Disability in amyotrophic lateral sclerosis compared with traumatic brain injury using the World Health Organization Disability Assessment Schedule 2.0 and the International Classification of Functioning minimal generic set.
We compared the functioning of two neurological patient groups, amyotrophic lateral sclerosis (ALS) and traumatic brain injury (TBI), using brief and validated International Classification of Functioning (ICF)-based tools. A 12-item World Health Organization Disability Assessment Schedule (WHODAS 2.0) questionnaire was mailed to ALS and TBI patients and their significant others 2 weeks before their appointment at an outpatient clinic of a university hospital. In addition, a neurologist filled in the ICF minimal generic set. Two years after diagnosis, no significant differences between the two diagnosis groups were found in overall functioning or in working ability using either patient or proxy WHODAS or physician-rated minimal generic set. In single items, however, clear differences were found. Patients and significant others rated household activities, mobility, and self-care as more impaired in the group with ALS, and learning, concentrating, and maintaining friendships in the group with TBI. There were no differences between the two diagnosis groups in the WHODAS items emotional functions, engaging in community, relating with strangers, or in working ability. Both brief ICF-based generic scales, WHODAS and the ICF generic set, could show differences between these patient groups with severe disability. The results of this study should promote assessment of disability with WHODAS 2.0 in ALS and TBI.


Toll-like Receptor 4 (TLR4) is Associated with Cerebral Vasospasm and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.
In the present prospective study, the Toll-like receptor 4 (TLR4) levels on peripheral blood mononuclear cells (PBMCs) were investigated in 30 patients with aneurysmal subarachnoid hemorrhage (aSAH) and in 20 healthy controls (HCs). The relationship between TLR4 levels and the occurrence of cerebral vasospasm (CVS) was also analyzed. TLR4 expression level on cell surface of PBMCs on days 1, 3, and 7 after admission was determined by flow cytometry. Results showed that patients with aSAH presented a significantly higher TLR4 levels. For patients with Hunt-Hess grades IV-V, higher TLR4 levels were also observed; higher TLR4 levels have already been seen in patients developing CVS and/or delayed cerebral ischemia (DCI). Higher TLR4 levels were also associated with modified Fisher score, occurrence of dCVS, DCI, cerebral infarction (CT), and poor neurological functional recovery. Binary logistic regression analysis indicated that high TLR4 expression on blood monocytes was an independent predictive factor of the occurrence of dCVS, DCI, and poor neurological functional recovery. Taken together, TLR4 levels on PBMCs is significantly altered in the early stage of aSAH, especially in those patients experiencing CVS and DCI. Furthermore, higher TLR4 levels in the early stage of aSAH is also associated with the neurological function outcome. As far as we know, this is the first clinical study about TLR4's significance for patients with aSAH.


Doxepin in the management of pruritus associated with allergic cutaneous reactions.
The primary treatment of urticaria involves identification and discontinuation of the offending agent. Addition of an antihistaminic agent may then be necessary to control pruritus. Because of variable response rates between patients, several alternative agents may need to be tried before the most effective regimen is found. Based on the studies reviewed here, it appears that low-dose doxepin (10 mg po tid) is a potentially effective and well-tolerated alternative in patients who do not respond to conventional antihistamines. This success may be in part due to the more potent H1- and H2-blocking properties associated with doxepin. Data regarding the topical use of doxepin are less convincing; however, the drug appears to have some clinical use for the short-term treatment of pruritus. Doxepin cream does not appear to be as effective as systemic therapy, and adverse effects (including sedation) and drug interactions are still problematic. Topical use may be best suited to conditions involving intact skin that do not require application to large areas of the body, thereby reducing systemic absorption and adverse effects.


Calretinin-positive L5a pyramidal neurons in the development of the paralemniscal pathway in the barrel cortex.
The rodent barrel cortex has been established as an ideal model for studying the development and plasticity of a neuronal circuit. The barrel cortex consists of barrel and septa columns, which receive various input signals through distinct pathways. The lemniscal pathway transmits whisker-specific signals to homologous barrel columns, and the paralemniscal pathway transmits multi-whisker signals to both barrel and septa columns. The integration of information from both lemniscal and paralemniscal pathways in the barrel cortex is critical for precise object recognition. As the main target of the posterior medial nucleus (POm) in the paralemniscal pathway, layer 5a (L5a) pyramidal neurons are involved in both barrel and septa circuits and are considered an important site of information integration. However, information on L5a neurons is very limited. This study aims to explore the cellular features of L5a neurons and to provide a morphological basis for studying their roles in the development of the paralemniscal pathway and in information integration. 1. We found that the calcium-binding protein calretinin (CR) is dynamically expressed in L5a excitatory pyramidal neurons of the barrel cortex, and L5a neurons form a unique serrated pattern similar to the distributions of their presynaptic POm axon terminals. 2. Infraorbital nerve transection disrupts this unique alignment, indicating that it is input dependent. 3. The formation of the L5a neuronal alignment develops synchronously with barrels, which suggests that the lemniscal and paralemniscal pathways may interact with each other to regulate pattern formation and refinement in the barrel cortex. 4. CR is specifically expressed in the paralemniscal pathway, and CR deletion disrupts the unique L5a neuronal pattern, which indicates that CR may be required for the development of the paralemniscal pathway. Our results demonstrate that L5a neurons form a unique, input-dependent serrated alignment during the development of cortical barrels and that CR may play an important role in the development of the paralemniscal pathway. Our data provide a morphological basis for studying the role of L5a pyramidal neurons in information integration within the lemniscal and paralemniscal pathways.


Heritability of daytime ambulatory blood pressure in an extended twin design.
The present study estimated the genetic influences on ambulatory systolic and diastolic blood pressure, and on hypertensive status derived from ambulatory levels, in a family sample of 535 twins and 257 singleton siblings. This "extended twin design" was used to explicitly test the possibility that results obtained in singleton siblings are different from those obtained in twins. To examine the effects of excluding (medicated) hypertensive subjects, the genetic analyses were first performed under strict exclusion (medication and/or blood pressure >135/85 mm Hg), then without the medicated subjects, and, finally, without any exclusion. For the latter analysis, the untreated blood pressure values in subjects using antihypertensive medication were estimated by augmenting the observed blood pressure by the published efficacy of the specific antihypertensive medication used. No evidence was found for differential means, variances, or covariances of ambulatory blood pressure in singletons compared with twins. This indicates that estimates of heritability of ambulatory blood pressure from twin studies can be generalized to the singleton population. Heritability of hypertension, defined as a mean daytime blood pressure >135/85 mm Hg or antihypertensive medication use, was 61%. Genetic contribution to ambulatory blood pressure was highest when all subjects were included (systolic, 44% to 57%; diastolic, 46% to 63%) and lowest under strict exclusion (systolic, 32% to 50%; diastolic, 31% to 55%). We conclude that exclusion of (medicated) hypertensives removes part of the true genetic variance in ambulatory blood pressure.


Thermal [1,3] carbon sigmatropic rearrangements of vinylcyclobutanes.
Stereochemical, kinetic, and theory-based studies of the [1,3] carbon sigmatropic rearrangements of bicyclo[2.1.1]hex-2-enes, bicyclo[3.2.0]hept-2-enes, and monocyclic vinylcyclobutanes support the judgment that such reactions involve transient diradical structures traversing relatively flat potential energy surfaces.


The reciprocal effects of pain intensity and activity limitations: implications for outcomes assessment in clinical trials.
To examine the reciprocal effects of pain intensity and limitations in physical functioning over time. This study presents findings from a reanalysis of a 7-center trial conducted in Ontario, Canada, included 209 adults with chronic knee pain secondary to osteoarthritis. Patients were randomized to receive 28 days of therapy with an active solution (1.5% w/w diclofenac sodium in dimethyl sulfoxide) or 1 of 2 control solutions containing no diclofenac. The key outcome measures used in the current analyses were administered throughout the study period and assessed pain intensity, perceived activity limitations, and a composite score measuring both domains. A structural cross-lagged regression approach was used to determine the reciprocal effects of pain and activity limitations over time. In both study groups, participants (N=209) experienced significant reductions in mean pain intensity and activity limitations from baseline to weeks 1, 2, 3, and 4 (P<0.001 for both variables). Similarly, there were significant reductions in the activity limitations outcome at weeks 1 and 4 for the active versus control group (P<0.05 for both). Higher levels of perceived activity limitations predicted more future pain at all time points. Cross-lagged associations in which pain predicted subsequent perceived activity limitations were not significant at any time point. All 3 outcome measures evidenced similar responsiveness to the treatment. These analyses showed that a decrease in activity limitations results in a decrease in pain intensity. However, changes in pain intensity had no effect on subsequent activity limitations in the study sample. None of the 3 outcome variables emerged as being more responsive to treatment than the others.


Safety and efficacy of dedicated guidewire and microcatheter technology for chronic total coronary occlusion revascularization: principal results of the Asahi Intecc Chronic Total Occlusion Study.
Limited study has detailed the procedural outcomes and utilization of contemporary coronary guidewires and microcatheters designed for chronic total occlusion (CTO) percutaneous revascularization and with application of modern techniques. A prospective, multicenter, single-arm trial was conducted to evaluate procedural and in-hospital outcomes among 163 patients undergoing attempted CTO revascularization with specialized guidewires and microcatheters. The primary endpoint was defined as successful guidewire recanalization and absence of in-hospital cardiac death, myocardial infarction, or repeat target vessel revascularization (major adverse cardiac events). The prevalence of diabetes was 42.9%; prior myocardial infarction, 41.1%; and previous bypass surgery, 36.8%. Average (mean±SD) CTO length was 41±29 mm, and mean Japanese CTO score was 2.6±1.3. A guidewire support catheter was used in 91.7% of cases, and the mean number of CTO-specific guidewires per procedure was 3.1±2.9. Overall, procedural success was observed in 73.0% of patients. The rate of successful guidewire recanalization was 89.0%, and absence of in-hospital major adverse cardiac event was 81.0%. Methods included antegrade (45.4%), retrograde (5.5%) and combined antegrade/retrograde techniques (49.1%). Total mean procedure time was 119±68 min; mean radiation dose, 2613±1881 mGy; and contrast utilization, 287±142 ml. Clinically significant perforation resulting in hemodynamic instability and/or requiring intervention occurred in 13 (8.0%) patients. In this multicenter, prospective registration trial representing contemporary technique, favorable procedural success and early clinical outcomes inform technique and strategy using dedicated CTO guidewires and microcatheters in a high lesion complexity patient population.


Mosquito-fungus interactions and antifungal immunity.
The mosquito immune system has evolved in the presence of continuous encounters with fungi that range from food to foes. Herein, we review the field of mosquito-fungal interactions, providing an overview of current knowledge and topics of interest. Mosquitoes encounter fungi in their aquatic and terrestrial habitats. Mosquito larvae are exposed to fungi on plant detritus, within the water column, and at the water surface. Adult mosquitoes are exposed to fungi during indoor and outdoor resting, blood and sugar feeding, mating, and oviposition. Fungi enter the mosquito body through different routes, including ingestion and through active or passive breaches in the cuticle. Oral uptake of fungi can be beneficial to mosquitoes, as yeasts hold nutritional value and support larval development. However, ingestion of or surface contact with fungal entomopathogens leads to colonization of the mosquito with often lethal consequences to the host. The mosquito immune system recognizes fungi and mounts cellular and humoral immune responses in the hemocoel, and possibly epithelial immune responses in the gut. These responses are regulated transcriptionally through multiple signal transduction pathways. Proteolytic protease cascades provide additional regulation of antifungal immunity. Together, these immune responses provide an efficient barrier to fungal infections, which need to be overcome by entomopathogens. Therefore, fungi constitute an excellent tool to examine the molecular underpinnings of mosquito immunity and to identify novel antifungal peptides. In addition, recent advances in mycobiome analyses can now be used to examine the contribution of fungi to various mosquito traits, including vector competence.


Impact of climate change on insect-human interactions.
To update the influence of the global climate change on Hymenoptera venom allergy. Climate change facilitates biological invasions of hymenopteran species and plays a role in the impact of introduced species relevant for human health. It contributes to a rise in the incidence of sting injuries and allergy reactions across the world. Global climate change has contributed to the expansion and the redistribution of allergenic insect species, increasing the number of allergy cases caused by stinging insects worldwide. Imported insects are trending species in systemic reactions for multiple stings or hymenopteran venom allergy. They represent a threat for humans and a challenge for the allergists.


Three laboratory strains of spleen focus-forming virus: comparison of their genomes and translational products.
The molecular properties of three laboratory strains of the spleen focus-forming virus were compared. All strains contain genetic sequences related to the env gene of mink cell focus-inducing murine type C leukemia viruses, and each strain codes for a glycoprotein of 50,000 to 52,000 daltons which shares specific immunological properties with the gp70's of mink cell focus-inducing viruses. In contrast to this constancy, gag gene products coded for by these strains vary significantly. The gag and env gene products are synthesized from separate mRNA's, and the mRNA for the env gene product is approximately 18S. Unlike other acute leukemia viruses, which can transform various undifferentiated cells, have large unique sequence cellular gene inserts fused to helper virus gag genes, and have one known genome-length intracellular mRNA, the spleen focus-forming virus transforms only specific hematopoietic stem cells, is an env gene rather than a gag gene recombinant virus, and has a second distinct and smaller class of intracellular mRNA. Our data therefore indicate that the Friend strain of the spleen focus-forming virus is a unique replication-defective acute leukemia virus.


Markers of dietary protein intake are associated with successful weight loss in the POUNDS Lost trial.
To assess the association of markers for dietary protein intake, measures of dietary adherence and demographic variables with weight loss in the POUNDS Lost study over the first 6 months and again between 6 and 24 months using data from those who completed each period. This is a secondary analysis of pooled data on completers assigned to one of four diets: 65%C/15%P/20%F (AP/LF), 55%C/25%P/20%F (HP/LF), 45%C/15%P/40%F (AP/HF) or 35%C/25%P40%F (HP/HF) in the POUNDS Lost study. Urinary nitrogen excretion, dietary adherence measured by 24-h recall and attendance at sessions, age (above and below 50 years), gender, race/ethnicity and activity by pedometry were analysed. Increased spread between protein intake at baseline and protein at 6 or 24 months, assessed by urinary nitrogen excretion, was associated with greater weight loss from baseline to 2 years. At 6 and 24 months, older age, male gender, body mass index > 30 kg m-2 and adherence to the fat and protein diets were associated with more weight loss. None of these variables was associated with a regain from 6 to 24 months. Weight regain for women in the highest carbohydrate (65%) group was significantly greater (-4.4 kg [95% CI: -5.9, -3.0]) than for women in the lowest carbohydrate group (-1.8 kg [95% CI: -3.2, -0.4 kg]) (P for interaction = 0.012). An increased spread in the difference between baseline and follow-up protein intake was associated with greater weight loss, consistent with the 'protein spread theory'. Women eating the highest carbohydrate diet regained more weight from 6 to 24 months.


Grazing Is Associated with ADHD Symptoms, Substance Use, and Impulsivity in a Representative Sample of a Large Metropolitan Area in Brazil.
Grazing is a clinically relevant eating behaviour, especially when it presents with a sense of loss of control (compulsive grazing). There is evidence that other disordered eating patterns are associated with problematic substance use and impulsivity-related conditions, such as attention-deficit/hyperactivity disorder (ADHD). This overlap contributes to higher psychopathology and treatment complications. Less is known about grazing, and most information originates in high-income countries. Hence, we sought to investigate relationships between grazing, tobacco and alcohol use, ADHD, and impulsivity in a large representative sample from Brazil. Data were collected by trained interviewers from adults (N = 2297) through an in-person household survey based on a stratified and clustered probability sample. We found significant associations between compulsive grazing and problematic alcohol use (OR = 3.02, 95% CI: 1.65, 5.53), ADHD (OR = 8.94, 95% CI: 5.11, 15.63), and smoking (OR = 1.67, 95% CI: 1.12, 2.47), with impulsivity contributing to the first two relationships. The substantial association with ADHD suggests that other executive functions may promote disordered eating, possibly expressed through difficulties in adhering to regular meals. Clinically, these findings highlight the importance of assessing problematic eating patterns, such as compulsive grazing, in those presenting with difficulties with substance use or impulsivity, and vice versa.


Extreme precision in rhythmic interaction is enabled by role-optimized sensorimotor coupling: analysis and modelling of West African drum ensemble music.
Human social interactions often involve carefully synchronized behaviours. Musical performance in particular features precise timing and depends on the differentiation and coordination of musical/social roles. Here, we study the influence of musical/social roles, individual musicians and different ensembles on rhythmic synchronization in Malian drum ensemble music, which features synchronization accuracy near the limits of human performance. We analysed 72 recordings of the same piece performed by four trios, in which two drummers in each trio systematically switched roles (lead versus accompaniment). Musical role, rather than individual or group differences, is the main factor influencing synchronization accuracy. Using linear causal modelling, we found a consistent pattern of bi-directional couplings between players, in which the direction and strength of rhythmic adaptation is asymmetrically distributed across musical roles. This differs from notions of musical leadership, which assume that ensemble synchronization relies predominantly on a single dominant personality and/or musical role. We then ran simulations that varied the direction and strength of sensorimotor coupling and found that the coupling pattern used by the Malian musicians affords nearly optimal synchronization. More broadly, our study showcases the importance of ecologically valid and culturally diverse studies of human behaviour. This article is part of the theme issue 'Synchrony and rhythm interaction: from the brain to behavioural ecology'.


Simultaneous determination of fuel oxygenates and BTEX using direct aqueous injection gas chromatography mass spectrometry (DAI-GC/MS).
A direct aqueous injection-gas chromatography/mass spectrometry (DAI-GC/MS) method for trace analysis of gasoline components in water is presented. The method allows for the simultaneous quantification of the following solutes: methyl tert-butyl ether (MTBE), its major degradation products (tert-butyl formate, tert-butyl alcohol (TBA), methyl acetate, and acetone), and possible substitutes of MTBE as an octane enhancer in gasoline (tert-amyl methyl ether, ethyl tert-butyl ether) as well as benzene, toluene, ethylbenzene, p-xylene, m-xylene, and o-xylene (BTEX). No enrichment or pretreatment steps are required, and sample volumes of only 50 microL are needed for analysis. The detection limits in two different matrixes (spiked lake water and contaminated groundwater) are < or = 2 microg/L for most analytes and < 0.2 microg/L for MTBE, benzene, and toluene. The accuracy of the DAI-GC/MS method was excellent as determined from comparison with headspace-GC/MS and purge-and-trap-GC/MS. The DAI-GC/MS method has been applied to various environmental studies, which demonstrated its versatility. The applications comprised both laboratory (MTBE degradation in water treatment, quantification of polar gasoline components) and field (MTBE degradation ata gasoline spill site) investigations.


Observations on the structure of the subepithelial nerve plexus in the tongue.
The intrinsic innervation of the anterior two thirds of the tongue in adult dogs of both sexes was studied in paraffin sections stained with Bodian, Holmes, cholinesterase and other stains. In all the sections, a subepithelial plexus of nerve fibres and cells was always seen on the dorsum of the tongue. Nerve endings were seen extending in between the epithelial cells on the dorsum of the tongue. The nerve cells were usually spindle-shaped and collected to form numerous ganglia in the submucosa. There were other ganglia in the tongue whose structure was very much similar to terminal autonomic ganglia. The significance of the ganglia consisting of biopolar nerve cells is being discussed.


The Measurement of Intraocular Biomarkers in Various Stages of Proliferative Diabetic Retinopathy Using Multiplex xMAP Technology.
Purpose. To determine the intraocular levels of growth factors and cytokines in patients with various degrees of severity of proliferative diabetic retinopathy (PDR) using multiplex xMAP technology. Methods. A prospective cohort study of 61 eyes from 56 patients who were divided into 3 groups based on the severity of PDR. Patients in group number 1 are those who presented PDR with no need of repeated surgical intervention; patients in group number 2 had repeated vitreous bleeding; and patients in group number 3 had refractory neovascular glaucoma. The concentrations of proangiogenic, antiangiogenic, inflammatory, and neurotrophic factors were measured in intraocular fluid. The results were also compared with levels of factors measured in 50 eyes from 50 patients prior to senile cataract surgery (control group). Results. Patients with refractory neovascular glaucoma (the highest clinical severity group) had higher levels of interleukin 6 (IL-6) (median1 37.19; median3 384.74; P = .00096), transforming growth factor beta 1 (TGFβ-1) (median1 49.00; median3 414.40; P = .0017), and vascular endothelial growth factor (VEGF) (median1 211.62; median3 352.82; P = .0454) compared with other PDR patients. Conclusions. Results of our study imply that levels of IL-6, TGFβ-1, and VEGF correlate with the severity of PDR.


Recent metformin ingestion does not increase in-hospital morbidity or mortality after cardiac surgery.
Perioperative treatment of type 2 diabetes with metformin, an oral hypoglycemic drug, is thought to increase the risk of life-threatening postoperative lactic acidosis. In contrast, metformin improves serum glucose control and has beneficial cardiovascular effects, which may decrease the risk of adverse outcomes. In this investigation we sought to determine the influence of metformin treatment on mortality and morbidity compared with treatment with other oral hypoglycemic drugs in diabetic patients undergoing cardiac surgery. In this retrospective investigation, 1284 diabetic patients, with recent oral hypoglycemic ingestion (presumed to be 8-24 h preoperatively), underwent cardiac surgery from 1994-2004. Propensity scores were calculated from a logistic model which included baseline characteristics and perioperative variables. Four-hundred-forty-three (85%) of the metformin-treated patients were matched on nearest propensity score using greedy matching techniques with 443 nonmetformin-treated patients. Postoperative outcomes were compared between matched metformin- and nonmetformin-treated patients. In-hospital mortality, cardiac, renal, and neurologic morbidities were similar between groups. Metformin-treated patients had less postoperative prolonged tracheal intubation [OR (95% CI), 0.3 (0.1, 0.7), P = 0.003], infection [0.2 (0.1, 0.7), P = 0.007] and overall morbidities [0.4 (0.2, 0.8), P = 0.005]. These data suggest that recent metformin ingestion is not associated with increased risk of adverse outcome in cardiac surgical patients. Alternatively, metformin treatment may have beneficial effects.


Negative association between anterior insula activation and resilience during sustained attention: an fMRI twin study.
While previous studies have suggested that higher levels of cognitive performance may be related to greater wellbeing and resilience, little is known about the associations between neural circuits engaged by cognitive tasks and wellbeing and resilience, and whether genetics or environment contribute to these associations. The current study consisted of 253 monozygotic and dizygotic adult twins, including a subsample of 187 early-life trauma-exposed twins, with functional Magnetic Resonance Imaging data from the TWIN-E study. Wellbeing was measured using the COMPAS-W Wellbeing Scale while resilience was defined as a higher level of positive adaptation (higher levels of wellbeing) in the presence of trauma exposure. We probed both sustained attention and working memory processes using a Continuous Performance Task in the scanner. We found significant negative associations between resilience and activation in the bilateral anterior insula engaged during sustained attention. Multivariate twin modelling showed that the association between resilience and the left and right insula activation was mostly driven by common genetic factors, accounting for 71% and 87% of the total phenotypic correlation between these variables, respectively. There were no significant associations between wellbeing/resilience and neural activity engaged during working memory updating. The findings suggest that greater resilience to trauma is associated with less activation of the anterior insula during a condition requiring sustained attention but not working memory updating. This possibly suggests a pattern of 'neural efficiency' (i.e. more efficient and/or attenuated activity) in people who may be more resilient to trauma.


Capture-SELEX: Selection of DNA Aptamers for Aminoglycoside Antibiotics.
Small organic molecules are challenging targets for an aptamer selection using the SELEX technology (SELEX-Systematic Evolution of Ligans by EXponential enrichment). Often they are not suitable for immobilization on solid surfaces, which is a common procedure in known aptamer selection methods. The Capture-SELEX procedure allows the selection of DNA aptamers for solute targets. A special SELEX library was constructed with the aim to immobilize this library on magnetic beads or other surfaces. For this purpose a docking sequence was incorporated into the random region of the library enabling hybridization to a complementary oligo fixed on magnetic beads. Oligonucleotides of the library which exhibit high affinity to the target and a secondary structure fitting to the target are released from the beads for binding to the target during the aptamer selection process. The oligonucleotides of these binding complexes were amplified, purified, and immobilized via the docking sequence to the magnetic beads as the starting point of the following selection round. Based on this Capture-SELEX procedure, the successful DNA aptamer selection for the aminoglycoside antibiotic kanamycin A as a small molecule target is described.


Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers.
Cancer cells often have supernumerary centrosomes that promote genomic instability, a pathognomonic feature of cancer. During mitosis, cancer cells with supernumerary centrosomes undergo bipolar cell division by clustering centrosomes into two poles. When supernumerary centrosome clustering is antagonized, cancer cells are forced to undergo multipolar division leading to death of daughter cells. This proapoptotic pathway, called anaphase catastrophe, preferentially eliminates aneuploid cancer cells and malignant tumors in engineered mouse models. Anaphase catastrophe occurs through the loss or inhibition of the centrosomal protein CP110, a direct cyclin-dependent kinase 1 (CDK1) and CDK2 target. Intriguingly, CP110 is repressed by the KRAS oncoprotein. This sensitizes KRAS-driven lung cancers (an unmet medical need) to respond to CDK2 inhibitors. Anaphase catastrophe-inducing agents like CDK1 and CDK2 antagonists are lethal to cancer cells with supernumerary centrosomes, but can relatively spare normal cells with two centrosomes. This mechanism is proposed to provide a therapeutic window in the cancer clinic following treatment with a CDK1 or CDK2 inhibitor. Taken together, anaphase catastrophe is a clinically tractable mechanism that promotes death of neoplastic tumors with aneuploidy, a hallmark of cancer. Mol Cancer Ther; 17(4); 724-31. ©2018 AACR.


New Fault Recognition Method for Rotary Machinery Based on Information Entropy and a Probabilistic Neural Network.
Feature recognition and fault diagnosis plays an important role in equipment safety and stable operation of rotating machinery. In order to cope with the complexity problem of the vibration signal of rotating machinery, a feature fusion model based on information entropy and probabilistic neural network is proposed in this paper. The new method first uses information entropy theory to extract three kinds of characteristics entropy in vibration signals, namely, singular spectrum entropy, power spectrum entropy, and approximate entropy. Then the feature fusion model is constructed to classify and diagnose the fault signals. The proposed approach can combine comprehensive information from different aspects and is more sensitive to the fault features. The experimental results on simulated fault signals verified better performances of our proposed approach. In real two-span rotor data, the fault detection accuracy of the new method is more than 10% higher compared with the methods using three kinds of information entropy separately. The new approach is proved to be an effective fault recognition method for rotating machinery.


Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme. The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.


MicroRNA-124 inhibits colorectal cancer cell proliferation and suppresses tumor growth by interacting with PLCB1 and regulating Wnt/β-catenin signaling pathway.
Colorectal cancer (CRC) is the most common malignancy for cancer-associated death. This study aimed to investigate the effects of microRNA-124 (miR-124) on tumor proliferation of CRC in vivo and in vitro. MiR-124 mimics were synthesized and transfected into SW620 cells, which were divided into SW620, microRNA-normal control (miR-NC) and miR-124 mimics group. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to examine miR-124, chemokine (C-C motif) ligand-20 (CCL20), tankyrase-2 (TNKS2), phospholipase Cbeta1 (PLCB1) and Wnt4. Cell counting kit-8 (CCK-8) was employed to evaluate cell proliferation. The interaction between miR-124 and PLCB1 was tested with the Dual-Luciferase assay. Cell cycle, apoptosis and invasion were also evaluated. CRC xenograft mouse model was established and tumor size was measured. Hematoxylin and eosin (HE) was used to examine inflammation. Western blot was utilized to detect Wnt4. MiR-124 was over-expressed in SW620 cells, significantly reduced CCL20 and enhanced TNKS2 compared to that of the miR-NC group (p<0.05). MiR-124 might play roles by initiating PLCB1 expression. MiR-124 significantly decreased cell viability compared to the miR-NC group (p<0.05). MiR-124 regulated cell cycle and markedly induced apoptosis and inhibited cell invasion compared to the miR-NC group (p<0.05). MiR-124 significantly decreased tumor size of CRC models compared to miR-NC mice (p<0.05). MiR-124 remarkably alleviated inflammation of tumor tissues. MiR-124 markedly enhanced Wnt4 expression compared to the miR-NC group (p<0.05). MiR-124 inhibited tumor cell proliferation in vitro and suppressed tumor growth in vivo by interacting with PLCB1 and regulating the Wnt/β-catenin signaling pathway.


Tributylphosphate extraction behavior of bismuthate-oxidized americium.
Higher oxidation states of americium have long been known; however, options for their preparation in acidic solution are limited. The conventional choice, silver-catalyzed peroxydisulfate, is not useful at nitric acid concentrations above about 0.3 M. We investigated the use of sodium bismuthate as an oxidant for Am (3+) in acidic solution. Room-temperature oxidation produced AmO 2 (2+) quantitatively, whereas oxidation at 80 degrees C produced AmO 2 (+) quantitatively. The efficacy of the method for the production of oxidized americium was verified by fluoride precipitation and by spectroscopic absorbance measurements. We performed absorbance measurements using a conventional 1 cm cell for high americium concentrations and a 100 cm liquid waveguide capillary cell for low americium concentrations. Extinction coefficients for the absorbance of Am (3+) at 503 nm, AmO 2 (+) at 514 nm, and AmO 2 (2+) at 666 nm in 0.1 M nitric acid are reported. We also performed solvent extraction experiments with the hexavalent americium using the common actinide extraction ligand tributyl phosphate (TBP) for comparison to the other hexavalent actinides. Contact with 30% tributyl phosphate in dodecane reduced americium; it was nevertheless extracted using short contact times. The TBP extraction of AmO 2 (2+) over a range of nitric acid concentrations is shown for the first time and was found to be analogous to that of uranyl, neptunyl, and plutonyl ions.


Effectiveness of a brief cognitive-behavioural therapy intervention in the treatment of schizophrenia.
Little evidence exists to indicate whether community psychiatric nurses can achieve the results reported by expert cognitive-behavioural therapists in patients with schizophrenia. To assess the effectiveness and safety of a brief cognitive-behavioural therapy (CBT) intervention in a representative community sample of patients with schizophrenia in secondary care settings. A pragmatic randomised trial was performed involving 422 patients and carers to compare a brief CBT intervention against treatment as usual. Patients who received CBT (n=257) improved in overall symptomatology (P=0.015; number needed to treat [NNT]=13), insight (P<0.001; NNT=10) and depression (P=0.003; NNT=9) compared with the control group (n=165). Insight was clinically significantly improved (risk ratio=1.15, 95% CI 1.01-1.31). There was no increase in suicidal ideation. Community psychiatric nurses can safely and effectively deliver a brief CBT intervention to patients with schizophrenia and their carers.


Effect of four lighting regimes on broiler performance, leg abnormalities and plasma corticoid levels.
The effect of four lighting regimes: (1) continuous light (5 to 10 lux); (2) an intermittent system of 1 hr. of light (5 to 10 lux) and 3 hr. of darkness; (3) an intermittent system of 1 hr. of light (5 to 10 lux) and 3 hr. of darkness interrupted by 13 hr. of regular light (5 to 10 lux); (4) as with (3) but with low intensity light (less than 1 lux) during the 13 hr. period while the intermittent system continued, was studied in 2400 broilers of two commercial crosses over two trials. Lighting regime had a significant effect of body weight in trial 2 with birds on treatments 3 and 4 being lighter than those on treatments 1 and 2 which did not differ. Lighting regime had no significant effect on feed to gain ratio, percent crooked toes or mortality to 8 weeks. Birds grown on continuous light had significantly more leg abnormalities than those grown on any of the intermittent regimes. In trial 1 birds grown on continuous light had significantly higher plasma corticoid levels than those grown on any of the intermittent regimes. The same trend existed in trial 2, except that birds on treatment 3 had the highest plasma corticoid level.


Characterization of a novel effect of hPinX1 on hTERT nucleolar localization.
The factor PinX1 has been shown as a telomerase inhibitor evolutionarily conserved in both the yeast and the human being. yPinX1 inhibits telomerase activity by sequestering yTERT (telomerase reverse transcriptase) from uniting with yTR (telomerase template RNA) in the nucleolus of yeast cells. However, the mechanism underlying the action of hPinX1 on telomerase regulation in human cells is not known. We here demonstrated that hPinX1 actually has an effect on mediating hTERT nucleolar localization and this effect is mediated by a novel domain enclosed within the central section of the polypeptide. Interestingly, we showed that a reported cancerous mutant form of hPinX1, in which residues of Ser254 and Cys265 are, respectively, mutated to Cys and Tyr, lost the activity on mediating hTERT nucleolar localization. Finally, we provided evidence that mediation of hTERT nucleolar localization and telomerase enzymatic inhibition are two separated function of hPinX1 on telomerase regulation in human cells.


Fentiazac in the treatment of osteoarthritis and tendinitis.
In a double-blind trial in 20 patients with osteoarthritis, treatment was given at random with either 200 mg fentiazac or 50 mg indomethacin twice daily for 6 weeks. Both treatments produced marked improvement in pain and the other variables studied but, apart from blood pressure which was raised in the indomethacin group, no significant differences between treatments were observed. In a second double-blind trial involving 24 patients with acute non-articular rheumatism, mainly tendinitis, 200 mg fentiazac twice daily was compared with 200 mg phenylbutazone twice daily over a period of 2 weeks. No significant difference in improvement was found between treatments in any of the clinical variables studied, although there was a trend in favour of fentiazac, particularly in the relief of tenderness. No difference was noted in the incidence or nature of side-effects, which were mainly gastro-intestinal in origin, reported by patients in the treatment groups in either study.


Clinical significance of microbiota changes under the influence of psychotropic drugs. An updated narrative review.
Relationship between drugs and microbiota is bilateral. Proper composition thus function of microbiota is a key to some medications used in modern medicine. However, there is also the other side of the coin. Pharmacotherapeutic agents can modify the microbiota significantly, which consequently affects its function. A recently published study showed that nearly 25% of drugs administered to humans have antimicrobial effects. Multiple antidepressants are antimicrobials,. and antibiotics with proven antidepressant effects do exist. On the other hand, antibiotics (e.g., isoniaside, minocycline) confer mental phenotype changes, and adverse effects caused by some antibiotics include neurological and psychological symptoms which further supports the hypothesis that intestinal microbiota may affect the function of the central nervous system. Here we gathered comprehensively data on drugs used in psychiatry regarding their antimicrobial properties. We believe our data has strong implications for the treatment of psychiatric entities. Nevertheless the study of ours highlights the need for more well-designed trials aimed at analysis of gut microbiota function.


Estimating Sustainable Live-Coral Harvest at Kamiali Wildlife Management Area, Papua New Guinea.
Live coral is harvested throughout the Indo-West Pacific to make lime, used in the consumption of the world's fourth-most consumed drug, betel nut. Coral harvesting is an environmental concern; however, because lime-making is one of the few sources of income in some areas of Papua New Guinea (PNG), the practice is unlikely to stop. To better manage coral harvest, we used standard fishery-yield methods to generate sustainable-harvest guidelines for corymbose Acropora species found on the reef flat and crest at Lababia, PNG. We constructed a yield curve (weight-specific net annual-dry-weight production) by: 1) describing the allometric relationship between colony size and dry weight, and using that relationship to estimate the dry weight of Acropora colonies in situ; 2) estimating annual growth of Acropora colonies by estimating in situ, and describing the relationship between, colony dry weight at the beginning and end of one year; and 3) conducting belt-transect surveys to describe weight-frequencies and ultimately to predict annual weight change per square meter for each weight class. Reef habitat covers a total 2,467,550 m2 at Lababia and produces an estimated 248,397 kg/y (dry weight) of corymbose Acropora, of which 203,897 kg is produced on the reef flat/crest. We conservatively estimate that 30,706.6 kg of whole, dry, corymbose, Acropora can be sustainably harvested from the reef flat/crest habitat each year provided each culled colony weighs at least 1805 g when dry (or is at least 46 cm along its major axis). Artisanal lime-makers convert 24.8% of whole-colony weight into marketable lime, thus we estimate 7615.2 g of lime can be sustainably produced annually from corymbose Acropora. This value incorporates several safety margins, and should lead to proper management of live coral harvest. Importantly, the guideline recognizes village rights to exploit its marine resources, is consistent with village needs for income, and balances an equally strong village desire to conserve its marine resources for future generations.


Advances in mesoporous silica nanoparticles for targeted stimuli-responsive drug delivery.
Mesoporous silica nanoparticles (MSNPs) are one of the most promising inorganic drug delivery systems (DDSs). The design and development of tumour-targeted MSNPs with stimuli-responsive drug release capability aim at enhancing the efficiency and minimising the side effects of anti-tumour drugs for cancer therapy. This review provides an overview of the scientific advances in MSNPs for tumour-targeted stimuli-responsive drug delivery. The key factors that govern the passive accumulation of MSNPs within solid tumours such as size, shape and surface functionalisation are roughly described. The different active targeting strategies for the specific retention and uptake of MSNPs by tumour cells are also outlined. The approaches developed so far for the synthesis of smart MSNPs capable of releasing the trapped drugs in response to internal or external stimuli and their applications are reviewed. Critical considerations in the use of MSNPs for the treatment of cancer treatment are discussed. The future prospects and key factors concerning the clinical application of MSNPs are considered throughout the manuscript. MSNPs are promising nanocarriers to efficiently transport and site-specifically deliver highly toxic drugs, such as chemotherapeutic agents for cancer treatment. However, there are certain issues that should be overcome to improve the suitability of MSNPs for clinical applications. Increasing the penetration capability of MSNPs within tumour tissues, providing them of appropriate colloidal stability in physiological fluids and ensuring that their active targeting capability and stimuli-responsive performance are preserved in complex biological media are of foremost significance. Few in vivo evaluation tests of MSNPs have been reported and much research effort into this field is mandatory to be able to move from bench to bedside.


Isoliquiritigenin, one of the antispasmodic principles of Glycyrrhiza ularensis roots, acts in the lower part of intestine.
Glycyrrhizae radix is used to treat abdominal pain as a component of shakuyakukanzoto (shaoyao-gancao-tang), a traditional Chinese medicine formulation. Previously, we have reported the isolation of glycycoumarin as a potent antispasmodic with an IC50 value of 2.93+/-0.94 microM for carbamylcholine (CCh)-induced contraction of mouse jejunum from an aqueous extract of Glycyrrhizae radix (licorice), and clarified that its mechanism of action involves inhibition of phosphodiesterase 3. The purpose of the present study was to examine an antispasmodic principle of licorice other than glycycoumarin. Isoliquiritigenin was isolated from an aqueous extract of licorice as a potent relaxant, which inhibited the contraction induced by various types of stimulants, such as CCh, KCl, and BaCl2 with IC50 values of 4.96+/-1.97 microM, 4.03+/-1.34 microM and 3.70+/-0.58 microM, respectively, which are close to those of papaverine. However, the amount of isoliquiritigenin in the aqueous extract of licorice was very small. When the aqueous licorice extract was treated with naringinase, the amounts of glycosides such as isoliquiritin, which were abundant but had much less potent relaxant activity, were decreased while isoliquiritigenin was increased. At the time, the relaxant activity of the treated sample was increased significantly, shifting the IC50 from 358+/-104 to 150+/-38 microg/ml for CCh-induced contraction. Isoliquiritigenin also showed the most potent inhibition of mouse rectal contraction induced by CCh with an IC50 value of 1.70+/-0.07 microM. These results suggest that isoliquiritigenin acts as a potent relaxant in the lower part of the intestine by transformation from its glycosides.


Environmental factors and their role in the transmission of SARS-CoV-2.
In December of 2019, several cases of atypical pneumonia caused by an unknown agent were reported in Wuhan, the capital city of Hubei Province in China. In early January 2020, it was announced that these cases were caused by a novel coronavirus. The virus was later named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes a disease associated with atypical pneumonia termed Corona virus disease 2019 (COVID-19). Several respiratory viruses, including coronaviruses and influenza viruses tend to have prominent peaks of infection during colder seasons, especially in temperate regions. The cold temperatures, along with accompanying dry conditions can drive respiratory tract infections by assisting with viral transmission, weakening the human immune system, and increasing viral molecular stability. Though the topic of SARS-CoV-2 transmission and warm weather has been associated with misinformation campaigns, it is worth investigating since an informative answer may give an indication of the future behavior of SARS-CoV-2.


Significant association between interleukin-10 gene polymorphisms and cervical cancer risk: a meta-analysis.
Previous studies have suggested that interleukin-10 (IL-10) polymorphisms may be associated with an increased risk of developing cervical cancer. However, the published results on this subject matter are controversial. The aim of this study was to conduct a meta-analysis of published reports to more precisely investigate the relationship between IL-10 polymorphisms and cervical cancer risk. Five online databases (PubMed, Embase, Web of SCI, CNKI and Wanfang) were searched, and seventeen articles with sufficient quantitative information were included in our meta-analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between IL-10 polymorphisms and cervical cancer risk. Publication bias, sensitivity and cumulative analyses were also performed to support our findings. Overall, there was a significant association between the IL-10 -1082A > G polymorphism and cervical cancer risk observed in the total population (G vs. A: OR = 1.60, 95% CI = 1.12-2.29, P = 0.01, I2 = 92.3%; AG vs. AA: OR = 1.34, 95% CI = 1.04-1.74, P = 0.03, I2 = 65.9%; AG + GG vs. AA: OR = 1.58, 95% CI = 1.11-2.25, P = 0.01, I2 = 84.4%), and the same results were obtained in the subgroup analysis. Moreover, the IL-10 -819 T > C polymorphism exhibited a significant, protective effect against cervical cancer. In summary, our meta-analysis suggests that IL-10 polymorphisms may play a variety of roles in regard to cervical cancer risk, especially in Asians.


Early ovarian follicular development in prepubertal Wistar rats acutely exposed to androgens.
Androgens may directly modulate early ovarian follicular development in preantral stages and androgen excess before puberty may disrupt this physiological process. Therefore, the aim of this study was to investigate the dynamics of follicular morphology and circulating androgen and estradiol levels in prepubertal Wistar rats acutely exposed to androgens. Prepubertal female Wistar rats were distributed into three groups: control, equine chorionic gonadotropin (eCG) intervention and eCG plus dehydroepiandrosterone (DHEA) intervention (eCG+DHEA). Serum DHEA, testosterone and estradiol levels were determined, and ovarian morphology and morphometry were assessed. The eCG+DHEA group presented increased serum estradiol and testosterone levels as compared with the control group (P<0.01), and higher serum DHEA concentration v. the eCG-only and control groups (P<0.01). In addition, the eCG+DHEA group had a higher number of, and larger-sized, primary and secondary follicles as compared with the control group (P<0.05). The eCG group presented intermediate values for number and size of primary and secondary follicles, without significant differences as compared with the other two groups. The number of antral follicles was higher in the eCG+DHEA and eCG groups v. controls (P<0.05). The number of primordial, atretic and cystic follicles were similar in all groups. In conclusion, the present experimental model using an acute eCG+DHEA intervention was useful to investigate events involved in initial follicular development under hyperandrogenic conditions, and could provide a reliable tool to study defective follicular development with possible deleterious reproductive consequences later in life.


Chiral analysis of pollutants and their metabolites by capillary electromigration methods.
Chiral separation of enantiomers is one of the most challenging tasks for any analytical technique including CE. Since the first report in 1985 showing the great possibilities of CE for the separation of chiral compounds, the amount of publications concerning this topic has quickly increased. Although chiral electromigration methods have mainly been used for enantioseparation of drugs and pharmaceuticals, they have also been applied to analyze chiral pollutants. This article intends to provide an updated overview, including works published till January 2005, on the principal applications of CE to the chiral analysis of pollutants and their metabolites, with special emphasis on articles published in the last 10 years. The main advantages and drawbacks regarding the use of CE for chiral separation of pollutants are addressed including some discussion on the foreseen trends of electromigration procedures applied to chiral analysis of contaminants.


Effects of arbuscular mycorrhizal fungi on CH4 emissions from rice paddies.
Arbuscular mycorrhizal fungi (AMF) play a key role in soil carbon storage and release; however, they have never been considered as a factor affecting methane (CH4) emissions from rice paddies. To reveal the role of AMF, the diurnal variations of CH4 emissions from the noninoculated and inoculated rice field plots were compared at midseason drainage, reflooding stage, and end-of-season drainage. The results showed that the diurnal variation patterns in the two treatments both closely tracked soil water content at midseason drainage and end-of-season drainage, while correlated very well with the stomatal conductance of rice at reflooding stage. There were no significant differences between treatments in soil water content and stomatal conductance. However, the diurnal CH4 emission fluxes at the three stages ranged from 4.8 to 39.3, 0.9 to 12.4, and 0.2 to 2.3 mg m-2 h-1 in the noninoculated plots, and those in the inoculated plots ranged from 2.1 to 18.7, 0.9 to 5.0, and 0.3 to 1.2 mg m-2 h-1. The significant differences resulted from carbon-to-nitrogen ratios (C:N) of the noninoculated and inoculated soil, which had a negative linear correlation with maximum diurnal CH4 fluxes. Compared with the noninoculated treatment, inoculating with AMF significantly increased soil C:N by improving the dry matter of rice, which intensified N limit for CH4 production.


Light-Induced Iron-Catalyzed Trifluoromethylative Thiolation of Alkenes.
A series of novel trifluoromethylative thiolations of alkene are realized by using visible light as a driving force and iron salts as a catalyst, and 1,2-bis(trifluoromethylated) compounds could be obtained in moderate to good yields. These multicomponent protocols proceed in an atom-economical way with a broad substrate scope. Biologically active chemicals can also be tolerated to provide desired products, suggesting that the catalytic protocol could be viable for late-stage modification in pharmaceutical discovery. At last, flow-setup synthesis of the desired product is successfully applied on a gram scale, indicating the synthetic power of these reactions in industrial applications.


Disagreements in chest roentgen interpretation.
Each of 100 chest radiographs selected randomly from a hospital population were read by five experienced radiologists. The films were rich in abnormal findings. Disagreement analysis was performed considering the entire content of the interpretation. The disagreements were graded by a panel as to type (false negative, false positive, and indeterminate) and significance. The overall repeatability of the panel's performance was 75 percent. Forty-one percent of the reports contained potentially significant errors and 56 percent indeterminate disagreements. Among all errors 78 percent were false negatives and 22 percent were false positives. The error rate varied among readers. An average of 25 percent of important findings were omitted by an individual reader. An association between specific abnormalities and the types of disagreement was found.


A randomized, controlled trial of manual therapy and specific adjuvant exercise for chronic low back pain.
This article examines the effectiveness of manual therapy with specific adjuvant exercise for treating chronic low back pain and disability. A single blind, randomized, controlled trial was employed. Patients were prescribed an exercise program that was tailored to treat their musculoskeletal dysfunctions or given a nonspecific program of general stretching and aerobic conditioning. In addition, patients received manual therapy or sham manual therapy. Participants were seen for 6 weekly sessions and were asked to perform their exercise program twice daily. Seventy-two out of 100 patients completed the study. Multivariate tests conducted for measures of pain and disability revealed a significant group by time interaction (P = 0.04 and P = 0.05, respectively), indicating differential change in these measures pretreatment to posttreatment as a function of the treatment received. When controlling for pretreatment scores, patients receiving manual therapy with specific adjuvant exercise reported significant reductions in pain. No change in perceived disability was observed, with the exception that patients receiving sham manual therapy with specific adjuvant exercise reported significantly greater disability at posttreatment. Manual therapy with specific adjuvant exercise appears to be beneficial in treating chronic low back pain. Despite changes in pain, perceived function did not improve. It is possible that impacting chronic low back pain alone does not address psychosocial or other factors that may contribute to disability. Further studies are needed to examine the long-term effects of these interventions and to address what adjuncts are beneficial in improving function in this population.


Nutritional and hypoglycemic effect of fruit pulp of Annona squamosa in normal healthy and alloxan-induced diabetic rabbits.
The nutritive value of the pulp of the edible fruit of Annona squamosa and its effect on various biochemical parameters has been assessed in normal and alloxan-induced diabetic rats. Different doses (2.5, 5.0, 10.0 g/kg b.w.) of fresh fruit pulp of A. squamosa were given to the three groups each of normal healthy and diabetic rabbits orally daily for 1 month. There was a control group of normal as well as diabetic animals which did not receive fruit pulp. Protein efficiency ratio (PER), digestibility coefficient (DC), biological value (BV) and net protein utilization (NPU) were calculated and improvement in the nutritional level was studied by comparing with the control group. Effect of the fruit pulp was also studied on various biochemical parameters, namely fasting blood glucose (FBG), total cholesterol (TCH), HDL-cholesterol, triglyceride (TG), total protein (TPR), alkaline phosphatase (ALKP), serum glutamate oxaloacetate and pyruvate transaminases (SGOT and SGPT), serum creatinine (CRTN) and serum bilirubin (BIL). Protein and glucose in urine were also estimated. Total hemoglobin and glycohemoglobin (HbAc) were estimated in blood before and after 1 month of feeding fruit pulp. Fruit pulp increased the net protein utilization by 29.3 in normal healthy rabbits with 10 g/kg b.w. and 34.1 in induced diabetic (induced by alloxan) animals with 5 g/kg b.w. of the fruit pulp feeding when compared with the control group of rabbits (p < 0.001). Feeding fruit pulp with the same amount increased the total hemoglobin content by 21.0% in normal rabbits and 10.8% in diabetic rabbits. Fruit pulp also reduced the total cholesterol level by 45-46% in normal and 32.4% in diabetic animals with increased HDL-cholesterol. Feeding pulp improved the liver function in normal as well as diabetic rabbit as shown by reduction in the serum SGOT, SGPT, ALKP and bilirubin levels. The optimal improvement in nutritive value of normal animals was found with 5.0-10.0 g/kg b.w. of the fruit pulp feeding, while in diabetic animals it was 2.5-5.0 g/kg b.w. In the diabetic animals pulp feeding between 2.5 and 5.0 g/kg b.w. showed improvement in the glucose tolerance. Further, 5 g/kg b.w. of fruit pulp brought down urine sugar, urine protein and glycohemoglobin in diabetic rabbits. Feeding pulp had increased utilization of dietary protein, body weight as well as the ratio of gain in body weight per gram of protein consumed. It had a protective effect on liver and heart as indicated by reduction in the SGOT, SGPT, ALKP and serum bilirubin levels.


Designing Nonconventional Luminescent Materials with Efficient Emission in Dilute Solutions via Modulation of Dynamic Hydrogen Bonds.
Nonconventional luminescent materials (NLMs) which do not contain traditional aromatic chromophores are of great interest due to their unique chemical structures, optical properties, and their potential applications in various areas, such as cellular imaging and chemical sensing. However, most reported NLMs show weak or no emission in dilute solutions, which severely limits their applications. In this work, dynamic hydrogen bonds were utilized to design NLMs with efficient emission in dilute solutions. To further validate the results, polymers P1 and P2 were successfully prepared and investigated. It was found that the luminescence quantum efficiency of P1 and P2 at a concentration of 0.1 mg/mL in water solution was 8.9 and 0.6%, respectively. The high efficiency can be attributed to the fact that polymer P1 has more intra- or intermolecular dynamic hydrogen bonds and other short interactions than P2 in dilute solutions, allowing P1 to achieve the through-space conjugation effect to increase the degree of system conjugation, restrict molecular motion, and decrease nonradiative transitions, which can effectively improve luminescence. In addition, polymer P2 exhibits the characteristics of clustering-triggered emission, excitation wavelength-dependent and concentration-dependent fluorescence properties, excellent photobleaching resistance, low cytotoxicity, and selective recognition of Fe3+. The present study investigates the manipulation of luminescence properties of NLMs in dilute solutions through the modulation of dynamic hydrogen bonds. This approach can serve as a semi-empirical technique for designing and building innovative NLMs in the times ahead.


Standard Clinical Screening Tests, Sural Radial Amplitude Ratio and F Wave Latency Compared to Conventional Nerve Conduction Studies in the Assessment of Sensorimotor Polyneuropathy in Patients with Type 2 Diabetes Mellitus.
The measuring tools used for assessment of neuropathy include various questionnaires, monofilament testing, Biothesiometry and the gold standard test, nerve conduction studies (NCS). This study aims to evaluate the diagnostic accuracies of Michigan Neuropathy Screening Instrument (MNSI), Biothesiometry, Semmes Weinstein Monofilament (SWMF), Sural Radial Amplitude Ratio (SRAR) and minimal F wave latency as compared to conventional NCS and arrive at a simple diagnostic algorithm for early detection of Diabetic Peripheral Neuropathy (DPN). In a cross-sectional observational study on 48 Type 2 diabetes mellitus patients, MNSI, Biothesiometry, SWMF and NCS including F waves and SRAR were done and diagnostic accuracies (sensitivity, specificity, positive and negative predictive values) calculated taking NCS as gold standard. MNSI, Biothesiometry, SWMF, SRAR and minimal F wave latency had a sensitivity of 64.3%, 78.6%, 14.3%, 100% and 78.6% and specificity of 67.7%, 52.9%, 94.1%, 23.53% and 76.47% respectively, with reference to NCS. Based on combined sensitivities and specificities, we arrived at a simple algorithm for early diagnosis of DPN, which showed that DPN could either be diagnosed or ruled out in 75% of the patients by a combination of the Biothesiometry, SRAR and left lower limb minimal F wave latency results. In the setting of an outpatient, multidisciplinary diabetic clinic, simple tests such as questionnaires, monofilament testing and biosthesiometer could be performed with greater ease while considering NCS as the gold standard. This algorithm, combining Biothesiometry, SRAR and left lower limb minimal F wave latency would be less time consuming and help in early diagnosis of DPN.


Failure to purge: population and individual inbreeding effects on fitness across generations of wild Impatiens capensis.
Inbreeding exposes deleterious recessive alleles in homozygotes, lowering fitness and generating inbreeding depression (ID). Both purging (via selection) and fixation (via drift) should reduce segregating deleterious mutations and ID in more inbred populations. These theoretical predictions are not well-tested in wild populations, which is concerning given purging/fixation have opposite fitness outcomes. We examined how individual- and population-level inbreeding and genomic heterozygosity affected maternal and progeny fitness within and among 12 wild populations of Impatiens capensis. We quantified maternal fitness in home sites, maternal multilocus heterozygosity (using 12,560 single-nucleotide polymorphisms), and lifetime fitness of selfed and predominantly outcrossed progeny in a common garden. These populations spanned a broad range of individual-level (fi = -0.17-0.98) and population-level inbreeding (FIS = 0.25-0.87). More inbred populations contained fewer polymorphic loci, less fecund mothers, and smaller progeny, suggesting higher fixed loads. However, despite appreciable ID (mean: 8.8 lethal equivalents per gamete), ID did not systematically decline in more inbred population. More heterozygous mothers were more fecund and produced fitter progeny in outcrossed populations, but this pattern unexpectedly reversed in highly inbred populations. These observations suggest that persistent overdominance or some other force acts to forestall purging and fixation in these populations.


A simple alternative method for rapid detection of slime produced by Staphylococcus epidermidis isolates in bacterial keratitis.
Slime is a known virulence factor of Staphylococcus epidermidis. The conventional Christensen's method for detection of slime in the laboratory takes at least 48 h. We, therefore, tried to evaluate the efficacy of the Congo red agar method as a routine procedure for detecting slime among isolates from corneal ulcers. A total of 244 isolates from corneal ulcers were identified as S. epidermidis by the standard procedures. Slime was detected both by the conventional Christensen's method as well as by the Congo red agar method. Ninety two (37.7%) isolates were positive and 86 (35.2%) were negative for slime by both the techniques. Fifty four (22.1%) isolates were positive in Congo red agar, but negative by Christensen's method; whereas only 12 (4.9%) were negative by Congo red but positive by Christensen's method. Detection of slime by Congo red agar method was rapid i.e., all the 146 strains were positive within 24 h of incubation. On the other hand, Christensen's method had a delayed response; 42.3 per cent (44/104) strains being negative during the first 24 h of incubation. Our results suggested that culture on Congo red agar was a sensitive and rapid test for detecting slime. This might help in the quick identification in a routine laboratory of slime positive isolates in bacterial keratitis.


Investigating Paracetamol's Role as a Potential Treatment for Parkinson's Disease: Ab Initio Analysis of Dopamine, l-DOPA, Paracetamol, and NAPQI Interactions with Enzymes Involved in Dopamine Metabolism.
Recently, it was found that paracetamol can extend the therapeutic window of l-DOPA treatment for Parkinson's disease [Golding (2019) BJPharm, 4(2), Article 619]. It has been posited that the effect could be due to paracetamol and its metabolite, NAPQI, inhibiting pain signals in the spinal column. In this work, we examine the possibility that the therapeutic effect of the paracetamol for the Parkinson's disease patient may be due to an inhibition of the enzymes that metabolize dopamine and/or l-DOPA, thus effectively extending the lifetime of the l-DOPA treatment. In this work, we use the M062X/6-311+G* level of theory to calculate the electronic binding energies (including explicit desolvation) of several ligands (paracetamol, NAPQI, dopamine, and l-DOPA) with a series of enzymes important to the production and metabolism of dopamine and compare them to calculated binding energy values for the natural substrates for those enzymes in order to predict possible inhibition. Benchmark interaction energies for a subset of the systems studied are calculated using the more accurate second-order Møller-Plesset perturbation (MP2) method in order to calibrate the accuracy of the M062X method. If we assume that the interaction energies calculated here can serve as a proxy for in vivo inhibition, then we can predict that paracetamol and NAPQI should not inhibit the natural production of dopamine and may in fact inhibit the metabolism of l-DOPA and dopamine, thus extending the length of l-DOPA treatments.


Solar photocatalytic degradation of metformin by TiO2 synthesized using Calotropis gigantea leaf extract.
A novel TiO2 nanoparticle was prepared through green synthesis using Calotropis gigantea (CG) leaf extract. Morphological analysis showed dispersed spherical CG-TiO2 nanoparticles with an average size of 42 nm. The prepared catalyst was used for the degradation of metformin (a widely used diabetic medicine) by solar photocatalysis. A three-factor central composite design (CCD) was used to explore the effect of independent variables, i.e., pH 3-7, metformin concentration 1-10 mg/L, and catalyst (CG-TiO2) dosage 0.5-2.0 g/L. A maximum metformin degradation of 96.7% was observed under optimum conditions i.e., pH = 9.7, initial metformin concentration = 9.7 mg/L and catalyst dosage = 0.7 g/L, with ∼86% mineralization efficiency. A quadratic model with an error <±5% was developed to predict the metformin degradation and the rate of degradation under the optimum conditions followed pseudo-first-order kinetics (k = 0.014/min). CG-TiO2 exhibited higher metformin degradation efficiency (96.7%) compared to P-25 (23.9%) at optimum conditions. The recyclability study indicated effective reuse of the catalyst for up to three cycles. The proposed metformin degradation route is hydroxyl radical (•OH) generation on the CG-TiO2 surface, transfer of •OH to the aqueous phase from CG-TiO2 and subsequent oxidation of metformin in the aqueous phase.


Continuous venous hemodiafiltration with trisodium citrate anticoagulation in cardiac surgery patients.
Despite advances in perioperative organ protection during cardiovascular surgery, acute renal failure remains a serious complication. The purpose of this clinical article is to describe the role of continuous renal replacement therapy (CRRT) in proactive maintenance of fluid and electrolyte balance and treatment of acute renal failure in patients following cardiovascular surgery. Implications for nursing practice, education, and future research will be delineated using a case study of a patient who required mechanical circulatory support and CRRT. The complexity of the patient's care was compounded by the need to alter conventional anticoagulation therapy to trisodium citrate.


Comparative study of (18)F-DOPA, (13)N-Ammonia and F18-FDG PET/CT in primary brain tumors.
To determine the diagnostic reliability of (18)F-FDOPA, (13)N-Ammonia and F18-FDG PET/CT in primary brain tumors. We evaluated the amino acid and glucose metabolism of brain tumors by using PET with (18)F-FDOPA, (13)N-Ammonia and F18-FDG PET/CT. Nine patients undergoing evaluation for brain tumors were studied. Tracer uptake was quantified by the use of standardized uptake values and the ratio of tumor uptake to normal identical area of contra lateral hemisphere (T/N). In addition, PET uptake with (18)F-FDOPA was quantified by use of ratio of tumor uptake to striatum uptake (T/S). The results were correlated with the patient's clinical profile. Both high-grade and low-grade tumors were well visualized with (18)F-FDOPA. The sensitivity for identifying tumors was substantially higher with (18)F-FDOPA PET than with F18-FDG and (13)N-Ammonia PET as determined by simple visual inspection. The sensitivity for identifying recurrence in low grade gliomas is higher with (13)N-Ammonia than with F18-FDG. (18)F-FDOPA PET is more reliable than F18-FDG and (13)N-Ammonia PET for evaluating brain tumors.


Abiotic Deposition of Fe Complexes onto Leptothrix Sheaths.
Bacteria classified in species of the genus Leptothrix produce extracellular, microtubular, Fe-encrusted sheaths. The encrustation has been previously linked to bacterial Fe oxidases, which oxidize Fe(II) to Fe(III) and/or active groups of bacterial exopolymers within sheaths to attract and bind aqueous-phase inorganics. When L. cholodnii SP-6 cells were cultured in media amended with high Fe(II) concentrations, Fe(III) precipitates visibly formed immediately after addition of Fe(II) to the medium, suggesting prompt abiotic oxidation of Fe(II) to Fe(III). Intriguingly, these precipitates were deposited onto the sheath surface of bacterial cells as the population was actively growing. When Fe(III) was added to the medium, similar precipitates formed in the medium first and were abiotically deposited onto the sheath surfaces. The precipitates in the Fe(II) medium were composed of assemblies of globular, amorphous particles (ca. 50 nm diameter), while those in the Fe(III) medium were composed of large, aggregated particles (≥3 µm diameter) with a similar amorphous structure. These precipitates also adhered to cell-free sheaths. We thus concluded that direct abiotic deposition of Fe complexes onto the sheath surface occurs independently of cellular activity in liquid media containing Fe salts, although it remains unclear how this deposition is associated with the previously proposed mechanisms (oxidation enzyme- and/or active group of organic components-involved) of Fe encrustation of the Leptothrix sheaths.


Edward Trautner (1890-1978), a pioneer of psychopharmacology.
This article examines the scientific career of Edward Trautner, who did pioneering research in the 1950s on lithium treatment for psychiatric disorders. Trautner was the first scientist to study the mechanism of action of lithium as a psychiatric medication. His research established that lithium could be used safely and rationally, and anticipated by a decade the large volume of research in the 1960s and 1970s that led to international acceptance of lithium treatment for mood disorders. Trautner was a pioneer of biological psychiatry who considered pharmacology to be a useful therapeutical tool rather than a permanent cure for putative chemical imbalances. His research involved cross-disciplinary collaborations that combined clinical and laboratory research in the disciplines of psychiatry, physiology, biochemistry, teratology, and even oncology. Trautner himself had a multidisciplinary background that included publications in literature and philosophy.


[Antitumor effect and mechanism of different extracts of cultivated Phellinus vaninii on H22 tumor bearing mice].
In order to explore the antitumor effect and mechanism of different extracts of cultivated Phellinus vaninii fruit body on H22 tumor bearing mice, 150 ICR mice were randomly divided into blank group, model group, CTX group, P. vaninii water extract group, ethanol extract group, petroleum ether extract group and crude polysaccharide group. H22 liver cancer cells were used to establish a solid tumor model and the mice were sacrificed on the 10th day after administration. The spleen and thymus organ index and tumor inhibition rate were calculated, the serum levels of TNF-α, INF-γ, VEGF, and hematoxylin-eosin were detected, and the immunohistochemical staining method was used to observe the pathological changes of tumor tissues, while Western blotting was used to detect the expression of tumor-related proteins. The high-dose petroleum ether extract group showed the best tumor inhibition rate (73.21%), increased serum levels of TNF-α, IFN-γ, and VEGF, as well as significantly promoted tumor necrosis and ablation. The immunohistochemistry of the water extract group showed negative regulation, indicating an insignificant tumor suppression. Western blotting showed the apoptosis genes Caspase-3, Caspase-9 and pathway genes NF-κB and JAK were all highly expressed in each administration group compared with the model group, and their expression levels gradually decreased with increasing doses. In summary, the petroleum ether extract of P. vaninii fruit body showed a significant anti-tumor effect which is presumably mediated through the mitochondrial pathway. The metabolism of drug in the body induces activation of Caspase-3 and Caspase-9 apoptotic proteins by Bax, Bcl-2, and TNF, which further caused nuclear chromatin or DNA to condense or degrade, and subsequently destroy the normal proliferation of tumor cells, thereby inducing their apoptosis and inhibiting tumor growth.


The CYP2W1 enzyme: regulation, properties and activation of prodrugs.
CYP2W1 is expressed in the course of development of the gastrointestinal tract, silenced after birth in intestine and colon by epigenetic modifications, but activated following demethylation in colorectal cancer (CRC). The expression levels in CRC positively correlate with the degree of malignancy, are higher in metastases and are predictive of colon cancer survival. The CYP2W1 transcripts have been detected also in hepatocellular carcinoma, adrenocortical carcinoma, childhood rhabdomyosarcoma and breast cancer; however, here the protein expression remains to be confirmed. The CYP2W1 enzyme has an inverted orientation in the endoplasmic reticulum membrane, as compared to other cytochrome P450s and its immediate electron donor is unknown. Several lipid ligands have been proposed as endogenous substrates, among which retinol derivatives appear to have the highest affinities. However, the role of CYP2W1 in the endogenous and tumor localized metabolism of retinol derivatives has yet to be clarified. Indolines constitute high affinity exogenous compounds and specific chloromethylindolines have been shown to be activated by CYP2W1 into cytotoxic products in vitro and also in vivo, inhibiting the growth of human colon tumors in a mouse xenograft model. The CRC specific localization of CYP2W1 and its effective prodrug activation makes it a very promising target for future development of cancer therapeutics.


Strict and fussy mode splitting in the tangent space of the Ginzburg-Landau equation.
In the tangent space of some spatially extended dissipative systems one can observe "physical" modes which are highly involved in the dynamics and are decoupled from the remaining set of hyperbolically "isolated" degrees of freedom representing strongly decaying perturbations. This mode splitting is studied for the Ginzburg-Landau equation at different strength of the spatial coupling. We observe that isolated modes coincide with eigenmodes of the homogeneous steady state of the system; that there is a local basis where the number of nonzero components of the state vector coincides with the number of "physical" modes; that in a system with finite number of degrees of freedom the strict mode splitting disappears at finite value of coupling; that above this value a fussy mode splitting is observed.


Guild structure and coexistence mechanisms in the parasitoid assemblage associated with a leafminer, Coptotriche japoniella (Lepidoptera, Tischeriidae), on an evergreen tree, Eurya japonica (Theaceae).
The parasitoid assemblage associated with a lepidopteran leafminer, Coptotriche japoniella (Tischeriidae), on an evergreen tree, Eurya japonica (Theaceae), was studied in the center of Japan to explore parasitoid coexistence mechanisms. The leafminer supported 12 parasitoid species. Eight abundant or common species were classified into five guilds according to their koinobiont/idiobiont mode and host-instar utilization pattern: early larval koinobiont, mid-larval idiobiont, mid-larval-late larval idiobiont, late larval-pupal idiobiont, and pupal idiobiont. The early larval koinobiont (Orgilus kumatai) and mid-larval idiobiont (Achrysocharoides sp.) seemed to be specialized on the host, whereas the members of the other guilds had a wide host range. The mid-larval-late larval (Cirrospilus diallus and Pnigalio sp.) or late larval-pupal idiobionts (Chrysocharis albipes, Apleurotropis kumatai, and Pleurotroppopsis japonica) facultatively hyperparasitized half of spinning larvae or pupae of the early larval koinobiont. These results suggest that parasitoid coexistence in this assemblage is greatly promoted by high levels of facultative hyperparasitism by idiobionts with wide host ranges on the dominant koinobiont.


Verification of gene expression profiles for colorectal cancer using 12 internet public microarray datasets.
To verify gene expression profiles for colorectal cancer using 12 internet public microarray datasets. Logistic regression analysis was performed, and odds ratios for each gene were determined between colorectal cancer (CRC) and controls. Twelve public microarray datasets of GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105, which included 519 cases of adenocarcinoma and 88 normal mucosa controls, were pooled and used to verify 17 selective genes from 3 published studies and estimate the external generality. We validated the 17 CRC-associated genes from studies by Chang et al (Model 1: 5 genes), Marshall et al (Model 2: 7 genes) and Han et al (Model 3: 5 genes) and performed the multivariate logistic regression analysis using the pooled 12 public microarray datasets as well as the external validation. The goodness-of-fit test of Hosmer-Lemeshow (H-L) showed statistical significance (P = 0.044) for Model 2 of Marshall et al in which observed event rates did not match expected event rates in subgroups of the model population. Expected and observed event rates in subgroups were similar, which are called well calibrated, in Models 1, 3 and 4 with non-significant P values of 0.460, 0.194 and 1.000 for H-L tests, respectively. A 7-gene model of CPEB4, EIF2S3, MGC20553, MS4A1, ANXA3, TNFAIP6 and IL2RB was pairwise selected, which showed the best results in logistic regression analysis (H-L P = 1.000, R (2) = 0.951, areas under the curve = 0.999, accuracy = 0.968, specificity = 0.966 and sensitivity = 0.994). A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.


Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial.
Scheduled treatment interruptions are being evaluated in an effort to decrease costs and side effects of highly active antiretroviral therapy (HAART). A schedule of 1 week on and 1 week off therapy offers the promise of 50% less drug exposure with continuously undetectable HIV RNA concentration. In the Staccato study 600 patients on successful HAART were to be randomized to either continued therapy, CD4-guided therapy, or one week on, one week off therapy. A scheduled preliminary analysis evaluated effectiveness in the 1-week-on-1-week-off arm. Of 36 evaluable patients, 19 (53%) had two successive HIV RNA concentrations > 500 copies/ml at the end of the week off therapy, and were classified as virological failure. Most of those who failed took didanosine, stavudine, saquinavir, and ritonavir (11 patients). In these patients, there was no evidence of mutations suggestive of drug resistance, and plasma saquinavir levels were within the expected range. Two of three patients failing on triple nucleotides had drug resistance mutations, but nonetheless responded to reintroduction of triple nucleotide therapy. One of two patients taking nevirapine, and one of eight taking efavirenz, also failed. Both had resistance mutations at the time of failure, but not at baseline. The 1-week-on-1-week-off schedule, as tested in the Staccato study, showed an unacceptably high failure rate and was therefore terminated.


Controlling film topography to form highly hydrophobic waterborne coatings.
Coatings have a tremendous impact on economy as they reduce corrosion that has an estimated cost of 3% of the world's GDP. Hydrophobic coatings are particularly efficient for this purpose and the challenge is to produce cost effective and environmentally friendly, highly hydrophobic, cohesive and non-porous coatings applicable to large and irregular surfaces. This work shows that this goal can be achieved by forming wrinkles on the surface of waterborne coatings through fine-tuning of the film forming conditions. The proof of concept was demonstrated by using waterborne dispersions of copolymers of 1H,1H,2H,2H-perfluorodecyl acrylate and 2-ethylhexyl acrylate, and using the temperature and hardness of the copolymer as control variables during film formation. This allowed the formation of transparent films with a wrinkled surface that had a contact angle of 133°, which represents an increase of 20° with respect to the film cast under standard conditions.


Open Anatomic Reconstruction of the Medial Collateral Ligament and Posteromedial Corner.
Injuries to the medial collateral ligament (MCL) and posteromedial corner can occur in isolation or in the setting of multiligamentous knee injuries. Reconstruction of the MCL and posteromedial corner is indicated in the setting of a multiligamentous knee injury. Isolated cases failing nonoperative treatment may also undergo surgical treatment. Our preferred technique for anatomic medial-sided knee reconstruction is an open anatomic MCL reconstruction using an Achilles tendon allograft along with direct repair of all associated medial and posteromedial structures.


Surgical technique determines the outcome of the Brescia/Cimino AVF.
Over the past 50 years, since Dr. Appel performed the first internal vascular access procedure for hemodialysis, the distal radiocephalic arteriovenous fistula continues to be the access of choice. Over time, failure to maturation has evolved as a major problem associated with this procedure depriving its benefits to many patients with end-stage renal disease. A variable incidence of this problem within similar patients suggests that surgical technique may play an important role in the development of non-maturation. Evaluating the current surgical techniques based on the hemodynamic consequences of anatomic and physiologic alterations following this procedure highlights the role of surgical technique in mitigating or reducing complications. Piggy-back straight line on-lay, a technique that helps to tailor the blood flow and reduce the oscillatory shear stress appears to reduce the incidence of early juxta-anastomotic problems, which contribute significantly to the problem of non-maturation.


CRISPR-Cas and Contact-Dependent Secretion Systems Present on Excisable Pathogenicity Islands with Conserved Recombination Modules.
Pathogenicity islands (PAIs) are mobile integrated genetic elements that contain a diverse range of virulence factors. PAIs integrate into the host chromosome at a tRNA locus that contains their specific bacterial attachment site, attB, via integrase-mediated site-specific recombination generating attL and attR sites. We identified conserved recombination modules (integrases and att sites) previously described in choleragenic Vibrio cholerae PAIs but with novel cargo genes. Clustered regularly interspaced short palindromic repeat (CRISPR)-associated proteins (Cas proteins) and a type VI secretion system (T6SS) gene cluster were identified at the Vibrio pathogenicity island 1 (VPI-1) insertion site in 19 V. cholerae strains and contained the same recombination module. Two divergent type I-F CRISPR-Cas systems were identified, which differed in Cas protein homology and content. The CRISPR repeat sequence was identical among all V. cholerae strains, but the CRISPR spacer sequences and the number of spacers varied. In silico analysis suggests that the CRISPR-Cas systems were active against phages and plasmids. A type III secretion system (T3SS) was present in 12 V. cholerae strains on a 68-kb island inserted at the same tRNA-serine insertion site as VPI-2 and contained the same recombination module. Bioinformatics analysis showed that two divergent T3SSs exist among the strains examined. Both the CRISPR and T3SS islands excised site specifically from the bacterial chromosome as complete units, and the cognate integrases were essential for this excision. These data demonstrated that identical recombination modules that catalyze integration and excision from the chromosome can acquire diverse cargo genes, signifying a novel method of acquisition for both CRISPR-Cas systems and T3SSs.IMPORTANCE This work demonstrated the presence of CRISPR-Cas systems and T3SSs on PAIs. Our work showed that similar recombination modules can associate with different cargo genes and catalyze their incorporation into bacterial chromosomes, which could convert a strain into a pathogen with very different disease pathologies. Each island had the ability to excise from the chromosome as distinct, complete units for possible transfer. Evolutionary analysis of these regions indicates that they were acquired by horizontal transfer and that PAIs are the units of transfer. Similar to the case for phage evolution, PAIs have a modular structure where different functional regions are acquired by identical recombination modules.


Subcuticular Rejection: an Advanced Mode of the Allogeneic Rejection in the Compound Ascidians Botrylloides simodensis and B. fuscus.
Allogeneic rejection between colonies (colony specificity) was described by electron microscopy in two compound ascidians, Botrylloides simodensis and B. fuscus. When two incompatible colonies are brought into contact at their growing edges, the tunic cuticle dissolves and the tunics of the colonies partially fuse. Alloreactive, humoral factors may diffuse to the opposite colony through the partially fusing tunic, and the tunic cells (free cells distributed in the tunic) possibly recognize these factors and induce a rejection reaction. Then, blood cells--mainly morula cells--infiltrate into the tunic, while tunic cells are disintegrating near where the partial fusion of the tunic is occurring. The infiltrating blood cells aggregate, disintegrate, and discharge electron-dense materials in the tunic at the subcuticular regions where the tunics have partially fused. Since the rejection lesion is restricted to the subcuticular area, some regulatory systems may be involved in this restriction. At the end, new walls are formed in the tunic matrix to separate the rejection lesion from the contacting colonies. The new wall is a continuous layer composed of electron-dense fibers and is structurally identical to the regenerating tunic cuticle. The mode of occurrence of colony specificity (Hirose et al., 1994) and the present results indicate that tunic cells are the only allorecognition sites in B. fuscus.


Ectopic expression of DICE1 suppresses tumor cell growth.
The tumor suppressor gene DICE1 is located within a previously reported critical region of loss of heterozygosity on chromosome 13q14.3. Expression of the remaining DICE1 allele is down-regulated in non-small cell lung carcinomas. Ectopic expression of DICE1 cDNA by DICE1-green fluorescent protein fusion constructs resulted in inhibition of colony formation of human non-small cell lung carcinoma cell line SK-MES-1 and NCI-H520 and prostate carcinoma cell line DU145. In IGF-IR transformed Balb/c 3T3, DICE1 substantially sup-pressed growth in soft agar. These results demonstrate that DICE1 has a growth-suppressing activity and interferes with anchorage-independent growth of IGF-IR transformed tumor cells dependent upon IGF-I signaling.


Co-morbidity of PTSD and immune system dysfunction: opportunities for treatment.
Posttraumatic stress disorder (PTSD) is defined as a psychiatric disorder; however, PTSD co-occurs with multiple somatic manifestations. People living with PTSD commonly manifest dysregulations in the systems that regulate the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis, and development of a pro-inflammatory state. Additionally, somatic autoimmune and inflammatory diseases and disorders have a high rate of co-morbidity with PTSD. Recognition and understanding of the compounding effect that these disease states can have on each other, evidenced from poorer treatment outcomes and accelerated disease progression in patients suffering from co-morbid PTSD and/or other autoimmune and inflammatory diseases, has the potential to lead to additional treatment opportunities.


Brain metastases from colorectal cancer: microenvironment and molecular mechanisms.
Colorectal cancer is one of the most common digestive tract malignancies in the world. Owing to the newer and more effective systemic therapies, the life of colorectal cancer patients can be remarkably prolonged, and the incidence of brain metastases is increasing. However, little is known about the underlying mechanisms of brain metastasis from colorectal cancer. Here we review the tumor microenvironment and metastasis associated molecules in brain metastases from colorectal cancer. A further understanding of these mechanisms will help us to propose better strategies for colorectal cancer patients with brain metastasis and improve their life quality.


Therapeutic effect of Xue Niao An on glyoxylate-induced calcium oxalate crystal deposition based on urinary metabonomics approach.
The anti-nephrolithiasis effect of Xue Niao An (XNA) capsules is explored by analyzing urine metabolic profiles in mouse models, with ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An animal model of calcium oxalate crystal renal deposition was established in mice by intra-abdominal injection of glyoxylate. Then, treatment with XNA by intra-gastric administration was performed. At the end of the study, calcium deposition in kidney was measured by Von Kossa staining under light microscopy, and the Von Kossa staining changes showed that XNA significantly alleviated the calcium oxalate crystal deposition. Meanwhile, urine samples for fifteen metabolites, including amino acids and fatty acids, with significant differences were detected in the calcium oxalate group, while XNA treatment attenuated metabolic imbalances. Our study indicated that the metabonomic strategy provided comprehensive insight on the metabolic response to XNA treatment of rodent renal calcium oxalate deposition.


Comprehensive Metabolic Profiling Reveals a Lipid-Rich Fingerprint of Free Thyroxine Far Beyond Classic Parameters.
Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular patterns associated with alterations in thyroid hormones levels remain to be explored in detail. A number of recent studies took great advantage of metabolomics profiling to outline the metabolic actions of thyroid hormones in humans. Among 952 participants in the Study of Health in Pomerania, data on serum free thyroxine (FT4) and thyrotropin and comprehensive nontargeted metabolomics data from plasma and urine samples were available. Linear regression analyses were performed to assess the association between FT4 or thyrotropin and metabolite levels. After accounting for major confounders, 106 of 613 plasma metabolites were significantly associated with FT4. The associations in urine were minor (12 of 587). Most of the plasma metabolites consisted of lipid species, and subsequent analysis of highly resolved lipoprotein subclasses measured by proton nuclear magnetic resonance spectroscopy revealed a consistent decrease in several of these species (e.g., phospholipids) and large low-density lipoprotein and small high-density lipoprotein particles. The latter was unique to men. Several polyunsaturated and saturated fatty acids displayed an association with FT4 in women only. A random forest-based variable selection approach using phenotypic characteristics revealed higher alcohol intake in men and an adverse thyroid state and menopause in women as the putative mediating factors. In general, our observations have confirmed the lipolytic and lipogenic effect of thyroid hormones even in the physiological range and revealed different phenotypic characteristics (e.g., lifestyle differences) as possible confounders for sex-specific findings.