Glycated fibrinogen: a new index of short-term diabetic control.
Fibrinogen is a plasma protein with a short half-life of four days and, therefore, glycated fibrinogen may be valuable as an index of short-term diabetic control. We have developed a simple, rapid method for determining glycated fibrinogen using affinity chromatography. The differences in the percentage of glycated fibrinogen between normal subjects, well-controlled diabetics and poorly-controlled diabetics were highly significant. There was a significant correlation between glycated fibrinogen and glycated haemoglobin for all these subjects. However, in selected subjects with rapidly improving diabetic control the difference between the fall over three days in glycated fibrinogen and glycated haemoglobin was highly significant. In subjects with deteriorating control over an average of four weeks there was a significant difference between the increase in glycated fibrinogen and glycated haemoglobin. We suggest that glycated fibrinogen may be a valuable adjunct to glucose measurements in the assessment of short-term diabetic control due to its rapid change following alterations in control.


Lifting the gloom.
Age Concern says that the majority of older people who have depression go undiagnosed and untreated. Its Down, But Not Out campaign urges the government to make depression in old age a priority for the NHS.


The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma.
Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.


N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells.
N-Myristoyltransferase (NMT) covalently attaches a C14 fatty acid to the N-terminal glycine of proteins and has been proposed as a therapeutic target in cancer. We have recently shown that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells, and cytotoxicity in cancer cells. N-myristoylation lies upstream of multiple pro-proliferative and oncogenic pathways, but to date the complex substrate specificity of NMT has limited determination of which diseases are most likely to respond to a selective NMT inhibitor. We describe here the phenotype of NMT inhibition in HeLa cells and show that cells die through apoptosis following or concurrent with accumulation in the G1 phase. We used quantitative proteomics to map protein expression changes for more than 2700 proteins in response to treatment with an NMT inhibitor in HeLa cells and observed down-regulation of proteins involved in cell cycle regulation and up-regulation of proteins involved in the endoplasmic reticulum stress and unfolded protein response, with similar results in breast (MCF-7, MDA-MB-231) and colon (HCT116) cancer cell lines. This study describes the cellular response to NMT inhibition at the proteome level and provides a starting point for selective targeting of specific diseases with NMT inhibitors, potentially in combination with other targeted agents.


Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion.
Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl2, and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over-expression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over-expressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease.


A patient with primary biliary cirrhosis accompanied by Graves disease and Hurthle cell adenoma.
A case of Hurthle cell adenoma and Graves disease associated with primary biliary cirrhosis is reported in a 51-year-old woman, who developed elevated liver enzymes and hyperthyroidism. Thyroid disorders accompanying primary biliary cirrhosis, especially hypothyroidism, are well documented. Concomitance of primary biliary cirrhosis and hyperthyroidism is rare. Moreover, there has been no previous report of a case with Hurthle cell adenoma accompanied by Graves disease and primary biliary cirrhosis.


Relationships between mutant prevention concentrations and mutation frequencies against enrofloxacin for avian pathogenic Escherichia coli isolates.
Clinical efficacies of mutant prevention concentration (MPC) and mutant selection window (MSW) hypotheses have been evaluated for human clinical isolates. We tested the MSW hypothesis by evaluating the relationships between MPCs and mutation frequencies against enrofloxacin for avian pathogenic Escherichia coli (APEC) isolates. Mutation frequencies of strains with MPC:MIC ratios of 8 to 16 were significantly higher than those of strains with an MPC:MIC ratio of 4. Mutation frequencies and MPCs of serogroup O2 strains were lower than those of the other strains; these results may correlate with the absence of fluoroquinolone-resistant O2 strains. Our results support the MSW hypothesis that the range of the MSW is involved in selection of resistant mutants.


Design of infrared radiation diagnostic calorimeter for the prototype radio frequency driven negative ion source for neutral beam injection.
In order to study the generation and extraction of negative ions for neutral beam injection application, a prototype radio frequency driven negative ion source and the corresponding test bench are under construction at the Institute of Plasma Physics, Chinese Academy of Sciences. A new design of infrared radiation diagnostic calorimeter for testing beam characteristics is put forward. Compared with the conventional calorimeter, the calorimeter adopts the block structure (8 × 28 tungsten hexahedron blocks) and modularization design (4 modules), so it has higher precision and good scalability. The thermal performance of the calorimeter is assessed using a finite element method. Simulation results show that the design can be achieved to operate in the stable-state mode at the maximum thermal flux 6.45 MW/m2 and meet the full requirement of beam diagnosis.


Dioxins, polychlorinated biphenyls and other organohalogen compounds in human milk. Levels, correlations, trends and exposure through breastfeeding.
Polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDF), together simplified termed "dioxins", polychlorinated biphenyls (PCB), polybrominated diphenylethers (PBDE) and organochlorine pesticides constitute lipophilic, persistent organic pollutants that bioaccumulate in the food chain and consequently can be found in humans at considerable concentrations. During the past 30 years our institute analyzed far more than 2,000 individual human milk samples for organochlorine pesticides and PCB and over 1,000 specimens for PCDD/PCDF. The results of these analyses provide an overview and reliable basis as to contamination of human milk with these compounds, their correlations among each other, the temporal trend of exposure through breastfeeding and the predominant parameters that influence the maternal body burden. It was found that the levels of most persistent organohalogen compounds in human milk decreased significantly over the past three decades and equally did their exposure through breastfeeding. Exceptions are PBDE, which are still extensively used as flame-retardants. PBDE levels in milk samples collected in the early 2,000s are approximately 60% higher compared to specimens sampled 10 years before. Moreover, in contrast to PCB, PBDE show no significant correlation with PCDD/PCDF in human milk, which might be interpreted as an indication for another mode of human exposure.


Improving Pediatric Survival from Resuscitation Events: The Role and Organization of Hospital-based Rapid Response Systems and Code Teams.
During the past 10-15 years it has become evident that in spite of the sophistication of medicine, hospitalized patients frequently experience cardiac arrests from which the majority do not survive. A substantial number of these arrests occur on general inpatient units where patients begin to deteriorate but there is a failure of timely recognition so that appropriate intervention can be instituted before the arrest takes place. Much work has been done to determine how survival from adult in-hospital cardiac arrests can be improved by (1) teaching health care providers about resuscitation management using a team approach and (2) more recently, by developing rapid response systems to recognize deteriorating patients early and intervening to prevent the cardiac arrest. The purpose of this review is to outline what is known about the use and organization of resuscitation teams (code teams) and rapid response systems as they apply to pediatric patients. Effort has been made to include the most current pediatric science available as a basis for encouraging the ongoing implementation of hospital team-based systems which appear to be able to improve the outcomes of pediatric in-hospital cardiac and respiratory arrests. Practical suggestions, implementation strategies, potential barriers, and ways to integrate pediatric code teams and rapid response systems into the quality and safety fabric of the hospital are provided.


Degradable Dextran Nanopolymer as a Carrier for Choline Kinase (ChoK) siRNA Cancer Therapy.
Although small interfering RNA (siRNA) therapy has proven to be a specific and effective treatment in cells, the delivery of siRNA is a challenge for the applications of siRNA therapy. We present a degradable dextran with amine groups as an siRNA nano-carrier. In our nano-carrier, the amine groups are conjugated to the dextran platform through the acetal bonds, which are acid sensitive. Therefore this siRNA carrier is stable in neutral and basic conditions, while the amine groups can be cleaved and released from dextran platform under weak acid conditions (such as in endosomes). The cleavage and release of amine groups can reduce the toxicity of cationic polymer and enhance the transfection efficiency. We successfully applied this nano-carrier to deliver choline kinase (ChoK) siRNA for ChoK inhibition in cells.


[Anomalous systemic arterial supply to normal basal segments of the left lung (Pryce type I)].
Patient 1 was a 54-year-old female diagnosed with anomalous systemic arterial supply to normal basal segments of the left lung discovered as an abnormality on chest X-ray radiography. Patient 2 was a 47-year-old male in whom the disease was diagnosed by close examination of bloody sputum. Division of the abnormal artery and left lower lobectomy were performed in patient 1. Arterial congestion and serpentine distribution were noted in the basal segments of the lung, which was the region perfused by the abnormal artery, on histopathological examination. Arteriosclerotic changes were noted in the vascular wall, but no abnormal vascular wall or alveolar structure was noted in S6, which was not included in theperfused region. Based on the above findings, division of the abnormal artery and left basal segmentectomy were performed in patient 2. Bloody sputum disappeared, and activity of daily living( ADL) were not impaired after surgery.


[Development of an adenovirus vector containing a hepatitis C virus expression cassette and its application].
Hepatitis C virus (HCV) is a hepatotropic member of the Flaviviridae family and contains a 9.6 kb positive-sense RNA genome. Approximately 170-million people are infected with HCV worldwide. These people face increased risks of chronic hepatitis, cirrhosis and hepatocellular carcinoma compared with the general population. Transduction of the HCV genome into hepatocytes is essential for understanding the mode of action of HCV infection, and for preparing HCV, evaluating HCV replication, and screening anti-HCV drugs. Although electroporation of in vitro-synthesized HCV genome and transduction of plasmid vectors containing the HCV genome are widely used in HCV research, a more convenient system with higher transduction efficiency is needed. Among viral transduction systems, adenovirus (Ad) vector is one of the most efficient and convenient systems; Ad vector has been widely used in clinical gene therapies. Therefore, Ad vector is a promising system for the delivery of the HCV genome; however, an Ad vector expressing the HCV genome has never been developed. We here describe the preparation of an Ad vector expressing the HCV genome, and outline future directions of HCV research using this vector system.


Chinese herbal injections for unstable angina pectoris: A protocol for systematic review and network meta-analyses.
Chinese herbal injections (CHIs) have been commonly used in the treatment of unstable angina pectoris (UAP) in China. However, there is no consensus or evidence on how to select CHIs for patients with UAP. The choice often depends on the personal experience or preference of clinician. This study aims to compare the effect of different CHIs for UAP using Bayesian network meta-analysis (NMA). A systematic search will be conducted in PubMed, the Cochrane Central Register of Controlled Trials, Embase, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and Wanfang Data from inception to February 2018. We will include randomized controlled trials (RCT) regarding CHIs in the treatment of UAP. Quality of included RCTs will be assessed according to the Cochrane Handbook 5.1.0. A Bayesian NMA will be performed with WinBUGS 14 to compare the efficacy of different CHIs. GRADE will be used to assess the quality of evidence. The results of this NMA will be submitted to a peer-reviewed journal for publication. Our study will generate evidence for CHIs in the treatment of UAP and help clinicians make more accurate therapeutic schedule. In addition, it might provide suggestions for Chinese medicine clinical practice or guideline.


Antarctic Bottom Water: Major Change in Velocity during the Late Cenozoic between Australia and Antarctica.
Paleomagnetic and micropaleontological studies of deep-sea sedimentary cores between Australia and Antarctica define an extensive area centered in the south Tasman Basin, where sediment as old as Early Pliocene has been systematically eroded by bottom currents. This major sedimentary disconformity has been produced by a substantial increase in velocity of Antarctic bottom water, possibly associated with late Cenozoic climatic cooling and corresponding increased glaciation of Antarctica.


[Features of health preserving for the elderly in Shouqin Yanglao Xinshu].
Shouqin Yanglao Xinshu, written by CHEN Zhi in the Song dynasty and revised by ZOU Xuan in the Yuan dynasty, is an extant older book on health preservation for the elderly. The book emphasizes that old people should keep a peaceful mind and descendants should show filial obedience to them. Also, diet and medicine regulation could be used as a combination. Those records, which are in accord with old people's physiological and pathological characteristics, embody the features of ancient Chinese civilization and are also of great value for old people's health preservation in modern times.


Surviving sepsis: a guide to the guidelines.
The revised Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis and septic shock have recently been published. These guidelines represent the end product of an intense process and provide a template approach to the early resuscitation and support of patients with sepsis, based on a synthesis of evidence that has been shown to improve the outcome of the septic patient. The SSC guidelines arose from a recognition that care of the septic patient was suboptimal for at least three reasons. First, the entity of sepsis was frequently not diagnosed in a timely fashion, allowing the process to evolve into a life-threatening syndrome of major physiologic organ system dysfunction. Secondly, even when sepsis was recognized, the urgency of treatment was underappreciated - and so haemodynamic resuscitation was tentative, and the administration of effective antibiotic therapy was often delayed. Finally, treatment was often suboptimal, and failed to take advantage of emerging insights into optimal approaches to patient management. The revised guidelines are far from perfect, but they represent the best available synthesis of contemporary knowledge in this area and as such should be promoted.


Clinical and immune responses correlate in glatiramer acetate therapy of multiple sclerosis.
Glatiramer acetate (GA) treatment for relapsing remitting multiple sclerosis (RRMS) leads to decreased GA-specific proliferative responses and a Th2 cytokine shift. To study a possible correlation between immunological and clinical responses to GA therapy, we prospectively followed RRMS patients clinically, by magnetic resonance imaging and by primary immunological assays. Fluctuation of GA-specific proliferative responses was significantly lower in treatment responders than in untreated patients, and GA-specific proliferative responses were increased during relapses. These associations suggest a possible causal relationship between immunological and clinical responses to GA therapy. Primary proliferation assays may thus be a useful marker for treatment response.


Present state of cardiovascular community control programme in the Czech Socialist Republic.
The high incidence, great import, and long duration of cardiovascular diseases are reflected in high demands placed on the health services. Experience shows that utilization of the results of research in general practice is lagging behind. The application of any improvement in the diagnosis, therapy, and prevention in health care waits several years for its accomplishment. In order to improve this situation, the Ministry of Health of the CSR constituted, in line with WHO recommendations, a Department for Cardiovascular Diseases Control. The Department has worked out a programme of prevention and control of the major cardiovascular diseases, in particular, ischaemic heart disease, systemic hypertension and its complications, rheumatic heart disease, congenital cardiac and vascular defects, and cor pulmonale. New diagnostic, therapeutic, and preventive procedures are first tried out in so-called model areas and are only after this introduced into the national health care of people suffering from or endangered by cardiovascular diseases. In parallel, organizational measures necessary for comprehensive care are implemented. The authors report on the experience gained so far with the realization of the programme of care of people suffering from IHD and acute myocardial infarction. They emphasize the importance of continual schooling of medical personnel and of health education of the entire population. They describe the implementation on a national scale of postgraduate cardiological courses intended especially for first-line doctors.


[Experimental research into the inhibitory effect of 131I-recombinant human epidermal growth factor on the growth of breast cancer in vivo].
This experiment was designed to study the effect of 131I-recombinant human epidermal growth factor (131I-rhEGF) on the growth of tumor in nude mice loaded with human breast cancer. Bioactivity of 131I-rhEGF and uptake of 131I-rhEGF in breast cancer tissue were verified using biodistribution experiment of 131I-rhEGF in the nude mice loaded with human breast cancer. The effect of 131I-rhEGF on the growth of tumor was assessed via the growth experiment of tumor in the nude mice loaded with human breast cancer. The ultrastructural change of the tumor cell treated with 131I-rhEGF was observed under transmission electron microscope, and the pathological change of the tumor tissue treated with 131I-rhEGF was detected by biopsy. The results showed that the tumor tissue of nude mice bearing human breast cancer obviously takes in 131I-rhEGF; that intravenous administration and intratumoral administration of 131I-rhEGF both obviously inhibit the growth of tumor, the inhibition rates (82.00% and 80.70%) being remarkably higher than that of 131I (7.49%) and that of 131I-HSA (6.91%) (P<0.05); and that intravenous and intratumoral administration of 131I-rhEGF both obviously damage and kill tumor cells. Therefore, 131I-rhEGF can inhibit the growth of human breast cancer cell in nude mice; it is a potential receptor-mediated radioactivity targeting drug for treating breast cancer.


Contraction-excitation feedback in atrial reentry: role of velocity of mechanical stretch.
To determine the effects of atrial stretch on atrial flutter, we analyzed variations in atrial flutter cycle length (CL) caused by ventricular contraction in five dogs with artificially induced atrioventricular block. In contrast to absence of variations in CL during sustained ventricular asystole, atrial stretch by ventricular contraction consistently produced phasic variations in CL. The variations were not confined to any specific atrial sites, but depended on the time of ventricular contraction relative to atrial activation phase. The phase-response curve of the variations was closely related to that of the velocity of changes in the atrial pressure with no time lags, but not to that of the atrial pressure itself. Pharmacological denervation did not abolish the variations. Conventional electrophysiological study revealed greater changes in intra-atrial activation time by atrial stretch at a short pacing cycle length than at a longer one, suggestive of changes in repolarization by mechanical stretch. In conclusion, atrial stretch caused by ventricular contraction produces phasic variations in CL, the extent of which depends on the velocity of the mechanical stretch of atrial muscles.


Rapid and Accurate Differentiation of Mycobacteroides abscessus Complex Species by Liquid Chromatography-Ultra-High-Resolution Orbitrap™ Mass Spectrometry.
In this study, a Liquid Chromatography-Mass Spectrometry (LC-MS) method for the identification of clinically relevant Mycobacteroides abscessus (Mabs) complex organisms is tested using a set of microbial Type strains. This methodology is based on profiling proteins derived from Mycobacteroides abscessus complex isolates. These protein profiles are then used as markers of species differentiation. To test the resolving power, speed, and accuracy of this assay four ATCC type strains and 32 recent clinical isolates of closely related Mabs species collected at ARUP laboratories (10 clinical isolate strains of M. abscessus subsp. abscessus, 10 M. abscessus subsp. massiliense, 2 M. abscessus subsp. bolletii and 10 M. chelonae) were subjected to this approach. Using multiple deconvolution algorithms, we identified hundreds of individual proteins, with subpopulations of these used as species-specific markers. This assay identified 150, 130, 140 and 110 proteoforms with isocratic elution and 230, 180, 200 and 190 proteoforms with gradient elution for M. abscessus (ATCC 19977), M. massiliense (DSM 45103), M. bolletii (DSM 45149) and M. chelonae (ATCC 35752) respectively. Taxonomic species were identified correctly down to the species level with 100% accuracy. The ability to differentiate Mycobacteroides abscessus complex at sub-species level can in-turn be helpful for patient management. Data analysis showed ~7-17 proteoforms potentially able to differentiate between subspecies. Here, we present a proof-of-principle study employing a rapid mass spectrometry-based method to identify the clinically most common species within the Mabs species complex.


Simultaneous measurement of free thyroxine and free 3,5,3'-triiodothyronine in undiluted serum by direct equilibrium dialysis/radioimmunoassay: evidence that free triiodothyronine and free thyroxine are normal in many patients with the low triiodothyronine syndrome.
We have devised a practical, sensitive and specific method for simultaneous measurement of free thyroxine (FT4) and free triiodothyronine (FT3) in undiluted serum by direct equilibrium dialysis radioimmunoassay (RIA). Two hundred microliters serum sample was dialyzed against buffer (pH 7.4) for 20 hours at 37 degrees C and approximately 800 microL of the dialysate was used for measuring FT4 and FT3 simultaneously. The assay was set up in polystyrene tubes coated with anti-T4 antibody and available commercially for FT4 measurement (Quest-Nichols Institute, San Juan Capistrano, CA). The mean +/- SE (range) FT4 concentration (ng/dL) was 1.2 +/- 0.04 (0.7.0 to 2.30) in 54 normal subjects. It was significantly increased (3.6 +/- 0.4 [1.8 to 9.6], n = 20) in hyperthyroidism and clearly decreased (0.40 +/- 0.04 [1.10 to 0.70], n = 26] in hypothyroidism. All nonthyroid illness (NTI) patients had normal FT4 except 3, 2 of whom were on amiodarone and 1 had received heparin. Serum FT4 concentration was minimally elevated in 18 newborn cord blood serum (1.40 +/- 0.08 [0.90 to 2.2], cf. normal p < .05). The mean serum FT3 concentration (pg/dL) was 285 +/- 10 (134 to 454) in 54 normal sera. It was clearly increased in hyperthyroidism (1033 +/- 98 [593 to 2134], n = 20, p < .001). However, serum FT3 varied widely in hypothyroidism (27 to 597, mean 235 +/- 24, NS) as did serum total T3 (19 to 175). Interestingly, however, the mean serum FT3 concentration was normal (273 +/- 28 [62 to 575, NS]) in 25 NTI patients. All of these patients had low serum total T3 (46 +/- 5.0 [10 to 84], ng/dL; normal 84 to 160, p < 0.001), while FT3 was clearly normal in 21 of 25 patients and low in the remaining 4 patients. Similarly, among 18 newborn cord blood sera serum FT3 concentration was normal in 15 and subnormal only in the remaining 3 while all had clearly subnormal total T3 (28 to 74 ng/dL). (1) A practical, sensitive, and specific assay for simultaneous measurement of FT4 and FT3 is described; (2) FT3 is consistently elevated in hyperthyroidism while FT4 is elevated in most (approximately 85%) cases; (3) FT4 is consistently decreased in hypothyroidism but FT3 varies widely; (4). Serum FT3 concentration is normal in approximately 83% of patients with the low T3 syndrome in NTI and newborn cord blood serum. These data suggest that normal FT3 may explain clinical euthyroidism in many patients with the low T3 syndrome.


Effect of asthma, aeroallergen category, and gender on the psychological status of patients with allergic rhinitis.
Despite increasing evidence for an association between allergy and psychological disorders in patients with allergic rhinitis (AR), the relationship between comorbid AR and asthma is not clear. The objective of this study was to investigate the effect of concomitant asthma, gender, and sensitization to a particular aeroallergen category on the psychological status of AR patients. We analyzed 524 AR patients (311 males/213 females) aged 16 to 60 years using the Symptom Checklist-90 (SCL-90) and found that 34.2% had persistent AR and 65.8% intermittent AR. Overall, 61 patients (11.6%) had concomitant asthma. The SCL-90 scores of AR patients were significantly higher for the somatization, obsessive-compulsive, hostility, and psychoticism dimensions than those of the healthy controls. In contrast, the SCL-90 scores for persistent AR and intermittent AR patients were significantly different. Concomitant asthma significantly impacted theAR individuals' SCL-90 dimension scores for the obsessive-compulsive, interpersonal sensitivity, depression, and paranoid ideation subscales. Gender and sensitization to a particular aeroallergen category did not affect the SCL-90 scores of AR patients individually, but led to significant differences in SCL-90 scores for the phobic anxiety and psychoticism subscales when considered in combination. Our results suggest that comorbid asthma exerts an independent main effect on the psychological status of AR patients.


Returns to scientific publications for pharmaceutical products in the United States.
Drug-specific clinical and health economic and outcomes research (HEOR) publications have amassed, but their effect on drug sales is largely unknown. We estimated the impact of publications on pharmaceutical sales in 3 markets (statins, rheumatoid arthritis, and asthma drugs) with varying generic competition. An event-study approach with fixed effects and difference-in-fixed-effects modeling was used to estimate the causal effects of drug-specific publications on subsequent quarter's drug-specific sales and volume. High-impact clinical and HEOR publications have significant positive effects on sales (mediated through price) and volume in the statin market (high generic competition). High-impact clinical publications have a significant positive effect on sales (mediated through volume) in low-generic competition market (asthma). The effects of publications in the rheumatoid arthritis market (no generic competition) on sales were null. Manufacturers' investment in clinical and HEOR publications needs to be strategic and should be anticipated and complemented by public investments in such studies.


Evaluation of the Lyophilized Platelets Function by Thromboelastography in an In Vitro Platelet Transfusion Model.
At present, liquid conserved platelets (PLTs) can only be stored at 22°C for up to 5 days. Waste of outdated PLTs and short supply of fresh PLTs were both seen in blood banks. Lyophilized PLTs were considered as one of the candidate replacements for liquid conserved PLTs. It is important to evaluate the function before it can be used in clinical trial. In this study, an in vitro platelet transfusion model was established to evaluate the function of rehydrated lyophilized platelets (RLPs) by thromboelastography (TEG). Blood samples from 11 patients were spiked with 3 preparations of specific donors' apheresis platelets (stored at room temperature, frozen, and lyophilized) to an increment equivalent to transfusion with 3x10^11 platelets. Whole blood TEG assay was performed and the maximum amplitude (MA) value was used to evaluate the function of "transfused" platelets. The recovery of rehydrated lyophilized platelets (RLPs) in our study was 81.38% ± 2.38, and mean platelet volume (MPV) was 9.02 ± 0.54 fL. MA was significantly enhanced in the three different groups after the addition of PLTs when compared with the whole blood (WB) group. Our findings suggest that RLPs are capable of enhancing the MA value as well as fresh and frozen PLTs in vitro. The clinical significance of this remains to be determined.


The Microenvironment of the Pathogenesis of Cardiac Hypertrophy.
Pathological cardiac hypertrophy is a key risk factor for the development of heart failure and predisposes individuals to cardiac arrhythmia and sudden death. While physiological cardiac hypertrophy is adaptive, hypertrophy resulting from conditions comprising hypertension, aortic stenosis, or genetic mutations, such as hypertrophic cardiomyopathy, is maladaptive. Here, we highlight the essential role and reciprocal interactions involving both cardiomyocytes and non-myocardial cells in response to pathological conditions. Prolonged cardiovascular stress causes cardiomyocytes and non-myocardial cells to enter an activated state releasing numerous pro-hypertrophic, pro-fibrotic, and pro-inflammatory mediators such as vasoactive hormones, growth factors, and cytokines, i.e., commencing signaling events that collectively cause cardiac hypertrophy. Fibrotic remodeling is mediated by cardiac fibroblasts as the central players, but also endothelial cells and resident and infiltrating immune cells enhance these processes. Many of these hypertrophic mediators are now being integrated into computational models that provide system-level insights and will help to translate our knowledge into new pharmacological targets. This perspective article summarizes the last decades' advances in cardiac hypertrophy research and discusses the herein-involved complex myocardial microenvironment and signaling components.


The spherical deformation model.
Miller et al. (1994) describe a model for representing spatial objects with no obvious landmarks. Each object is represented by a global translation and a normal deformation of a sphere. The normal deformation is defined via the orthonormal spherical-harmonic basis. In this paper we analyse the spherical deformation model in detail and describe how it may be used to summarize the shape of star-shaped three-dimensional objects with few parameters. It is of interest to make statistical inference about the three-dimensional shape parameters from continuous observations of the surface and from a single central section of the object. We use maximum-likelihood-based inference for this purpose and demonstrate the suggested methods on real data.


Propranolol-induced psychosis.
A 53-year-old black male with no history of neuropsychiatric behavioral problems was treated successfully with propranolol, furosemide, and minoxidil for previously uncontrolled hypertension. However, paranoid ideations, illusions, severe combativeness, and visual hallucinations developed shortly after initiation of the listed therapy. When atenolol was substituted for propranolol, all psychotic behavior resolved.


Cranial fasciitis.
A 26-year-old man presented with an 18-month history of a subcutaneous mass on his forehead that occurred shortly after being struck by a blunt object. Histopathologic examination showed a proliferation of bland spindle cells and a collagenous stroma that was consistent with cranial fasciitis. Cranial fasciitis, which is a variant of nodular fasciitis, is a benign fibroblastic neoplasm that overlies the skull and often is associated with trauma. Although its rapid onset may give the clinical impression of a malignant condition, cranial fasciitis typically is cured by simple excision without further sequelae.


Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints.
Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders. The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints. Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, neuropsychological functioning, and proteomic markers. Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers. Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified.


A clinico-radiological study of the contralateral ear in acquired unilateral cholesteatoma.
Clinico-audiological and CT scan assessments of the contralateral ear in patients with unilateral cholesteatoma can be a good predictive method for the fate of these ears. Fifty patients with unilateral cholesteatoma and 25 control subjects with bilateral normal ears were subjected to otomicroscopical and audiological assessment. Axial and coronal computed tomography (CT) for the mastoid bone at 1 mm slice thickness was done for all ears. A simplified method was used to find out the surface area (SA) of the air cells at each individual section and semi-automatically calculate the total volume of the matstoid air cells. Otomicroscopically, 72% of the contralateral ears showed signs of retraction pockets, granulation tissues and other signs of chronicity. Audiologically 20% of the control ears showed moderate to severe conductive hearing loss while 10% showed mixed hearing loss. As regards mastoid pneumatization, the mean air cell volumes were 6.1, 12.68 and 29.92 CC in cholesteatomatous, contralateral and control ears respectively. This indicates a highly significant difference in the mean air cell volume between the control ears and the other two groups. It can be concluded that continuous follow up of the contralateral ear in cholesteatomatous ears is mandatory to detect subtle pathological changes and manage them early. Volumetry of contralateral ear using the applied simple method can lead to a reduction in major surgery and can affect the choice of the surgical approach.


Proteome and Transcriptome Analysis of the Antioxidant Mechanism in Chicken Regulated by Eucalyptus Leaf Polyphenols Extract.
Eucalyptus leaf polyphenols extract (EPE) has been proved to have various bioactivities, but few reports focus on its antioxidant mechanism in vivo. The purpose of this study was to elucidate the effect and mechanism of EPE dietary supplements on antioxidant capacity in chicken. A total of 216 chickens were randomly selected for a 40-day experiment. Four treatment groups received diets including the control diet only, the control diet + low EPE (0.6 g/kg), the control diet + moderate EPE (0.9 g/kg), and the control diet + high EPE (1.2 g/kg). Compared with control group, the glutathione peroxidase (GSH-Px) activity and glutathione (GSH) content in the breast muscle of the moderate EPE treatment group was significantly higher (p < 0.05), while the malonaldehyde (MDA) content in the moderate EPE group was reduced (p < 0.05). Moreover, proteomic and transcriptomic analyses of the breast muscle revealed that glutathione metabolism and the peroxisome were the two crucial metabolic pathways responsible for increased antioxidant capacity of the muscle. Accordingly, nine candidate genes and two candidate proteins were identified related to improved antioxidant status induced by EPE supplements. This research provides new insights into the molecular mechanism of antioxidant capacity in chickens treated with EPE dietary supplements.


Therapeutic effects of Allium sativum and Allium cepa in Schistosoma mansoni experimental infection.
The effects of both garlic (Allium sativum) and onion (Allium cepa) on some biochemical parameters in Schistosoma mansoni infected mice individually and mixed either with or without the currently used drug, praziquantel (PZQ) were investigated. These involved some immunological parameters, namely IgM, IgG, interleukins 2 and 6 (IL-2 and 6) and tumor necrosis factor (TNF-α), some antioxidant enzymes [catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPX)]. In addition, parasitological and histopathological investigations were performed. No changes were observed in the normal control mice treated with dry extract of onion or garlic, individually or mixed, with or without PZQ, compared to the normal healthy control group. Infection with S. mansoni showed an increase in IgG, IgM, IL-2, IL-6, TNF-α and catalase enzyme, accompanied with a decrease in GPX and SOD antioxidant enzyme activities. Remarkable amelioration was noticed in the levels of all the measured parameters in S. mansoni infected mice after administration of the studied extracts. Moreover a significant reduction in worm burden, hepatic and intestinal eggs and oogram count was noticed which was reflected in normalization of liver architecture.


Stabilization of ceramics particles with anionic polymeric dispersants.
The dispersion of colloidal ceramic particles in an aqueous media using a charged polymer has been investigated extensively. Most often, such a dispersion is obtained by an electrosteric mechanism. The stabilizing forces that result from electrical double layer repulsion and/or steric interaction must be sufficiently large in magnitude to provide an energy barrier against aggregation. Several factors, such as pH, temperature and ionic strength, nature, structure and molecular weight of the polyelectrolyte and its degree of dissociation can affect the respective contribution of electrostatic and steric interactions. In this study we applied silver nanoparticles prepared by reduction method with modifications. The hydroxyapatite was obtained from pork bone sludge. Polymer system contained poly(acrylic acid) and poly(ethylene glycol). The effects of dispersant structure on particle stabilization were investigated through properties of the suspensions. Viscosity and sedimentation height measurements indicated that addition of the dispersants improve particle stabilization. A dispersants were characterized using Scanning electron microscopy (SEM) with BSE detector (Back Scaterred Electrons), X-ray diffraction (XRD) and pH determination.


Genetic alterations in cervical cancer.
In the pathogenesis of cervical cancer the role of human papillomavirus (HPV) infection is well established. However, other than HPV infection the genetics of cervical cancer remains poorly understood. In the pathogenesis of cervical cancel three major factors are involved, two of which are related to the presence of HPV and the third is the recurrent genetic alterations not linked to HPV infection. Several chromosomal regions with recurrent loss of heterozygosity (LOH) in cervical cancer have been identified. However; the putative tumor suppressor genes located in these chromosomal locations are yet to be identified. Recurrent amplifications have been mapped to the short arm of chromosome 3 in invasive cancer. Microsatellite instability and mutator phenotype do not play a major role in cervical carcinogenesis. As in other cancers, cervical cancer too requires the accumulation of genetic alterations for carcinogenesis to occur. Identification of these alterations could help to provide a better understanding of the disease and thus improve treatment.


A comparison study of the reference curves of bone mineral density at different skeletal sites in native Chinese, Japanese, and American Caucasian women.
To understand the differences among reference curves for bone mineral density (BMD) for Chinese, Japanese, and American Caucasian women, we measured the BMD at the anteroposterior (AP) lumbar spine (L1-L4), lateral lumbar spine (L2-L4), hip (including the femoral neck, trochanter, intertrochanter, Ward's triangle, and total hip), and ultradistal forearm by the dual-energy X-ray absorptiometry (DXA) in a total of 2728 healthy Chinese women, aged 5-96 years. Documented BMD data for Japanese women and device manufacturer's BMD new reference databases (including the NHANES III dataset) for American Caucasian women were also used in this study. The cubic regression model was found to fit best in analyzing the age-associated variations of BMD at various sites in Chinese women, i.e., the equations had the largest coefficient of determination (R2). At the AP/Lat spine, trochanter, intertrochanter, and Ward's triangle, BMD reference curves for Chinese women were lower than those for Japanese or Caucasian women, while at the femoral neck, total hip, and ultradistal forearm, the reference curves for Chinese women were higher than those for Japanese women, with overlaps and crossing of the curves for some age spans in comparing the Chinese and Caucasian women. There were significant differences in the peak BMD (PBMD) at various sites among the Chinese, Japanese, and Caucasian women (P = 0.000). The PBMDs for Chinese women at the lumbar spine and various sites of the hip were 5.7% +/- 2.1% (mean +/- SD, range, 2.7-7.9%) lower than those for Japanese women and 5.1% +/- 2.7% (range, 0.5-7.2%) lower than those for Caucasian women; however, the PBMDs for Chinese women were 26.2% higher than those for Japanese women and 10% higher than those for Caucasian women at the ultradistal forearm. After the PBMD, average T-scores of Chinese women for losses at the AP lumbar spine with increasing age were nearly identical to those for Japanese women, but both were greater than those for Caucasian women. The average T-scores for BMD loss at various sites in Chinese women were higher than those for both Japanese and Caucasian women except at the femoral neck, where the T-scores of Chinese women were exceeded by those of both Japanese and Caucasian women. Estimated from the T-score curve of BMD loss, the age of osteoporosis occurrence at the femoral neck in Chinese women was about 10 years later than that in Japanese or Caucasian women; at the AP spine, Chinese women were similar to Japanese women; at the other sites, the age for occurrence of osteoporosis in Chinese women was about 5-15 years earlier than that in either Japanese or Caucasian women. There are differences in prevalence or odds ratio (OR) of osteoporosis at the same skeletal region for Chinese, Japanese, and Caucasian women aged > or = 50 years or at different skeletal regions in women of the same race. The prevalences of osteoporosis at various regions of the hip in Chinese women are 10.1-19.8% and ORs are 22.0-32.3, of which prevalence at the femoral neck is the lowest (10.1%); the prevalences of osteoporosis in Japanese women are 11.6-16.8% and ORs are 21.1-26.3, of which prevalence at the femoral neck is the lowest (11.6%); and the prevalences of osteoporosis in Caucasian women are 13.0-20.0% and ORs are 19.4-48.9, of which prevalence at the femoral neck is the highest (20%). In conclusion, racial differences in BMD reference curves, prevalences, and risks of osteoporosis at various skeletal sites exist among native Chinese, Japanese, and American Caucasian women.


Depressive and Anxiety Disorders in Patients with Inflammatory Bowel Diseases: Are There Any Gender Differences?
Gender differences were identified in the frequency and clinical presentations of inflammatory bowel disease (IBD) and depressive and anxiety disorders, which are more common in IBD patients than in the general population. The present manuscript provides a critical overview of gender differences in the frequency and clinical course of mood and anxiety disorders in IBD patients, with the aim of helping clinicians provide individualized management for patients. All of the included studies found that IBD patients reported a higher frequency of depressive and anxiety disorders than the general population. These findings should encourage healthcare providers to employ validated tools to monitor the mental health of their IBD patients, such as the Patient Health Questionnaire (PHQ-9). In addition, most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of women with IBD have depressive and anxiety disorders. Women with IBD require close mental health monitoring and ultimately a multidisciplinary approach involving mental health professionals. Drug treatment in women should be individualized and medications that may affect mental health (e.g., corticosteroids) should be thoroughly reconsidered. Further data are needed to ensure individualized treatment for IBD patients in a framework of precision medicine.


Physical exercise and blood pressure with reference to the angiotensinogen M235T polymorphism.
We investigated the role of the angiotensinogen (AGT) gene M235T polymorphism in determining blood pressure (BP) response to moderate intensity exercise in a 6-yr randomized controlled trial in 140 middle-aged men. Sitting, supine, and standing blood pressures were measured annually. Of the randomized men, 86% participated in the trial for 6 yr. Submaximal cardiorespiratory fitness increased by 16% in the exercise group. In the M homozygotes, sitting systolic BP decreased by 1.0 mmHg in the exercise but increased by 14.6 mmHg in the reference group (P = 0.007 for net effect). Sitting and supine diastolic BP decreased by 6.2 and 3.3 mmHg in the exercise but increased by 2.8 and 3.2 mmHg in the reference group (P = 0.026 and 0.024 for net effects), respectively. Regular moderate intensity exercise attenuates aging-related increase in systolic BP and decreases diastolic BP among the M homozygotes of the AGT gene M235T polymorphism.


Teaching genetics prior to teaching evolution improves evolution understanding but not acceptance.
What is the best way to teach evolution? As microevolution may be configured as a branch of genetics, it being a short conceptual leap from understanding the concepts of mutation and alleles (i.e., genetics) to allele frequency change (i.e., evolution), we hypothesised that learning genetics prior to evolution might improve student understanding of evolution. In the UK, genetics and evolution are typically taught to 14- to 16-y-old secondary school students as separate topics with few links, in no particular order and sometimes with a large time span between. Here, then, we report the results of a large trial into teaching order of evolution and genetics. We modified extant questionnaires to ascertain students' understanding of evolution and genetics along with acceptance of evolution. Students were assessed prior to teaching, immediately post teaching and again after several months. Teachers were not instructed what to teach, just to teach in a given order. Regardless of order, teaching increased understanding and acceptance, with robust signs of longer-term retention. Importantly, teaching genetics before teaching evolution has a significant (p < 0.001) impact on improving evolution understanding by 7% in questionnaire scores beyond the increase seen for those taught in the inverse order. For lower ability students, an improvement in evolution understanding was seen only if genetics was taught first. Teaching genetics first additionally had positive effects on genetics understanding, by increasing knowledge. These results suggest a simple, minimally disruptive, zero-cost intervention to improve evolution understanding: teach genetics first. This same alteration does not, however, result in a significantly increased acceptance of evolution, which reflects a weak correlation between knowledge and acceptance of evolution. Qualitative focus group data highlights the role of authority figures in determination of acceptance.


Divide and control: split design of multi-input DNA logic gates.
Logic gates made of DNA have received significant attention as biocompatible building blocks for molecular circuits. The majority of DNA logic gates, however, are controlled by the minimum number of inputs: one, two or three. Here we report a strategy to design a multi-input logic gate by splitting a DNA construct.


Providers' knowledge, attitudes, and practices related to colorectal cancer control in Brazil.
In Brazil, colorectal cancer (CRC) is the fourth most common cause of cancer-related death among men, and the third most common among women. We aimed to examine CRC screening-related knowledge, attitudes, and practices among physicians and nurses working in Brazil's network of health units, and to describe the capacity of these units for CRC screening. In 2011, 1600 health units were randomly selected from all 26 states and the Federal District. One coordinator and one health care provider were selected for the interview. Response rates were 78% for coordinators, 34% for physicians, and 65% for nurses. The Brazilian National Cancer Institute (INCA) recommendations for CRC screening were not often used in the health units, but screening outreach and use of CRC exams were more common in units that were using them. Physicians and nurses differed in most characteristics, and in their knowledge, attitudes, and practices of CRC screening. Forty-seven percent of physicians reported not conducting CRC screening compared to 65% of nurses. Fecal occult blood test was most often used by physicians and nurses, but fewer physicians than nurses perceived this exam as very effective in reducing CRC mortality. Physicians' gender, years since graduation, and geographical region of practice in Brazil were associated to CRC screening practice. The findings may reflect the low influence of INCA CRC screening recommendations, physicians receiving their medical education when CRC burden in Brazil was of low concern, and the lack of CRC screening capacity in some regions of Brazil.


Pseudoautologous blood stem cell transplantation for refractory chronic graft-versus-host disease.
A female patient with AML received an allogeneic BMT from her brother. She experienced two relapses managed with chemotherapy and donor leukocyte infusions. The patient subsequently developed extensive therapy-refractory chronic GVHD. Pseudoautologous blood stem cell transplantation was performed as a salvage treatment for chronic GVHD. Her blood stem cells were easily mobilized with cyclophosphamide and G-CSF. The conditioning regimen was well tolerated and consisted of 200 mg/kg cyclophosphamide and horse-derived antithymocyte globulin. A total of 4.03 x 10(6)/kg CD34+ cells were infused and hematological recovery was rapid. Chronic GVHD improved with the ability to taper steroids. Nine months post transplantation the patient died from leukemia.


Age-dependent alterations in key components of the nigrostriatal dopaminergic system and distinct motor phenotypes.
The nigrostriatal dopaminergic (DA) system, which includes DA neurons in the ventral and dorsal tiers of the substantia nigra pars compacta (vSNc, dSNc) and DA terminals in the dorsal striatum, is critically implicated in motor control. Accumulating studies demonstrate that both the nigrostriatal DA system and motor function are impaired in aged subjects. However, it is unknown whether dSNc and vSNc DA neurons and striatal DA terminals age in similar patterns, and whether these changes parallel motor deficits. To address this, we performed ex vivo patch-clamp recordings in dSNc and vSNc DA neurons, measured striatal dopamine release, and analyzed motor behaviors in rodents. Spontaneous firing in dSNc and vSNc DA neurons and depolarization-evoked firing in dSNc DA neurons showed inverse V-shaped changes with age. But depolarization-evoked firing in vSNc DA neurons increased with age. In the dorsal striatum, dopamine release declined with age. In locomotor tests, 12-month-old rodents showed hyperactive exploration, relative to 6- and 24-month-old rodents. Additionally, aged rodents showed significant deficits in coordination. Elevating dopamine levels with a dopamine transporter inhibitor improved both locomotion and coordination. Therefore, key components in the nigrostriatal DA system exhibit distinct aging patterns and may contribute to age-related alterations in locomotion and coordination.


Immunofluorescence of peritoneal phagocytes after infection of mice with L-cell-attenuated Chlamydia psittaci 6BC.
Large amounts of particulate antigen of Chlamydia psittaci 6BC attenuated by growth in L cells were phagocytized by peritoneal mononuclear phagocytes during the 1st h after intraperitoneal inoculation. The phagocytes subsequently destroyed the immunofluorescent (IF) properties of the chlamydial antigens. It is suggested that the early damage of phagocytes by lysosomal enzymes activation induced by chlamydiae contributed to the relatively early disappearance of IF antigens from the peritoneal fluids.


Peripheral effects of neurokinins: functional evidence for the existence of multiple receptors.
The ability of six neurokinins (substance P, neurokinin A, neurokinin B, physalaemin, eledoisin and kassinin) to induce hypotension, salivary secretion and to activate motility of the duodenum and of the urinary bladder was investigated in urethane-anaesthetized rats. A comparison of the relative potency of these substances in producing a given biological effect yielded results consistent with the hypothesis of the existence of three distinct types of receptor in rat peripheral tissues, namely SP-P, SP-K and SP-E according to the nomenclature proposed by Buck, Burcher, Shults, Lovenberg & O'Donohue (1984), or NK-P, NK-A and NK-B according to that of Regoli, D'Orleans-Juste, Drapeau, Dion & Escher (1985). An NK-P receptor is responsible for the production of the hypotensive effect and for the activation of salivary secretion. An 'NK-P like' receptor subtype may be involved in determining the direct contractile effects on muscle cells of neurokinins in the rat isolated urinary bladder and the 'phasic' contraction of the rat duodenum. An NK-A receptor mediates the 'tonic' contraction of the rat duodenum while an NK-B receptor mediates the activation of the micturition reflex. Evidence is presented that multiple neurokinin receptors are present in the same organ and participate with different modalities to the regulation of smooth muscle function.


Characterization of boar semen microbiome and association with sperm quality parameters.
Elevated levels of bacteria within fresh extended boar semen are associated with decreased sperm longevity, therefore reducing the fertility of a semen dose. The objective of this study was to characterize the bacterial communities using 16S rRNA sequencing in freshly extended boar semen samples and relate the prevalence and diversity of the microbial population to sperm quality parameters 1) between studs, 2) between pooled and single-sire doses, and 3) over a 5-day period. Eight single-sire (n = 4 per stud) and eight pooled (n = 4 per stud) non-frozen extended semen doses were obtained from two boar studs (A and B). Pooled doses were the composite of the boar's ejaculates used in single-sire doses. Doses were subsampled for 5 d post-collection. Ten negative controls of each pooled dose (n = 2) and single-sire dose (n = 8) remained sealed until the last day. Microbiome analysis was achieved by examining the V4 hypervariable region of the 16S rRNA gene of flash-frozen samples. Two evaluators determined the average sperm motility and agglutination (0: no adhesion to 3: >50% adhesion) by averaging their estimates together at 10 random locations per slide. Stud A had greater sperm agglutination (1.6 vs. 1.0 ± 0.1; P < 0.01) than stud B. Sperm motility decreased over the 5-day period (P < 0.01) and tended (P = 0.09) to be greater in stud B than A (67.4% vs. 61.5% ± 0.02%). Compared with stud A, stud B had a greater relative abundance of Proteobacteria (60.0% vs. 47.2% ± 1.5%; P < 0.01) and a lower relative abundance of Firmicutes (22.5% vs. 31.9% ± 1.4%; P < 0.01). Moreover, stud A had a greater relative abundance of Bacteroidetes (6.3% vs. 5.3% ± 0.4%; P < 0.01) and Actinobacteria (11.5% vs. 10.1% ± 0.5%; P = 0.05) than stud B. Differences were found in alpha diversity for both Chao1 (P < 0.01) and Shannon (P < 0.01) diversity indexes among days 2, 3, 4, and 5 post-collection to day 1. For beta diversity, unweighted UniFrac metric on days 2, 3, 4, and 5 post-collection differed from those on day 1 (P < 0.01). There were significant correlations between sperm motility and relative abundance of Prevotella (r = -0.29), Ruminococcus (r = -0.24), and Bacteroides (r = -0.32). Additionally, there were significant correlations between sperm motility and Chao1 (r = -0.50) and Shannon's index (r = -0.36). These results demonstrate that differences in bacterial communities over time and between boar studs can be associated with variation in sperm quality.


Carotid MRI: a tool for monitoring individual response to cardiovascular therapy?
Stroke remains a leading cause of morbidity and mortality. While stroke-related mortality has declined over the past four decades, data indicate that the mortality rate has begun to plateau. This change in trend may be attributable to variation in individual response to therapies that were derived from population-based studies. Further reductions in stroke mortality may require individualized care governed by directly monitoring the effects of cardiovascular therapy. In this article, carotid MRI is considered as a tool for monitoring in vivo carotid atherosclerotic disease, a principal etiology of stroke. Carotid MRI has been previously utilized to identify specific plaque features beyond luminal stenosis that are predictive of transient ischemic attack and stroke. To gain perspective on the possibility of monitoring plaque change within the individual, clinical trials and natural history studies that have used serial carotid MRI are considered. Data from these studies indicate that patients with a lipid-rich necrotic core with or without intraplaque hemorrhage may represent the desired phenotype for monitoring treatment effects in the individual. Advances in tissue-specific sequences, acquisition resolution, scan time, and techniques for monitoring inflammation and mechanical forces are expected to enable earlier detection of response to therapy. In so doing, cost-effective multicenter studies can be conducted to confirm the anticipated positive effects on outcomes of using carotid MRI for individualized care in patients with carotid atherosclerosis. In accordance, carotid MRI is poised to emerge as a powerful clinical tool for individualized management of carotid atherosclerotic disease to prevent stroke.


Placental site trophoblastic tumour: a case report.
Placental site trophoblastic tumour (PSTT) is a rare form of trophoblastic disease accounting for < 2% of all gestational trophoblastic neoplasms. Most of the cases follow a normal pregnancy and a small number have a preceeding molar pregnancy or spontaneous abortion. It can occur as early as several weeks or as late as 15 years after normal delivery, molar pregnancy or abortion. Excessive intermediate trophoblastic activity is the most important diagnostic criterion of this tumour originating from non villous trophoblast. But the possibility of a PSTT should be considered when there is excessive intermediate trophoblastic activity despite the presence of chorionic villi as in the present case. This case report highlights the unusual features like rarity of the tumour (< 2%), occurrence following spontaneous abortion which happens only in a minority of cases, and presence of chorionic villi in the tumour despite the fact that the tumour is of non villous trophoblastic origin.


Intracerebroventricular interleukin-1 alpha increases immunocyte beta-endorphin concentrations in the rat: involvement of corticotropin-releasing hormone, catecholamines, and serotonin.
The opioid peptide beta-endorphin (BE) is synthesized and secreted by the cells of the immune system and has been shown to participate in the modulation of immune responses, e.g. during stress. Interleukin-1 (IL-1) is a potent activator of the corticotropin-releasing hormone (CRH) system in the hypothalamus, and it has been shown to be involved in many stress responses, including immunosuppression. We studied the effect of centrally injected IL-1 alpha on immunocyte BE concentrations in the rat. IL-1 alpha (1 ng/rat, intracerebroventricularly) significantly (P < 0.01) increased the concentrations of the peptide in splenocytes, lymph node cells, and peripheral blood mononuclear cells 2 and 24 h after treatment. Intracerebroventricular, but not iv, administration of 2 micrograms IL-1 receptor antagonist blocked the IL-1 alpha-induced increase. These effects were also prevented by the intracerebroventricular administration of the CRH receptor antagonist alpha-helical CRH-(9-41). Treatment with 6-hydroxydopamine and 5,7-dihydroxytryptamine, which deplete the catecholaminergic or the serotoninergic systems, respectively, blocked the increase in BE induced by the cytokine. In contrast, hypophysectomy and treatment with indomethacin did not modify the effect of IL. The increase in immunocyte BE, therefore, seems to depend on the activation of CRH, catecholamines, and serotonin, but to be independent of activation of the hypothalamus-pituitary-adrenal-axis and prostaglandins. The immunocyte BE increase could be involved in the immunosuppression induced by central IL-1 alpha.


"Superscan" on F18‑fluorodeoxyglucose Positron Emission Tomography - Computed Tomography [18‑F] FDG PET-CT.
"Superscan" features have been described in 18F FDG PET-CT (F18 fluorodeoxyglucose Positron Emission Tomography‑Computed Tomography) scan; characterized by significantly increased uptake in one or more organ systems resulting in absent or decreased uptake in the organs which normally show physiological uptake. The importance of the awareness has evolved over the years in order to avoid false interpretation of scan findings as well as in determination of a high tumour burden. We present images of three patients who underwent 18F FDG PET-CT scan showing findings consistent with FDG PET-CT superscan.


The thermodynamic properties of hydrated γ-Al2O3 nanoparticles.
In this paper we report a combined calorimetric and inelastic neutron scattering (INS) study of hydrated γ-Al2O3 (γ-alumina) nanoparticles. These complementary techniques have enabled a comprehensive evaluation of the thermodynamic properties of this technological and industrially important metal oxide to be achieved. The isobaric heat capacity (C(p)) data presented herein provide further critical insights into the much-debated chemical composition of γ-alumina nanoparticles. Furthermore, the isochoric heat capacity (C(v)) of the surface water, which is so essential to the stability of all metal-oxides at the nanoscale, has been extracted from the high-resolution INS data and differs significantly from that of ice-Ih due to the dominating influence of strong surface-water interactions. This study also encompassed the analysis of four γ-alumina samples with differing pore diameters [4.5 (1), 13.8 (2), 17.9 (3), and 27.2 nm (4)], and the results obtained allow us to unambiguously conclude that the water content and pore size have no influence on the thermodynamic behaviour of hydrated γ-alumina nanoparticles.


Somatostatin-induced paradoxical increase in intracellular Ca2+ concentration and insulin release in the presence of arginine vasopressin in clonal HIT-T15 beta-cells.
Somatostatin, a hormone that signals via G(i)/G(o), usually inhibits increases in intracellular calcium concentration ([Ca(2+)](i)) and insulin release from beta-cells. We have found that in the presence of arginine vasopressin (AVP), which signals via G(q), somatostatin increased [Ca(2+)](i), leading to insulin release in HIT-T15 cells. The increase in [Ca(2+)](i) by somatostatin was observed even after 60 min of AVP treatment. Somatostatin alone failed to increase [Ca(2+)](i) and insulin release. Somatostatin induced changes in [Ca(2+)](i) in a biphasic pattern, characterized by a sharp and transient increase followed by a rapid decline to sub-basal levels. Pretreatment with pertussis toxin, which inactivates G(i)/G(o), abolished the effects of somatostatin. U-73122, an inhibitor of phospholipase C, antagonized the somatostatin-induced increase in [Ca(2+)](i). In Ca(2+)-free medium, somatostatin still increased [Ca(2+)](i). Depletion of intracellular Ca(2+) stores with thapsigargin, a microsomal Ca(2+)-ATPase inhibitor, abolished somatostatin's effect. In the presence of bradykinin, another G(q)-coupled receptor agonist, somatostatin also increased [Ca(2+)](i), but not in the presence of isoproterenol (a G(s)-coupled receptor agonist) or medetomidine (a G(i)/G(o)-coupled receptor agonist). Our findings suggest that somatostatin signals through G(i)/G(o), and involves phospholipase C and Ca(2+) release from the endoplasmic reticulum. The increase in [Ca(2+)](i) by somatostatin leads to insulin release. This cross-talk is specific to G(q) and G(i)/G(o), and is not limited to the AVP and somatostatin receptors.


Stimulated mass enhancement strategy-based highly sensitive detection of a protein in serum using quartz crystal microbalance technique.
A stimulated mass enhancement strategy based on enormous biocatalytic precipitation of 4-chloro-1-naphthol using magnetic bead-supported horseradish peroxidase and glucose oxidase bienzymes was developed for the highly sensitive detection of interleukin-6 in serum using a quartz crystal microbalance technique.


Coexistence of left-sided inferior vena cava, deep vein thrombosis of the upper and lower extremities and prothrombotic polymorphisms in a young patient: a case report.
A literature review suggests an interaction between an anomaly of the inferior vena cava and thrombophilia in the pathogenesis of deep vein thrombosis. Genetic thrombotic abnormalities have been found in some of the subjects having venous thromboembolic diseases. We report a case of a young man presenting with venous thrombosis of the upper and lower extremities, left-sided vena cava inferior and with combination of heterozygosity of the mutation of the genes Methylenetetrahydrofolate reductase 677 and Factor V 1691.


Inhibition of induced-hepatic cancer in vivo through IQGAP1-shRNA gene therapy and modulation of TRAIL-induced apoptosis pathway.
Liver cancer is the deadliest malignancy among common tumors. It is the top cause of cancer-related deaths in Egypt, and it is characterized by increasing occurrence among the population. The objective of this study was to determine the outcome of pre-treatment of IQGAP1-shRNA on induced mouse hepatocellular carcinoma model and evaluate the potency of this IQGAP1-shRNA plasmid to recover hepatic cancer as a new tool of cancer therapy. Therefore, we will use RNA interference (RNAi) technology to silence IQGAP1 oncogene to completely recover the chemically induced models for hepatic cancer by designing short RNAi specific for IQGAP1 gene in HCC cells in vivo and construct new vectors suitable for this purpose. We assigned mice into three groups: the first negative control group (NC) was injected with saline, the second control group was injected with shRNA (shNC), the third positive control group was injected with diethylnitrosamine (DENAA), and the fourth group was treated with the IQGAP1-shRNA prior to its exposure to DENA. Our results revealed that the treated group with IQGAP1-shRNA with DENA developed very few cases of hepatic cancer when compared with the positive control group. The positive control group exhibited significant increases in the liver function level as well as a decrease in serum albumin levels when compared to both the treated and the negative control groups. The altered levels of the serum α-fetoprotein as well as of the tumor necrosis factor-alpha, and interleukin-4 in DENA-treated mice were significantly ameliorated by IQGAP1-shRNA administration. Flow cytometer analyses have indicated that the silencing of IQGAP1 cannot significantly modulate DENA-induced apoptosis in the circulating blood cells. Moreover, the elevated mRNA expression levels of IQGAP1, IQGAP3, KRas, HRas, interleukin-8, nuclear factor kappa B, caspase-3, caspase-9 and Bcl-2, were significantly decreased by the IQGAP1-shRNA treatment. However, the IQGAP2, DR4, DR5, p53 and BAX genes were found to be significantly up-regulated post-therapy. In agreement with these findings, IQGAP1-shRNA was able to modulate the DENA-induced histological changes in the mice liver which were represented by severe necrosis and hydropic degenerative changes. Our study revealed that IQGAP1-shRNA was able to preserve hepatocyte integrity and the liver histological architecture through the regulation of the expression of IQGAPs, Ras, TRAILs and IL-8 receptors, as well as of pro-apoptotic and anti-apoptotic genes. Therefore, the silencing of IQGAP1 could be part of a promising therapeutic strategy against hepatic cancer.


Rehabilitation in transverse myelitis.
The consequences of neurologic injuries related to transverse myelitis (TM) are long-lasting and require rehabilitative interventions in about two-thirds of cases. Because numerous neural repair mechanisms are dependent on maintenance of an optimal amount of activity both above and below the injury level, rehabilitation and exercise are useful not only for compensatory functional purposes but also as tools in neural system restoration. The application of established neurophysiologic principles to post-TM rehabilitation has substantial impact on optimizing residual functional capabilities while facilitating the processes of central plasticity and reorganization of sensory and motor programming. The process of neurorehabilitation thereby serves both to treat the patient with TM and to help physicians interrogate and dissect the mechanisms involved in spinal cord injury, neuroprotection, and, ultimately, recovery. Post-TM rehabilitation is lifelong and should be integrated into daily living in a home setting as part of the global management of paralysis, a chronic condition with significant comorbidities.


Vitamin D-fence.
The role of vitamin D in the immune system is complex. Vitamin D is produced in the skin following exposure to ultraviolet radiation. There is compelling evidence that vitamin D compounds protect against ultraviolet radiation-induced DNA damage and immune suppression, suggesting it may be beneficial as a skin cancer preventive agent. However, vitamin D has many modulatory effects on the immune system and it has in fact been suggested that the immune suppression generally attributed to the UVB portion of sunlight is mediated through vitamin D. Here we describe the role of vitamin D compounds as "defence" molecules against UVR-induced damage, and investigate both sides of the "fence" regarding the effects of vitamin D compounds and the immune system.


Medium-term results of ceramic-on-polyethylene Zweymüller-Plus total hip arthroplasty.
The need for better durability and longevity in total hip arthroplasty for patients with various hip joint diseases remains a challenge. This study aimed to obtain medium-term results at a follow-up of >10 years for Zweymüller-Plus total hip arthroplasty with ceramic-on-polyethylene bearing. A retrospective study was conducted to review the results after a minimum of 12.4 years of 207 consecutive total hip arthroplasties in 185 patients in Peking University People's Hospital in China using the Zweymüller SL-Plus stem in combination with the Bicon-Plus threaded cup and ceramic-on-polyethylene bearing between October 1994 and April 2000. During the study period, two patients (2 hips) died and 25 patients (28 hips) were lost to follow-up. Two hips were revised for aseptic loosening of the Bicon-Plus cup. The mean clinical and radiological follow-up was 14.1 years (range, 12.4-16.5 years) for the remaining 156 patients (175 hips). The mean (standard deviation) Harris Hip score for the 175 hips increased significantly from 39.3 (3.8) preoperatively to 94.1 (2.5) postoperatively at a mean follow-up of 14.1 years (P<0.05). Focal osteolysis was observed in seven (4.0%) of 175 stems and three (1.7%) of 175 cups. The Kaplan-Meier survival with revision for any reason as the end-point was 99.03% (95% confidence interval, 95%-100%). The high survival rate of the cementless Zweymüller-Plus system with ceramic-on-polyethylene bearing at mid-term follow-up makes this total hip arthroplasty system reliable for patients with various hip joint diseases.


e-Health Literacy Status of Individuals with Multiple Sclerosis in Turkey.
Background: This research aims to compare e-health literacy of technology users and nonusers in people with multiple sclerosis (MS) and to investigate whether there are correlations between age, duration of MS, gender, marital status, and e-health total scores. Methods: This descriptive study was carried out with a web-based questionnaire. The questionnaire was sent to 300 patients with MS who were registered at Istanbul University-Cerrahpasa Medical Faculty Neurology Department. Results: A total of 156 people (mean age: 35.33 ± 10.47 years) participated in the survey. Smartphone 98.1% (n = 153) was the mostly used device. Rate of using Google and recommended websites about MS was 94.25% (n = 145) and 73.9% (n = 113), respectively. e-Health literacy of both the tablet and recommended websites users significantly differed from that of nonusers (p = 0.007 for both). Participants' e-health literacy total score was found to weakly, but significantly, correlate with their age, marital status, and education level (rho: -0.161, p = 0.044; rho: 0.172, p = 0.032; rho: -0.192, p = 0.016, respectively). Conclusions: With developments in digital technologies, it is important to identify the access status of people with MS to improve daily clinical management and implement further motor and cognitive rehabilitation. Therefore, determining the health literacy of individuals with MS and providing education on this subject will reduce the information pollution.


Influence of Structure Development on Performance of Copper Composites Processed via Intensive Plastic Deformation.
Designing a composite, possibly strengthened by a dispersion of (fine) oxides, is a favorable way to improve the mechanical characteristics of Cu while maintaining its advantageous electric conductivity. The aim of this study was to perform mechanical alloying of a Cu powder with a powder of Al2O3 oxide, seal the powder mixture into evacuated Cu tubular containers, i.e., cans, and apply gradual direct consolidation via rotary swaging at elevated temperatures, as well as at room temperature (final passes) to find the most convenient way to produce the designed Al2O3 particle-strengthened Cu composite. The composites swaged with the total swaging degree of 1.83 to consolidated rods with a diameter of 10 mm were subjected to measurements of electroconductivity, investigations of mechanical behavior via compression testing, and detailed microstructure observations. The results revealed that the applied swaging degree was sufficient to fully consolidate the canned powders, even at moderate and ambient temperatures. In other words, the final structures, featuring ultra-fine grains, did not exhibit voids or remnants of unconsolidated powder particles. The swaged composites featured favorable plasticity regardless of the selected processing route. The flow stress curves exhibited the establishment of steady states with increasing strain, regardless of the applied strain rate. The electroconductivity of the composite swaged at elevated temperatures, featuring homogeneous distribution of strengthening oxide particles and the average grain size of 1.8 µm2, reaching 80% IACS (International Annealed Copper Standard).


The Global Rise of Zero Liquid Discharge for Wastewater Management: Drivers, Technologies, and Future Directions.
Zero liquid discharge (ZLD)-a wastewater management strategy that eliminates liquid waste and maximizes water usage efficiency - has attracted renewed interest worldwide in recent years. Although implementation of ZLD reduces water pollution and augments water supply, the technology is constrained by high cost and intensive energy consumption. In this critical review, we discuss the drivers, incentives, technologies, and environmental impacts of ZLD. Within this framework, the global applications of ZLD in the United States and emerging economies such as China and India are examined. We highlight the evolution of ZLD from thermal- to membrane-based processes, and analyze the advantages and limitations of existing and emerging ZLD technologies. The potential environmental impacts of ZLD, notably greenhouse gas emission and generation of solid waste, are discussed and the prospects of ZLD technologies and research needs are highlighted.


Impact of Preoperative Tumor Size on Prognosis of Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinomas.
Tumor size (TS) is a well-established prognostic factor of pancreatic ductal adenocarcinoma (PDAC). However, whether a uniform treatment strategy can be applied for all resectable PDACs (R-PDACs) and borderline resectable PDACs (BR-PDACs), regardless of TS, remains unclear. This study aimed to investigate the impact of preoperative TS on surgical outcomes of patients with R-PDACs and BR-PDACs. Chart data from three institutions were reviewed to select patients who underwent pancreatectomy for R-PDACs and BR-PDACs between January 2006 and December 2020. The patients were divided into TSsmall and TSlarge groups according to a TS cutoff value determined for each of R- and BR-PDAC using the minimum P value approach for the risk of R1 resection. TS of 35 mm and 24 mm was the best cutoff value in R-PDAC and BR-PDAC, respectively. The R1 rate was higher in the TSlarge than TSsmall group, in both R- (n = 35, 37% versus n = 294, 19%; P = 0.011) and BR-PDAC (n = 89, 37% versus n = 27, 15%; P = 0.030). Overall survival was significantly better in the TSsmall than TSlarge group in R-PDAC (38.2 versus 12.1 months; P < 0.001), but comparable between the two groups in BR-DPAC (21.2 versus 22.7 months; P = 0.363). Multivariate analysis revealed TS > 35 mm as an independent predictor of worse survival in patients with R-PDAC. Larger TS was associated with a higher R1 rate and is a worse prognostic factor in patients with R-PDAC.


Cross-category adaptation of reflexive social attention.
Social attention is crucial for efficient social interactions and adaptive functioning in humans. However, whether this indispensable ability is unique and qualitatively distinct from nonsocial attention remains equivocal. Using the visual adaptation technique in conjunction with a modified central cueing paradigm, the current study investigated the specificity of social attention. Results revealed that adaptation to the walking direction of biological motion (BM) affected the reflexive attentional effect triggered by subsequent BM cues. Critically, preexposure to another type of social cues (i.e., eye gaze) could produce a similar aftereffect on attentional orienting elicited by BM, reflecting that social attention induced by different types of cues might share common neural substrates. By contrast, such cross-category adaptation aftereffect disappeared when adaptors changed to nonsocial cues (i.e., arrows). In the same vein, adaptation to BM cues could also exert an aftereffect on gaze cueing but not arrow cueing effect. Taken together, these findings provide evidence for the view that "social attention is special" and support the existence of "social attention detector" in the human brain. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Anterior Hox Genes and the Process of Cephalization.
During evolution, bilateral animals have experienced a progressive process of cephalization with the anterior concentration of nervous tissue, sensory organs and the appearance of dedicated feeding structures surrounding the mouth. Cephalization has been achieved by the specialization of the unsegmented anterior end of the body (the acron) and the sequential recruitment to the head of adjacent anterior segments. Here we review the key developmental contribution of Hox1-5 genes to the formation of cephalic structures in vertebrates and arthropods and discuss how this evolved. The appearance of Hox cephalic genes preceded the evolution of a highly specialized head in both groups, indicating that Hox gene involvement in the control of cephalic structures was acquired independently during the evolution of vertebrates and invertebrates to regulate the genes required for head innovation.


The Clinical Significance of Genetic Variation in Ovarian Cancer.
Genetic variation is a well-known contributor to the onset and progression of cancer. The goal of this study is to provide a comprehensive examination of the nucleotide and chromosomal variation associated with the onset and progression of serous ovarian cancer. Using a variety of computational and statistical methods, we examine the exome sequence profiles of genetic variants present in the primary tumors of 432 ovarian cancer patient samples to compute: (1) the tumor mutational burden for all genes and (2) the chromosomal copy number alterations associated with the onset/progression of ovarian cancer. Tumor mutational burden is reduced in the late vs. early stages, with the highest levels being associated with loss-of-function mutations in DNA-repair genes. Nucleotide variation and copy number alterations associated with known cancer driver genes are selectively favored over ovarian cancer development. The results indicate that genetic variation is a significant contributor to the onset and progression of ovarian cancer. The measurement of the relative levels of genetic variation associated with individual ovarian cancer patient tumors may be a clinically valuable predictor of potential tumor aggressiveness and resistance to chemotherapy. Tumors found to be associated with high levels of genetic variation may help in the clinical identification of high-risk ovarian cancer patients who could benefit from more frequent monitoring.


Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation.
Afatinib is a highly selective, irreversible inhibitor of EGFR and HER-2. It is orally administered for the treatment of patients with EGFR mutation-positive types of metastatic NSCLC. We investigated whether afatinib is a substrate for the multidrug efflux transporters ABCB1 and ABCG2 and whether these transporters influence oral availability and brain and other tissue accumulation of afatinib. We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of afatinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral afatinib disposition, we used appropriate knockout mouse strains. Afatinib was transported well by hABCB1, hABCG2 and mAbcg2 in vitro. Upon oral administration of afatinib, Abcg2-/-, Abcb1a/1b-/- and Abcb1a/1b-/-;Abcg2-/- mice displayed a 4.2-, 2.4- and 7-fold increased afatinib plasma AUC0-24 compared with wild-type mice. Abcg2-deficient strains also displayed decreased afatinib plasma clearance. At 2h, relative brain accumulation of afatinib was not significantly altered in the single knockout strains, but 23.8-fold increased in Abcb1a/1b-/-;Abcg2-/- mice compared to wild-type mice. Abcg2 and Abcb1a/1b restrict oral availability and brain accumulation of afatinib. Inhibition of these transporters may therefore be of clinical importance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.


Regulation of membrane type-matrix metalloproteinases.
Pericellular proteolysis is a hallmark of tumor cell metastasis. The membrane type (MT)-matrix metalloproteinases (MMPs) constitute a distinctive group of membrane-bound MMPs that are central mediators of surface proteolytic events that regulate tumor cell motility, metastasis and angiogenesis. As membrane-tethered proteases, the MT-MMPs exhibit unique regulatory mechanisms and interactions with metalloproteinase inhibitors and other relevant molecules. This review will focus on new emerging information on the mechanisms that regulate MT-MMP processing, activity and inhibition, and their significance for enzyme function in the tumor microenvironment.


Intra-erythrocytic death of the parasite in mice recovering from infection with Babesia microti.
As mice recover from infection with Babesia microti, abnormal forms of the parasite are present in some red cells. These forms are non-infective, indistinguishable by light microscopy from those present after treatment with amicarbalide, a babesicidal drug, and persist in splenectomized mice. Electron microscopy confirmed that these abnormal forms are degenerating intra-erythrocytic parasites. In the absence of evidence for death of B. microti elsewhere in the body, it appears that infections of mice with this parasite are normally terminated by their death within circulating red cells. This has important implications for the mechanism of immunity to both this parasite and those Plasmodium spp. with which it cross-protects in this host.


DB-PABP: a database of polyanion-binding proteins.
The interactions between polyanions (PAs) and polyanion-binding proteins (PABPs) have been found to play significant roles in many essential biological processes including intracellular organization, transport and protein folding. Furthermore, many neurodegenerative disease-related proteins are PABPs. Thus, a better understanding of PA/PABP interactions may not only enhance our understandings of biological systems but also provide new clues to these deadly diseases. The literature in this field is widely scattered, suggesting the need for a comprehensive and searchable database of PABPs. The DB-PABP is a comprehensive, manually curated and searchable database of experimentally characterized PABPs. It is freely available and can be accessed online at http://pabp.bcf.ku.edu/DB_PABP/. The DB-PABP was implemented as a MySQL relational database. An interactive web interface was created using Java Server Pages (JSP). The search page of the database is organized into a main search form and a section for utilities. The main search form enables custom searches via four menus: protein names, polyanion names, the source species of the proteins and the methods used to discover the interactions. Available utilities include a commonality matrix, a function of listing PABPs by the number of interacting polyanions and a string search for author surnames. The DB-PABP is maintained at the University of Kansas. We encourage users to provide feedback and submit new data and references.


[Therapeutic and prophylactic action of monensin and nicotinic acid in cows with subclinical ketosis].
Experiments were carried out with sheep and cows on the basis of a limited feed ration--the giving of concentrates was discontinued, and the ration of alfalfa hay was replaced with meadow hay and a monensine supplement (at the rate of 20-25 mg for sheep and 250 mg for cows, daily), and nicotinic acid (at 0.8 g and 6.0 g, respectively). Observations revealed that in the course of 6-7 weeks in succession the drop of blood sugar was reduced, and monensine led to a rise of the alkali reserves of the blood by 27 to 41 per cent. Cows with ketonuria (from ++ up to + positive results with the nitroprusside tests) and hydroglycaemia (blood sugar up to 30 mg) were treated with monensine at the rate of 125 mg, in the morning and in the evening or with nicotinic acid at 3 g and the same frequency for 6-7 consecutive days. The symptoms receded to a greater extent (12.1 to 60 per cent) as compared to the process of self-healing for the same time period. In this respect the effect of monensine was better manifested. It was demonstrated that the prophylactic use of these drugs inhibited to a minimum the manifestation of hypoglycaemia and ketonuria.


Thrombosis of portal vein in absence of hepatic disease.
Of 602 patients referred for portal hypertension during a 20 year period, 18 children (mean age of 5.0 years) and 29 adults (mean age of 26.5 years) had thrombosis in the portal bed with a healthy liver (7.8 per cent incidence). In 29 of the 47 patients we studied, the causative factor remained obscure. Variceal hemorrhage occurred in all and was the indication for our observation and treatment. In 11 adult patients (mean age of 22.1 years), surgical treatment was not performed because of reluctance of the patient or because of technical reasons: nine of the patients rebled and one patient died because of massive bleeding. Direct procedures on esophageal varices had a high rate of rebleeding (seven of 11 patients) independent of the age of the patient when the operation was performed. In 13 patients, shunting offered a good chance of long term protection: three of the 13 rebled at a mean follow-up study of 5.7 years. No recurrence of bleeding was observed in 15 patients when variceal eradication had been obtained after chronic endoscopic sclerotherapy at one to eight years of follow-up study (mean of 3.9 years). The data from this study indicate that sclerotherapy should be the first choice of treatment to control recurrent bleeding in extrahepatic portal hypertension caused by thrombotic obstruction, particularly in the young patient.


Global epidemiology of HTLV-I infection and associated diseases.
Epidemiologic aspects of human T-lymphotropic virus type I (HTLV-I) infection have been thoroughly studied over the course of approximately 25 years since its first description. The geographic distribution of the virus has been defined, with Japan, Africa, Caribbean islands and South America emerging as the areas of highest prevalence. The reasons for HTLV-I clustering, such as the high ubiquity in southwestern Japan but low prevalence in neighboring regions of Korea, China and eastern Russia are still unknown. The major modes of transmission are well understood, although better quantitative data on the incidence of transmission, and on promoting/inhibiting factors, are needed. Epidemiologic proof has been obtained for HTLV-I's causative role in major disease associations: adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-associated uveitis and infective dermatitis. However, more and better studies are needed for other apparent disease outcomes such as rheumatologic, psychiatric and infectious diseases. Since curative treatment of ATL and HAM/TSP is lacking and a vaccine is unavailable, the social and financial cost for the individual, his/her family and the health system is immense. For this reason, public health interventions aimed at counseling and educating high-risk individuals and populations are of paramount importance.


The role of heavy metals in autoimmunity.
Our understanding of autoimmune diseases has progressed tremendously in the past 20 years. Estimates of the prevalence of autoimmune diseases in the population may be 4% or higher. It is evident that heavy metals present serious risk to human health. Heavy metals are capable of altering the immune response; they have been implicated in influencing autoimmunity. In fact, they are usually inhibitory to immune cell proliferation and activation. This paper reviews the possible mechanisms which may play a role in metal-induced autoimmunity. A better understanding of these interactions remains a priority for the future.


Port site metastases following laparoscopic liver resection for hepatocellular carcinoma.
A laparoscopic approach is being used increasingly in specialist centres for the resection of hepatocellular carcinomas and compares favourably with the traditional open approach, in terms of perioperative morbidity and mortality as well as long-term survival. We present a case of port site recurrence in a patient who underwent a laparoscopic left lateral segmentectomy for a hepatocellular carcinoma diagnosed during investigation of symptomatic gallstones. Nearly three years following surgery, surveillance computed tomography demonstrated a suspicious lesion at the site of one of the laparoscopic ports. Further resection was carried out and the lesion was confirmed histologically to be an isolated recurrence of the primary hepatocellular carcinoma, involving peritoneum and adominal wall. This case demonstrates that it is possible to encounter port site metastasis following laparoscopic resection of primary liver tumours although the incidence is very rare.