High-Efficiency Cooper-Pair Splitter in Quantum Anomalous Hall Insulator Proximity-Coupled with Superconductor.
The quantum entanglement between two qubits is crucial for applications in the quantum communication. After the entanglement of photons was experimentally realized, much effort has been taken to exploit the entangled electrons in solid-state systems. Here, we propose a Cooper-pair splitter, which can generate spatially-separated but entangled electrons, in a quantum anomalous Hall insulator proximity-coupled with a superconductor. After coupling with a superconductor, the chiral edge states of the quantum anomalous Hall insulator can still survive, making the backscattering impossible. Thus, the local Andreev reflection becomes vanishing, while the crossed Andreev reflection becomes dominant in the scattering process. This indicates that our device can serve as an extremely high-efficiency Cooper-pair splitter. Furthermore, because of the chiral characteristic, our Cooper-pair splitter is robust against disorders and can work in a wide range of system parameters. Particularly, it can still function even if the system length exceeds the superconducting coherence length.


Family history of ischemic heart disease and risk of acute myocardial infarction.
Several aspects of the relation between family history of ischemic heart disease (IHD) and risk of acute myocardial infarction (AMI) need further quantification. A case-control study was conducted in Italy in 1995-1999 on 378 men and 129 women with a first nonfatal AMI, and 297 male and 181 female controls in a hospital for selected acute conditions. Odds ratios (OR) of AMI according to family history of IHD were estimated using unconditional logistic regression, adjusting for other AMI risk factors and family size. The overall OR for those having > or =1 first-degree relatives with IHD was 2.1, and 3.8 for > or =2 relatives. The OR for those with an affected parent or sibling were similar. The OR were also similar across strata of sex, age at diagnosis of the proband or the relative, and selected AMI risk factors, which were risk factors also in those with a positive family history. Family history of IHD is an independent risk factor for AMI, and intervention on modifiable risk factors may be beneficial also in those with a family history of the disease.


Toxic effects of microcystin-LR on the HepG2 cell line under hypoxic and normoxic conditions.
Microcystins (MCs) are highly liver-specific and evidenced as a liver tumor promoter. Oxidative stress is one of the most important toxicity mechanisms of MCs, which is tightly related to oxygen concentration. The effects of MCs on animals and cell lines in normoxia and the mechanisms have been well studied, but such effects in different oxygen conditions were still unclear. The aim of the present study was to explore the cellular response of the human hepatocellular carcinoma cell line (HepG2) to MC-LR exposure under hypoxic (1% O2 ) and normoxic (21% O2 ) conditions. We examined cell viability, mitochondrial membrane potential (MMP), superoxide dismutase (SOD) activity and gene expression posttoxin exposure. Cell viability was increased by MC-LR in normoxia although decreased in hypoxia. MC-LR markedly induced MMP loss under hypoxic condition but only slightly MMP loss under normoxic condition. SOD activity was significantly induced by MC-LR in hypoxia, indicating prolonged oxidative stress. Inhibitory apoptosis protein (c-IAP2) was significantly up-regulated by MC-LR under normoxic condition, suggesting that c-IAP2 played an important role in the promotion of cell proliferation by MC-LR. These results indicate that MC-LR promotes cell proliferation under normoxic condition whereas induces cell apoptosis under hypoxic condition.


Augmentation and proliferation of T lymphocytes and Th-1 cytokines by Withania somnifera in stressed mice.
Stress has been associated with reports of both greater severity and prolongation of diseases in patients with the infectious origin as well as other immune-mediated diseases. Withania somnifera, an Indian medicinal plant used widely in the treatment of many clinical conditions in India, was investigated for its anti-stress properties using BALB/c mice subjected to chronic stress. The study aimed to investigate chronic stress-induced alterations on Th1 lymphocyte subset distribution and corresponding cytokine secretion patterns. Oral administration of chemically standardized and identified aqueous fraction of W. somnifera root (WS) at the graded doses of 25, 50, 100 and 200 mg/kg p.o. caused significant increase in the stress-induced depleted T-cell population and increased the expression of Th1 cytokines in chronically stressed mice.


Alcohol consumption and casualties; drinking in the event.
The data reported are from a 20% probability sample (n = 2516) of all adult patients seeking care in the emergency room at San Francisco General Hospital during a 60-day period. Thirty-five percent (35%) of the injured and 18% of the non-injured reported drinking prior to the event. This paper compares the following variables related to drinking-in-the-event for injured and non-injured: drinking places, drinking companions, amount consumed, time lapsed between drinking and the event, effects of drinking and causality attributed by the patient to drinking and the event. When these variables were entered into a logistic regression to evaluate their predictive value on injury status, only time lapsed since the last drink and drug use prior to the event were predictive of injury with both being negatively associated with admission to the emergency room for an injury. Injuries were more likely than non-injuries to occur in close proximity to drinking (44% of injuries occurred in less than 1 h of the last drink), and close to a third of the injured attributed a causal association of drinking with the event, with 60% of these feeling they were drunk at the time of injury.


A simple method for sampling murine pulmonary and cardiac tissues for analysis of cyclic nucleotide levels.
A simple method for the rapid removal and freezing of mouse cardiac and pulmonary tissues is described. Samples thus obtained were judged to be suitable for valid estimation of in vivo levels of cyclic AMP and cyclic GMP based on the following findings: (a) the samples could be obtained and frozen in the very short time period of a few seconds; (b) no indication of adverse effects of the collection procedure was found upon examination of chemical indicators of energy metabolism; (c) the apparent rates of change of cyclic AMP and cyclic GMP levels during the first seconds after tissue isolation could produce small, but acceptable errors; and (d) dose-dependent elevations of pulmonary cAMP levels consistent with known effects in vitro were found after in vivo administration of isoproternol.


Crystal structures of (2,2'-bipyridyl-κ(2) N,N')bis-[N,N-bis-(2-hydroxy-eth-yl)di-thio-carbamato-κ(2) S,S']zinc dihydrate and (2,2'-bipyridyl-κ(2) N,N')bis-[N-(2-hydroxy-eth-yl)-N-iso-propyl-dithio-carbamato-κ(2) S,S']zinc.
The common feature of the title compounds, [Zn(C5H10NO2S2)2(C10H8N2)]·2H2O, (I), and [Zn(C6H12NOS2)2(C10H8N2)], (II), is the location of the Zn(II) atoms on a twofold rotation axis. Further, each Zn(II) atom is chelated by two symmetry-equivalent and symmetrically coordinating di-thio-carbamate ligands and a 2,2'-bi-pyridine ligand. The resulting N2S4 coordination geometry is based on a highly distorted octa-hedron in each case. In the mol-ecular packing of (I), supra-molecular ladders mediated by O-H⋯O hydrogen bonding are found whereby the uprights are defined by {⋯HO(water)⋯HO(hy-droxy)⋯} n chains parallel to the a axis and with the rungs defined by 'Zn[S2CN(CH2CH2)2]2'. The water mol-ecules connect the ladders into a supra-molecular layer parallel to the ab plane via water-O-H⋯S and pyridyl-C-H⋯O(water) inter-actions, with the connections between layers being of the type pyridyl-C-H⋯S. In (II), supra-molecular layers parallel to the ab plane are sustained by hy-droxy-O-H⋯S hydrogen bonds with connections between layers being of the type pyridyl-C-H⋯S.


Apixaban, Rivaroxaban, and Dabigatran in Patients Undergoing Atrial Fibrillation Ablation.
Data on the novel oral anticoagulants (NOACS) during catheter ablation (CA) of atrial fibrillation (AF) are still limited. This study evaluated the periprocedural major complications (MC) of CA of AF, and compared Apixaban, Dabigatran, and Rivaroxaban with continuous phenoprocoumon. A total of 444 patients (mean age = 65.1 ± 9.4 years; 283 [64%] male) with paroxysmal (n = 180 [41%]), persistent (n = 256 [58%]), or longstanding-persistent AF were enrolled. CA was performed in all patients using radiofrequency energy in conjunction with a 3D-mapping system. MCs were defined according to the current guidelines. Continuous phenprocoumon-therapy was administered in 120/444 (27%) patients (group 1) and 324/444 (73%) patients were treated with NOACs (group 2; Dabigatran: n = 51 [15.7%]; Rivaroxaban: n = 193 [59.6%]; Apixaban: n = 80 [24.7%]). Procedure times were comparable between groups 1 and 2 (128.2 ± 39.7 minutes vs. 129.7 ± 51.2 minutes; P = 0.77). CHA2 DS2-Vasc (3.0 [2.0, 4.0)] vs. 2.0 [1.0, 3.0]; P < 0.01) and HASBLED scores (2.0 [2.0, 2.5] vs. 2.0 [1.0, 2.0]; P = 0.002) were higher in group 1 patients. The incidence of MCs in the overall group was 8/444 (2%) and was equally distributed between groups 1 and 2 (2/120 [2%] vs. 6/324 [2%], P = 0.90). The incidence of MCs was comparable between the three different NOACs. There were no significant differences between patients with and without MCs with regard to age, CHA2 DS2-Vasc-score or HASBLED-score. The major complication rate between all three NOACs currently available and continuous phenprocoumon during AF ablation seem to be comparable. Complication rates were similar between patients treated with the three different available NOACs.


Health and fitness at work: a participants' perspective.
In the 1980s worksite health promotion or wellness programs have become more common in American corporations. Corporations see them as a way to control rising health care costs and to improve employee health. This paper examines participants' perspectives on participation in a health and fitness program, based on participant-observation and 35 in-depth interviews with members of one corporate program. Participants have a decided fitness-orientation (as opposed to a health-orientation), focusing on staying in shape and controlling weight. The consequences of this orientation for the promotion of health, the future of wellness programs, and the corporation are discussed.


The organization and reorganization of audiovisual speech perception in the first year of life.
The period between six and 12 months is a sensitive period for language learning during which infants undergo auditory perceptual attunement, and recent results indicate that this sensitive period may exist across sensory modalities. We tested infants at three stages of perceptual attunement (six, nine, and 11 months) to determine 1) whether they were sensitive to the congruence between heard and seen speech stimuli in an unfamiliar language, and 2) whether familiarization with congruent audiovisual speech could boost subsequent non-native auditory discrimination. Infants at six- and nine-, but not 11-months, detected audiovisual congruence of non-native syllables. Familiarization to incongruent, but not congruent, audiovisual speech changed auditory discrimination at test for six-month-olds but not nine- or 11-month-olds. These results advance the proposal that speech perception is audiovisual from early in ontogeny, and that the sensitive period for audiovisual speech perception may last somewhat longer than that for auditory perception alone.


Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab.
Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014.


Correlation plasma levels, NSAID and therapeutic response.
A regular control of nonsteroidal anti-inflammatory drug (NSAID) plasma levels may be useful to avoid undesirable side-effects to monitor therapeutic progress to see if patients are complying with their prescription. Trying to establish a relationship between the plasma concentration of a drug and its clinical effects requires a few prerequisites which may or may not be fulfilled according to the NSAID (e.g. a drug acting by itself, a reversible action, no tolerance to the drug, a highly specific and sensitive enough analytical method of the drug, similar free drug concentrations in the plasma and at the receptor sites,...), the most important of them-which is also probably the most difficult to fulfil in the case of rheumatic diseases-being that the clinical effect of the drug must be easily measured. In fact, the evidence for a good correlation between clinical effects and drug plasma levels are very scarce in the field of NSAID. The best correlation was obtained with salicylates for which ranges of plasma concentrations needed for observing therapeutic effects in rheumatoid arthritis as well as in juvenile rheumatoid arthritis have been established. Similar correlations have been made for side effects such as tinnitus or headaches as well as for toxic manifestations of salicylism. However, many individual variations have been described and there is considerable overlap between therapeutic and toxic concentrations. According to different authors there are or there are no correlations between phenylbutazone plasma levels and either is therapeutic or its side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)


[The exposome in the context of preventive measures for Alzheimer's and Parkinson's diseases].
Preventive measures addressing the exposome can counteract neurodegenerative diseases. This article gives an overview on the influence of general and individual exogenous factors (environmental influences and lifestyle changes) as well as endogenous factors (e.g. metabolic alterations) on the development and progression of Alzheimer's disease (AD) and Parkinson's disease (PD). Summary and evaluation of current scientific studies and evidence regarding the exposome and prevention of AD and PD. Numerous studies could demonstrate a potential influence of environmental influences associated with industrialization (general exogenous factors), such as pesticides, solvents or air pollution on the development of AD and PD. Additionally, individually addressable changes of lifestyle (individual exogenous factors, e.g. physical activity, cognitive stimulation, nutrition and sleep) contribute to disease protection and modification and are becoming increasingly more important in light of still limited therapeutic interventions. Moreover, other exogenous factors (medication, noise pollution, head trauma and heavy metals) are discussed as risk factors for AD and/or PD. Endogenous factors (e.g., changes of the enteral microbiome, systemic inflammation and neuroinflammation, metabolic changes) can contribute to disease development by a higher potential for interacting with exogenous factors. Despite the comprehensive scientific evidence confirming the significance of the exposome for the pathogenesis of AD and PD, the great potential of preventive measures has not yet been exploited. A clarification of the high potential of lifestyle changes should be a therapeutic standard not only for individuals with manifest PD/AD but also for individuals with a risk profile or with suspected prodromal disease. Further investigations on the influence of environmental factors and the implementation of preventive strategies to avoid exposure should be the focus of international efforts.


Gel electrophoresis of rotavirus RNA derived from six different animal species.
Rotavirus RNA prepared from calf, pig, mouse, deer, foal and dog-adapted human isolates was compared using polyacrylamide gel electrophoresis. Reproducible differences in the RNA migration patterns were found between all isolates. There were 11 clearly resolved segments in the pig, mouse and foal samples. The calf rotavirus RNA and deer rotavirus RNA separated into 9 bands and 10 bands, respectively. The dog-adapted human virus migrated in 12 bands, and this probably results from the complex passage history of the original human rotavirus isolate.


Does ministernotomy improve postoperative outcome in aortic valve operation? A prospective randomized study.
The aim of this study was to compare the postoperative outcome obtained in patients undergoing elective aortic valve operation, either through ministernotomy or conventional sternotomy. Between January 1999 and July 2001, 80 consecutive patients undergoing elective aortic valve replacement were randomly divided into two groups: group I (n = 40 patients) undergoing a ministernotomy approach (reversed-C or reversed-L), and group II (n = 40 patients) undergoing conventional sternotomy. The length of skin incision was significantly shorter in group I than in group II (8.2+/-1.3 cm versus 23.7+/-2.6 cm, p < 0.001). No significant differences were found in cardiopulmonary bypass duration, associated procedures, or aortic cross-clamping times. Total operating time was 3.7+/-0.46 hours in group I compared with 3.4+/-0.6 hours in group II (p = 0.014). A similar incidence of cardiac, neurologic, infective, and renal complications between groups was found. Mean mediastinal drainage and mean blood transfusions (amount of blood transfused) per patient were greater in group II (p < 0.004 and p < 0.001, respectively). Twenty-five (62.5%) patients in group II and 15 (37.5%) patients in group I required postoperative blood transfusion (p = 0.04). Mechanical ventilation time was significantly longer in group II (6.2+/-1.8 hours versus 4.4+/-0.9 hours, p = 0.006). Five days after the surgical procedure, spirometric data analysis demonstrated a significantly lower total lung capacity and maximum inspiratory and expiratory pressures in group II compared with group I (p = 0.003, p = 0.007, and p < 0.001, respectively). Our results showed that ministernotomy had not only important cosmetic advantages but also beneficial effects in blood loss and transfusion, postoperative pain, and probably in sternal stability. Ministernotomy also improved recovery of respiratory function and allowed earlier extubation and hospital discharge.


Mechanisms of transcription-coupled DNA repair.
Several types of helix-distorting DNA lesions block the passage of elongating RNA polymerase II. Surprisingly, such transcription-blocking lesions are usually repaired considerably faster than non-obstructive lesions in the non-transcribed strand or in the genome overall. In this review, our knowledge of eukaryotic transcription-coupled repair (TCR) will be considered from the point of view of transcription, and current models for the mechanism of TCR will be discussed.


N-azamonobactams. 2. Synthesis of some N-iminoacetic acid and N-glycyl analogues.
The synthesis of the title compounds has been accomplished. The N-iminoacetic acid analogues (12a and 12b) containing the aminothiazole type side chain exhibited good in vitro antibacterial activity against Gram-negative organisms. The corresponding N-glycyl derivative (17) was not active.


Use of biologic or targeted-synthetic disease-modifying anti-rheumatic drugs and risk of diabetes treatment intensification in patients with rheumatoid arthritis and diabetes mellitus.
Given that RA treatment might affect the severity of diabetes mellitus (DM), we compared the risk of DM treatment intensification in patients with both RA and DM newly initiating a biologic DMARD or tofacitinib. Using claims data from the IBM MarketScan database (2005-2016), we identified patients aged ≥18 years with RA who initiated abatacept, a TNF inhibitor (TNFi), rituximab, tocilizumab or tofacitinib. Patients were required to have type 1 or type 2 DM and to use at least one antidiabetic drug at baseline. We assessed DM treatment intensification (i.e. addition of a new insulin or non-insulin antidiabetic medication). We also assessed non-insulin antidiabetic medication switching events. We included 10 019 patients with RA and DM initiating a biologic DMARD or tofacitinib. Baseline insulin use was the highest in rituximab initiators (44%) and lowest in tofacitinib initiators (35%). The incidence rate per 1000 person-years for DM treatment intensification ranged from 148.2 (tofacitinib) to 198.0 (rituximab). The risk of DM treatment intensification was similar between abatacept and TNFi [hazard ratio (HR) 0.97, 95% CI: 0.82, 1.15], rituximab (HR 0.99, 95% CI: 0.79, 1.23) and tocilizumab (HR 0.94, 95% CI: 0.74, 1.19), but lower for tofacitinib compared with abatacept (HR 0.67, 95% CI: 0.50, 0.90). The risk of non-insulin DM treatment switching was not different between abatacept and other biologic DMARDs. In patients with both RA and DM, we found no difference in the risk of DM treatment switching or intensification after initiating abatacept vs TNFi, rituximab and tocilizumab, whereas the risk appeared to be lower for tofacitinib.


13C nuclear magnetic resonance spectroscopy to determine olive oil grades.
13C nuclear magnetic resonance spectroscopy was used in a first attempt to differentiate olive oil samples by grades. High resolution 13C NMR Distortionless Enhancement by Polarization Transfer (DEPT) spectra of 137 olive oil samples from the four grades, extra virgin olive oils, olive oils, olive pomace oils and lampante olive oils, were measured. The data relative to the resonance intensities (variables) of the unsaturated carbons of oleate (C-9 and C-10) and linoleate (L-9, L-10 and L-12) chains attached at the 1,3- and 2-positions of triacylglycerols were analyzed by linear discriminant analysis. The 1,3- and 2- carbons of the glycerol moiety of triacylglycerols along with the C-2, C-16 and C-18 resonance intensities of saturated, oleate and linoleate chains were also analyzed by linear discriminant analysis. The three discriminanting functions, which were calculated by using a stepwise variable selection algorithm, classified in the true group by cross-validation procedure, respectively, 76.9, 70.0, 94.4 and 100% of the extra virgin, olive oil, olive pomace oil and lampante olive oil grades.


Evaluation of a simple and cost effective filter paper-based shipping and storage medium for environmental sampling of F-RNA coliphages.
Male specific RNA (F-RNA) coliphages are used as indicators of fecal contamination and for source tracking. However, collecting fecal samples for analysis from remote sites is problematic due to the need for an uninterrupted cold chain to guarantee sample suitability for downstream molecular detection of these coliphages. Here, we investigated the feasibility of using filter paper as a collection and storage vehicle for F-RNA coliphages. Various concentrations (10(1) to 10(4)pfu) of two F-RNA coliphages, MS2 and Qβ, were prepared in lambda buffer or a 10% bovine manure slurry, spotted onto filter paper disks, dried, and maintained at 37 °C for up to 37 days. Nucleic acids were extracted from the spotted filter paper disks at 0, 6, 13, and 37 days post inoculation and analyzed by real time RT-PCR. F-RNA coliphages at concentrations of 10(2)pfu/filter paper unit were readily detected, and only a slight decrease in nucleic acid detection was observed over time. Furthermore, the sensitivity of real time RT-PCR detection of the F-RNA coliphage RNA was similar between the developed filter paper sampling methodology and traditional cold storage. These results indicate that filter paper is a suitable storage and transport medium for F-RNA coliphages when refrigeration is not possible.


[Postoperative intestinal obstruction: introduction (author's transl)].
Postoperative intestinal obstruction is the indication for one-third of early reoperations. Mortality increases with age and time interval. Operations on the lower intestinal tract are predominant among the primary procedures. The main causes of obstruction are adhesions involving the small intestine. Diagnosis requires differentiation from paralytic ileus and physiologic postoperative paralysis. The outcome depends on early recognition, immediate reoperation, and adequate surgical management.


Dialysis-related amyloidosis of the temporomandibular joint.
Dialysis-related amyloidosis (DRA) is a serious complication occurring most commonly in patients undergoing long-term hemodialysis. We describe a case of amyloidosis of the bilateral temporomandibular joint (TMJ) that developed after long-term hemodialysis therapy.


Clomiphene treatment may be effective in refractory episodic and chronic cluster headache.
To describe the evolution of 15 patients who were treated for difficult-to-control episodic and chronic cluster headaches with clomiphene. Clomiphene treatment was used for seven chronic and eight episodic cluster headache patients. The chronic patients were refractory to the medication being used, and the episodic patients, in addition to being resistant to conventional medication, had longer cluster headache periods, exceeding the average time of previous cluster cycles. Our main analysis was of the time to pain-free, complete remission, and the length of pain-free time and complete remission. Clomiphene was used for 45-180 days. The average time to being pain-free was 15 days and cluster remission was up to 60 days. The average time between being pain-free until cluster remission was 26 days. Clomiphene treatment was significantly efficient. It interrupted chronicity in all patients, suggesting the capability of changing the pattern of attacks. It proved to be safe and well tolerated.


Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11C]NNC-112.
The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D(1) receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [(11)C]NNC-112, to selectively assess D(1) receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [(11)C]NNC-112 nondisplaceable binding potential (BP(ND)) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean D(1) receptor BP(ND) was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D(1) receptor BP(ND) in this region correlated negatively with illness duration (r=-0.53; p=0.02), and the left-to-right BP(ND) ratio correlated inversely with anhedonia ratings (r=-0.65, p=0.0040). The D(1) receptor BP(ND) was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F=7.33, p=0.01). These data extended a previous finding of decreased striatal D(1) receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D(1) receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior.


Etiology of Chronic Abnormal Uterine Bleeding According to the FIGO's PALM-COEIN Classification in Bangladeshi Women of Reproductive Age: A Cross-Sectional Study.
Chronic abnormal uterine bleeding (AUB) is common, but there is a lack of standardized methods for investigating and etiological categorization of AUB. The PALM-COEIN classification system of AUB is getting important to overcome this issue. This cross-sectional study was conducted from January 2019 to December 2019 at Mymensingh Medical College Hospital, Mymensingh, Bangladesh, to determine the causes of AUB in women of the reproductive age group and categorize the causes of AUB as per the PALM-COEIN classification. A total of 380 women with chronic AUB were evaluated. The distribution of PALM-COEIN causes of AUB were AUB-P (1.8%), AUB-A (9.2%), AUB-L (13.2%), AUB-M (5.8%), AUB-C (1.1%), AUB-O (24.7%), AUB-E (1.6%), AUB-I (6.6%), and AUB-N (36.1%). The participants' mean age was 29.6 (±10.5) years, the majority (78.2%) of them was married, only a few (9.5%) had comorbid diseases, including hypertension (HTN) (1.1%), diabetes mellitus (DM) (5.3%), and hypothyroidism (8.7%). Women in the AUB-M classification had higher age than others; anemia was more prevalent in the AUB-P group, the AUB-O group had the highest TSH levels and hypothyroidism frequency. The PALM-COEIN classification helps ascertain the cause of AUB practically and should be used in routine clinical practices to manage these patients better.


Effect of center of pressure and trunk center of mass optimization methods on the analysis of whole body lifting mechanics.
This study evaluates methods to optimize the trunk center of mass position, the center of pressure position, or both to minimize the difference between horizontal location of the whole body center of mass estimated by the model and center of pressure measured during static postures. Within subjects repeated measures. Methods to optimize the trunk center of mass position have been proposed in the past, but have not been fully evaluated nor have accounted for errors in the location of the center of pressure. Accurately determining these locations affects the understanding of the control of balance. Six methods were compared using kinematic and force plate data from 22 subjects. Static postures resembling both leg and back lifting techniques were used to optimize the center of mass. A typical lifting movement was used to evaluate the effectiveness of the methods in reducing the difference between external moment and time derivative of the angular momentum. Optimization of the center of pressure had a statistically significant effect on reducing errors (P<0.05), whereas optimization of the trunk center of mass alone had not (P>0.05). Optimizing the center of pressure was simple and compensated for systematic errors introduced from the model and instrumentation. The addition of the center of mass optimization improved some results but added much complexity to the experimental procedures. Reducing errors in determining the relative position of the center of pressure and center of mass enhances the understanding of balance control as this relationship reflects the dynamic stability of the system.


Examining Changes in Central and Peripheral Pain as Mediates of Fatigue Improvement: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis.
Following anti-tumor necrosis factor (anti-TNF) therapy, improvements in rheumatoid arthritis (RA) fatigue are driven by reductions in pain. However, therapies may modify both central and peripheral pain. This study sought to examine the hypothesis that reductions in fatigue after anti-TNF therapy reflect changes in central, not peripheral, pain mechanisms. Data came from patients with severe baseline fatigue (Short Form 36 health survey [SF-36] vitality scale ≤12.5; n = 2,652), recruited to the British Society for Rheumatology Biologics Register for RA for commencing anti-TNF therapies between October 2000 and November 2008. Data of interest comprised change over 6 months in fatigue, pain (SF-36 bodily pain scale), and disease activity constituents (Disease Activity Score in 28 joints, erythrocyte sedimentation rate [ESR], global health, swollen joints, and tender joints). Principal components factor analysis with varimax rotation determined latent variables of symptom change; variables were accepted provided they had eigenvalues ≥1. Six factors were identified, of which 2 met acceptance criteria (eigenvalues of 2.39 and 1.14, respectively). Following rotation, loadings indicated that factor 1 comprised markers of peripheral inflammation: change in ESR, swollen joints, tender joints, and global health. This distinct loading led to factor 1 being labeled peripheral inflammation. Conversely, factor 2 comprised change in pain, fatigue, and global health and an absence of peripheral inflammation markers and was therefore labeled central inflammation. Following anti-TNF therapies, reductions in fatigue and pain appear to reflect improvements in central, rather than peripheral, inflammation. Therefore, for those seeking to treat fatigue via pain mechanisms, improvements may be maximized by the application of treatment modalities that effectively target central mechanisms.


Wild rodents as laboratory models and their part in the study of diseases.
The paper describes the use of 14 South African wild rodent species as experimental models and demonstrates the proven value of many of these as laboratory animals in research on bacterial infections (plague, relapsing fever), rickettsial infections (tickbite fever, louse typhus), viral infections (poliomyelitis. Rift-Valley fever and other arbovirus infections, Lassa fever), fungal infections (histoplasmosis), parasitic infections (schistosomiasis) and in diabetes mellitus and cancer research.


Antitumour Metallocenes: Effect of DMSO on the Stability of Cp(2)TiX(2) and Implications for Anticancer Activity.
The rate of hydrolysis of the aromatic rings of Cp(2)TiX(2) [X = CI 1, O(2)CCCl(3)8 and O(2)CCH(2)NH(3)Cl 13], in aqueous solutions, 10%DMSO and 100% DMSO have been studied by (1)H NMR spectroscopy. Rapid hydrolysis of both the carboxylate and cyclopentadienyl ligands in Cp(2)TiX(2)[X = O(2)CCCl(3),O(2)CCH(2)NH(3)Cl] occurs in DMSO to give biologically inactive species. The rate of these reactions are concentration dependent as dilution of these samples with saline or water to give the therapeutic conditions of 10%DMSO/90%H(2)O slows the hydrolysis chemistry. In contrast, samples of Cp(2)TiX(2) [X = CI 1, O(2)CCH(2)NH(3)Cl13 ], dissolved in water give solutions containing the presumed antitumour active species in which the halide or glycine ligands have been hydrolysed but the Cp rings remain metal bound.


Ultrasensitive Poly(boric acid) Hydrogel-Coated Quartz Crystal Microbalance Sensor by Using UV Pressing-Assisted Polymerization for Saliva Glucose Monitoring.
Quartz crystal microbalance (QCM) has attracted extensive attention in the field of biological analysis and detection because of its high sensitivity, fast response, real-time measurement, good operability, and low-cost production. However, to detect the trace amounts of small molecules, such as low-concentration saliva glucose under physiological conditions, is still a major challenge. Herein, the surface of a QCM chip was coated with a poly(boric acid)-based hydrogel using UV pressing-assisted polymerization to obtain a simple device for glucose detection. The designed QCM sensor shows a record-low detection limit of glucose (3 mg/L at pH 7.5), which is ∼30 times lower than that of sensors fabricated by conventional surface initiation-spin coating. The outperformance of the poly(boric acid) hydrogel-coated QCM sensor is probably due to the uniform and compact microstructure, as well as the presence of sufficient glucose-binding sites resulting from the hydrogel coating generated by UV pressing-assisted polymerization. This method provides an important solution to detect the trace amounts of small organic molecules or ions and has the potential to push forward the practical applications of QCM sensors.


Identification of the MT3 molecule using two-dimensional gel electrophoresis and alloantisera.
The MT3 antigen is defined serologically as a DR supertypic specificity and is strongly associated with DR4, DR7, and DRw9. To determine whether the MT3 molecule is distinct from the DR molecule, DR4 and MT3 antigens were immunoprecipitated from 125I-labeled plasma membrane glycoproteins of a DR4-homozygous, MT3-homozygous B lymphoid cell line, Wa, and compared by two-dimensional (2-D) gel electrophoresis. The precipitates with two different anti-DR4 alloantisera and with three different mouse antibodies against human Ia monomorphic determinants gave the same 2-D gel pattern consisting of one heavy chain with a molecular weight of 34 000 and a set of light chains with a molecular weight of 30 000, indicating that these polypeptides are the components of the DR4 molecule. On the other hand, all three anti-MT3 alloantisera used precipitated an identical set of anti-MT3 alloantisera specific light chains with a molecular weight of 30 000, and one heavy chain with a molecular weight of 34 000. The pI of the MT3 light chain was more acidic than that of the DR4 light chain. The amount of MT3 light chains was much smaller than that of DR4 light chains in unlabeled plasma membrane glycoproteins. Thus, we have demonstrated directly using 2-D gel electrophoresis and anti-MT3 alloantisera that the MT3 antigen is a new human Ia molecule distinct from DR4.


Vegetative responses to defoliation of two Chilean matorral shrubs.
This paper reports the results of experimental defoliation of two common matorral species: Lithraea caustica and Colliguaya odorifera. L. caustica and C. odorifera are the matorral species previously shown to exhibit the highest and lowest levels of natural defoliation by browsing. Experimental defoliation was performed at four levels: 0% (controls), 25%, 66%, and 100%. C. odorifera exhibited vegetative responses stronger than controls only in the two highest levels of defoliation (66% and 100%), whereas L. caustica responded vigorously at the 25% and 100% levels. The results are related to the observed position of both species in the matorral community and their relative defoliation risks by natural and introduced herbivores.


Cerebral peak time mapping uniformity of the value of peak time.
By studying patients with clinically suspected cerebrovascular occlusive disease using dynamic CT technique, we have shown that contrast peak attenuation of the whole normal cerebral tissue was uniformly reached at the same time within a given individual. On the other hand, the delay of peak time was shown to correlate with some vascular occlusive mechanism. The main implications of delayed contrast peak time can be summarized as follows: Reduced regional blood flow due to stenosis or occlusion of main vessel without tissue damage. Delayed contrast arrival time due to occlusion of main vessel, but with sufficient circulation. Tissue organically injured by cerebrovascular occlusion.


Purification and properties of a heat-stable inulin fructotransferase from Arthrobacter ureafaciens.
An inulin fructotransferase producing difructose dianhydride I (EC 188.8.131.52) was purified from Arthrobacter ureafaciens A51-1. It had maximum activity at pH 5.5 and 45 degrees C, and was stable up to 80 degrees C. This is the highest thermal stability for this enzyme reported to date. The molecular mass was estimated to be 38000 by SDS-PAGE, and 61000 by gel filtration. It was therefore estimated to be a dimer.


Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells.
The prostate gland of humans and other animals accumulates a level of zinc that is 3-10 times greater than that found in other tissues. Associated with this ability to accumulate zinc is a rapid zinc uptake process in human prostate cells, which we previously identified as the hZIP1 zinc transporter. We now provide additional evidence that hZIP1 is an important operational transporter that allows for the transport and accumulation of zinc. The studies reveal that hZIP1 (SLC39A1) but not hZIP2 (SLC39A2) is expressed in the zinc-accumulating human prostate cell lines, LNCaP and PC-3. Transfected PC-3 cells that overexpress hZIP1 exhibit increased uptake and accumulation of zinc. The V(max) for zinc uptake was increased with no change in K(m). Along with the increased intracellular accumulation of zinc, the overexpression of hZIP1 also results in the inhibition of growth of PC-3 cells. Down-regulation of hZIP1 by treatment of PC-3 cells with hZIP1 antisense oligonucleotide resulted in a decreased zinc uptake. Uptake of zinc from zinc chelated with citrate was as rapid as from free zinc ions; however, the cells did not take up zinc chelated with EDTA. The cellular uptake of zinc is not dependent upon an available pool of free Zn(2+) ions. Instead, the mechanism of transport appears to involve the transport of zinc from low molecular weight ligands that exist in circulation as relatively loosely bound complexes with zinc.


GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141.
Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE. Patient fibroblasts and GTF3A gene-edited cells displayed impaired HSV-1-induced innate immune responses and enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis identified the 5S ribosomal RNA pseudogene 141 (RNA5SP141), an endogenous ligand of the RNA sensor RIG-I, as a transcriptional target of TFIIIA. GTF3A mutant cells exhibited diminished RNA5SP141 expression and abrogated RIG-I activation upon HSV-1 infection. Our work unveils a crucial role for TFIIIA in transcriptional regulation of a cellular RIG-I agonist and shows that GTF3A genetic defects lead to impaired cell-intrinsic anti-HSV-1 responses and can predispose to HSE.


Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice.
Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5mg/kg) or morphine (10mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age.


Failure to detect evidence of human immunodeficiency virus type 1 (HIV-1) infection by polymerase chain reaction assay in blood donors with isolated core antibodies (anti-p24 or -p17) to HIV-1.
Individuals with isolated and persistent core antibodies (anti-p24 or -p17) to HIV-1 are sometimes diagnosed through the systematic screening of blood donations. The significance of such serum reactivities remains unknown. Polymerase chain reaction (PCR) is a new technique allowing the direct detection of HIV-1 DNA in blood samples. In this study, PCR was used to detect HIV-1 DNA in 20 individuals with isolated and persistent core antibodies (14 anti-p24 and 6 -p17), in seven sexual partners of these individuals, in 55 HIV-1-seropositive individuals (positive controls), and in 105 HIV-1-seronegative blood donors at low risk of HIV-1 infection (negative controls). No HIV-1 DNA was detected in individuals with isolated and persistent core antibodies, in their sexual partners, or in negative control individuals, although PCR was positive in 54 of 55 seropositive control individuals. These results strongly suggest that individuals with isolated and persistent core antibodies are not infected with HIV-1.


Comparison between Cardiac CTA and Echocardiography for Assessment of Ventricular Septal Rupture Diameter and Its Effect on Transcatheter Closure.
This study is aimed at comparing cardiac computed tomographic angiography (CTA) with echocardiography in the assessment of ventricular septal perforation diameter. A total of 44 ventricular septal rupture (VSR) patients undertaking transcatheter occlusion were included and randomly divided into the CTA group and echocardiography group with a 1 : 1 ratio. Clinical data, operation-related data, and 30 d follow-up data were collected and analyzed. Incidence of closure failure, occluder displacement, poor occluder molding, and occluder waist diameter shrinkage between the two groups were not statistically different. The mean residual shunt volume in the echocardiography group (4.2 (3.1, 5.9) mm) was significantly higher than that in the CTA group (2.1 (0, 4.0) mm) with a p value of 0.005. However, no significant differences were found in all-cause mortality and incidence of operative complications within 30 days after surgery. Within the CTA group, the correlation was strongest between postoperative occluder diameter and long diameter measured by CTA with a correlation coefficient of 0.799 and p < 0.001, followed by the correlation between postoperative occluder diameter and mean diameter measured by CTA with a correlation coefficient of 0.740 and p < 0.001. The diameter measured by echocardiography was not correlated to postoperative occlude diameter. Assessment of VSR diameter by cardiac CTA is more accurate than by echocardiography.


[Diagnostics and treatment of post-stroke dysphagia].
Post-stroke dysphagia is highly prevalent and leads to severe complications, such as aspiration pneumonia and malnutrition. Despite the high clinical relevance dysphagia management is heterogeneous and often inadequate. The aim of this review article is to provide an overview of the diagnostic and treatment strategies for post-stroke dysphagia based on recent studies. Narrative literature review. Dysphagia screening should be performed as early as possible in every stroke patient, e.g., with a simple water swallowing test or a multiconsistency protocol. Subsequently, flexible endoscopic evaluation of swallowing (FEES) is indicated in patients with abnormal screening results or existing risk factors for dysphagia. Dietary modifications, oral hygiene measures, and nutritional therapy can help reduce complications. Behavioral swallowing therapy or experimental therapies, such as neurostimulation procedures and pharmacological approaches aim to improve swallowing function and have shown promising results in studies. Timely management of dysphagia is necessary to reduce complications.


Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells.
Histone modifications have emerged as important regulators of transcription. Histone H2B monoubiquitination has also been implicated in transcription; however, better understanding of the biological significance of this modification in mammalian cells has been hindered by the lack of suitable reagents, particularly antibodies capable of specifically recognizing ubiquitinated H2B (ubH2B). Here, we report the generation of anti-ubH2B monoclonal antibodies using a branched peptide as immunogen. These antibodies provide a powerful tool for exploring the biochemical functions of H2B monoubiquitination at both a genome-wide and gene-specific level. Application of these antibodies in high resolution chromatin immunoprecipitation (ChIP)-chip experiments in human cells, using tiling arrays, revealed preferential association of ubiquitinated H2B with the transcribed regions of highly expressed genes. Unlike dimethylated H3K4, ubH2B was not associated with distal promoter regions. Furthermore, experimental modulation of the transcriptional activity of the tumour suppressor p53 was accompanied by rapid changes in the H2B ubiquitination status of its p21 target gene, attesting to the dynamic nature of this process. It has recently been demonstrated that the apparent extent of gene expression often reflects elongation rather than initiation rates; thus, our findings suggest that H2B ubiquitination is intimately linked with global transcriptional elongation in mammalian cells.


A mouse model of type B cystinuria due to spontaneous mutation in FVB/NJcl mice.
Cystinuria is an autosomal metabolic disorder caused by mutations in the SLC3A1 and SLC7A9 genes, encoding the amino acid transporter proteins rBAT and b0,+AT, respectively. Based on the causative gene, cystinuria is classified into 3 types: type A (SLC3A1), type B (SLC7A9), and type AB (SLC3A1 and SLC7A9). Patients with cystinuria exhibit hyperexcretion of cystine and dibasic amino acids in the urine and develop cystine crystals due to its low solubility in the urine, often resulting in calculus formation. In this study, we present an inbred strain FVB/NJcl mice affected with cystinuria. In the affected mouse kidney, Slc7a9 expression was completely abolished because of a large sequence deletion in the promoter region of the Slc7a9 mutant allele. Slc7a9-deficient mice with FVB/NJcl genetic background developed cystine calculi in the bladder with high penetrance, as compared to the previously reported mouse models of cystinuria. This model may be useful to understand the determinants of crystal aggregation, affecting calculus formation.


A cross-sectional study on the tea consumption effects of ankle-brachial index.
This thesis aims to explore the relationship between tea consumption and ankle-brachial index (ABI) and further studies the relationship between tea consumption and lower extremity atherosclerosis. This is a cross-sectional, epidemiological survey of 17,373 subjects selected from the staff of Kailuan Group who had come to Kailuan General Hospital for a health examination from January 2016 to December 2017. Tea consumption was obtained by questionnaires. ABI was measured using an automated analyzer. The other data, such as age, gender, body mass index (BMI), and so on, was collected on the same day of the health examination results. The relationship between tea drinking habits and ABI was studied using logistic regression and multivariate linear regression analysis. Among the 17,373 analyzed subjects, the difference in age, gender, BMI, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), uric acid (UA), C-reactive protein (CRP), fasting blood-glucose (Fbg), and ABI was statistically significant in the tea-drinking group and the nontea-drinking group (p < 0.05). Multiple logistic regression models revealed that tea consumption was a positive predictor for ABI (odds ratio (OR) = 0.782, confidence interval (CI), 0.615-0.994) (p < 0.05). Multivariate linear regression analysis of the ABI value showed that frequent tea-drinking has a positive correlation with the ABI value (p < 0.05). The higher tea consumption is significantly associated with higher ABI which means less risk for lower extremity atherosclerosis.


Disruption of memory reconsolidation impairs storage of other, non-reactivated memory.
Two hypotheses were tested in this study. First, blockade of neural activity by lidocaine immediately following the retrieval of a memory may impair the reconsolidation and subsequent expression of that memory. Second, a non-retrieved memory would not be affected by this lidocaine treatment. Since the basolateral nucleus of the amygdala (BLA) is involved in emotion-related memory, an intra-BLA lidocaine infusion was used immediately after the retrieval of two emotion-related memories, the step-through passive avoidance response (PA) and cocaine-induced conditioned place preference (CPP). Intra-BLA lidocaine infusion immediately after cocaine-induced CPP retrieval diminished CPP magnitude in retests. However, intra-BLA lidocaine infusion alone did not affect cocaine-induced CPP performance. Intra-BLA lidocaine infusion immediately after PA retrieval decreased PA performance in retests. Omission of PA retrieval procedure, intra-BLA lidocaine infusion did not affect subsequent PA performance. Surprisingly, intra-BLA lidocaine infusion immediately following the retrieval of PA or cocaine-induced CPP diminished both PA and cocaine-induced CPP performance in the retests. Finally, Fos-staining results revealed that a number of BLA neurons were activated by the retrieval of both cocaine-induced CPP and PA. We conclude that inactivation of neural activity in BLA immediately following retrieval of a fear or cocaine-conditioned memory can impair subsequent expression of both memories. More importantly, retrieval of a memory does not seem to be an absolute condition for rapidly changing the memory.


Clinical, laboratory and immune aspects of Zika virus-associated encephalitis in children.
To evaluate the clinical, laboratory, and immune characteristics of Zika virus (ZIKV)-associated encephalitis in pediatric patients after the epidemic in Huila, southern Colombia. A pediatric neuro-surveillance hospital study was conducted in a referral health center in southern Colombia, from October 2016 to October 2017. Cases of encephalitis were confirmed by nucleic acid amplification tests and serological methods in cerebrospinal fluid (CSF), plasma, and/or urine. Levels of six cytokines were evaluated by flow cytometry. Patients underwent daily clinical and laboratory follow-up. Twenty children with probable encephalitis were included for further studies and 16 of them were confirmed. Four cases of bacterial meningoencephalitis (Streptococcus pneumoniae, group B Streptococcus, Staphylococcus epidermidis, and Escherichia coli) and 12 cases of viral encephalitis were identified, six of them associated with ZIKV infection. Other viral encephalitis cases were caused by herpes viruses (n=3), enterovirus (n=2), and dengue virus type 2 (DENV-2; n=1) infections. ZIKV-associated encephalitis symptoms subsided faster than those of patients with encephalitis caused by other agents. CSF analysis revealed lymphocytic pleocytosis. Compared to healthy controls, children with ZIKV-associated encephalitis presented modest plasma interleukin (IL)-10 but not IL-2, IL-4, IL-6, interferon gamma (IFN-γ), or tumor necrosis factor alpha (TNF-α). Cytokine expression was differentially regulated, as dramatically elevated IL-6, IL-10, and IFN-γ levels were observed in CSF but not in paired plasma samples in one of the patients with ZIKV detectable in CSF. This study provides evidence that ZIKV is responsible for pediatric encephalitis in endemic areas, and the local presence of the virus may induce cephalic but not systemic expression of cytokines.


Estimation of cancer burden in Brezice municipality, a community neighboring Krsko nuclear power plant in Slovenia.
To evaluate cancer risk in Brezice municipality in the period 1984-2003 and compare it with the period 1970-1983, before Krsko nuclear power plant started operating in the vicinity. A descriptive geographical epidemiological study was performed to compare the cancer relative risks (RR) on the national, regional, and local level. We estimated RR for all cancers combined, the five most common cancer sites, and thyroid cancer and leukemias. Standardized incidence ratio (SIR) was used as RR indicator. If the number of cancer cases was small, raw SIRs were smoothed by Bayesian hierarchical model. The number of new cancer cases, as well as the estimated RR for all and individual cancer sites, increased in the period 1984-2003 in Brezice municipality and all over Slovenia. In the period 1984-2003, SIR for all cancers combined in Brezice was below the national and regional average, but RR for colorectal and cervical cancer was above this average. There were no evident clusters of districts with higher/lower RR within Brezice municipality in the period 1984-2003. RR of thyroid cancer and leukemias in Brezice was comparable with Slovenian average both in this period and before it. The obvious increase in cancer burden in Brezice municipality cannot be associated with Krsko nuclear power plant, but most likely with unhealthy lifestyle.


Alterations of the 11p15 imprinted region and the IGFs system in a case of recurrent non-islet-cell tumour hypoglycaemia (NICTH).
Non-islet-cell tumour hypoglycaemia (NICTH) is a rare disorder and has been explained by oversecretion of non mature IGF-II and dysregulation of the IGFs sytem. The mechanisms responsible for tumoural IGF-II overexpression in NICTH have been rarely studied. We report an extensive study of IGF-II and IGFBPs as well as chromosome 11p15 gene expression regulation in a case of a pleural fibrosarcoma in a 63-year-old patient presenting with NICTH. Abnormal high molecular weight precusor forms of IGF-II were present in the patient's serum and were associated with dramatic alterations in the circulating levels of IGF-I, IGF-II and their binding proteins, as well as an inhibition of the somatotroph axis. These alterations returned to normal following complete surgical removal of the tumour. No structural change in chromosome 11p15 region was apparent in the tumour. However, dysregulation of this imprinted region was demonstrated, leading to the loss of imprinting of the IGF-II gene associated with high IGF-II expression, and by contrast decreased level of expression of H19 and p57KIP2 genes. Recurrence of the tumour four years latter was not associated with hypoglycaemia or changes in the levels of circulating IGFs or IGFBPs, despite IGF-II overexpression by the tumour. This suggests that a large tumour volume is required to reach high enough levels to cause changes in the levels of circulating IGFs and IGFBPs, and to cause hypoglycaemia. These results suggest that a dysregulation of gene expression and imprinting of chromosome 11p15 region is associated with tumour growth and IGF-II overexpression in non-islet-cell tumour hypoglycaemia.


Progressive essential iris atrophy, Chandler's syndrome, and the iris nevus (Cogan-Reese) syndrome: a spectrum of disease.
Progressive essential iris atrophy, Chandler's syndrome, and the iris nevus (Cogan-Reese) syndrome are considered to be variations of a single disease process, which is characterized by abnormalities of the cornea, anterior chamber angle, and iris. In each variation, the typical patient is a white woman with unilateral disease, negative family history, and an onset of symptoms in early to middle adulthood. Since the membrane theory of Campbell suggests that the disease is a fundamental abnormality of the corneal endothelium, rather than the iris, the term "iridocorneal endothelial syndrome," as proposed by Yanoff, may be an appropriate inclusive term for the spectrum of disease, although further study of the pathogenesis is needed. For each variation of the disease, corneal edema and secondary glucoma are both treated primarily by medical or surgical reduction of the intraocular pressure, although penetrating keratoplasty is occasionally required for cases with advanced corneal edema.


Unusually long germline DH genes contribute to large sized CDR3H in bovine antibodies.
We demonstrated earlier the existence of an exceptionally long third complementarity-determining region of the heavy chain (CDR3H) (up to 61 amino acids (aa)), with multiple cysteine residues, in some functional IgM antibodies of cattle. To understand the origin of such a long CDR3H, we have now characterized the germline diversity gene (D(H)) of the cattle. A 2.3kb genomic DNA fragment hybridizing with a newly developed DNA probe to putative bovine D(H) gene sequences was isolated, cloned and its nucleotide sequence determined. Inspection of the nucleotide sequence led to identification of three bovine germline D(H) gene segments of varying size: 42bp (14 possible codons), 58bp (19 possible codons) and 148bp (49 possible codons). The characteristic repetitive GGT and TAT codons, remarkable in the CDR3H region of fetal VDJ rearrangements likely encoded by germline genes, are noted in two of the identified germline D(H) genes. These D(H) genes are preferentially expressed in the third reading frame to encode hydrophilic glycine and tyrosine residues in the CDR3H region. Phylogenetic analysis suggests that bovine D(H) genes are closest to rabbit and chicken D(H) genes. Thus, both short and long germline D(H) genes exist in cattle and these are capable of directly contributing to CDR3H size heterogeneity including the exceptionally long CDR3H region, apart from recombination associated mechanistic factors.


Impacts of pregnane X receptor and cytochrome P450 oxidoreductase gene polymorphisms on trough concentrations of apixaban in patients with non-valvular atrial fibrillation.
We examined the impact of polymorphisms in genes encoding cytochrome P450 (CYP) 3A5 (gene code CYP3A5), P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), cytochrome P450 oxidoreductase (POR), and pregnane X receptor (PXR; NR1I2) on the daily dose-adjusted steady-state trough concentrations (C0h/D) of apixaban. The analyses included 104 patients with non-valvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3; ABCG2 421C > A; ABCB1 1236C > T, 2677G > A/T, 3435C > T, and 2482-2236G > A; NR1I2 11156A > C, 11193T > C, and 8055C > T; and POR*28 genotypes were determined. The combination of the noted NR1I2 genotypes determined the PXR*1B haplotype. Multiple linear regression analyses demonstrated that decreased creatinine clearance (Ccr) and the PXR*1B/*1B haplotype correlated with increased C0h/D of apixaban, while the presence of the POR*28 allele correlated with decreased C0h/D of apixaban (partial R2 = 0.168, 0.029, and 0.044, all P < 0.05). The mean (95% CI) of estimated marginal means of apixaban C0h/D calculated using Ccr as a covariate was the highest in POR*28 noncarriers with PXR*1B/*1B (23.5 [21.0-25.9] ng/mL/[mg/day]) and lowest in POR*28 carriers with other haplotypes (16.6 [15.5-17.7] ng/mL/[mg/day]). The PXR*1B haplotype and POR*28 genotype statuses, which involve genes that impact the expression of multiple drug-metabolizing enzymes and drug-transporters, may have modest effects on the C0h/D of apixaban, but these effects were found to be small.


Perturbed gut microbiota is gender-segregated in unipolar and bipolar depression.
This study aimed to explore the gender specificity of gut microbiome in patients with unipolar and bipolar depression disorder by analyzing the data of gut microbiome in this two mental disorders and healthy people. A case-control study using 16S ribosomal RNA gene sequencing from fecal samples of MDD (male set, n = 43; female set, n = 77) and BD (male set, n = 82; female set, n = 83) compared with HCs (male set, n = 71; female set, n = 100) was conducted. Linear discriminant analysis was used to identify microbial characteristics. Through cooccurrence analysis, the potential correlations of the differential gut microbiota in different genders was explored. Finally, the gender-specific distinguishing microorganisms were identified as biomaker, and the diagnostic performance was verified by five-fold cross validation. A specific cluster was found enriched only in female MDD set, including 4 Bacteroideae OTUs. Similarly, 3 Lachnospiraceae OTUs was found significantly increased in female BD compared with other groups. In addition, the consistent enrichment of Pseudomonadacea in male and female may be the characteristic disease-related gut microbiota of BD. Besides, the diagnostic potential of gender specific biomarker panel in male (male validation AUC: 0.758-0.874, accurancy: 0.693-0.792; female validation AUC: 0.727-0.883, accurancy: 0.678-0.781) and female (male validation AUC: 0.787-0.883, accurancy: 0.719-0.784; female validation AUC: 0.795-0.898, accurancy: 0.689-0.838) has also been identified and confirmed. The microbiological changes in both MDD and BD are sex specific, and gender specific biomarker panel has better diagnostic performance, which provide a certain reference in sex difference for future clinical differentiation and microbial intervention.


Small, bilateral, calcified intrarenal aneurysms--a case report.
With increased use of renal angiography and ultrasonography, intrarenal aneurysms and arteriovenous malformations have been easily diagnosed. The authors report a case of small, bilateral intrarenal aneurysms with calcifications that were associated with a visible pulsatile wall motion recorded by M-mode ultrasonography. The finding of selective renal angiography was consistent with bilateral intrarenal aneurysms. Accelerated atherosclerosis and long-term history of hypertension were thought to have caused them.


Disentangling the lifestyle of bacterial communities in tropical soda lakes.
Microbial lifestyles may reveal niche-specific signatures and can contribute to detecting the effects of abiotic fluctuations on biogeochemical cycles. Microorganisms make a tradeoff between optimizing nutrient uptake, improving biomass yield, and overcoming environmental changes according to environmental hostility. Soda lakes are natural environments rich in carbonate and bicarbonate water, resulting in elevated pH and salinities that frequently approach saturation. We hypothesized that during the dry period (elevated pH and salinity), microorganisms try to overcome this harshness by allocating energy to the cellular maintenance process. As these environmental conditions improve during the wet period, microorganisms will begin to invest in nutrient uptake. To test this hypothesis, we evaluated four soda lakes in two different seasons by applying metagenomics combined with flow cytometry (estimate heterotrophic bacterial biomass). The natural occurrence of cyanobacterial blooms in some lakes is the main driver of carbon. These primary producers provide organic carbon that supports heterotrophic bacterial growth and, consequently, a high biomass yield. Under harsh conditions (dry season), cyanobacteria invest in nutrient uptake mechanisms, whereas heterotrophic bacteria allocate energy to survive at the expense of biomass yield. Lakes without cyanobacteria blooms invest in nutrient uptake independent of environmental hostility. This study clarifies the microbial tradeoffs in hostile environments and the impact of this choice on carbon and energy flux in tropical alkaline lakes.


Ultrasound thrombolysis.
Ultrasound energy for thrombolysis dates back to 1976. Trubestein et al. demonstrated first in vitro that a rigid wire delivery low frequency ultrasound energy could disrupt clot. These investigators also showed that this system had potential for peripheral arterial clot dissolution in vivo in animal studies [G. Trubestein, C. Engel, F. Etzel, Clinical Science 51 (1976) 697s-698s]. Subsequently, four basic approaches to ultrasonic thrombolysis have been pursued--two without pharmacological agents: (1) catheter-delivered external transducer ultrasound, (2) transcutaneous-delivered HIFU external ultrasound without drug delivery and ultrasound in conjunction with thrombolytic drugs and/or microbubbles or other agents, (3) Catheter-delivered transducer-tipped ultrasound with local drug delivery, and (4) transcutaneous-delivered low frequency ultrasound with concomitant systemic (intravenous) drug delivery for site specific ultrasound augmentation. This article reviews recent data on therapeutic ultrasound for thrombolysis in vitro, in vivo, in animal studies, as well as in human clinical trials.


Childhood IQ predicts age-38 oral disease experience and service-use.
Given that people with higher intelligence have been shown to live longer, enjoy better health and have more favourable health behaviours, we investigated the association between childhood IQ and a range of important dental health and service-use indicators at age 38. Long-standing prospective study of a complete birth cohort, with childhood IQ (assessed at ages 7, 9, 11 and 13 years) used to allocate participants (N = 818) to one of four ordinal categories of childhood IQ. There were distinct and consistent gradients by childhood IQ in almost all of the dental caries experience measures (with the exception of filled teeth) whereby each was most severe in the lowest child IQ category and least severe in the highest; the exception was the mean FT score, for which there was no discernible gradient. Indicators of self-care and periodontal disease experience showed similar gradients, and multivariate modelling using the continuous IQ score confirmed the observed patterns. Childhood cognitive function is a key determinant of oral health and dental service-use by midlife, with those of lower cognitive capacity as children likely to have poorer oral health, less favourable oral health-related beliefs, and more detrimental self-care and dental visiting practices by age 38. There is a need to shape dental clinical services and public health interventions so that people with the poorest cognitive function do not continue to be disadvantaged.


NaBH4-InCl3-mediated one-pot chemo- and stereoselective decarboxylative reduction of alpha-aza gem-dicarboxylic esters to monoalcohols.
[reaction: see text] The combination of NaBH4 and a catalytic amount of InCl3 provides a one-pot method for chemo- and stereoselective decarboxylative reduction of gem-dicarboxylic esters 1 to monoalcohols 2 in the presence of the lactam carbonyl in refluxing acetonitrile under inert atmosphere.


The bliss (not the problem) of motor abundance (not redundancy).
Motor control is an area of natural science exploring how the nervous system interacts with other body parts and the environment to produce purposeful, coordinated actions. A central problem of motor control-the problem of motor redundancy-was formulated by Nikolai Bernstein as the problem of elimination of redundant degrees-of-freedom. Traditionally, this problem has been addressed using optimization methods based on a variety of cost functions. This review draws attention to a body of recent findings suggesting that the problem has been formulated incorrectly. An alternative view has been suggested as the principle of abundance, which considers the apparently redundant degrees-of-freedom as useful and even vital for many aspects of motor behavior. Over the past 10 years, dozens of publications have provided support for this view based on the ideas of synergic control, computational apparatus of the uncontrolled manifold hypothesis, and the equilibrium-point (referent configuration) hypothesis. In particular, large amounts of "good variance"-variance in the space of elements that has no effect on the overall performance-have been documented across a variety of natural actions. "Good variance" helps an abundant system to deal with secondary tasks and unexpected perturbations; its amount shows adaptive modulation across a variety of conditions. These data support the view that there is no problem of motor redundancy; there is bliss of motor abundance.


LncRNA PCAT6 promotes tumor progression in osteosarcoma via activation of TGF-β pathway by sponging miR-185-5p.
Long noncoding RNAs (lncRNAs) play crucial roles in tumor development of osteosarcoma (OS). LncRNA PCAT6 was involved in the progression of multiple human cancers. However, the biological function of PCAT6 in OS remains largely unknown. We found that PCAT6 was elevated in OS tissues relative to that in their adjacent normal tissues. The upregulation of PCAT6 was positively associated with metastasis status and advanced stages and predicted poor overall and progression-free survivals in patients with OS. Functionally, silencing PCAT6 inhibited the proliferation, migration and invasion abilities of OS cells. Mechanistically, PCAT6, acting as a competitive endogenous RNA, upregulated expression of TGFBR1 and TGFBR2 to activate TGF-β pathway via sponging miR-185-5p. This study uncovers a novel underlying molecular mechanism of PCAT6-miR-185-5p-TGFBR1/2-TGF-β signaling axis in promoting tumor progression in OS, which indicates that PCAT6 may serve as a promising prognostic factor and therapeutic target again OS.


A newly developed immunoliposome--an egg phosphatidylcholine liposome coated with pullulan bearing both a cholesterol moiety and an IgMs fragment.
An improved methodology for providing a more stable and targetable drug carrier has been developed. This method involves the synthesis of a newly designed immunoliposome by coating the outermost surface of large oligolamellar vesicles of egg phosphatidylcholine with the polysaccharide pullulan, modified to carry both cholesterol, as the hydrophobic anchor, and the monoclonal antibody fragment (anti-sialosyl Lewis X, IgMs) as the sensory device. Compared with the binding of pullulan-coated liposomes, that of this immunoliposome to specific cells in vitro was significantly increased by factors of 447 to PC-9 and 295 to KATO-III, but only by a factor of 148 to the less specific cell, 3LL. This strong and specific binding of the immunoliposome to the cell surface of PC-9 was also confirmed by a fluorescence-microscopic investigation using the immunoliposome, which bore the hydrophobic fluorescent probe, terbium trisacetylacetonate, in the liposomal membrane.


A self-analyzing double-loop digital controller in laser frequency stabilization for inter-satellite laser ranging.
We present a digital controller specially designed for laser frequency stabilization in the application of inter-satellite laser ranging. The prototype of controller is developed using field programmable gate arrays programmed with National Instruments LabVIEW software. The controller is flexible, self-analyzing, and easily optimized with build-in system analysis. Application and performance of the controller to a laser frequency stabilization system designed for spaceborne scientific missions are demonstrated.


Microfabricated liquid chromatography columns based on collocated monolith support structures.
There is great interest today in massively parallel analytical strategies as a way to accelerate the rate of discovery in biological research; among them being 'biochips' and 'laboratories-on-a-chip'. The concept in the 'chip' approach is that minaturization will allow large numbers of operations to be performed in parallel in a small space, as in electronics. Proceeding with the semiconductor analogy, this paper demonstrates that in situ micromachining can be used to simultaneously fabricate millions of micrometer size, particle like structures in multiple liquid chromatography columns on a single wafer. Reduction of this widely used bioanalytical tool to the nanoliter volume, parallel processing, chip format is a significant step toward laboratories-on-a-chip.


Automated Design by Structure-Based Stabilization and Consensus Repair to Achieve Prefusion-Closed Envelope Trimers in a Wide Variety of HIV Strains.
Soluble envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit neutralizing responses against HIV-1 strains closely related to the immunizing trimer. However, to date such stabilization has succeeded with only a limited number of HIV-1 strains. To address this issue, here we develop ADROITrimer, an automated procedure involving structure-based stabilization and consensus repair, and generate "RnS-DS-SOSIP"-stabilized Envs from 180 diverse Env sequences. The vast majority of these RnS-DS-SOSIP Envs fold into prefusion-closed conformations as judged by antigenic analysis and size exclusion chromatography. Additionally, representative strains from clades AE, B, and C are stabilized in prefusion-closed conformations as shown by negative-stain electron microscopy, and the crystal structure of a clade A strain MI369.A5 Env trimer provides 3.5 Å resolution detail into stabilization and repair mutations. The automated procedure reported herein that yields well-behaved, soluble, prefusion-closed Env trimers from a majority of HIV-1 strains could have substantial impact on the development of an HIV-1 vaccine.


Differential susceptibility of the axilla and groin of the mouse to chemical oncogenesis.
INCIDENTAL to investigations of chemical oncogenesis, we have observed that 3-methylcholanthrene (3-MC)-induced subcutaneous sarcogenesis occurred more rapidly in the axillary than in the inguinal region of the mouse. Recently Auerbach et al. have described what may be a similar phenomenon-a marked tendency for tumour transplants to grow better cephalically(1,2).


PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease.
Alcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet. At the end of the alcohol exposure protocol, serum and liver samples were obtained for molecular characterization and histopathological analysis. PCSK9 inhibition with alirocumab attenuated alcohol-induced hepatic triglyceride accumulation through regulation of lipid metabolism (mRNA expression of modulators of fatty acid synthesis (FAS) and catabolism (PPARα and CPT1)), hepatocellular injury (ALT), hepatic inflammation (mRNA expression of pro-inflammatory cytokines/chemokines (TNFa, IL-1β, IL-22, IL-33, IL-17α, IL-2, MIP-2, and MCP-1), and neutrophil infiltration (myeloperoxidase staining)). Alirocumab treatment also attenuated alcohol-induced PCSK9 mRNA elevation and upregulated LDL-receptor (LDL-R) via modulation of the transcription factors (SREBP-1, SREBP-2, and E2F1) in liver. We demonstrated that chronic anti-PCSK9 treatment using the monoclonal antibody alirocumab attenuated alcohol-induced steatohepatitis in the rat model. Given the large unmet clinical need for effective and novel treatments for ALD, anti-PCSK9 treatment with the monoclonal antibody that spares liver metabolism is a viable new therapeutic possibility. Future studies are needed to elucidate the exact role of PCSK9 in ALD and alcohol use disorder (AUD) and to evaluate efficacy and safety of anti-PCSK9 treatment in clinical populations with ALD/AUD.


Cloning of hippocampal poly(A) RNA sequences that increase after entorhinal cortex lesion in adult rat.
Evidence is given for altered gene expression in the hippocampus in response to entorhinal cortex lesioning. Three RNA markers encoding glial fibrillary acidic protein, apolipoprotein E and alpha-tubulin were isolated from a rat hippocampal cDNA library by differential screening with cDNA probes from entorhinal cortex lesioned and control rat hippocampus RNA. By Northern blot analysis, mRNA for apolipoprotein E and alpha-tubulin increased to peak around 6 days after the lesion and returned to near control level at 30 days. The increased synthesis of both mRNAs coincides with the acute phase of synaptogenesis, protein synthesis, and polyribosomes accumulation in the deafferented hippocampal area.


Bioassay of TSH using dog thyroid cells in monolayer culture.
The cAMP response to TSH stimulation in dog thyroid cells in monolayer culture was adapted as a means to assay TSH bioactivity. Of a variety of polypeptide hormones examined, only TSH and LH stimulated thyroid cell cAMP generation, but stimulation by LH probably represented contamination with TSH. Serum was found to be a potent, noncompetitive inhibitor of the thyroid cell cAMP response to TSH stimulation. The inhibitor(s) present in serum was nondialyzable and, on Sephadex G-200 gel filtration, eluted over a wide range between the void volume and the albumin peak. Because of this inhibitory effect of serum, partial purification of TSH from serum was necessary, and was achieved using Sephacryl S-200 gel filtration. Columns were calibrated with human TSH as measured by radioimmunoassay and bovine TSH as measured by bioassay. Intraassay variation of the thyroid cell cAMP response to a 100 microU/ml TSH standard was 9.2%. TSH standards were added to human serum following which the TSH was extracted by gel filtration and assayed for bioactivity. With TSH standards of 100 microU/ml intra-assay variation was 19.9%; and with TSH standards of 25 microU/ml, interassay variation was 34.5%. TSH bioactivity was demonstrable in serum from 21 of 25 patients with primary hypothyroidism, 4 of 14 normal subjects and none of 3 patients on exogenous thyroxine replacement. Although a positive correlation was observed between serum TSH bioactivity and immunoactivity, numerous individual samples displayed a dichotomy between the two measurements. This study provides new evidence that immunoassayable TSH in the serum of patients with primary hypothyroidism is not necessarily synonymous with TSH bioactivity.


Post-translational modification of low molecular mass GTP-binding proteins by isoprenoid.
Several proteins in mammalian cells are modified post-translationally by the isoprenoid, farnesol. Incubation of cultured cells with [3H]mevalonate, an isoprenoid precursor, results in the labeling of multiple polypeptides, the most prominent of which migrate in the range of 21-26 kDa on sodium dodecyl sulfate-polyacrylamide gels. In Rat-6 fibroblasts transformed by H-ras, one of the farnesylated proteins was identified as p21ras by two-dimensional immunoblotting. However, this protein accounted for only a small proportion of the [3H]mevalonate-derived radioactivity incorporated into 21-26-kDa proteins. Murine erythroleukemia cells, which did not express immunodetectable quantities of p21ras, contained several 21-26-kDa farnesylated proteins distributed in both the cytosolic and particulate fractions. At least eight of these proteins were capable of binding [alpha-32P]GTP on nitrocellulose membranes. Pulse-chase studies showed that the isoprenoid modification did not necessarily result in the translocation of the cytosolic proteins to the cell membrane. A prominent group of carboxyl-methylated proteins in murine erythroleukemia cells overlapped with the 21-26-kDa farnesylated proteins on one-dimensional sodium dodecyl sulfate gels. Methylation of this group of proteins was selectively abolished when cells were treated with lovastatin, an inhibitor of isoprenoid synthesis. Addition of exogenous mevalonate to the lovastatin-treated cells fully restored carboxyl methylation. These studies suggest that the 21-26-kDa farnesylated proteins in mammalian cells are members of a recently discovered family of low molecular mass GTP-binding proteins which, although ras-related, appear to be distinct structurally and possibly functionally from the products of the ras genes. The observed isoprenoid-dependent carboxyl methylation of a group of 21-26-kDa proteins suggests that the low molecular mass GTP-binding proteins may undergo a series of post-translational C-terminal cysteine modifications (i.e. farnesylation, carboxyl methylation) analogous to those recently elucidated for p21ras.


Cortical modulation of striatal function.
The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.


Local synchronization of one-to-one coupled neural networks with discontinuous activations.
In this paper, local synchronization is considered for coupled delayed neural networks with discontinuous activation functions. Under the framework of Filippov solution and in the sense of generalized derivative, a novel sufficient condition is obtained to ensure the synchronization based on the Lyapunov exponent and the detailed analysis in Danca (Int J Bifurcat Chaos 12(8):1813-1826, 2002; Chaos Solitons Fractals 22:605-612, 2004). Simulation results are given to illustrate the theoretical results.


Experimental cerebral concussion. A histochemical study.
The activity of mitochondrial enzymes (succinic dehydrogenase and cytochrome oxidase) and enzymes associated with blood-brain barrier function (butyrylcholinesterase and alkaline phosphatase) in the CNS of rats was studied from 5 minutes to 62 hours after cerebral concussion. There was a transient increase in succinic dehydrogenase activity during the first hour after concussion in the neurons of the structures close to the impact. The alkaline phosphatase activity, strongly positive in the walls of normal blood vessels, decreased within five minutes after concussion; it virtually disappeared in 15 minutes but returned to normal level after 62 hours. These findings are in good correlation with previous electron microscopic observations. Their significance is discussed.


Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution.
A series of P1 C alpha gem-disubstituted succinamide hydroxamate matrix metalloproteinase inhibitors were prepared stereoselectively and evaluated in vitro for their ability to inhibit MMP-1, MMP-2, and MMP-3. It was found that while methyl/allyl substitution as in 2 and 18 provided compounds that were broad spectrum inhibitors and nearly equipotent with parent inhibitor 1, a larger group such as bis-allyl as in 13 or gem-cyclopentyl as in 14 significantly reduced enzyme inhibition.


The zinc uptake regulator Zur is essential for the full virulence of Xanthomonas campestris pv. campestris.
Zur is a regulator of the high-affinity zinc uptake system in many bacteria. In Xanthomonas campestris pv. campestris 8004, a putative protein encoded by the open reading frame designated as XC1430 shows 42% amino acid similarity with the Zur of Escherichia coli. An XC1430-disrupted mutant 1430nk was constructed by homologous suicide plasmid integration. 1430nk failed to grow in rich medium supplemented with Zn2+ at a concentration of 400 microM and in nonrich medium supplemented with Zn2+ at a concentration of 110 microM, whereas the wild-type strain grew well in the same conditions. In rich medium with 400 microM Zn2+, 1430nk accumulated significantly more Zn2+ than the wild-type strain. 1430nk showed a reduction in virulence on the host plant Chinese radish (Raphanus sativus L. var. radiculus Pers.) and produced less extracellular polysaccharide (EPS) than did the wild-type strain in the absence of added zinc. These results revealed that XC1430 is a functional member of the Zur regulator family that controls zinc homeostasis, EPS production, and virulence in X. campestris pv. campestris.


Characterisation of the calcium responses to histamine in capsaicin-sensitive and capsaicin-insensitive sensory neurones.
Adult rat sensory neurones were maintained in short-term tissue culture and their response to histamine was studied by monitoring changes in intracellular [Ca(2+)] with Fura-2. The proportion of histamine-sensitive neurones increased as the concentration increased from 10 microM to 10 mM. The fraction of responding cells did not change significantly over the first week in culture. About 60% of histamine-sensitive cells were insensitive to capsaicin and these cells tended to be of small diameter. The integrated calcium response to histamine was greatest at 100 microM when the response consisted of two phases: an initial short-lasting transient followed by a sustained plateau that was dependent on extracellular calcium. This response was blocked by the histamine H(1) receptor antagonist mepyramine but not by cimetidine or thioperamide which block H(2) and H(3) receptors, respectively. Moreover, application of histamine increased the intracellular concentration of inositol 1,4,5-trisphosphate -- an effect blocked by mepyramine. These data show that the response is mediated by H(1) receptors. The phospholipase C inhibitor U73122 blocked the response to 100 microM histamine and significantly reduced the fraction of cells responding to 1 mM and 10 mM histamine as did removal of extracellular calcium. A combination of U73122 and calcium-free medium abolished all responses to histamine. These data suggest that in addition to activating phospholipase C, high concentrations of histamine gate an influx of calcium that is independent of store depletion. The implications of these results for the transduction of pruritic stimuli is discussed.


BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis.
Epidemiologic studies have evaluated the association between BRAF mutations and resistance to the treatment of anti-EGFR monoclonal antibodies (MoAb) in patients with metastatic colorectal cancer (mCRC). However, the results are still inconclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. A total of 11 studies were included in the final meta-analysis. There were seven studies for unselected mCRC patients and four studies for patients with wild type KRAS mCRC. Among unselected mCRC patients, BRAF V600E mutation was detected in 48 of 546 primary tumors (8.8%). The objective response rate (ORR) of patients with mutant BRAF was 29.2% (14/48), whereas the ORR of patients with wild-type BRAF was 33.5% (158/472).The overall RR for ORR of mutant BRAF patients over wild-type BRAF patients was 0.86 (95% CI=0.57-1.30; P=0.48). For patients with KRAS wild-type mCRC, BRAF V600E mutation was detected in 40 of 376 primary tumors (10.6%). The ORR of patients with mutant BRAF was 0.0% (0/40), whereas the ORR of patients with wild-type BRAF was 36.3% (122/336). The pooled RR of mutant BRAF patients over wild-type BRAF patients was 0.14 (95% CI=0.04-0.53; P=0.004). In conclusion, this meta-analysis provides evidence that BRAF V600E mutation is associated with lack of response in wild-type KRAS mCRC treated with anti-EGFR MoAbs. BRAF mutation may be used as an additional biomarker for the selection of mCRC patients who might benefit from anti-EGFR MoAbs therapy.


DNA-binding protein from HeLa cells that binds preferentially to supercoiled DNA damaged by ultraviolet light or N-acetoxy-N-acetyl-2-aminofluorene.
A DNA-binding protein was partially purified from extracts of HeLa cells by high-speed centrifugation and chromatography on DEAE-cellulose, phosphocellulose and ultraviolet light-irradiated DNA-cellulose columns. It eluted from the phosphocellulose column with 0.375 M potassium phosphate and from the ultraviolet light-irradiated DNA-cellulose column between 0.5 M and 1 M NaCl. The protein binds preferentially to supercoiled PM2 DNA treated with ultraviolet light or N-acetoxy-N-acetyl-2-aminofluorene, as compared to native supercoiled PM2 DNA. The binding is non-cooperative. Nicked or linear forms of PM2 DNA (damaged or untreated) are not efficient substrates, indicating a requirement of DNA supercoiling for DNA binding. The sedimentation coefficient of the protein estimated by glycerol gradient centrifugation is 2.0-2.5 S, corresponding to a molecular weight of about 20000-25000 if the protein is spherical. The binding to DNA irradiated with ultraviolet light or treated with acetoxyacetylaminofluorene is optimal at around 100-200 mM NaCl and is relatively independent of temperature and pH. MgCl2 and MnCl2 at concentrations between 1 and 5 mM do not markedly affect the binding, but it is inhibited by sucrose, ATP and caffeine. The biological significance of the DNA-binding protein remains to be determined. It does not possess significant glycosylase, endonuclease or exonuclease activities. The dissociation equilibrium constant for the binding reaction of the protein to the ultraviolet light or acetoxyacetylaminofluorene-induced binding sites on DNA is estimated to be 4.10(-11) M. There are at least 1.10(5) DNA-binding protein molecules/HeLa cell.


The association between genetic variation in interleukin-10 gene and susceptibility to Henoch-Schönlein purpura in Chinese children.
Interleukin-10 (IL-10), one of the anti-inflammatory cytokines, plays a major role in the pathogenesis of Henoch-Schönlein purpura (HSP). In present study, we investigated the association between genetic variation in IL-10 gene and susceptibility to HSP in a Chinese childhood population. Considering the overlapping clinical manifestations during the course of disease, the relation between IL-10 gene polymorphisms and HSP clinical heterogeneity was also assessed. We analyzed three IL-10 tag single nucleotide polymorphisms (SNPs; rs3021094, rs3790622, and rs1800872) using the Sequenom MassARRAY system by means of matrix-assisted laser desorption ionization-time of flight mass spectrometry method in 182 patients with HSP and 202 healthy controls. For the frequency of alleles, genotypes, and haplotypes of IL-10 SNPs, no significant differences were observed between HSP patients and controls. In addition, we did not find any association of IL-10 gene polymorphisms with the clinical manifestations of HSP. Our results suggest that genetic variation in IL-10 gene is unlikely to confer susceptibility to HSP in Chinese children.