[Some methodological aspects of age-period-cohort models. Application to cancer mortality trends].
Age-period-cohort models are usually used in descriptive epidemiological studies to analyze time trends in incidence or mortality. The exact linear relationship between the three effects of these models has the effect of making the parameters of the full model impossible to estimate, which is called non-identifiability. In these notes two of the most frequently used methods to analyze age-period-cohort models will be explained. One is based on penalty functions and the other on estimable functions (drift and curvatures or deviation from linearity). Both methods will be illustrated with two examples in which temporal trends of breast and lung cancer mortality in women from Catalonia in Spain will be studied. These examples show how the methods based on penalty functions tend to attribute the trend exclusively to a cohort effect. Consequently, the use of methods based on estimate functions is recommended.


[Effectiveness evaluation of Prodisc-C prosthesis for more than 10 years follow-up after total cervical disc replacement].
To evaluate long-term radiographic and clinical effectiveness of total cervical disc replacement (TDR) with Prodisc-C prosthesis at a minimum of 10 years follow-up. The clinical data of 118 patients with cervical disc degeneration disease (CDDD) treated with TDR by using Prodisc-C prosthesis between December 2005 and April 2008 were retrospectively analyzed. There were 66 males and 52 females, with the age of 25-62 years (mean, 46.8 years). There were 38 cases of cervical spondylotic radiculopathy, 28 cases of cervical spondylotic myelopathy, and 52 cases of mixed cervical spondylotic myelopathy. The operative segments were C 3-7, including 90 cases of single segment, 20 cases of continuous double segments, and 8 cases of continuous three segments. A total of 154 Prodisc-C prostheses were used during the operation. The clinical effectiveness was evaluated by pain visual analogue scale (VAS) score, neck disability index (NDI), Japanese Orthopaedic Association (JOA) score, and Odom grade before and after operation. Imaging evaluation indicators included range of motion (ROM), sagittal lordosis angle, intervertebral disc height (IDH), and prosthesis displacement, subsidence, loosening, locking, and heterotopic ossification (HO), adjacent segment degeneration (ASD), and other complications. Patients were grouped according to whether HO or ASD occurred or not, the ROM of surgical segment was compared. All patients were followed up 121-150 months (mean, 135.8 months). No revision operation was performed during the follow-up period. The VAS, NDI, JOA scores and Odom grades were significantly improved at 1 week after operation and last follow-up when compared with preoperative ones ( P<0.05); VAS and NDI scores were further improved at last follow-up than those at 1 week after operation ( P<0.05); there was no significant difference in JOA scores and improvement rates between at 1 week after operation and at last follow-up ( P>0.05). The ROM of the whole cervical spine and the operative segment decreased at 1 week and 10 years after operation when compared with preoperative ones ( P<0.05), but there was no significant difference in the other time points ( P>0.05); there was no significant difference in the ROM between the upper adjacent segment (UAS) and the lower adjacent segment (LAS) at each time point after operation ( P>0.05). There was no significant difference in sagittal lordosis angle of cervical spine before and after operation ( P>0.05); the sagittal lordosis angle of operative segment increased significantly at 1 week, 6 months, 1 year, and 2 years after operation ( P<0.05). The IDH of operative segment was significantly improved at each time point after operation ( P<0.05), but there was no significant difference in IDH between UAS and LAS at each time point after operation ( P>0.05). No prosthesis displacement, subsidence, or loosening occurred at each time point after operation. There was no significant difference of the prosthetic displacement and subsidence distance between all time points after 6 months after operation ( P>0.05). At last follow-up, the incidence of prosthetic locking/fusion was 10.4%, showing no significant difference when compared with 6 months (1.9%) ( P<0.05). The incidence of upper ASD and lower ASD was 1.3% and 2.6% respectively at 1 week after operation. The incidence of upper ASD and lower ASD increased gradually with time prolonging, and there were significant differences between different time points ( P<0.05). The ROM of operative segment in ASD group was lower than that in non-ASD group at each time point after operation, but there was no significant difference ( P>0.05). HO appeared in 58.4% of the segments at 6 months after operation, and the incidence of HO increased significantly with time, which was significantly different from that at 6 months after operation ( P<0.05). The ROM of operative segments in HO group was significantly lower than that in non-HO group at 6 months, 2 years, 5 years, and 10 years after operation ( P<0.05). TDR has little effect on adjacent segments, although there are some imaging complications, it has no significant effect on the improvement of overall clinical effectiveness. Prodisc-C prosthesis can provide long-term, safe, and definite clinical effectiveness in the treatment of CDDD.


Serum adipokines as non-invasive biomarkers in Crohn's disease.
Adipose tissue secretes molecules that can promote activity in Crohn's disease. We aimed to evaluate the role of serum adipokines as possible biomarkers in Crohn's disease. Serum samples were obtained from 40 patients with endoscopically active or quiescent Crohn's disease and 36 healthy controls. Serum leptin, ghrelin, resistin and adiponectin levels were analysed by Multiplex in a Luminex 200 system technology. Receiver Operating Characteristic curves were performed to evaluate the adipokines discriminatory capacity. A logistic regression adjusted by possible confounders (i.e. gender, age, BMI) was performed for those adipokines that showed an area under the curve > 0.7. No differences were found in age, gender or BMI among groups. Distribution for serum resistin was different among the three groups of study, and only this adipokine showed an area under the curve of 0.75 comparing actives patients and healthy control groups. Resistin median concentration was selected as a cut-off for a logistic regression analysis; odds ratio along its 95% confidence interval adjusted by gender, age, and BMI yielded a value of 5.46 (1.34-22.14) comparing actives patients and healthy controls. High concentration of serum resistin is probably associated to activity, being this association independent of gender, age or BMI.


Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects.
Although heparin is used as an anticoagulant, its biologic function remains unclear. Substantial evidence exists that suggests it may modulate many aspects of immune function and inflammation. We demonstrated, in a double-blind, placebo-controlled, crossover study involving 10 allergic subjects, that a small dose of heparin (25 U/kg) administered intravenously 10 min before challenge reduced the acute cutaneous reaction to 10 allergens and histamine from a group-average sum of mean (+/- SD) wheal diameters at a baseline of 29.9 +/- 10 mm and after normal saline placebo (29.5 +/- 10.7 mm) to after heparin (14.4 +/- 10.4 mm) (p < 0.02, Wilcoxon's signed rank test). In 15 subjects with asthma and dust mite allergy, nebulized heparin 20,000 units administered in a double-blind, placebo-controlled, crossover fashion 10 min before challenge inhibited the bronchospasm induced by inhaled dust mite extract. Log2 of the provocative dose of mite extract causing a 20% fall in FEV1 at baseline was 4.1 +/- 1.5 protein nitrogen units (PNU); after normal saline it was 4.5 +/- 2.0 PNU, and after heparin it was 5.1 +/- 2.5 PNU (p = 0.04). These data suggest heparin may have an inhibitory role in acute mast-cell-mediated allergic inflammation.


Evaluation for hierarchical diagnosis and treatment policy proposals in China: A novel multi-attribute group decision-making method with multi-parametric distance measures.
The policy 'hierarchical medical treatment system' promulgated by the State Council of China is an effective way to solve the problem of insufficient and unbalanced medical resources. In response, governments in different provinces explore a variety of different strategies to promote this policy, producing different results. To better strengthen the policy development, it is worthy to help policy-makers make decisions to elect the best one from different proposals. Thus, the aim of this paper is to develop a multi-attribute group decision-making (MAGDM) framework to better assist government select the optimal proposal. This study proposes a MAGDM method based on a family of q-rung orthopair fuzzy interaction power point Hamy mean operators to solve the above problem. To this end, new multi-parametric distance measures based on point operators in the framework of q-rung orthopair fuzzy set are proposed. With the help of the point distance measures, new power point operators average operator is also proposed. The results show that the proposed MAGDM method in this paper outperforms some existing methods and provides promising results for policy-makers seeking to identify the optimal hierarchical diagnosis and treatment policy (HDTP) proposal. Specifically, the results also revealed the best proposal for developing the HDTP proposals is Xiamen mode.


Automatic initialization for active contour model in breast cancer detection utilizing conventional ultrasound and Color Doppler.
Regular examination of breasts may prevent and help to cure because breast cancer is treatable when it is detected early. Therefore, a breast cancer screening modality being sensitivity and cost-effective like ultrasonic imaging modality (US), is strongly required. In addition, the combination of a conventional US and its adjunct, Color Doppler has been proved for decreasing the rate of false-positive in breast cancer diagnosis. Thus, combination of these imaging modalities in a breast cancer segmentation would provide some benefits as well. An effective method for feature segmentation, active contour model has been widely utilized for decades. A crucial stage that affects the performance of active contour model is the initialization. This paper proposes a novel method for an automatic initialization of active contour model designed specifically for US-based imaging modalities. The method estimates an initial contour by utilizing the fusion of conventional US and Color Doppler. Examples and comparisons with three state-of-the-art automatic initialization methods are demonstrated to present the advantages of the proposed method. The evaluation results show high accuracy of initialization as well as fast convergence to features of interest.


Cell cycle regulation of DNA replication initiator factor Dbf4p.
The precise duplication of eukaryotic genetic material takes place once and only once per cell cycle and is dependent on the completion of the previous mitosis. Two evolutionarily conserved kinases, the cyclin B (Clb)/cyclin-dependent kinase (Cdk/Cdc28p) and Cdc7p along with its interacting factor Dbf4p, are required late in G1 to initiate DNA replication. We have determined that the levels of Dbf4p are cell cycle regulated. Dbf4p levels increase as cells begin S phase and remain high through late mitosis, after which they decline dramatically as cells begin the next cell cycle. We report that Dbf4p levels are sensitive to mutations in key components of the anaphase-promoting complex (APC). In addition, Dbf4p is modified in response to DNA damage, and this modification is dependent upon the DNA damage response pathway. We had previously shown that Dbf4p interacts with the M phase polo-like kinase Cdc5p, a key regulator of the APC late in mitosis. These results further link the actions of the initiator protein, Dbf4p, to the completion of mitosis and suggest possible roles for Dbf4p during progression through mitosis.


Endopeptidase from rat liver membranes, which generates miniglucagon from glucagon.
An endopeptidase activity that cleaves glucagon, producing miniglucagon or glucagon (19-29), a Ca2+ pump inhibitory peptide, was isolated from rat liver membranes. The purified enzyme has a molecular mass of approximately 100 kDa and a pH optimum of approximately 8. It is inhibited by both sulfhydryl-blocking reagents and metal-chelating reagents and activated by thiol compounds. The partial N-terminal amino acid sequence of the 100-kDa protein does not correspond to any known protein. An antiserum was raised against a synthetic octapeptide corresponding to the N-terminal sequence. Immunoblot analysis of crude liver membranes revealed a single band at 100 kDa. Immunoreactivity was found in liver, pancreas, and heart, which are glucagon and miniglucagon target tissues, and in gastric mucosa and kidney. Low levels were detected in spleen, whereas immunoreactivity was undetectable in skeletal muscle and intestinal mucosa. The endopeptidase activity was inhibited by insulin, glucagon-like peptide-1, and glucagon-like peptide-1 (7-36) amide, whereas other peptides that contain dibasic sites had no effect on its activity, indicating that the endopeptidase does not display strict selectivity toward basic doublets.


Closed-loop low-frequency DBS restores thalamocortical relay fidelity in a computational model of the motor loop.
Closed-loop modulation of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) is investigated to automatically adjust the stimulation to the patients' conditions, optimize the clinical outcomes, and reduce the energy requirements. This study proposes a closed-loop control system for real-time adaptation of the STN-DBS amplitude based on the neural activity in the motor thalamus. Population-averaged post-stimulus time histograms are used to measure the average effects of STN-DBS on the thalamocortical neurons and a L2-norm minimization problem is solved to design the control algorithm, while the frequency of stimulation is kept constant. Applied on a large-scale, biophysically-based, anatomically-compliant model of the cortico-basal ganglia-thalamo-cortical motor loop under PD conditions, our adaptive DBS significantly (P-value P<;0.05) improved the relay fidelity of the thalamocortical neurons and restored the average power of the thalamocortical spike trains in the band [3, 100] Hz, two indicators of restored thalamocortical activity. Furthermore, adaptive-DBS significantly decreased the energy requirements when compared with non-adaptive-DBS at the same frequency. Finally, 30- and 60-Hz-adaptive-DBS determined the maximal restoration of thalamocortical activity and outperformed high-frequency, non-adaptive-DBS. Overall, results suggest that a feedback-controlled, low-frequency DBS pattern may result in significant restoration of the thalamocortical encoding while lowering the energy requirements.


Acute histopathological changes produced by Penicillium aurantiogriseum nephrotoxin in the rat.
Shredded wheat moulded by an isolate of Penicillium aurantiogriseum elicited progressive histopathological changes at the rat renal cortico-medullary junction during 5 days of dosing, when incorporated into diet as a 20% component. The changes of acute tubular necrosis and regeneration were seen in the P3 segment of the nephron. In rats exposed to contaminated diet for 5 days the histopathological changes regressed in severity by about one-half within a further 4 days on normal diet and by 7 days the tubular epithelium was nearly normal. A partially purified fraction of an alcohol extract, selected by preparative high-voltage electrophoresis and anion exchange and notably rich in amino-compounds, was typically nephrotoxic when given in diet over 4 days. Acute marked tubular necrosis also occurred when the same fraction was given intraperitoneally over a similar period. The acute histological changes provide a rapid bioassay for this Penicillium nephrotoxicity and facilitate the search for the toxic metabolite(s). The cumulative expression of necrosis and repair over only a few days in tubular epithelium suggests that chronic exposure will elicit a more complex pathology which might serve as an experimental model for the idiopathic Balkan endemic nephropathy.


Reductions in regimen distress are associated with improved management and glycemic control over time.
OBJECTIVE Cross-sectional and longitudinal associations among regimen distress (RD), self-management, and glycemic control were undertaken to explore mechanisms of operation among these variables. RESEARCH DESIGN AND METHODS In a behavioral randomized control trial (RCT) to reduce RD, 392 adults with type 2 diabetes were assessed for RD, diet, exercise, medication adherence, and HbA1c at baseline and at 4 and 12 months. Associations among RD, self-management, and HbA1c were examined in cross-sectional analyses at baseline, in prospective analyses using baseline values to predict change over time, and in time-varying analyses. RESULTS At baseline, greater RD and poorer medication adherence were independently associated with higher HbA1c (P = 0.05 and P < 0.001, respectively), and greater RD was associated with poorer medication adherence (P = 0.03). No consistent pattern of significant prospective associations was found. Significant time-varying findings showed that decreases in RD were associated with improvements in medication adherence (P < 0.01), physical activity (P < 0.001), and HbA1c (P = 0.02) over time following intervention. Changes in self-management were not associated with changes in HbA1c over time. CONCLUSIONS In the context of an RCT to reduce distress, RD, self-management, and HbA1c were interrelated in cross-sectional and time-varying analyses. Decreases in RD were associated with improvements in both self-management and HbA1c over 12 months. Findings point to the complex and likely multifaceted pathways of association among these key constructs, with results indicating significant linkages between RD and both self-management and glycemic control over time.


Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data.
Combinations of aspirin, clopidogrel, and vitamin K antagonists are widely used in patients after myocardial infarction. However, data for the safety of combinations are sparse. We examined the risk of hospital admission for bleeding associated with different antithrombotic regimens. By use of nationwide registers from Denmark, we identified 40 812 patients aged 30 years or older who had been admitted to hospital with first-time myocardial infarction between 2000 and 2005. Claimed prescriptions starting at hospital discharge were used to determine the regimen prescribed according to the following groups: monotherapy with aspirin, clopidogrel, or vitamin K antagonist; dual therapy with aspirin plus clopidogrel, aspirin plus vitamin K antagonist, or clopidogrel plus vitamin K antagonist; or triple therapy including all three drugs. Risk of hospital admission for bleeding, recurrent myocardial infarction, and death were assessed by Cox proportional hazards models with the drug exposure groups as time-varying covariates. During a mean follow-up of 476.5 days (SD 142.0), 1891 (4.6%) patients were admitted to hospital with bleeding. The yearly incidence of bleeding was 2.6% for the aspirin group, 4.6% for clopidogrel, 4.3% for vitamin K antagonist, 3.7% for aspirin plus clopidogrel, 5.1% for aspirin plus vitamin K antagonist, 12.3% for clopidogrel plus vitamin K antagonist, and 12.0% for triple therapy. With aspirin as reference, adjusted hazard ratios for bleeding were 1.33 (95% CI 1.11-1.59) for clopidogrel, 1.23 (0.94-1.61) for vitamin K antagonist, 1.47 (1.28-1.69) for aspirin plus clopidogrel, 1.84 (1.51-2.23) for aspirin plus vitamin K antagonist, 3.52 (2.42-5.11) for clopidogrel plus vitamin K antagonist, and 4.05 (3.08-5.33) for triple therapy. Numbers needed to harm were 81.2 for aspirin plus clopidogrel, 45.4 for aspirin plus vitamin K antagonist, 15.2 for clopidogrel plus vitamin K antagonist, and 12.5 for triple therapy. 702 (37.9%) of 1852 patients with non-fatal bleeding had recurrent myocardial infarction or died during the study period compared with 7178 (18.4%) of 38 960 patients without non-fatal bleeding (HR 3.00, 2.75-3.27, p<0.0001). In patients with myocardial infarction, risk of hospital admission for bleeding increased with the number of antithrombotic drugs used. Treatment with triple therapy or dual therapy with clopidogrel plus vitamin K antagonist should be prescribed only after thorough individual risk assessment. Danish Heart Foundation and the Danish Medical Research Council.


Evidence of the E*-E equilibrium from rapid kinetics of Na+ binding to activated protein C and factor Xa.
Na(+) binding to thrombin enhances the procoagulant and prothrombotic functions of the enzyme and obeys a mechanism that produces two kinetic phases: one fast (in the microsecond time scale) due to Na(+) binding to the low activity form E to produce the high activity form E:Na(+) and another considerably slower (in the millisecond time scale) that reflects a pre-equilibrium between E and the inactive form E*. In this study, we demonstrate that this mechanism also exists in other Na(+)-activated clotting proteases like factor Xa and activated protein C. These findings, along with recent structural data, suggest that the E*-E equilibrium is a general feature of the trypsin fold.


Fear of COVID-19 and Trust in the Healthcare System Mediates the Association between Individual's Risk Perception and Preventive COVID-19 Behaviours among Iranians.
Problems caused by the novel coronavirus disease-2019 (COVID-19) and its mutations have brought challenges in pandemic control for all countries worldwide. The present study examines the mediating roles of fear of COVID-19 and trust in the healthcare system in the association between individual's risk perception and performing preventive COVID-19 behaviours among Iranians. A cross-sectional study design was used to collect data from 3652 residents of Qazvin province in Iran from 3 February to 15 April 2021 using a multistage stratified cluster sampling method. Participants responded to an online questionnaire concerning their fear of COVID-19, risk perception, trust in the healthcare system, and preventive COVID-19 behaviours. Small to medium positive interrelationships were observed between the variables of the study. Fear of COVID-19, trust in the healthcare system or both (fear of COVID-19 and trust in the healthcare system) mediated the association between an individual's risk perception and performing preventive COVID-19 behaviours. The study demonstrated there are at least four ways through which an individual's risk perception can influence preventive COVID-19 behaviours. Therefore, clinicians, health communicators, and researchers may capitalize on these findings to enhance preventive COVID-19 behaviours to help mitigate the spread of COVID-19 infection.


The main immunogenic region of the acetylcholine receptor. Structure and role in myasthenia gravis.
Auto-antibodies to the nicotine acetylcholine receptor (AChR) cause the disease myasthenia gravis (MG). Animals immunized with AChR or receiving anti-AChR antibodies acquire MG symptoms. The majority of the monoclonal antibodies (mAbs) raised in rats against intact AChR bind to a region on the extracellular side of the AChR's alpha-subunit, the main immunogenic region (MIR). The major loop of the overlapping epitopes for several anti-MIR mAbs has been localised between residues 67-76 of the alpha-subunit. Anti-MIR mAbs are very potent in accelerating AChR degradation (antigenic modulation) in muscle cell cultures and transferring experimental MG in animals. Fab fragments of single anti-MIR mAbs when bound to the AChR inhibit two-thirds of the MG patients' antibodies from binding and from inducing antigenic modulation of the AChR. This suggest that the majority of the human MG antibodies are also directed against the MIR. It has however to be verified by direct experiments.


Preoperative prism adaptation in acquired esotropia.
41 patients with acquired esotropia who did not have preoperative prism adaptation were compared to 50 patients who were prism-adapted prior to surgery. Surgical success was evaluated at a postoperative period of 6 months. 82% of the patients who responded to prism adaptation had a successful surgical result as compared to only 51% of the patients who did not wear prisms preoperatively.


Use of competition ELISA for monitoring of West Nile virus infections in horses in Germany.
West Nile virus (WNV) is a mosquito-borne viral pathogen of global importance and is considered to be the most widespread flavivirus in the World. Horses, as dead-end hosts, can be infected by bridge mosquito vectors and undergo either subclinical infections or develop severe neurological diseases. The aim of this study was to detect WNV specific antibodies in horses in Germany as an indicator for an endemic circulation of WNV. Sera from more than 5,000 horses (primarily fallen stock animals) were collected in eight different federal states of Germany from 2010 to 2012. Sera were screened by a competitive ELISA and positive reactions were verified by an indirect IgM ELISA and/or by virus neutralization tests (VNT) for WNV and Tick-borne encephalitis virus (TBEV) in order to exclude cross-reacting antibody reactions. In essence WNV specific antibodies could not be detected in any of the horse sera. Not surprisingly, a small number of sera contained antibodies against TBEV. It is noteworthy that equine sera were often collected from horse carcasses and therefore were of poor quality. Nonetheless, these sera were still suitable for WNV ELISA testing, i.e., they did not produce a high background reaction which is a frequently observed phenomenon. According to these data there is no evidence for indigenous WNV infections in horses in Germany at present.


Is Endoscopic Assessment of the Esophagus and Stomach Enough to Determine the Need for Biopsy at These Sites in Pediatric Patients Undergoing Endoscopy for Elevated TTG?
The goal of our study was to determine whether visual assessment of the esophagus and stomach could predict abnormal histology and determine the frequency of interventions based on biopsies in patients undergoing endoscopy for elevated tissue transglutaminase immunoglobulin A antibody (TTG). Pathology records were searched for patients with biopsy performed for elevated TTG. Pathology report, endoscopy report, and follow-up were obtained and slides from the duodenum reviewed. Pathology was considered gold standard for sensitivity and specificity calculations. 240 patients were included. 215 patients had esophageal biopsies performed. Esophageal endoscopic visual assessment had sensitivity of 47% and specificity of 93% for abnormal histology. 16(7%) patients had therapy or referral related to results and, of these, 6(38%) had visually normal endoscopy. 237 biopsies were performed of stomach. Gastric endoscopic visual assessment had a sensitivity and specificity of 20% and 87%. 24(10%) patients had therapy based on findings and, of these, 12 (50%) had visually normal endoscopy. Endoscopic assessment of esophagus and stomach has low sensitivity and high specificity for pathologic abnormalities when indication for endoscopy is elevated TTG. When endoscopy is visually normal clinical interventions based on biopsy are rare, and foregoing biopsy may be considered.


GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis.
Temporal lobe epilepsy (TLE) is the most prevalent form of adult focal onset epilepsy often associated with drug-resistant seizures. Numerous studies suggest that neuroinflammatory processes are pathologic hallmarks of both experimental and human epilepsy. In particular, the interleukin (IL)-1β/IL-1 receptor type 1 (R1) axis is activated in epileptogenic tissue, where it contributes significantly to the generation and recurrence of seizures in animal models. In this study, we investigated whether IL-1β affects the GABA-evoked currents (I(GABA)) in TLE tissue from humans. Given the limited availability of fresh human brain specimens, we used the "microtransplantation" method of injecting Xenopus oocytes with membranes from surgically resected hippocampal and cortical tissue from 21 patients with TLE and hippocampal sclerosis (HS), hippocampal tissue from five patients with TLE without HS, and autoptic and surgical brain specimens from 15 controls without epilepsy. We report the novel finding that pathophysiological concentrations of IL-1β decreased the I(GABA) amplitude by up to 30% in specimens from patients with TLE with or without HS, but not in control tissues. This effect was reproduced by patch-clamp recordings on neurons in entorhinal cortex slices from rats with chronic epilepsy, and was not observed in control slices. In TLE specimens from humans, the IL-1β effect was mediated by IL-1R1 and PKC. We also showed that IL-1R1 and IRAK1, the proximal kinase mediating the IL-1R1 signaling, are both up-regulated in the TLE compared with control specimens, thus supporting the idea that the IL-1β/IL-R1 axis is activated in human epilepsy. Our findings suggest a novel mechanism possibly underlying the ictogenic action of IL-1β, thus suggesting that this cytokine contributes to seizure generation in human TLE by reducing GABA-mediated neurotransmission.


Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging.
Interleukin-1β is a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer's disease, Parkinson's disease, stroke and persistent pain. Activated microglia are the main cellular source of interleukin-1β in the brain. Cathepsin B is associated with the production and secretion of interleukin-1β through pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes. The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A, which can stabilize mitochondrial DNA. Therefore, microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging. Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.


Synthesis and photochemistry of a two-position Ru(terpy)(phen)(L)2+ scorpionate complex.
A dissymmetric 1,10-phenanthroline chelate (N-phen-S) bearing two polyether chains terminated by two monodentate ligands of the benzonitrile (N) and dialkylesulfoxide (S) types was synthesized, characterized, and coordinated to ruthenium. The corresponding Ru(terpy)(N-phen-S)2+ complexes (terpy = 4'-(3,5-ditertiobutylphenyl)-2,2';6',2' '-terpyridine) were fully characterized as being two coordination isomers of the scorpionate type with one of the two tails occupying the sixth position on the coordination sphere. Photoexpulsion of the coordinated tail led to opening of the ruthena-macrocycle and subsequent rearrangement of the bidentate chelate. This rearrangement consisted of a 90 degrees rotation of the phenanthroline around the ruthenium atom. Selective irradiation of one isomer in a mixture of the two was undertaken using band-pass filters; this resulted in an enrichment of the nonirradiated isomer in the mixture. Thermal back-coordination of the tail was investigated in the dark. It took place quantitatively from the corresponding ruthenium chloride complex by trapping of the anion with silver salts.


Cholesterol contributes to the organization of tetraspanin-enriched microdomains and to CD81-dependent infection by malaria sporozoites.
Tetraspanins constitute a family of widely expressed integral membrane proteins that associate extensively with one another and with other membrane proteins to form specific membrane microdomains distinct from conventional lipid rafts. So far, because of the lack of appropriate tools, the functionality of these microdomains has remained largely unknown. Here, using a new monoclonal antibody that only binds to the tetraspanin CD81 associated with other tetraspanins, we show that membrane cholesterol contributes to the organization of tetraspanin microdomains on the surface of live cells. Furthermore, our data demonstrate involvement of host membrane cholesterol during infection by Plasmodium yoelii and Plasmodium falciparum sporozoites, which both depend on host CD81 expression for invasion, but not during CD81-independent infection by Plasmodium berghei sporozoites. Our results unravel a functional link between CD81 and cholesterol during infection by malaria parasites, and illustrate that tetraspanin microdomains constitute a novel type of membrane microdomains that could be used by pathogens for infection.


Identification of a new chemically induced allele (Lp(m1Jus)) at the loop-tail locus: morphology, histology, and genetic mapping.
Loop-tail (Lp) is a semidominant mutation that affects neurulation in mice. Heterozygous animals are characterized by a looped-tail appearance (pig tail) and wobbly head movements while homozygous embryos exhibit a neural tube closure defect that extends from the caudal midbrain to the tip of the tail. The Lp gene has been finely mapped to the distal part of chromosome 1, and a positional cloning strategy has been initiated to isolate the defective gene. This study represents the characterization of a new Lp allele (Lp(m1Jus)) induced by N-ethyl-N-nitrosurea mutagenesis. Lp(m1Jus)/+ mice have a looped-tail appearance, and both Lp(m1Jus)/Lp(m1Jus) homozygotes and Lp/Lp(m1Jus) compound heterozygotes fail to initiate neural tube closure along most of the embryonic axis. These data indicate that the Lp(m1Jus) allele causes a neural tube defect and overall phenotype similar to that of the original Lp allele. Segregation analysis of 90 (Lp(m1Jus)/+ x C57BL/6J)F(1) x C57BL/6J looped-tail mice with seven markers that define the Lp genetic map (D1Mit455/D1Mit146/D1Mit148/D1Mit270-1 cM-D1Mit113-0.4 cM-Lp-0.2 cM-D1Mit149-0.8 cM-D1Mit115) showed significant linkage between Lp(m1Jus) and all loci analyzed (P < 0.0001). Eight crossovers were detected with the proximal cluster of D1Mit455, D1Mit146, D1Mit148, and D1Mit270, indicating a recombination rate higher than expected in this region, and a single recombinant was encountered with the distal markers D1Mit149 and D1Mit115. Based on these phenotypic and genetic data, Lp(m1Jus) is most likely allelic to Lp, thereby representing a valuable additional tool for the positional cloning of the Lp gene and its subsequent molecular characterization.


Differential gaze behavior towards sexually preferred and non-preferred human figures.
The gaze pattern associated with image exploration is a sensitive index of our attention, motivation, and preference. To examine whether an individual's gaze behavior can reflect his or her sexual interest, this study compared gaze patterns of young heterosexual men and women (M = 19.94 years, SD = 1.05) while they viewed photographs of plain-clothed male and female figures aged from birth to 60 years old. The analysis revealed a clear gender difference in viewing sexually preferred figure images. Men displayed a distinctive gaze pattern only when viewing 20-year-old female images, with more fixations and longer viewing times dedicated to the upper body and waist-hip regions. Women also directed more attention at the upper body on female images in comparison to male images, but this difference was not age-specific. Analysis of local image salience revealed that observers' eye-scanning strategies could not be accounted for by low-level processes, such as analyzing local image contrast and structure, but were associated with attractiveness judgments. The results suggest that the difference in cognitive processing of sexually preferred and non-preferred figures can be manifested in gaze patterns associated with figure viewing. Thus, eye-tracking holds promise as a potential sensitive measure for sexual preference, particularly in men.


Quercetin, coenzyme Q10, and L-canavanine as protective agents against lipid peroxidation and nitric oxide generation in endotoxin-induced shock in rat brain.
The present study was designed to evaluate the possible protective effect of quercetin, coenzyme Q10 (CoQ10), or L-canavanine treatments against endotoxin-induced shock in rat brain. Shock was induced by i.p. injection of 10 mg x kg(-1)of lipopolysaccharide (LPS) and was biochemically manifested 2 h after injection as an increase in brain malondialdehyde (MDA), total nitrite/nitrate (NO(x)), glutathione peroxidase (GSHPx), and blood lactate level/activity. On the other hand, endotoxemia resulted in reduced brain glutathione (GSH) and phospholipids' content as well as the serum sulfhydryl groups' (SH-group) value. Pretreatment with quercetin (200 mg x kg(-1)per os) 2 h before LPS injection diminished the shock-induced increases in brain MDA, and NO(x)levels while elevating the reduced brain phospholipids' and serum SH groups' content. CoQ10 administered at a dose of 200 mg x kg(-1)per os for 7 days prior to shock induction, reduced the elevated levels of brain MDA, NO(x), and GSHPx level/activity due to redundancy. The same treatment caused a 3-fold increase in the reduced brain GSH level and normalized the depressed phospholipids' content. Treatment of animals with L-canavanine (50 mg x kg(-1)i.p.) simultaneously with LPS injection, reduced the elevated level of blood lactate. Brain superoxide dismutase (SOD) level was neither affected by endotoxin nor by different treatments. In conclusion, this study indicates that SOD may not reflect the level of peroxidation and points to the value of quercetin, CoQ10, and L-canavanine in ameliorating the oxidative status of brain during the early phase of endotoxic shock.


Pleural actinomycosis in a free-ranging river otter (Lontra canadensis).
Actinomycosis, presenting as chronic proliferative pyogranulomatous pleuritis associated with sulfur granules, was diagnosed in a mature male river otter (Lontra canadensis) captured near Victoria, British Columbia, Canada, in April 2010. The river otter died during sedation for clinical examination and was necropsied immediately. Bacteria of the genus Actinomyces are commensals of the mucous membranes in a wide range of animals and people that act as opportunistic pathogens. This is the first report of actinomycosis in a river otter.


Control of hypertension in Turkey--is it improving? The Kocaeli 2 study.
In a previous study conducted in Kocaeli, Turkey, ten years before, a very low rate of hypertension control (6.2%) was reported. This hypertension survey was conducted to determine whether the treatment and control rates of hypertension improved in the same region. Using a stratified sampling method, 1222 subjects (559 males, 663 females, mean age 44.8+/-13.6 years) living in Kocaeli, aged 25 or over, were included. After administration of a standardized questionnaire, blood pressure was measured in the sitting position from both arms after at least five minutes of resting. The measurement was repeated after 10 minutes on the arm with the higher initial reading. Hypertension was defined as the presence of a mean systolic blood pressure = or >140 mmHg and/or a mean diastolic blood pressure = or >90 mmHg, or a previous diagnosis of hypertension and/or use of antihypertensive drugs. The prevalence of hypertension was 33.6% (37.1% in women, and 29.5% in men, p<0.001). Of the hypertensive subjects, 59.3% were aware of their condition. Hypertension was controlled in 8.7% of the subjects (systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg). Our results showed that about one-third of the adult population in Kocaeli had hypertension, with low rates of control and awareness. Since the previous survey, there has been a small improvement in hypertension control rate, but uncontrolled hypertension is still remarkably high in this geographical region. These findings are consistent with the recent Turkish Hypertension Prevalence study (PatenT) reporting a control rate of 8.1%.


A case of prenatal diagnosis of meckel-gruber syndrome in one of the dizygotic twin of a naturally conceived pregnancy.
Meckel-Gruber syndrome in one twin of a naturally conceived dizygotic twin pregnancy is largely unknown and has not been reported till date. This report illustrates the sonographic features in a case of 20-week twin pregnancy where one twin had an occipital encephalocele, bilateral enlarged and cystic kidneys, hepatic cyst and oligohydramnios but the other twin was normal. The affected twin succumbed within few days after normal vaginal delivery while the normal twin survived and is healthy.


Cardiorenal risk prevalence in sickle cell hemoglobinopathy.
The spectrum of kidney functional and structural alterations in sickle cell hemoglobinopathy (SCH) is broad. Also, morbidity and mortality from end organ dysfunction, especially cardiorenal dysfunction, are substantial. Consequently, screening an SCH population prospectively for surrogate markers of cardiorenal risk such as albuminuria and intima-media thickness (IMT) was the aim of this cross-sectional study. We screened 165 patients with SCH over 4 months at the Primary Care Department, King Abdulaziz Armed Forces Hospital, Saudi Arabia. The 133 who fulfilled the inclusion criteria have been referred for further investigations. Anthropometric evaluation of body mass index (BMI) and blood pressure (BP), determination of 24-hour urine albuminuria, fasting lipids, computed atherogenic risk ratio (ARR), estimated glomerular filtration rate (eGFR), common carotid artery (CCA) IMT measurements, and hemoglobin (Hb) electrophoresis were done. Increased urinary albumin excretion (UAE) rate [380 (272.2-489.6) mg/day; mean and 95% confidence interval (95% CI) of mean] was detected in 24% of SCH patients (6 males and 26 females). Microalbuminuria (168.8 +/- 59.7 mg/day) was noted in the majority (63.6%) while macroalbuminuria (752.7 +/- 205.4 mg/day) was detected in a smaller percentage (36.4%). Patients with sickle cell disease (SCD) contributed about 66.6% of subjects with microalbuminuria and 100% of those with macroalbuminuria, while most individuals with sickle cell trait (89%) were normoalbuminuric (p < 0.0001). Preclinical atherosclerosis (increased CCA IMT and/or atheromatous plaques) was noticed in 68.8% of SCH individuals with increased UAE (ANOVA p = 0.003). The microalbuminuric and macroalbuminuric patients had comparable BMI, BP values and lipid profiles. However, the microalbuminuric sicklers were significantly younger (28.4 +/- 6.7 vs. 34.0 +/- 7.2 years, p = 0.04), less anemic (Hb: 9.13 +/- 2 vs. 7.47 +/- 0.8 g/dl, p = 0.015), with lesser atherosclerosis (IMT; 0.68 +/- 0.1 vs. 0.78 +/- 0.1 mm, p = 0.004) and higher eGFR (83.3 +/- 17.2 vs. 61 +/- 10.7 ml/min/1.73 m(2), p = 0.0004) compared to those with macroalbuminuria. UAE correlated positively with age (r = 0.591, p = 0.0001), systolic BP (r = 0.483, p = 0.005), IMT (r = 0.399, p = 0.024) and negatively with Hb (r = -0.409, p = 0.02), and eGFR (r = -0.620, p = 0.0001). By univariate analysis, the significant indicators of UAE in SCH patients were age (p = 0.05), BMI (p = 0.041), IMT (p = 0.018) and eGFR (p = 0.016). Also, increased risk (odds ratio) of albuminuria was noted with SCD, age, anemia, abnormal eGFR, obesity, and ARR. Markers of cardiorenal risk such as albuminuria and IMT are common findings in SCH patients of Arabic descent and could be useful screening tools to identify sicklers at risk for cardiovascular and renal events.


Detection of Regional Mechanical Activation of the Left Ventricular Myocardium Using High Frame Rate Ultrasound Imaging.
We have investigated the feasibility of noninvasive mapping of mechanical activation patterns in the left ventricular (LV) myocardium using high frame rate ultrasound imaging for the purpose of detecting conduction abnormalities. Five anesthetized, open-chest dogs with implanted combined sonomicrometry and electromyography (EMG) crystals were studied. The animals were paced from the specified locations of the heart, while crystal and ultrasound data were acquired. Isochrone maps of the mechanical activation patterns were generated from the ultrasound data using a novel signal processing method called clutter filter wave imaging (CFWI). The isochrone maps showed the same mechanical activation pattern as the sonomicrometry crystals in 90% of the cases. For electrical activation, the activation sequences from ultrasound were the same in 92% of the cases. The coefficient of determination between the activation delay measured with EMG and ultrasound was R 2 = 0.79 , indicating a strong correlation. These results indicate that high frame rate ultrasound imaging processed with CFWI has the potential to be a valuable tool for mechanical activation detection.


Management of a postradiation esophageal web in the setting of a coexisting Zenker's diverticulum.
We present a case of postradiation obstructive esophageal web, seen in the setting of a coexisting Zenker's diverticulum, that was treated with combined anterograde and retrograde esophagoscopy puncture and dilation. We also review the relevant literature. Obstructing esophageal webs and stenoses are well-documented complications seen in patients with head and neck cancer treated with radiation therapy. For thin webs, combined anterograde and retrograde esophagoscopy along with puncture and dilation can be a relatively safe treatment option for selected patients. The presence of a coexisting Zenker's diverticulum may predispose the patient to the development of postradiation esophageal complications and make subsequent assessment more difficult to perform.


The interaction of the cellular export adaptor protein Aly/REF with ICP27 contributes to the efficiency of herpes simplex virus 1 mRNA export.
Herpes simplex virus 1 (HSV-1) protein ICP27 enables viral mRNA export by accessing the cellular mRNA export receptor TAP/NXF, which guides mRNA through the nuclear pore complex. ICP27 binds viral mRNAs and interacts with TAP/NXF, providing a link to the cellular mRNA export pathway. ICP27 also interacts with the mRNA export adaptor protein Aly/REF, which binds cellular mRNAs and also interacts with TAP/NXF. Studies using small interfering RNA (siRNA) knockdown indicated that Aly/REF is not required for cellular mRNA export, and similar knockdown studies during HSV-1 infection led us to conclude that Aly/REF may be dispensable for viral RNA export. Recently, the structural basis of the interaction of ICP27 with Aly/REF was elucidated at atomic resolution, and it was shown that three ICP27 residues, W105, R107, and L108, interface with the RNA recognition motif (RRM) domain of Aly/REF. Here, to determine the role the interaction of ICP27 and Aly/REF plays during infection, these residues were mutated to alanine, and a recombinant virus, WRL-A, was constructed. Virus production was reduced about 10-fold during WRL-A infection, and export of ICP27 protein and most viral mRNAs was less efficient. We conclude that interaction of ICP27 with Aly/REF contributes to efficient viral mRNA export.


Breast ultrasonographic and histopathological characteristics without any mammographic abnormalities.
We evaluated ultrasonographic findings and the corresponding histopathological characteristics of breast cancer patients with Breast Imaging Reporting and Data System (BI-RADS) category 1 mammogram. We retrospectively reviewed the ultrasonographic findings and the corresponding histopathological features of 45 breast cancer patients with BI-RADS category 1 mammogram and 537 controls with mammographic abnormalities. We evaluated the ultrasonographic findings including mass shape, periphery, internal and posterior echo pattern, interruption of mammary borders and the distribution of low-echoic lesions, and the corresponding histopathological characteristics including histological classification, hormone receptor and human epidermal growth factor receptor 2 status of invasive ductal carcinoma and ductal carcinoma in situ, histological grade, mitotic counts and lymphovascular invasion in individual cases of BI-RADS category 1 mammograms and compared with those of the control group. The ultrasonographic characteristics of the BI-RADS category 1 group were characterized by a higher ratio of round shape (P< 0.001), non-spiculated periphery (P= 0.021), non-interruption of mammary borders (P< 0.001) and non-attenuation (P= 0.011) compared with the control group. A total of 52.6% of low-echoic lesions were associated with spotted distribution in the BI-RADS 1 group, whereas 25.8% of low-echoic lesions were associated with spotted distribution in the control group (P= 0.012). As for histopathological characteristics, there was a statistically higher ratio of triple-negative subtype (P= 0.021), and this particular tendency was detected in histological grade 3 in the BI-RADS category 1 group (P= 0.094). We evaluated ultrasonographic findings and the corresponding histopathological characteristics for BI-RADS category 1 mammograms and noted significant differences among these findings in this study. Evaluation of these ultrasonographic and histopathological characteristics may provide a more accurate ultrasonographic screening system for breast cancer in Japanese women.


Regional differences in dialysis care and mortality among American Indians and Alaska Natives.
American Indians/Alaska Natives (AIANs) compose a heterogeneous population that includes geographically distinct tribal communities, many with high rates of ESRD. Regional features of dialysis care and mortality are unknown in this population. Here, we describe the structure of dialysis care and mortality of adult AIANs who initiated maintenance dialysis during 1995-2008 in different regions of the US. Overall, 13,716 AIANs received dialysis at 2054 facilities. Approximately 10% (n = 197) of these facilities provided care to two-thirds (n = 9011) of AIANs. AIANs from the Southwest and Alaska were concentrated in relatively few dialysis facilities whereas those in the Eastern US and Pacific Coast were distributed more diffusely. Despite comparably high rates of poverty, diabetes, and cardiovascular disease, annual mortality rates were lower in the Southwest (13.9%) compared with the Southern Plains (23.2%), Alaska (21.2%), Eastern US (20.0%), Northern Plains (20.8%), and Pacific Coast (22.0%). These regional differences were consistent over time and persisted after adjusting for sociodemographic and clinical variables and area-based poverty. In conclusion, regional differences in the structure of dialysis care and patient mortality exist among AIANs. Southwestern AIANs experience the highest concentration of dialysis care and the lowest mortality. Our findings suggest that an area-based approach examining the care structure of relatively few dialysis facilities may delineate determinants of these differences and improve the quality of care to many AIAN communities.


[Case report of hereditary hemorrhagic telangiectasia in children and literature review].
Objective: To analyze the clinical features of 2 children with hereditary hemorrhagic telangiectasia (HHT) and review relevant literature. Methods: The clinical data of 2 children with HHT who were admitted to Beijing Children's Hospital, Capital Medical University from February 2017 to June 2018 were retrospectively analyzed. Meanwhile, the relevant papers published before December 2019 in Wanfang and Pubmed database were searched with the key words of "hereditary hemorrhagic telangiectasia" in Chinese and English, and reviewed. Results: The first case was an 11-year-old boy, presented with fever and cough for 6 days. His past history revealed 3 times of left pneumonia and mild epistaxis. Ultrasound of the chest soft tissue found hemangioma and vascular malformation. Enhanced CT with vascular reconstruction suggested pulmonary arteriovenous malformation and multiple arteriovenous fistulas in the liver. After being treated with interventional pulmonary arteriovenous fistula embolization, his condition improved. The second case was a 12-year-old girl, presented with iron deficiency anemia during the past 3 years. Endoscopic resection of polyps had been performed before due to multiple polyps in the colon. High-resolution lung CT revealed multiple ground-glass nodules in bilateral lungs. Ultrasound of the digestive tract suggested small intestine polyps and secondary chronic loose intussusception. After admission, small bowel intussusception reduction was performed, and the polyps were ligated. Her whole exon gene testing suggested SMAD4 heterozygous variation. In the large number of reported cases, HHT1 and HHT2 are the main type. Conclusions: Children with HHT may present with anemia and repeated intestinal polyps. It is worth noting that visceral arteriovenous malformations, such as pulmonary arteriovenous malformations, which is easily misdiagnosed as recurrent pneumonia, can also occur in children with HHT. Enhanced CT with vascular reconstruction can help find pulmonary arteriovenous malformation, and timely genetic test can confirm the diagnosis.


A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.
Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.


Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: the FIL FOLL05 trial.
The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP. DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months. At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (<1 × 10(-4) copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3-year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD(-) cases versus 41% for those MRD(+) at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR(-) vs. 32% for those CR/PCR(+) vs. 62% for those PR/PCR(-) and 25% for patients in PR/PCR(+); P = 0.001). The prognostic value of MRD at 12 and 24 months of follow-up was confirmed also in multivariate analysis. In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy.


Driven hematopoietic differentiation of embryonic stem cells: epigenetic perspectives.
Hematopoietic progenitors derived from human embryonic stem cells (hESCs) present both a potential cell source for cell-replacement therapies and an in vitro model for hematopoietic stem cell (HSC) development. Current protocols for the hematopoietic differentiation of hESCs suffer from low efficiency and functional defects in the derived HSCs. Epigenetic mechanisms of HSC development should be addressed to overcome these imperfections. The focus of this review is to summarize the knowledge on the epigenetic regulation of pluripotency and lineage-specific genes with the emphasis on the hematopoietic cell lineage. The potential utilization of this knowledge to improve the generation of HSCs for clinical application is also discussed.


Measures of Relative Dentary Strength in Rancho La Brea Smilodon fatalis over Time.
The late Pleistocene megafaunal extinction of approximately 12,000 years ago, included the demise of Smilodon fatalis, a hypercarnivore from the Rancho La Brea deposits, which has been studied across time by looking at different deposits or pits to determine morphological size and shape changes and trends during this time. To better understand functional aspects of these changes, this study focused on a measure of jaw strength over time, which can give an indication of morphological changes within the jaw that cannot be seen using surface morphometrics. By radiographing dentaries, cortical bone can be seen, which provides an estimate of resistance to bending forces while biting, and can be measured and used as an indicator of jaw strength. Measurements were taken at repeatable locations on the dentary of the depth of the cortical bone, and of a standardized measure of cortical bone, which allows for the comparison between different individuals. Specimens included those of five different pits ranging from about 37 Kybp to 13 Kybp (just before the extinction of S. fatalis). No significant difference was found in the depth of jaws at any of the measurement points from any of the pits. However, significant differences were found in both the actual thickness of cortical bone, and the standardized thickness of cortical bone at the lower P4 between pit 13 (which had the lowest amount of bone) and pit 61/67 (which had the highest). These conclusions support other studies that have shown that individuals in pit 13 were under physiological and perhaps dietary stress, which may be reflected in the deposition of cortical bone, while the opposite trend is seen in the individuals in pit 61/67. Our results further support findings suggesting Smilodon did not appear to be morphologically most vulnerable right before its extinction.


Accumulation of macrophages expressing myeloid-related protein 8 associated with the progression of sclerotic changes in children with IgA nephropathy.
Myeloid-related protein (MRP) 8 is a calcium-binding protein of the S100 family. The renal accumulation of macrophages expressing MRP8 is associated with the inflammatory activity of glomerulonephritis. We evaluated the renal accumulation of macrophages expressing MRP8 in children with IgA nephropathy (IgAN). We collected data on 25 IgAN children who had been treated with prednisolone and divided these patients into two groups: Favorable group, consisting of 11 patients with normal urine and 6 with minor urinary abnormalities at 4.3 +/- 1.3 years after initial treatment; and Unfavorable group, consisting of 8 patients with persistent nephropathy. The pathological renal findings were compared between both groups. The second biopsy was performed at two years after first biopsy at 5.5 +/- 4.9 months from onset. In Favorable group, the glomerular accumulation of macrophages expressing MRP8, and mesangial cells expressing alpha-smooth muscle actin (alpha-SMA) were lower in the second biopsy specimens than those of the first biopsy specimens. In Unfavorable group, the glomerular accumulation of macrophages expressing MRP8 detected in the second biopsy specimens was similar to that of the first biopsy, while the number of mesangial cells expressing alpha-SMA and the index of renal sclerosis were higher in the second biopsy than in the first biopsy. The indexes of renal sclerosis were higher in children with more macrophages expressing MRP8 than in children with less macrophages expressing MRP8. Our results suggest that renal macrophages expressing MRP8 may be involved in the progression of sclerotic changes in children with IgAN.


Chromosome and bcr rearrangement in chronic myelogenous leukaemia and their correlation with clinical states and prognosis of the disease.
Among 77 unselected patients with chronic myelogenous leukaemia (CML), 70 had Philadelphia chromosome (Ph1) in blood cells. Extra chromosomal abnormalities were noted in 4%, 55% and 78% of Ph1-positive patients in chronic phase, accelerated phase and acute blast crisis, respectively. Rearrangement of the bcr was detected in 46 of 47 Ph1-positive patients studied and also in three of five Ph1-negative ones. The locations of the breakpoints were mapped to one of four zones of the bcr in 45 patients. The median duration from diagnosis of CML to onset of acute blast crisis was not significantly different between the two groups of patients with breakpoints in the 5' portion (34 months), and in the 3' portion (39 months) of the bcr. In addition, the locations of the breakpoints within the bcr did not change as the disease progressed in the six patients who had DNA analysed both in the chronic phase and subsequently in transformation. In one of them, an additional aberrant band which was not present in the beginning of the acute phase was detected in blood cells taken 2 months later. It is suggested from the studies that transformation of CML may not be related to alterations within the bcr.


Vibration spectroscopy reveals light-induced chromophore and protein structural changes in the LOV2 domain of the plant blue-light receptor phototropin 1.
Phototropins (phot1 and phot2), the plant blue-light receptors for phototropism, chloroplast movement, and stomatal opening, are flavoproteins that contain two approximately 12 kDa FMN-binding domains, LOV1 and LOV2, at their N-terminus, and a serine/threonine protein kinase domain at their C-terminus. The light-activated LOV2 domain forms a metastable intermediate which has been shown to be a protein-chromophore cysteinyl adduct (Cys39) at C(4a) of FMN. This species thermally relaxes back to the ground state in the dark. We measured the light-minus-dark FTIR difference spectra for the LOV2 domain of oat phot1. These spectra show the disappearance of bands at 1580, 1550, and 1350 cm(-1) that originate from, or are strongly coupled to, the N5=C(4a) stretching vibrations, consistent with the perturbations expected upon C(4a) adduct formation. Assignment of these negative difference FTIR bands to native chromophore vibrations is based on the alignment with resonance Raman bands of FMN. Prominent positive bands include a doublet at 1516 and 1536 cm(-1) and one at 1375 and 1298 cm(-1). Normal-mode vibrational-frequency calculations for both lumiflavin and lumiflavin with a sulfur attached at the C(4a) position agree with many of the positive and negative bands observed in the difference spectra. Both calculated and experimental difference FTIR spectra for deuterium isotope substitutions at exchangeable positions in the flavin chromophore are consistent with the assignment of the above positive bands to vibrational modes involving both the newly formed tetrahedral geometry of C(4a) and the N5-H bond in the long-lived LOV2(S)(390) cysteinyl species.


Cytokeratin expression in human stomach. Immunofluorescence study.
Twenty one samples of normal human stomach were examined for the cytokeratin pattern by immunofluorescence microscopy of cryostat sections. In all cases epithelial cells of stomach showed reactivity with monoclonal antibodies directed against individual cytokeratins No. 8,18 and 19. In 5 cases epithelial cells of stomach were also positive for keratin 7. The results show that there are "subtype" of gastric epithelial cells, positive for keratin No. 7.


Human chymotrypsinogen B production from Pichia pastoris by integrated development of fermentation and downstream processing. Part 2. Protein recovery.
The purification of human chymotrypsinogen B (hCTRB) after expression and secretion by the yeast Pichia pastoris is described based on two different approaches using integrated initial recovery. Extraction employing aqueous two-phase systems (ATPS) from poly(ethylene glycol) and sodium sulfate allows direct processing of cell containing yeast suspensions of 50% wet weight. The target protein is obtained partially purified in the top phase while cells and cell debris are partitioned to the bottom phase of the system. hCTRB is further purified by adsorption from the top phase to the cation exchanger SP Sepharose Big Beads and elution in a salt step. The single step isolation of hCTRB is possible by expanded bed adsorption (EBA) using a fluidized cation exchanger (Streamline SP XL). A design strategy is shown taking both target protein binding and stable fluidization of the stationary phase in cell containing suspensions into consideration. For the example of hCTRB isolation from cell containing P. pastoris suspensions, a successful use of this strategy is demonstrated. Both initial recovery strategies deliver a product that can be further purified and formulated by ultrafiltration/diafiltration followed by lyophilization, resulting in a homogeneous product. Scale-up to 30-90 L of culture suspension was shown for both methods, resulting in a product of similar quality. Comparing both strategies reveals that the two-step ATPS route is better suited for high cell density cultures, while the single step EBA method is preferred for cultures of moderate cell density. This is due to the fact that application of EBA is restricted to suspensions of 10-12.5% wet weight cell concentration, thus necessitating dilution of the original broth prior to sample application. The data presented show that integrated recovery operations are a valuable alternative to traditional processing for systems that are problematic during initial solid-liquid separation.


Role of chemotherapy in prostate cancer.
Chemotherapy in prostate cancer (PCa) has undergone dramatic landscape changes. While earlier studies utilized varying chemotherapy regimens which were found to be largely palliative in nature and hardly resulted in durable or meaningful responses, docetaxel resulted in the first chemotherapy agent that showed improvement in overall survival in metastatic castration-resistant prostate cancer (mCRPC). However, combination chemotherapy or any agents added to docetaxel have failed to yield incremental benefits. The improvement in overall survival as well as secondary endpoints of prostate-specific antigen (PSA) and time to recurrence when using docetaxel in the metastatic hormone-sensitive state has changed the standard of care for treatment of newly diagnosed de novo metastatic PCa. There are also promising results in locally advanced PCa and high-risk PCa in both the neoadjuvant and adjuvant settings. This review summarizes the historical as well as the more contemporary use of chemotherapeutic agents in PCa in varying states and phases of disease.


Correlation of lipid peroxidation and ATP enzyme on erythrocyte membrane with fetal distress in the uterus in patients with intrahepatic cholestasis of pregnancy.
This paper aims to investigate the correlation of lipid peroxide in erythrocytes and ATP (Adenosine Triphosphate) enzyme activity of erythrocyte membrane with fetal distress in patients with intrahepatic cholestasis of pregnancy (ICP). Forty-three patients with ICP treated at Jining No. 1 People's Hospital were enrolled as a study group, and another forty healthy parturient women in the same period were enrolled as a control group, to extract their elbow venous blood and fetal umbilical cord blood. Thiobarbituric acid (TBA) was used to detect superoxide dismutase (SOD) activity of erythrocytes, malondialdehyde (MDA) activity in plasma, Na+-K+-ATP enzyme activity and Ca2+-Mg2+-ATP enzyme activity of erythrocytes, which were compared between the study and control groups. The correlation of MDA, Na+-K+-ATP enzyme and Ca2+-Mg2+-ATP enzyme activities with fetal distress in the study group was analyzed, and the correlation of MDA with Na+-K+-ATP enzyme activity was investigated. SOD and MDA activities of erythrocytes in maternal blood of the study group were significantly higher than those in the control group (p<0.05, p<0.001, respectively), but MDA activity in umbilical cord blood of the study group was markedly higher than that in the control group (p<0.001). Na+-K+-ATP enzyme and Ca2+-Mg2+-ATP enzyme activities of maternal and fetal erythrocytes of the study group were remarkably lower than those of the control group (p<0.001). MDA in the fetal distress group was significantly higher than that in the no fetal distress group in the study group (p<0.001). Na+-K+-ATP enzyme activity was negatively correlated with MDA concentration in maternal and fetal erythrocytes of patients with ICP (both p<0.001). Lipid peroxidation in patients with ICP will affect ATP enzyme activity of erythrocyte membrane, and the down-regulation of ATP enzyme activity in umbilical cord blood of patients with ICP may cause fetal distress in the uterus.


Association between insulin secretory pulse frequency and peripheral insulin action in NIDDM and normal subjects.
Abnormalities of both insulin secretion and insulin action occur in NIDDM. It is not clear, however, which is the primary defect. Recently, it has been suggested that the frequency of insulin pulses is an important factor regulating insulin action in normal humans. We examined the relationship between pulsatile insulin secretion and insulin action in eight NIDDM subjects and eight health matched control subjects. Insulin action was assessed prevailing fasting glucose levels before and after hype insulinemia (2-h insulin infusion at 2.0 mU / kg / min). Pulsatility of insulin was assessed by sampling every 2 min for 90 min after an overnight fast and identifying insulin pulses using the computer program Pulsar. Fasting plasma glucose and postabsorptive endogenous glucose production were both greater in diabetic subjects compared with control subjects (10.1 +/- 1.2 vs. 5.4 +/- 0.1 mmol/l, P < 0.01; 11.8 +/- 0.8 vs. 9.9 +/- 0.4 micromol / kg / min, P < 0.05). During the 2.0 mU insulin infusion, glucose clearance was lower in the diabetic subjects (3.6 +/- 0.7 vs. 6.9 +/- 0.5 ml / kg / min), P < 0.05), whereas endogenous glucose production was suppressed to a similar degree in both groups (4.5 +/- 0.8 vs. 3.6 +/- 0.7 micromol x kg(-1) x min(-1), NS). The frequency of insulin pulses and glucose clearance were negatively correlated in both diabetic subjects (r = -0.75, P < 0.05) and normal control subjects (r = -0.82, P < 0.01). This negative correlation was also present in both groups taken together (r = -0.72, P < 0.001). There was no correlation between insulin pulse frequency and endogenous glucose production either in the fasting state or during hyperinsulinemia. We concluded that the frequency of insulin pulses and peripheral insulin sensitivity are closely linked in NIDDM and normal subjects.


Influence of ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate (EGMP) on early stage colon carcinogenesis in rats treated with azoxymethane (AOM).
The influence of ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate (EGMP) on the initiation and post-initiation stages of colon carcinogenesis was investigated in male F344 rats treated with azoxymethane (AOM). In experimental protocol 1, EGMP was given in the diet at 0.1 or 0.2% for 1 week together with two s.c. 15 mg/kg body weight injections of AOM on days 1 and 7 (initiation period). In protocol 2, the test compound was administered starting at week 3(post initiation stage), and in protocol 3, the test compound was given throughout the experimental period(whole stage). Sacrifice and quantitation of aberrant crypt foci (ACF) was performed at the end of week 5. Dose-dependent decreases in numbers of ACF were noted with both cases of post-initiation and whole period exposure (protocol 2 and 3), large size lesions considered most likely to be precursor lesions also being significantly reduced in the protocol 2(4-9 crypt size total with the 0.2% dose group, 48.9% and 59.6% of control values, respectively). No effects on body or liver weights were evident. The present results thus suggest that EGMP might find application as a chemopreventive agent against colon tumor development.


Sequential hormonal changes in 21 patients with recurrent Cushing's disease after successful pituitary surgery.
To describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS). Retrospective study in a single center. We studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined 'overt recurrence', as presence of two classical parameters of excess cortisol (increased midnight--either serum or salivary--and 24 h urinary cortisol (UC)), leading to further specific therapeutic action, and 'mild recurrence', as presence of a single classical parameter, leading to simple surveillance. Of the 101 patients, 21 (20.8%) presented with recurrence, 'mild' or 'overt', during long-term follow-up (median 50.4 months, range 7-99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7-94 vs mean 21.5 months, median 17, range 3-61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively. A positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.


Phylogenetic relationships of Blepharisma americanum and Colpoda inflata within the phylum ciliophora inferred from complete small subunit rRNA gene sequences.
The complete small subunit rRNA gene sequences of the heterotrich Blepharisma americanum and the colpodid Colpoda inflata were determined to be 1719 and 1786 nucleotides respectively. The phylogeny produced by comparisons with other ciliates indicated that C. inflata is allied more closely with the nassophoreans and oligohymenophoreans than the spirotrichs. This is consistent with the placement of the colpodids in the Class Copodea. Blepharisma americanum was not grouped with the hypotrichs but instead was placed as the earliest branching ciliate. The distinct separation of B. americanum supports the elevation to class status given the heterotrichs based on morphological characters.


Effects of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms on Retinal Tissue Perfusion in Mild Diabetic Retinopathy Patients Receiving the Medical Food, Ocufolin®.
We evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on retinal tissue perfusion in patients with mild diabetic retinopathy (DR + PM) taking the medical food, Ocufolin®, for 6 months. Prospective, case-controlled study. Eight early diabetic retinopathy patients with common reduced function MTHFR polymorphisms (DR+PM) and 15 normal controls (NC) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The medical food is intended to address ocular ischemia with high doses of vitamin B-complexes and antioxidants, including L-methylfolate, methylcobalamin, zinc, copper, lutein, vitamins C, D, E, and n-acetylcysteine. The subjects were provided with a medical food for a period of 6 months. BCVA and vascular indices of DR + PM patients at baseline were initially below those of NC and improved after medical food. Compared to baseline, DR + PM patients after the medical food had significantly improved BCVA during the follow-up period (P < 0.05). In comparison, overall RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05). The changes varied with MTHFR subtypes. In patients with the C677T and the C677T/A1298C compound mutations, RTP was increased at 6 months as compared to that at baseline and 4 months (P < 0.05). In patients with only the A1298C mutation, all microcirculation metrics were increased from baseline at 4 and 6 months, but with less improvement at 6 months than at 4 months (P < 0.05). Medical food was effective in improving both visual acuity and retinal tissue perfusion in DR + PM patients. The degree of improvement of retinal microcirculation varied among MTHFR subtypes.


The vascular response to adrenergic stimulation in pithed rats following endotoxin.
In vivo and in vitro studies have shown that the vascular response to catecholamine is attenuated during endotoxemia. The mechanism of such attenuation is complex and might involve high catecholamine-induced desensitization of adrenoceptors. The purpose of this study was to assess the vascular response to adrenergic stimulation after endotoxin (ETX) administration in pithed rats. In pithed rats, sympathetic outflow is controlled by stimulation, ETX does not elevate norepinephrine (NE), and there are no compensatory reflexes. Rats were pithed, curarized, and adrenal-demedullated. Preganglionic thoracolumbar nerves were stimulated (3 Hz, 10 V, 0.5 msec) for 1 hr after pithing, at which time the first set of frequency and NE-dose responses were assessed by measuring the peak increase in diastolic blood pressure. Intravenous ETX (1.5 mg/kg or 0.5 mg/kg) or saline was administered immediately after these measurements. A sham group was designed to mimic the falling blood pressure pattern seen in the endotoxin group during 1 hr after ETX was given by gradually decreasing the stimulation frequency. The second set of frequency and NE-dose responses were evaluated 1 hr after ETX, saline, or sham treatment. Plasma NE and epinephrine (EPI) were determined before and 1 hr after ETX (1.5 mg/kg) or saline injection. The results showed that blood pressure response to adrenergic stimulation was markedly attenuated in pithed rats following both high and low doses of ETX compared with the saline and sham groups. Plasma NE was not elevated by ETX insult in pithed rats. We propose that mechanisms other than high-catecholamine-induced adrenergic desensitization or hypotension account for the attenuated adrenergic responsiveness of the vasculature following ETX.


[Tracheostomy in the intensive care unit].
During the last 22 months, a total number of 85 tracheostomies have been performed in our ICU, 40 of which have been surgical, and 45 percutaneous to patients under mechanical ventilation. This period has coincided with the learning process of the technique of percutaneous tracheostomy by our staff. The choice of the type of tracheostomy was not taken at random, but guided by clinical criteria. Our results confirm a lower rate of infection of the estoma in percutaneous tracheostomies than in surgical ones (5 percutaneous and 29 surgical, p < 0.001). The most serious complication was a tracheal perforation in a percutaneous tracheostomy. 17 of the 85 patients died in ICU, and 33 of the 68 patients who were discharged, survived the hospital, 27 of whom left with a closed tracheostomy. The other 6 permanent tracheostomies had been performed surgically and corresponded to 4 patients with worsening EPOC, one neurological patient and another patient suffering from anoxic encephalopathy. No percutaneous tracheostomy was left as permanent. The patients who benefitted especially from the tracheostomy presented the following characteristics: acute respiratory insufficiency with prolonged intubation, neurological patients, and worsening EPOC. The tracheostomy in persistent vegetative status allowed their moving to more suitable areas. Our study proves the existence of a learning curve in the practice of percutaneous tracheostomy. This aspect should be taken into account by other groups who are interested in including this technique in their services.


[Baseline characteristics and management of patients less than 45 years of age hospitalized for acute coronary syndromes: results from the nationwide French PREVENIR 1 and PREVENIR 2 studies].
Of 2,626 patients admitted for acute coronary syndromes and participating in the PREVENIR 1 and 2 registries, 202 (8%) were aged less than 45 years. Younger patients were more often smokers (79% versus 37%), but systemic hypertension and diabetes were less frequent. Reperfusion therapy was more frequently used in the younger patients (63% versus 46%). At hospital discharge, aspirin and angiotensin converting enzyme inhibitors were prescribed as often in younger and older patients. In contrast, beta-blocking agents and statins were used more often in the younger patients. More younger patients participated in a cardiac rehabilitation programme. Left ventricular ejection fraction was less altered in the younger age group and none of the younger patients died between hospital discharge and six months follow-up.


5S rRNA modification in the hyperthermophilic archaea Sulfolobus solfataricus and Pyrodictium occultum.
The 5S rRNAs from Sulfolobus solfataricus and Pyrodictium occultum were digested to nucleosides and analyzed using directly-combined HPLC/mass spectrometry. P. occultum 5S rRNA contains two modified nucleoside species, N4-acetylcytidine (ac4C) and N4-acetyl-2'-O-methylcytidine (ac4Cm). Oligonucleotides were generated from P. occultum 5S rRNA by RNase T1 hydrolysis, and their molecular weights were determined using electrospray mass spectrometry and compared with those predicted from the P. occultum 5S RNA gene sequence. Deviation in mass between expected and observed molecular weights permitted ac4Cm to be located at position 35, in the nonanucleotide CAA-CACC[ac4Cm]G, and the ac4C in one or both of two (C,U)G trinucleotides. 2'-O-Methylcytidine is unambiguously characterized in S. solfataricus 5S rRNA, confirming earlier tentative assignments at the analogous sequence position (Stahl, D.A., Luehrsen, K.R., Woese, C.R., and Pace, N.R. (1981) Nucleic Acids Res., Vol. 9, pp. 6129-6137; Dams, E., Londei, P., Cammarano, P., Vandenberghe, A., and De Wachter, R. (1983) Nucleic Acids Res. Vol. 11, pp. 4667-4676). Potential effects of the presence of ac4C and ac4Cm on thermal stabilization of 5S rRNA in thermophiles are discussed.


Evaluation of great heart vessels and pulmonary vasculature.
This year's literature relating to imaging of the great heart vessels was devoted primarily to measurements of aortic size and to comparisons of imaging modalities in evaluating aortic aneurysms, dissections, and coarctation. The imaging modalities compared were plain chest roentgenography, conventional CT, ultrafast CT, MR imaging, transcutaneous esophageal echocardiography, and Doppler echocardiography. The pulmonary vasculature literature dealt with MR imaging of pulmonary vessels and the estimations of pulmonary pressure using echocardiography and Doppler techniques.


Probing the versatility of metallo-electro hybrid catalysis: enabling access towards facile C-N bond formation.
The development of versatile and mild methodologies for C-N bond construction has always been a hot topic of interest in synthetic organic chemistry. In recent years, electrochemistry has emerged as a promising green and sustainable environmentally benign approach to carry out these transformations under mild conditions utilizing electrons as oxidizing/reducing agents. The current state-of-the-art in combining electrocatalysis with transition metal catalysis has gained significant attention. This hybrid synthetic methodology has increasingly become a common tool and offers many potential advantages compared to direct electrolysis. This review comprehensively highlights recent developments in the merging of transition metal catalysis in electro-organic synthesis for the facile construction of C-N bonds. In this review major emphasis is given to mechanistic investigations and their synthetic applications of this hybrid catalysis.


The Effectiveness of Electroconvulsive Therapy on Catatonia in a Case of Anti-N-Methyl-D-Aspartate (Anti-NMDA) Receptor Encephalitis.
Catatonia is a symptom seen in a variety of neuropsychiatric conditions, including anti-N-Methyl D-aspartate receptor (NMDAR) encephalitis. When associated with anti-NMDAR encephalitis, catatonia is resistant to standard therapy. However, electroconvulsive therapy (ECT) has shown promising success in management. This case report presents a 25-year-old African American female who presented to the emergency room with nervousness, sweating, insomnia, and visual and auditory hallucinations. She was treated symptomatically for anxiety but returned to the hospital after she continued to experience worsening symptoms. Her anxiety worsened, and she became more agitated, warranting an extensive workup, including magnetic resonance imaging (MRI) and electroencephalogram (EEG), which showed normal findings. She also had an anti-NMDA receptor antibodies titer done, which showed a positive titer result. She was treated with intravenous steroids, intravenous immunoglobulin G (IgG), plasma exchange, and rituximab, which did not improve her symptoms, and she was discharged home after a prolonged hospital stay. On follow-up visits, she reported worsening confusion, aggression, and suicidal behaviors. The patient was readmitted, during which she experienced catatonia and psychiatric symptoms, and her anti-NMDAR titer had increased to 1:1280. Further treatments with intravenous steroids, intravenous IgG, plasma exchange, and rituximab, including haloperidol and clonazepam, failed to improve her condition. However, her condition improved remarkably following treatment with 12 rounds of ECT. No randomized control trial has been done to demonstrate the effectiveness of ECT in the treatment of anti-NMDAR encephalitis despite various reports of the effectiveness of this treatment modality. This case report adds to the growing clinical evidence in support of the use of ECT in anti-NMDAR encephalitis patients with catatonia. ECT can be incorporated as standard protocol in the treatment of catatonia and associated psychiatric symptoms when managing a patient with anti-NMDAR encephalitis associated with catatonic features.


Dual-mode luminescence anti-counterfeiting and white light emission of NaGdF4:Ce,Eu,Tb/carbon dot hydrophilic nanocomposite ink.
NaGdF4:Ce,Eu,Tb nanocrystals were successfully prepared by a one-step hydrothermal method with Ce3+ ions as sensitizers, Eu3+ and Tb3+ ions as activators, and polyethylenimine (PEI) as surfactants. Color-adjustable fluorescence emission was achieved by the energy transfer effect between rare earth ions. Blue fluorescent carbon quantum dots (CDs) with a double UV response under 254 nm and 365 nm excitation were synthesized by a one-step hydrothermal method. A hydrophilic NaGdF4:Ce,Eu,Tb/CD composite ink was prepared by an easy physical mixing method. Because of the electrostatic self-assembly effect, the color adjustable luminescence was achieved in a few seconds, and the white light emission with color coordinates of (0.32, 0.32) was obtained. A dual-mode luminescence anti-counterfeiting pattern was designed and achieved by excitation with ultraviolet light at 254 nm and 365 nm.


Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid.
The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA. To this end, pregnant CD-1 mice were treated systemically with kynurenine (100 mg/kg), KYNA (10 mg/kg), or saline on embryonic day 18. As expected, administration of either kynurenine or KYNA increased KYNA levels in the maternal plasma and placenta. Maternal kynurenine treatment also raised kynurenine levels in the fetal plasma and brain, demonstrating the ability of this pivotal KP metabolite to cross the placenta and increase the levels of both KYNA and 3-HK in the fetal brain. In contrast, maternal administration of KYNA caused only a small, nonsignificant elevation in KYNA levels in fetal plasma and brain. Complementary experiments using an ex vivo placental perfusion procedure confirmed the significant transplacental transfer of kynurenine and demonstrated that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions. Jointly, these results help to clarify the contributions of the maternal circulation and the placenta to fetal KYNA in the late prenatal period.


Antihypertensive therapy and coronary prevention.
Antihypertensive therapy reduces cardiovascular risk in patients with malignant hypertension, but has not yet been shown to reduce risk in patients with mild to moderate hypertension. The lack of significant coronary prevention in the latter group, in large-scale trials, may have resulted from methodologic problems, statistical limitations, the adverse effects of antihypertensive medications, or failure to recognize the prognostic importance of concomitant regression of left ventricular hypertrophy. To date, primary prevention studies have focused on the use of beta-blockers and diuretics, both of which may have adverse metabolic effects and neither of which is capable of modifying left ventricular hypertrophy. Future research should be directed toward evaluating coronary prevention in patients with nonmalignant hypertension who have been treated with newer agents, such as calcium channel blockers and angiotensin-converting enzyme inhibitors, each of which has been shown to regress left ventricular hypertrophy and not to have adverse metabolic effects.


Comparison of rapid perfringens medium and lactose sulfite medium for detection of Clostridium perfringens.
Two tubed media, lactose sulfite (LS) and rapid perfringens medium (RPM), were evaluated and compared for their ability to detect and enumerate Clostridium perfringens in inoculated and naturally contaminated samples. In a 3-tube most probable number system, the number of organisms recovered from spiked samples was several-fold higher with RPM than with LS and was close to the numbers inoculated. Levels detected in 15 naturally contaminated samples were also higher with RPM. Only 13 of the samples were positive for C. perfringens with LS medium. These results indicate that RPM is a more effective medium than LS; therefore, its use is recommended.


Measurement of the Fluorescence Quantum Yield Using a Spectrometer With an Integrating Sphere Detector.
A method is proposed for measuring the fluorescence quantum yield (QY) using a commercial spectrophotometer with a 150 mm integrating sphere (IS) detector. The IS detector is equipped with an internal cuvette holder so that absorbance measurements can be performed with the cuvette inside the IS. In addition, the spectrophotometer has a cuvette holder outside the IS for performing conventional absorbance measurements. It is shown that the fluorescence quantum yield can be obtained from a combination of absorbance measurements of the buffer and the analyte solution inside and outside the IS detector. Due to the simultaneous detection of incident and fluorescent photons, the absorbance measurements inside the IS need to be adjusted for the wavelength dependence of the photomultiplier detector and the wavelength dependence of the IS magnification factor. An estimate of the fluorescence emission spectrum is needed for proper application of the wavelength-dependent adjustments. Results are presented for fluorescein, quinine sulfate, myoglobin, rhodamine B and erythrosin B. The QY of fluorescein in 0.1 mol/L NaOH was determined as 0.90±0.02 where the uncertainty is equal to the standard deviation of three independent measurements. The method provides a convenient and rapid estimate of the fluorescence quantum yield. Refinements of the measurement model and the characteristics of the IS detector can in principle yield an accurate value of the absolute fluorescence quantum yield.


Effects of supplemental methionine and potassium sulfate on the choline requirement of the turkey poult.
Two experiments were conducted to study the relationship of methionine and potassium sulfate (K2SO4) on the choline requirement of turkey poults from hatch to three weeks of age. A corn-soybean meal basal diet was used which contained no supplemental choline or methionine. Also sulfate-free trace minerals were used. In Experiment 1, a linear increase in body weight was obtained by adding supplemental choline up to 660 mg/kg when the diet did not contain supplemental methionine. No response was obtained from supplemental choline when the diet contained a level higher than required for methionine (.25%). Feed efficiency was not affected by supplemental choline regardless of the level of supplemental methionine. In Experiment 2, a linear response in body weight was obtained by adding supplemental choline up to 1100 mg/kg diet in the presence or absence of supplemental K2SO4. The addition of K2SO4 to the diet did not significantly increase body weight at any level of supplemental choline. However, when all levels of choline were combined, the addition of K2SO4 significantly increased body weight, which indicated that the response from the two supplements were additive.


Plasma adiponectin for prediction of cardiovascular events and mortality in high-risk patients.
The prognostic value of plasma levels of adiponectin, an adipocytokine with antiatherogenic, antiinflammatory, and insulin-sensitizing effects, is contentious. The objective of the study was to investigate whether plasma adiponectin levels predict cardiovascular (CV) events and mortality in high-risk coronary artery disease (CAD) patients. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURE: We measured plasma adiponectin and examined its impact on the incidence of CV deaths and events at follow-up in the context of all potentially relevant background covariates in 712 high-risk patients of the Genetic and ENvironmental factors in Coronary Atherosclerosis study who underwent coronary angiography for suspected CAD. Based on the population plasma adiponectin median (6.38 microg/ml, interquartile range 4.2-10.2), we split the patients in a high- and a low-plasma adiponectin subgroup. After a median follow-up of 3.8 years (interquartile range 3.3-4.3 yr), outcome data were obtained in 100% of the patients and 45 CV deaths (6.4%) were recorded. Kaplan-Meier analysis unexpectedly showed a higher CV death rate in high-plasma adiponectin than low-plasma adiponectin patients. By contrast, multivariate Cox regression analysis, in which potential confounders, including ongoing medical treatment, were considered, showed no impact of plasma adiponectin on CV death. Similar negative results were obtained using the propensity score that considered all relevant covariables and medical treatment rate, which differed between the high- and low-plasma adiponectin group. In high-risk CAD patients, plasma adiponectin above the median (6.38 microg/ml) implies a paradoxical higher risk of CV death. However, when relevant covariates that differ between high- and low-plasma adiponectin groups are considered, this association wanes, indicating that the clustering of plasma adiponectin with other covariates can abolish its impact on CV prognosis.