.498, 95%CI: 0.446-0.557, P < 0.0001), but a longer length of stay by 0.72 d (95%CI: 0.677-0.759 d, P < 0.0001) and approximately $2199 in increased costs. Although there was a lower percentage of LGIB patients that received colonoscopies in rural hospitals compared to urban hospitals, patients in both urban and rural hospitals with LGIB undergoing colonoscopy had decreased in-hospital mortality. In both settings, benefit came at a cost of extended stay, and higher total costs.


[Systematic review on the safety of concomitant use of hypoglycemia-inducing drugs and non-steroidal anti-inflammatory drugs in patients with musculoskeletal pathology].
To analyze the safety of combining nonsteroidal anti-inflammatory drugs (NSAID) and hypoglycemia-inducing drugs. A systematic review following a sensitive search strategy was performed. All articles published in MEDLINE (since 1961), EMBASE (since 1961), and Cochrane Library, up to December 2007, were examined. the population (subjects taking hypoglycemia-inducing drugs: insulin or oral antidiabetic drugs [OAD]), the intervention (concomitantly use of NSAID), and the outcomes related to safety (gastrointestinal, renal, cardiovascular toxicity) and glycemic control. Titles and abstracts of retrieved articles meeting inclusion criteria from the search were reviewed. Only randomized controlled trials (RCT), or cohort studies were included. A total of 33 studies were reviewed in detail, and 11 were finally included, 10 low quality RCT, and 1 prospective cohort study with moderate quality, which included 199 patients. All patients were diabetics; mostly young or middle aged men, on different NSAID and hypoglycemic drugs. There was no evidence of important changes in patient's glycemic controls, nor in their renal function, when combining NSAID with hypoglycemiainducing drugs. Moreover, there is no clear increase in the number of serious side effects. According to the published evidence, there are not enough arguments to contraindicate the use of NSAID with hypoglycemia-inducing drugs (insulin or OAD).


Role of tissue plasminogen activator and plasminogen activator inhibitor polymorphism in myocardial infarction.
A case-control association study on 229 Myocardial Infarction (MI) patients and 217 healthy controls was carried out to determine the role of tissue-plasminogen activator (t-PA) (Alu-repeat insertion (I)/deletion (D)) and plasminogen activator inhibitor (PAI-1) (4G/5G insertion/deletion) polymorphisms with MI in the Pakistani population. In MI patients the genotype distribution of the PAI-1 gene was not found to be different when compared with the unaffected controls (P>0.05, χ2=1.03). The risk allele 4G was also not associated with MI (P>0.05, χ2=0.46, odds ratio (OR)=1.1 (95% confidence interval (CI)=0.84-1.43), P>0.05). Similarly, the genotype frequencies of t-PA I/I, I/D and D/D were not different from the unaffected controls (P>0.05, χ2=1.60), and the risk allele "I" was not found to be associated with MI (P>0.05, χ2=1.35, OR=0.86 (95% CI=0.66-1.11), P>0.05). However, when the data were distributed along the lines of gender a significant association of the 4G/4G PAI-1 genotype was observed with only the female MI patients (P<0.05, z-test=2.21). When the combined genotypes of both the polymorphisms were analyzed, a significant association of MI was observed with the homozygous DD/4G4G genotype (P<0.01, z-test=2.61), which was specifically because of the female samples (P=0.01, z-test=2.53). In addition smoking (P<0.001, χ2=13.52, OR=3.45 (95% CI=1.77-6.94)), diabetes (P<0.001, χ2=22.45, OR=8.89 (95% CI=2.96-29.95)), hypertension (OR=7.76 (95% CI=2.88-22.68), P<0.001) family history (P<0.001, χ2=13.72, OR=3.7 (95% CI=1.71-8.18)) and lower HDL levels (P<0.05) were found to be significantly associated with the disease. In conclusion the PAI-1 gene polymorphism was found to have a gender specific role in the female MI patients.


Ultrastructural markers of tissue endometrial receptivity in patients with recurrent implantation failure.
The scanning electron microscopy of the endometrial surface epithelium during the 'implantation window' was performed in 119 patients with uterine factor of infertility or recurrent miscarriage due to endometrial hypoplasia. Ultramorphological picture of the surface endometrial epithelium was characterized by aplasia and hypoplasia of pinopodes (67.39%), dense cell - cell contacts (69.53%), heteromorphy of secretory cells (15.22%) in combination with atypia of microenvironment cells (50%) in patients with infertility. The asynchronous development of pinopodes (46.67%) and the absence of intercellular contacts separation during the 'implantation window' (84.44%) was observed in patients with recurrent miscarriage. The revealed disturbance determines the mechanisms of the blastocyst adhesion violation and trophoblast invasion in the different stages of implantation in patients with uterine factor of infertility and recurrent miscarriage.


Pain Behaviors and Pharmacological Pain Management Among Newly Admitted Nursing Home Residents.
Clinicians may place more weight on vocal complaints of pain than the other pain behaviors when making decisions about pain management. We examined the association between documented pain behaviors and pharmacological pain management among nursing home residents. We included 447,684 residents unable to self-report pain, with staff-documented pain behaviors (vocal, nonverbal, facial expressions, protective behaviors) and pharmacological pain management documented on the 2010-2016 Minimum Data Set 3.0. The outcome was no pharmacological pain medications, as needed only (pro re nata [PRN]), as scheduled only, or as scheduled with PRN medications. We estimated adjusted odds ratios and 95% confidence intervals from multinomial logistic models. Relative to residents with vocal complaints only, those with one pain behavior documented (i.e., nonverbal, facial, or protective behavior) were more likely to lack pain medication versus scheduled and PRN medications. Residents with multiple pain behaviors documented were least likely to have no treatment relative to scheduled with PRN medications, PRN only, or scheduled only pain medication regimens. The type and number of pain behaviors observed are associated with pharmacological pain management regimen. Improving staff recognition of pain among residents unable to self-report is warranted in nursing homes.


A meta-analysis of the relationship between psychosis and any type of criminal offending, in both men and women.
Psychosis is known to be associated with an increased risk of violent offending, but the risk of criminal offending of any type is not so well understood, including the nature and extent of any differences in offending risk for men and women with psychosis. A systematic search of electronic databases from 1970 to March 2020 was conducted to identify studies comparing criminal offending amongst those with psychosis to a general population sample. A meta-analysis was performed, with separate analyses undertaken for men and women. Eight studies, with a total of 15,446 individuals with psychosis and 186,752 controls from general population sources, met our inclusion criteria. The pooled odds ratio for any type of criminal offending for men with psychosis was 2.42 (95% CI = 1.63-3.59), and for women it was 2.81 (95% CI = 2.11-3.76). Substantial between study heterogeneity was identified. Although the pooled odds ratio for all types of offending was not as high as has been found for violence, those with psychotic illness were more than twice as likely to have had contact with the criminal justice system for any type of criminal offence, compared to the general population. Little difference in risk was seen for women compared to men with psychosis. Clinical risk assessments and the development of interventions to reduce risk of contact with the criminal justice system should consider that risk of offending for those with psychosis extends right across the spectrum of offence types.


Visible light photoredox-catalyzed deoxygenation of alcohols.
Carbon-oxygen single bonds are ubiquitous in natural products whereas efficient methods for their reductive defunctionalization are rare. In this work an environmentally benign protocol for the activation of carbon-oxygen single bonds of alcohols towards a reductive bond cleavage under visible light photocatalysis was developed. Alcohols were activated as 3,5-bis(trifluoromethyl)-substituted benzoates and irradiation with blue light in the presence of [Ir(ppy)2(dtb-bpy)](PF6) as visible light photocatalyst and Hünig's base as sacrificial electron donor in an acetonitrile/water mixture generally gave good to excellent yields of the desired defunctionalized compounds. Functional group tolerance is high but the protocol developed is limited to benzylic, α-carbonyl, and α-cyanoalcohols; with other alcohols a slow partial C-F bond reduction in the 3,5-bis(trifluoromethyl)benzoate moiety occurs.


Objective and subjective childhood socioeconomic disadvantage and incident depression in adulthood: a longitudinal analysis in the Sister Study.
Understanding of the role of objective versus subjective childhood socioeconomic disadvantage (SD) in depression onset in adulthood among women, independent of later life SD, and across birth cohorts, is limited. We examined the association between objective (i.e., household education level) and subjective (i.e., rank of family income and report of not enough food to eat) SD during childhood and diagnosis of clinical depression after age 30 among 47,055 women in the Sister Study. We used Cox proportional hazard models adjusting for women's race/ethnicity, childhood household composition, mother's age at her birth adulthood educational attainment, and calendar year of birth. Analyses were repeated stratified by 10-year birth group. A total of 8036 (17.1%) women were diagnosed with clinical depression over a mean follow-up of 24.0 (± 9.9) years. Those reporting being poor (versus well-off) or not having enough food to eat in childhood had a 1.28 (95% confidence interval (CI) 1.13, 1.44) and 1.30 (95% CI 1.21, 1.41) times higher rate of depression diagnosis, respectively, with consistent associations observed across birth year groups. An inverse association between low household education level and incident depression was observed at baseline (i.e., age 30) becoming positive over time in the total sample but only among women born between 1935-1954 in analyses stratified by 10-year birth group. Our findings suggest that subjective SD in childhood is a largely consistent predictor of depression onset among women in adulthood whereas the effects of household education level in childhood may vary across women born into different birth cohorts, and for some, across the lifecourse.


Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer's Disease: Experimental and Computational Insights.
Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.


The Correlation Between the Immune and Epithelial-Mesenchymal Transition Signatures Suggests Potential Therapeutic Targets and Prognosis Prediction Approaches in Kidney Cancer.
Both epithelial-mesenchymal transition (EMT) and immune regulation are important biological process in malignant tumours. The current research aims to comprehensively explore the potential association between the epithelial-mesenchymal transition (EMT) signature and immune checkpoint signature and its role in predicting the prognosis of clear-cell renal cell carcinoma (ccRCC) patients. EMT-related genes were collected from an experiment-based study and then were investigated using data from the Cancer Genome Atlas. A total of 357 genes were included, and 23 of them that were upregulated and correlated with prognosis were analysed further as core EMT genes in ccRCC. Interestingly, the emerging immune checkpoints CD276, OX40 and TGFB1 were found to be significantly co-expressed with core EMT genes, and TGFB1, CXCR4, IL10, and IL6 were the most important molecules potentially interacting with EMT molecules in our model, as determined from mRNA co-expression and protein-protein interaction network analysis. Additionally, an integrated scoring model based on FOXM1, TIMP1 and IL6 was successfully established to distinguish ccRCC patients with different clinical risks. Our results identified core genes in the EMT-immunophenotyping correlation and evaluated their risk assessment capabilities, providing more potential therapeutic targets and prediction approaches regarding the translational research of treatment and prognosis in ccRCC.


Acute urinary retention in pediatric cerebral palsy: Is there an optimal management strategy?
Cerebral palsy (CP) patients commonly have lower urinary tract dysfunction. Urinary retention (UR), which has been associated with dysfunctional voiding in CP can correlate to chronic upper tract dysfunction. We sought to provide insight into the pediatric presentation of acute UR in patients with CP and subsequent outcomes in this at-risk population. All children with perinatally acquired CP presenting to a regional health network were identified from 2009 to 2019. Retrospective analysis of a hospitalized subset concurrently diagnosed with a first episode of acute UR was performed. Factors associated with new-onset UR are described, as well as management. Using follow-up data, we also assessed the risk for recurrent UR and/or abnormal renal imaging after an initial UR presentation. 3404 CP patients were analyzed with only 33 fulfilling inclusion criteria. Median age was 10(IQR 7.5-16; range 1-22) years, 87.9% were GMFCS-V. 39.4% had a reported history of decreased urinary frequency. At presentation, median maximal time without void prior to catheterization was 13 h, and catheterized volume was a median 120% expected capacity-for-age. 84.8% of presentations were associated with a known transient/reversible etiology. 51.5% were post-anesthesia at median 3.5 days, 33.3% had associated constipation, 30.3% had received exacerbating medications. 11/33 were taught clean intermittent catheterization (CIC) after the initial presentation (all pro re nata [PRN] except one). At a median follow-up of 37 months: 50% of those without a CIC PRN no void plan had a repeat episode, at a median of 10.8 months later. Of the patients who had follow-up renal imaging at a median 22.0 months after presentation, 45% had abnormalities: 7 with debris or suspected stones and 2 with collecting system dilation. No factors associated with the initial UR presentation were found to be significantly predictive of recurrence or abnormal follow-up imaging. Patients with CP presenting with acute UR are often those with the most severe limitations and have a history of decreased urinary frequency. They usually have transient or reversible factors associated with UR presentation, however UR recurrence and abnormal imaging in this population subset is common. Pediatric patients with CP who present with acute UR usually present in the context of recent anesthesia and in the setting of exacerbating factors. They are at risk for recurrence and may be best managed with caretaker education of CIC PRN no void to address recurrent episodes. Providers should consider surveillance of these patients for the development of abnormal renal imaging.


Superiority of the triple combination of bortezomib, cyclophosphamide and dexamethasone versus cyclophosphamide, thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma, eligible for transplantation.
The treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. We retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. We retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p=0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. Our results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.


Rationale and staff evaluation of using a "therapeutic milieu" for substance users within a tuberculosis ward.
Approximately 30% of tuberculosis (TB) patients in Israel were treated, in part, in two dedicated hospital wards during the years 2003-2005. A portion of them manifested severe psychosocial conditions. An intervention based on the "Therapeutic Milieu" (TM) model was implemented in the larger ward and included a staff evaluation of this intervention. The concept of TM, based on psychosocial paradigms and behavioral medicine, is aimed at providing a supportive environment for patients. Weekly group patients' meetings and monthly group staff supervisions were performed during 15 months (2003-2005). Forty of the 196 (20%) TB patients, mainly "complex," and 13 of 20 staff members (65%) attended regularly and discussed how to deal with substance abuse, personality disorders, and immigration-related crises. Out of 40 TB cases, 30 (75%) were also substance users. Ten staff members self-analyzed the impact of this intervention in terms of (1) having given adequate tools for the staff, (2) reducing physical violence, (3) increasing adherence to TB treatment, and (4) more efficient treatment for their substance use. No direct evaluation was done among the TB patients. According to staff members, this intervention had a positive overall impact. However, using Therapeutic Milieu in TB ward hospitalization, as a "window of opportunity," remains the first step in a longer journey for rehabilitation. The study's limitations are noted.


Detective work in drug-induced liver injury: sometimes it is all about interviewing the right witness.
Diagnosing drug-induced liver injury (DILI) relies primarily on history taking. We report 4 cases in which DILI was missed or the drug was misidentified when physicians relied solely on patient history. We reviewed 27 cases referred with possible DILI from August 1, 2009, to February 1, 2010. Four patients seemed to be reliable historians, but their cases were greatly clarified by a call to their pharmacist. One subject, who forgot a new medication, underwent an unfruitful evaluation including surgery. Another patient had acetaminophen toxicity that was missed because she grossly underreported her pain medication use. The third and fourth patients forgot taking amoxicillin/clavulanate, so other agents mistakenly were implicated. Roussel Uclaf Causality Assessment Method scores were 8 (probable) or 9 (highly probable) for all 4 cases. Without pharmacy input, DILI was missed in 2 cases and the wrong agent was implicated twice. Reviewing pharmacy records can be crucial for patients and DILI research. We recommend calling the pharmacist directly for increased liver enzyme levels of unclear source or suspected DILI regardless of patient history.


Subsecond regulation of striatal dopamine release by pre-synaptic KATP channels.
ATP-sensitive K(+) (K(ATP)) channels are composed of pore-forming subunits, typically Kir6.2 in neurons, and regulatory sulfonylurea receptor subunits. In dorsal striatum, activity-dependent H(2)O(2) produced from glutamate receptor activation inhibits dopamine release via K(ATP) channels. Sources of modulatory H(2)O(2) include striatal medium spiny neurons, but not dopaminergic axons. Using fast-scan cyclic voltammetry in guinea-pig striatal slices and immunohistochemistry, we determined the time window for H(2)O(2)/K(ATP)-channel-mediated inhibition and assessed whether modulatory K(ATP) channels are on dopaminergic axons. Comparison of paired-pulse suppression of dopamine release in the absence and presence of glibenclamide, a K(ATP)-channel blocker, or mercaptosuccinate, a glutathione peroxidase inhibitor that enhances endogenous H(2)O(2) levels, revealed a time window for inhibition of 500-1000 ms after stimulation. Immunohistochemistry demonstrated localization of Kir6.2 K(ATP)-channel subunits on dopaminergic axons. Consistent with the presence of functional K(ATP) channels on dopaminergic axons, K(ATP)-channel openers, diazoxide and cromakalim, suppressed single-pulse evoked dopamine release. Although cholinergic interneurons that tonically regulate dopamine release also express K(ATP) channels, diazoxide did not induce the enhanced frequency responsiveness of dopamine release seen with nicotinic-receptor blockade. Together, these studies reveal subsecond regulation of striatal dopamine release by endogenous H(2)O(2) acting at K(ATP) channels on dopaminergic axons, including a role in paired-pulse suppression.


Mn-containing bioceramics inhibit osteoclastogenesis and promote osteoporotic bone regeneration via scavenging ROS.
Osteoporosis is caused by an osteoclast activation mechanism. People suffering from osteoporosis are prone to bone defects. Increasing evidence indicates that scavenging reactive oxygen species (ROS) can inhibit receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis. It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects. Previous studies have shown that manganese (Mn) can improve bone regeneration, and Mn supplementation may treat osteoporosis. However, the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear. In present research, a model bioceramic, Mn-contained β-tricalcium phosphate (Mn-TCP) was prepared by introducing Mn into β-TCP. The introduction of Mn into β-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals, demonstrating that Mn-TCP bioceramics might have antioxidant properties. The in vitro and in vivo findings revealed that Mn2+ ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts, promote the differentiation of osteoblasts, and accelerate bone regeneration under osteoporotic conditions in vivo. Mechanistically, Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation. These results suggest that Mn-containing bioceramics with osteoconductivity, ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.